Effects of valsartan and amlodipine on oxidative stress in type 2 diabetic patients with hypertension: a randomized, multicenter study

PubMed Central

Kim, Hae Jin; Han, Seung Jin; Kim, Dae Jung; Jang, Hak Chul; Lim, Soo; Choi, Sung Hee; Kim, Yong Hyun; Shin, Dong Hyun; Kim, Se Hwa; Kim, Tae Ho; Ahn, Yu Bae; Ko, Seung Hyun; Kim, Nan Hee; Seo, Ji A; Kim, Ha Young; Lee, Kwan Woo

2017-01-01

Background/Aims Oxidative stress plays an important role in the pathogenesis and progression of diabetic complications and antagonists of renin-angiotensin system and amlodipine have been reported previously to reduce oxidative stress. In this study, we compared the changes in oxidative stress markers after valsartan and amlodipine treatment in type 2 diabetic patients with hypertension and compared the changes in metabolic parameters. Methods Type 2 diabetic subjects with hypertension 30 to 80 years of age who were not taking antihypertensive drugs were randomized into either valsartan (n = 33) or amlodipine (n = 35) groups and treated for 24 weeks. We measured serum nitrotyrosine levels as an oxidative stress marker. Metabolic parameters including serum glucose, insulin, lipid profile, and urine albumin and creatinine were also measured. Results After 24 weeks of valsartan or amlodipine treatment, systolic and diastolic blood pressure decreased, with no significant difference between the groups. Both groups showed a decrease in serum nitrotyrosine (7.74 ± 7.30 nmol/L vs. 3.95 ± 4.07 nmol/L in the valsartan group and 8.37 ± 8.75 nmol/L vs. 2.68 ± 2.23 nmol/L in the amlodipine group) with no significant difference between the groups. Other parameters including glucose, lipid profile, albumin-to-creatinine ratio, and homeostasis model assessment of insulin resistance showed no significant differences before and after treatment in either group. Conclusions Valsartan and amlodipine reduced the oxidative stress marker in type 2 diabetic patients with hypertension. PMID:28490725

Comparison between valsartan and amlodipine regarding cardiovascular morbidity and mortality in hypertensive patients with glucose intolerance: NAGOYA HEART Study.

PubMed

Muramatsu, Takashi; Matsushita, Kunihiro; Yamashita, Kentaro; Kondo, Takahisa; Maeda, Kengo; Shintani, Satoshi; Ichimiya, Satoshi; Ohno, Miyoshi; Sone, Takahito; Ikeda, Nobuo; Watarai, Masato; Murohara, Toyoaki

2012-03-01

It has not been fully examined whether angiotensin II receptor blocker is superior to calcium channel blocker to reduce cardiovascular events in hypertensive patients with glucose intolerance. A prospective, open-labeled, randomized, controlled trial was conducted for Japanese hypertensive patients with type 2 diabetes mellitus or impaired glucose tolerance. A total of 1150 patients (women: 34%; mean age: 63 years; diabetes mellitus: 82%) were randomly assigned to receive either valsartan- or amlodipine-based antihypertensive treatment. Primary outcome was a composite of acute myocardial infarction, stroke, coronary revascularization, admission attributed to heart failure, or sudden cardiac death. Blood pressure was 145/82 and 144/81 mm Hg, and glycosylated hemoglobin was 7.0% and 6.9% at baseline in the valsartan group and the amlodipine group, respectively. Both of them were equally controlled between the 2 groups during the study. The median follow-up period was 3.2 years, and primary outcome had occurred in 54 patients in the valsartan group and 56 in the amlodipine group (hazard ratio: 0.97 [95% CI: 0.66-1.40]; P=0.85). Patients in the valsartan group had a significantly lower incidence of heart failure than in the amlodipine group (hazard ratio: 0.20 [95% CI: 0.06-0.69]; P=0.01). Other components and all-cause mortality were not significantly different between the 2 groups. Composite cardiovascular outcomes were comparable between the valsartan- and amlodipine-based treatments in Japanese hypertensive patients with glucose intolerance. Admission because of heart failure was significantly less in the valsartan group.

Combined Therapy with Renin-Angiotensin System and Calcium Channel Blockers in Type 2 Diabetic Hypertensive Patients with Proteinuria: Effects on Soluble TWEAK, PTX3, and Flow-Mediated Dilation

PubMed Central

Yilmaz, Mahmut Ilker; Carrero, Juan Jesús; Martín-Ventura, Jose Luis; Sonmez, Alper; Saglam, Mutlu; Celik, Turgay; Yaman, Halil; Yenicesu, Mujdat; Eyileten, Tayfun; Moreno, Juan Antonio; Egido, Jesús

2010-01-01

Background and objectives: Soluble TNF-like weak inducer of apoptosis (sTWEAK) and long pentraxin-3 (PTX3) concentrations have been associated with endothelial function in patients with chronic kidney disease (CKD). This study tested the hypothesis that the improvement in endothelial function after initiation of angiotensin II receptor blocker (valsartan), calcium channel blocker (amlodipine) therapy, or a combination of both is directly linked to the normalization of sTWEAK and PTX3. Design, setting, participants, & measurements: One-hundred-eight diabetic CKD stage I patients with hypertension (56% men, 46.7 ± 5.3 years) were allocated to a 12-week intervention with amlodipine (10 mg/d), valsartan (160 mg/d), or their combination. Plasma levels of sTWEAK, PTX3, and flow-mediated dilation (FMD) were studied during the interventions. Results: All treatment strategies effectively increased FMD and reduced proteinuria, confirming a more prone reduction with the combined therapy. These improvements were followed by significant PTX3 reductions. Valsartan alone and in combination with amlodipine achieved significant incremental raises in sTWEAK plasma levels. More importantly, the changes observed in sTWEAK (β = 0.25, P = 0.006) or PTX3 (β = −0.24, P = 0.007) plasma levels were independently associated with the improvement in ultrasonographically measured FMD. Conclusions: This study shows that treatment with antihypertensive drugs improves FMD and normalizes proteinuria, PTX3, and sTWEAK in diabetic CKD stage I patients with hypertension. The improvement in FMD was independently associated with PTX3 and sTWEAK normalization. Two surrogate biomarkers of endothelial function are therefore identified with potential as therapeutic targets. The study was registered in clinicaltrials.gov as NCT00921570. PMID:20430947

mRNA levels of circadian clock components Bmal1 and Per2 alter independently from dosing time-dependent efficacy of combination treatment with valsartan and amlodipine in spontaneously hypertensive rats.

PubMed

Potucek, Peter; Radik, Michal; Doka, Gabriel; Kralova, Eva; Krenek, Peter; Klimas, Jan

2017-01-01

Chronopharmacological effects of antihypertensives play a role in the outcome of hypertension therapy. However, studies produce contradictory findings when combination of valsartan plus amlodipine (VA) is applied. Here, we hypothesized different efficacy of morning versus evening dosing of VA in spontaneously hypertensive rats (SHR) and the involvement of circadian clock genes Bmal1 and Per2. We tested the therapy outcome in short-term and also long-term settings. SHRs aged between 8 and 10 weeks were treated with 10 mg/kg of valsartan and 4 mg/kg of amlodipine, either in the morning or in the evening with treatment duration 1 or 6 weeks and compared with parallel placebo groups. After short-term treatment, only morning dosing resulted in significant blood pressure (BP) control (measured by tail-cuff method) when compared to placebo, while after long-term treatment, both dosing groups gained similar superior results in BP control against placebo. However, mRNA levels of Bmal1 and Per2 (measured by RT-PCR) exhibited an independent pattern, with similar alterations in left and right ventricle, kidney as well as in aorta predominantly in groups with evening dosing in both, short-term and also long-term settings. This was accompanied by increased cardiac mRNA expression of plasminogen activator inhibitor-1. In summary, morning dosing proved to be advantageous due to earlier onset of antihypertensive action; however, long-term treatment was demonstrated to be effective regardless of administration time. Our findings also suggest that combination of VA may serve as an independent modulator of circadian clock and might influence disease progression beyond the primary BP lowering effect.

Comparison of valsartan and amlodipine on ambulatory blood pressure variability in hypertensive patients.

PubMed

Eguchi, Kazuo; Imaizumi, Yuki; Kaihara, Toshiki; Hoshide, Satoshi; Kario, Kazuomi

We tested the hypothesis that calcium channel blockers (CCBs: amlodipine group, n = 38)) are superior to angiotensin receptor blockers (ARBs: valsartan group, n = 38) against ambulatory blood pressure variability (BPV) in untreated Japanese hypertensive patients. Both drugs significantly reduced ambulatory systolic and diastolic BP values. With regard to BPV, standard deviation (SD) in SBP did not change with the administration of either drug, but the ARB significantly increased SD in awake DBP (12 ± 4-14 ± 4 mmHg). The ARB also significantly increased the coefficients of variation (CVs)in awake and 24-h SBP/DBP (all P < 0.05), but amlodipine did not change the CV. CCB significantly reduced the maximum values of awake SBP (193 ± 24-182 ± 27 mmHg, P = 0.02), sleep SBP (156 ± 18-139 ± 14 mmHg, P < 0 .001), and awake and sleep DBP (P < 0.01 in both cases), but the ARB did not change the maximum BP values. In conclusion, a once-daily morning dose of CCB amlodipine was more effective at controlling ambulatory BPV than ARB valsartan, especially in reducing maximum BP levels.

Multiway analysis methods applied to the fluorescence excitation-emission dataset for the simultaneous quantification of valsartan and amlodipine in tablets

NASA Astrophysics Data System (ADS)

Dinç, Erdal; Ertekin, Zehra Ceren; Büker, Eda

2017-09-01

In this study, excitation-emission matrix datasets, which have strong overlapping bands, were processed by using four different chemometric calibration algorithms consisting of parallel factor analysis, Tucker3, three-way partial least squares and unfolded partial least squares for the simultaneous quantitative estimation of valsartan and amlodipine besylate in tablets. In analyses, preliminary separation step was not used before the application of parallel factor analysis Tucker3, three-way partial least squares and unfolded partial least squares approaches for the analysis of the related drug substances in samples. Three-way excitation-emission matrix data array was obtained by concatenating excitation-emission matrices of the calibration set, validation set, and commercial tablet samples. The excitation-emission matrix data array was used to get parallel factor analysis, Tucker3, three-way partial least squares and unfolded partial least squares calibrations and to predict the amounts of valsartan and amlodipine besylate in samples. For all the methods, calibration and prediction of valsartan and amlodipine besylate were performed in the working concentration ranges of 0.25-4.50 μg/mL. The validity and the performance of all the proposed methods were checked by using the validation parameters. From the analysis results, it was concluded that the described two-way and three-way algorithmic methods were very useful for the simultaneous quantitative resolution and routine analysis of the related drug substances in marketed samples.

Effect of Sacubitril/Valsartan on Exercise-Induced Lipid Metabolism in Patients With Obesity and Hypertension

PubMed Central

Engeli, Stefan; Stinkens, Rudi; Heise, Tim; May, Marcus; Goossens, Gijs H.; Blaak, Ellen E.; Havekes, Bas; Jax, Thomas; Albrecht, Diego; Pal, Parasar; Tegtbur, Uwe; Haufe, Sven; Langenickel, Thomas H.

2018-01-01

Sacubitril/valsartan (LCZ696), a novel angiotensin receptor-neprilysin inhibitor, was recently approved for the treatment of heart failure with reduced ejection fraction. Neprilysin degrades several peptides that modulate lipid metabolism, including natriuretic peptides. In this study, we investigated the effects of 8 weeks’ treatment with sacubitril/valsartan on whole-body and adipose tissue lipolysis and lipid oxidation during defined physical exercise compared with the metabolically neutral comparator amlodipine. This was a multicenter, randomized, double-blind, active-controlled, parallel-group study enrolling subjects with abdominal obesity and moderate hypertension (mean sitting systolic blood pressure ≥130–180 mm Hg). Lipolysis during rest and exercise was assessed by microdialysis and [1,1,2,3,3-2H]-glycerol tracer kinetics. Energy expenditure and substrate oxidation were measured simultaneously using indirect calorimetry. Plasma nonesterified fatty acids, glycerol, insulin, glucose, adrenaline and noradrenaline concentrations, blood pressure, and heart rate were also determined. Exercise elevated plasma glycerol, free fatty acids, and interstitial glycerol concentrations and increased the rate of glycerol appearance. However, exercise-induced stimulation of lipolysis was not augmented on sacubitril/valsartan treatment compared with amlodipine treatment. Furthermore, sacubitril/valsartan did not alter energy expenditure and substrate oxidation during exercise compared with amlodipine treatment. In conclusion, sacubitril/valsartan treatment for 8 weeks did not elicit clinically relevant changes in exercise-induced lipolysis or substrate oxidation in obese patients with hypertension, implying that its beneficial cardiovascular effects cannot be explained by changes in lipid metabolism during exercise. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT01631864. PMID:29180454

Effect of Sacubitril/Valsartan on Exercise-Induced Lipid Metabolism in Patients With Obesity and Hypertension.

PubMed

Engeli, Stefan; Stinkens, Rudi; Heise, Tim; May, Marcus; Goossens, Gijs H; Blaak, Ellen E; Havekes, Bas; Jax, Thomas; Albrecht, Diego; Pal, Parasar; Tegtbur, Uwe; Haufe, Sven; Langenickel, Thomas H; Jordan, Jens

2018-01-01

Sacubitril/valsartan (LCZ696), a novel angiotensin receptor-neprilysin inhibitor, was recently approved for the treatment of heart failure with reduced ejection fraction. Neprilysin degrades several peptides that modulate lipid metabolism, including natriuretic peptides. In this study, we investigated the effects of 8 weeks' treatment with sacubitril/valsartan on whole-body and adipose tissue lipolysis and lipid oxidation during defined physical exercise compared with the metabolically neutral comparator amlodipine. This was a multicenter, randomized, double-blind, active-controlled, parallel-group study enrolling subjects with abdominal obesity and moderate hypertension (mean sitting systolic blood pressure ≥130-180 mm Hg). Lipolysis during rest and exercise was assessed by microdialysis and [1,1,2,3,3- 2 H]-glycerol tracer kinetics. Energy expenditure and substrate oxidation were measured simultaneously using indirect calorimetry. Plasma nonesterified fatty acids, glycerol, insulin, glucose, adrenaline and noradrenaline concentrations, blood pressure, and heart rate were also determined. Exercise elevated plasma glycerol, free fatty acids, and interstitial glycerol concentrations and increased the rate of glycerol appearance. However, exercise-induced stimulation of lipolysis was not augmented on sacubitril/valsartan treatment compared with amlodipine treatment. Furthermore, sacubitril/valsartan did not alter energy expenditure and substrate oxidation during exercise compared with amlodipine treatment. In conclusion, sacubitril/valsartan treatment for 8 weeks did not elicit clinically relevant changes in exercise-induced lipolysis or substrate oxidation in obese patients with hypertension, implying that its beneficial cardiovascular effects cannot be explained by changes in lipid metabolism during exercise. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01631864. © 2017 The Authors.

Comparative study between derivative spectrophotometry and multivariate calibration as analytical tools applied for the simultaneous quantitation of Amlodipine, Valsartan and Hydrochlorothiazide

NASA Astrophysics Data System (ADS)

Darwish, Hany W.; Hassan, Said A.; Salem, Maissa Y.; El-Zeany, Badr A.

2013-09-01

Four simple, accurate and specific methods were developed and validated for the simultaneous estimation of Amlodipine (AML), Valsartan (VAL) and Hydrochlorothiazide (HCT) in commercial tablets. The derivative spectrophotometric methods include Derivative Ratio Zero Crossing (DRZC) and Double Divisor Ratio Spectra-Derivative Spectrophotometry (DDRS-DS) methods, while the multivariate calibrations used are Principal Component Regression (PCR) and Partial Least Squares (PLSs). The proposed methods were applied successfully in the determination of the drugs in laboratory-prepared mixtures and in commercial pharmaceutical preparations. The validity of the proposed methods was assessed using the standard addition technique. The linearity of the proposed methods is investigated in the range of 2-32, 4-44 and 2-20 μg/mL for AML, VAL and HCT, respectively.

Protective effects of AT1-receptor blocker and CA antagonist combination on renal function in salt loaded spontaneously hypertensive rats.

PubMed

Gjorgjievska, K; Zafirov, D; Jurhar-Pavlova, M; Cekovska, S; Atanasovska, E; Pavlovska, K; Zendelovska, D

2015-01-01

Salt sensitive hypertension is known to be a contributing factor for the progression of kidney disease. This study was undertaken to investigate the role of excessive dietary salt on renal function and to evaluate the effect of valsartan and amlodipin given as a combination therapy on blood pressure and parameters specific to the renal function in salt loaded SHR rats. 48 male SHR rats at age of 20 weeks and body weight ranging between 270-350 g were used. SHR rats were divided into 3 groups: control group of rats -SHRC (n = 16) given tab water ad libitum and two salt treated groups in which tab water was replaced with a solution of NaCl (1%) from age of 8 weeks given ad libitum: SHRVAL+AMLO group (n = 16) where investigated drugs were administered at a dose of 10 mg/kg/ b.w. (valsartan) and 5 mg/kg/ b.w. (amlodipin) by gavage and SHR NaCl group (n = 16) that received saline in the same volume and the same time intervals as the SHRVAL+AMLO group. For a period of 12 weeks we have investigated the effect of the VAL+AMLO drug combination on systolic blood pressure (SBP), body weight and renal function tests. Salt loading with 1% solution in the SHR NaCl group has lead to significant increase of blood pressure, proteinuria and decrease in creatinine clearance. Combined treatment with AT1 receptor blocker and calcium antagonist has managed to control blood pressure and ameliorated renal damage.

Comparative study between derivative spectrophotometry and multivariate calibration as analytical tools applied for the simultaneous quantitation of Amlodipine, Valsartan and Hydrochlorothiazide.

PubMed

Darwish, Hany W; Hassan, Said A; Salem, Maissa Y; El-Zeany, Badr A

2013-09-01

Four simple, accurate and specific methods were developed and validated for the simultaneous estimation of Amlodipine (AML), Valsartan (VAL) and Hydrochlorothiazide (HCT) in commercial tablets. The derivative spectrophotometric methods include Derivative Ratio Zero Crossing (DRZC) and Double Divisor Ratio Spectra-Derivative Spectrophotometry (DDRS-DS) methods, while the multivariate calibrations used are Principal Component Regression (PCR) and Partial Least Squares (PLSs). The proposed methods were applied successfully in the determination of the drugs in laboratory-prepared mixtures and in commercial pharmaceutical preparations. The validity of the proposed methods was assessed using the standard addition technique. The linearity of the proposed methods is investigated in the range of 2-32, 4-44 and 2-20 μg/mL for AML, VAL and HCT, respectively. Copyright © 2013 Elsevier B.V. All rights reserved.

Azilsartan medoxomil in the management of hypertension: an evidence-based review of its place in therapy

PubMed Central

Angeloni, Emiliano

2016-01-01

Background Azilsartan (AZI) is a relatively new angiotensin receptor blocker available for the treatment of any stage of hypertension, which was eventually given in combination with chlorthalidone (CLT). Objective To review pharmacology and clinical role of AZI monotherapy and AZI/CLT or AZI/amlodipine combination therapies for hypertension management. Methods PubMed, Embase, and Cochrane Library were searched using search terms “ azilsartan”, “chlorthalidone,” “pharmacology,” “pharmacokinetics,” “pharmacodynamics,” “pharmacoeconomics,” and “cost-effectiveness.” To obtain other relevant information, US Food and Drug Association as well as manufacturer prescribing information were also reviewed. Results Randomized controlled trials demonstrated AZI to be superior to other sartans, such as valsartan, olmesartan, and candesartan, in terms of 24-hour ambulatory blood pressure monitoring (ABPM) reduction with respect. That beneficial effect of azilsartan was also associated with similar safety profiles. When compared to other antihypertensive drugs, azilsartan was found to be superior to any angiotensin-converting enzyme inhibitor, including ramipril, in terms of ABPM results, and noninferior to amlodipine in terms of sleep-BP control. The association of AZI and CLT was then found to be superior to other sartans + thiazide combination therapies in terms of both BP lowering and goal achievement. The combination of AZI and amlodipine has also been tested in clinical trials, but compared only with placebo, demonstrating its superiority in terms of efficacy and similarity in terms of safety. Conclusion Azilsartan is a safe and effective treatment option for every stage of hypertension, both alone or in fixed-dose combination tablets with chlorthalidone or amlodipine. Beneficial effects of AZI were also noted in patients with any degree of renal impairment. In addition, safety profiles of AZI were similar to that of the placebo. PMID:27103882

Azilsartan medoxomil in the management of hypertension: an evidence-based review of its place in therapy.

PubMed

Angeloni, Emiliano

2016-01-01

Azilsartan (AZI) is a relatively new angiotensin receptor blocker available for the treatment of any stage of hypertension, which was eventually given in combination with chlorthalidone (CLT). To review pharmacology and clinical role of AZI monotherapy and AZI/CLT or AZI/amlodipine combination therapies for hypertension management. PubMed, Embase, and Cochrane Library were searched using search terms " azilsartan", "chlorthalidone," "pharmacology," "pharmacokinetics," "pharmacodynamics," "pharmacoeconomics," and "cost-effectiveness." To obtain other relevant information, US Food and Drug Association as well as manufacturer prescribing information were also reviewed. Randomized controlled trials demonstrated AZI to be superior to other sartans, such as valsartan, olmesartan, and candesartan, in terms of 24-hour ambulatory blood pressure monitoring (ABPM) reduction with respect. That beneficial effect of azilsartan was also associated with similar safety profiles. When compared to other antihypertensive drugs, azilsartan was found to be superior to any angiotensin-converting enzyme inhibitor, including ramipril, in terms of ABPM results, and noninferior to amlodipine in terms of sleep-BP control. The association of AZI and CLT was then found to be superior to other sartans + thiazide combination therapies in terms of both BP lowering and goal achievement. The combination of AZI and amlodipine has also been tested in clinical trials, but compared only with placebo, demonstrating its superiority in terms of efficacy and similarity in terms of safety. Azilsartan is a safe and effective treatment option for every stage of hypertension, both alone or in fixed-dose combination tablets with chlorthalidone or amlodipine. Beneficial effects of AZI were also noted in patients with any degree of renal impairment. In addition, safety profiles of AZI were similar to that of the placebo.

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

PubMed

Ayalasomayajula, Surya; Langenickel, Thomas; Pal, Parasar; Boggarapu, Sreedevi; Sunkara, Gangadhar

2017-12-01

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.

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

PubMed

Ayalasomayajula, Surya; Langenickel, Thomas; Pal, Parasar; Boggarapu, Sreedevi; Sunkara, Gangadhar

2018-01-01

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.

Different approaches in Partial Least Squares and Artificial Neural Network models applied for the analysis of a ternary mixture of Amlodipine, Valsartan and Hydrochlorothiazide

NASA Astrophysics Data System (ADS)

Darwish, Hany W.; Hassan, Said A.; Salem, Maissa Y.; El-Zeany, Badr A.

2014-03-01

Different chemometric models were applied for the quantitative analysis of Amlodipine (AML), Valsartan (VAL) and Hydrochlorothiazide (HCT) in ternary mixture, namely, Partial Least Squares (PLS) as traditional chemometric model and Artificial Neural Networks (ANN) as advanced model. PLS and ANN were applied with and without variable selection procedure (Genetic Algorithm GA) and data compression procedure (Principal Component Analysis PCA). The chemometric methods applied are PLS-1, GA-PLS, ANN, GA-ANN and PCA-ANN. The methods were used for the quantitative analysis of the drugs in raw materials and pharmaceutical dosage form via handling the UV spectral data. A 3-factor 5-level experimental design was established resulting in 25 mixtures containing different ratios of the drugs. Fifteen mixtures were used as a calibration set and the other ten mixtures were used as validation set to validate the prediction ability of the suggested methods. The validity of the proposed methods was assessed using the standard addition technique.

Hypertension management: rationale for triple therapy based on mechanisms of action.

PubMed

Neutel, Joel M; Smith, David H G

2013-10-01

An estimated 25% of patients will require 3 antihypertensive agents to achieve blood pressure (BP) control; combination therapy is thus an important strategy in hypertension treatment. This review discusses the triple-therapy combination of an angiotensin receptor blocker (ARB) or direct renin antagonist (DRI) with a calcium channel blocker (CCB) and a diuretic, with a focus on mechanisms of action. Multiple physiologic pathways contribute to hypertension. Combining antihypertensive agents not only better targets the underlying pathways, but also helps blunt compensatory responses that may be triggered by single-agent therapy. DRIs and ARBs target the renin-angiotensin-aldosterone system (RAAS) at the initial and final steps, respectively, and both classes lower BP by reducing the effects of angiotensin-2; however, ARBs may trigger a compensatory increase in renin activity. Dihydropyridine CCBs target L-type calcium channels and lower BP through potent vasodilation, but can trigger compensatory activation of the sympathetic nervous system (SNS) and RAAS. Thiazide diuretics lower BP initially through sodium depletion and plasma volume reduction, followed by total peripheral resistance reduction, but can also trigger compensatory activation of the SNS and RAAS. The combination of an agent targeting the RAAS with a CCB and diuretic is rational, and triple combinations of valsartan/amlodipine/hydrochlorothiazide, olmesartan/amlodipine/hydrochlorothiazide, and aliskiren/amlodipine/hydrochlorothiazide have demonstrated greater effectiveness compared with their respective dual-component combinations. In addition, single-pill, fixed-dose combinations can address barriers to BP control including clinical inertia and poor adherence. Fixed-dose antihypertensive combination products capitalize on complementary mechanisms of action and have been shown to result in improved BP control. © 2012 John Wiley & Sons Ltd.

Efficacy and safety of valsartan/amlodipine single-pill combination in patients with essential hypertension (PEAK LOW).

PubMed

Kızılırmak, Pınar; Ar, Idilhan; Ilerigelen, Barış

2014-06-01

This study evaluated the efficacy as well as the safety and tolerability profile of low-dose valsartan/amlodipine (Val/Amlo) single-pill combination (SPC) (160/5 mg) in patients with essential hypertension in Turkey. Adult patients with essential hypertension [systolic blood pressure (SBP)>140 mmHg and/or diastolic blood pressure (DBP)>90 mmHg], who were on low dose Val/Amlo (160/5 mg) SPC before enrollment and gave informed consent, were accepted for this multi-centric observational study performed at 30 sites. The absolute changes in SBP and DBP from baseline were the primary efficacy outcomes. Safety assessments consisted of recording all adverse events. Of 381 patients enrolled, 327 completed the study; 39% were females. The mean age was 57.3±11.8 years. Median duration of hypertension was 38 months. Both SBP and DBP values showed reductions from 162.6±16.6 mmHg and 94.0±13.2 mmHg to 137.6±14.2 mmHg and 81.9±9.0 mmHg at 4th week and to 131.6±11.5 mmHg and 79.7±7.6 mmHg at 12th week, respectively. The control and response rates at the end of the study were 82.0% and 92.6%, respectively. Twelve patients (3.2%) experienced a total of 12 adverse events; there were no serious adverse events. The most common adverse event was edema (1.3%). Patient compliance was approximately 99%. Low-dose (160/5 mg) Val/Amlo SPC is efficacous and has a good tolerability and safety profile for the management of essential hypertension in Turkey.

Comparison of real-world effectiveness between valsartan and non-RAS inhibitor monotherapy on the incidence of new diabetes in Chinese hypertensive patients: An electronic health recording system based study.

PubMed

Shen, Tian; Wang, Jiwei; Yu, Yingjun; Yu, Jinming

2018-05-21

This study aimed to compare the real-world effectiveness of valsartan and non renin-angiotensin system (non-RAS) agent monotherapy on the incidence of new on-set diabetes (NOD) in Chinese hypertensive patients. It was based on an electronic Health Recording System database from Minhang District of Shanghai. Hypertensive patients aged ≥18 years continuously taking either valsartan or non-RAS agent monotherapy for >12 months were included. Hazard ratios (HR) of NOD events were estimated using propensity score matching method and multivariate regression. Of 29295 patients, there were 2107 in valsartan group, 21397 in CCB group, 4094 in β-blockers group and 1697 in diuretics group. Two-year follow-up revealed NOD rates of 11.09 and 14.22 per 100 persons per year in valsartan and non-RAS inhibitor groups (HR = 0.77, 95% confidence interval 0.65-0.93, P = 0.006), respectively. Among non-RAS agents, CCB group had the highest incidence of NOD (21.72 per 100 persons per year). Comparisons between CCB sub-groups revealed the highest NOD incidence for nifedipine, followed by amlodipine and felodipine. NOD incidences in β-blockers and diuretics groups (11.70 and 10.50 per 100 persons per year, respectively) were not significantly different from valsartan group. Compared with non-RAS inhibitors, particularly CCBs, valsartan could significantly reduce the incidence of NOD.

Effects of the combinations of amlodipine/valsartan versus losartan/hydrochlorothiazide on left ventricular hypertrophy as determined with magnetic resonance imaging in patients with hypertension

PubMed Central

Bruder, Oliver; Jensen, Christoph J.; Bell, Michael; Rummel, Reinhard; Boehm, Guenter; Klebs, Sven; Sieder, Christian; Senges, Jochen

2012-01-01

Background Left ventricular hypertrophy (LVH), a marker of cardiac end-organ damage, is frequently found in patients with arterial hypertension and is associated with cardiovascular and cerebrovascular morbidity and mortality. Therefore, LVH regression is an important treatment goal. For amlodipine plus valsartan (A/V) no specific study on LVH has been reported to date. Methods Prospective, open-label, randomized parallel-group study. Patients with essential hypertension and LVH were randomized to 52-week treatment with A/V 10/160 mg (n = 43) or the active comparator losartan/HCT 100/25 mg (L/H, n = 47). Add-on medication was allowed in case of inadequate blood pressure control. LV parameters were measured by cardiovascular magnetic resonance imaging (MRI), and adjudicated in a blinded manner. Study identifiers were NCT00446563 and EudraCT 2006-001977-17. Results In addition to the study treatment, 35% of patients in the A/V group and 49% in the L/H group received additional antihypertensive medication. Compared to baseline, both treatments reduced measures of LVH significantly after 52 weeks (e.g. LV mass index in the A/V group from 64.7 g/m2 by −3.5 g/m2, in the L/H group from 69.1 g/m2 by −4.4 g/m2, p < 0.01 for both). LV ejection fraction and LV volumes were not significantly changed by any regimen. A/V and L/H treatments were well tolerated. Conclusions Both regimen were effective in reducing LV mass compared to baseline and were well tolerated. PMID:27536421

Effects of the combinations of amlodipine/valsartan versus losartan/hydrochlorothiazide on left ventricular hypertrophy as determined with magnetic resonance imaging in patients with hypertension.

PubMed

Bruder, Oliver; Jensen, Christoph J; Bell, Michael; Rummel, Reinhard; Boehm, Guenter; Klebs, Sven; Sieder, Christian; Senges, Jochen

2012-01-01

Left ventricular hypertrophy (LVH), a marker of cardiac end-organ damage, is frequently found in patients with arterial hypertension and is associated with cardiovascular and cerebrovascular morbidity and mortality. Therefore, LVH regression is an important treatment goal. For amlodipine plus valsartan (A/V) no specific study on LVH has been reported to date. Prospective, open-label, randomized parallel-group study. Patients with essential hypertension and LVH were randomized to 52-week treatment with A/V 10/160 mg (n = 43) or the active comparator losartan/HCT 100/25 mg (L/H, n = 47). Add-on medication was allowed in case of inadequate blood pressure control. LV parameters were measured by cardiovascular magnetic resonance imaging (MRI), and adjudicated in a blinded manner. Study identifiers were NCT00446563 and EudraCT 2006-001977-17. In addition to the study treatment, 35% of patients in the A/V group and 49% in the L/H group received additional antihypertensive medication. Compared to baseline, both treatments reduced measures of LVH significantly after 52 weeks (e.g. LV mass index in the A/V group from 64.7 g/m(2) by -3.5 g/m(2), in the L/H group from 69.1 g/m(2) by -4.4 g/m(2), p < 0.01 for both). LV ejection fraction and LV volumes were not significantly changed by any regimen. A/V and L/H treatments were well tolerated. Both regimen were effective in reducing LV mass compared to baseline and were well tolerated.

Long-term (52-week) safety and efficacy of Sacubitril/valsartan in Asian patients with hypertension.

PubMed

Supasyndh, Ouppatham; Sun, Ningling; Kario, Kazuomi; Hafeez, Kudsia; Zhang, Jack

2017-05-01

Sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor-neprilysin inhibitor, demonstrated significant reductions in office and 24 h ambulatory blood pressure (BP) over 8 weeks in Asian patients with hypertension. This 52-week extension to the 8-week core study was aimed at evaluating the long-term safety, tolerability and efficacy of sacubitril/valsartan. Patients who completed an 8-week randomized study (the core study) were enrolled in this 52-week open-label study and received sacubitril/valsartan 200 mg QD. The sacubitril/valsartan dose was uptitrated to 400 mg QD if BP was uncontrolled (>140/90 mm Hg) after 4 weeks. Subsequently, in patients with uncontrolled BP, treatment was intensified every 4 weeks with amlodipine 5-10 mg followed by hydrochlorothiazide 6.25-25 mg. Of the 341 patients enrolled, 7 (2.1%) discontinued the study drug due to adverse events (AEs). The incidence of AEs and serious AEs were 63.9 and 3.8%, respectively, and no deaths were reported in this study. The most frequent AEs were nasopharyngitis (18.2%) and dizziness (8.8%). Events that were potentially indicative of low BP were infrequent. One patient reported mild transient angioedema (lasting 2.5 h) that resolved without treatment but led to study drug discontinuation. The sacubitril/valsartan-based regimen provided clinically significant mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) reductions from baseline (-24.7/-16.2 mm Hg). The overall BP control, msSBP and msDBP response rates were 75.3, 90.6 and 87.6%, respectively. Long-term use of sacubitril/valsartan was generally safe and well-tolerated in patients with hypertension and provided significant BP reductions from baseline.

Development and Validation of highly Sensitive Stability Indicating Spectrofluorimetric Method for Determination of Amlodipine in Pharmaceutical Preparations and Human Plasma.

PubMed

Mohamed, Abdel-Maaboud I; Omar, Mahmoud A; Hammad, Mohamed A; Mohamed, Abobakr A

2016-11-01

A highly sensitive and simple spectrofluorimetric method was developed for the determination of Amlodipine besylate (AML) in its pharmaceutical formulations and spiked human plasma. The proposed method is based on the investigation of the fluorescence spectral behaviour of AML in Tween-80 micellar system. In aqueous solution, the fluorescence intensity of AML was greatly enhanced (160 %) in the presence of Tween-80. The fluorescence intensity was measured at 427 nm after excitation at 385 nm. The fluorescence-concentration plot was rectilinear over the concentration range 0.1-4.0 μg/ml, with lower detection limit of 0.03 μg/ml. The suggested method was successfully applied for the analysis of AML in its commercial tablets alone or in combination with either Atorvastatin or Valsartan. The application of the proposed method was extended to the assay of AML in spiked human plasma and stability studies of AML after exposure to different forced degradation conditions, such as acidic, alkaline, photo- and oxidative conditions, according to ICH guidelines. The results were statistically compared to those obtained by comparison methods and were found to be in good agreement.

Gender difference in the response to valsartan/amlodipine single-pill combination in essential hypertension (China Status II): An observational study

PubMed Central

Wang, Huan; Chen, Hui

2016-01-01

Background: The China STATUS II is a prospective, multicentre, open-label, post-marketing, observational study including Chinese adults (aged ⩾ 18 years) with essential hypertension who were prescribed once-daily valsartan/amlodipine (Val/Aml 80/5 mg) single-pill combination. In order to examine gender differences in treatment response to Val/Aml, we further analysed data from the China STATUS II study. Methods: A total of 11,312 patients (6456 (57%) men and 4856 (43%) women) received the Val/Aml treatment for 8 weeks. After the treatment, we compared the proportion of patients not achieving the target systolic blood pressure (SBP: < 140 mm Hg) or diastolic blood pressure (DBP: < 90 mm Hg) in different age groups (by Fisher exact probability test) and estimated the changes in blood pressure (BP) according to age and gender, using a mixed model. Results: At enrolment, mean SBP was higher in the female versus the male patients (160.0 ± 12.71 versus 159.3 ± 12.31 mm Hg; p = 0.003), whereas the mean DBP was higher in the male versus the female patients (96.4 ± 10.65 versus 94.5 ± 10.72 mm Hg; p < 0.001). The overall proportion of women not achieving the target BP was less than that of men (57.41% versus 59.59%; p < 0.05) at 4 weeks and (22.22% versus 23.78%; p < 0.05) at 8 weeks after the Val/Aml treatment. Among both men and women, the proportion of patients not achieving the target SBP increased with age; however, the proportion not achieving the target DBP decreased with age. The mixed-model analysis showed that the changes in SBP were closely related to gender, indicating that the SBP-lowering effect after Val/Aml treatment might be better in women. In addition, the changes in DBP were closely related to age. Conclusions: Gender might be a factor for consideration in the decision-making process of individualised antihypertensive therapy, in the future. PMID:27127102

Gender difference in the response to valsartan/amlodipine single-pill combination in essential hypertension (China Status II): An observational study.

PubMed

Wang, Huan; Chen, Hui

2016-01-01

The China STATUS II is a prospective, multicentre, open-label, post-marketing, observational study including Chinese adults (aged ⩾ 18 years) with essential hypertension who were prescribed once-daily valsartan/amlodipine (Val/Aml 80/5 mg) single-pill combination. In order to examine gender differences in treatment response to Val/Aml, we further analysed data from the China STATUS II study. A total of 11,312 patients (6456 (57%) men and 4856 (43%) women) received the Val/Aml treatment for 8 weeks. After the treatment, we compared the proportion of patients not achieving the target systolic blood pressure (SBP: < 140 mm Hg) or diastolic blood pressure (DBP: < 90 mm Hg) in different age groups (by Fisher exact probability test) and estimated the changes in blood pressure (BP) according to age and gender, using a mixed model. At enrolment, mean SBP was higher in the female versus the male patients (160.0 ± 12.71 versus 159.3 ± 12.31 mm Hg; p = 0.003), whereas the mean DBP was higher in the male versus the female patients (96.4 ± 10.65 versus 94.5 ± 10.72 mm Hg; p < 0.001). The overall proportion of women not achieving the target BP was less than that of men (57.41% versus 59.59%; p < 0.05) at 4 weeks and (22.22% versus 23.78%; p < 0.05) at 8 weeks after the Val/Aml treatment. Among both men and women, the proportion of patients not achieving the target SBP increased with age; however, the proportion not achieving the target DBP decreased with age. The mixed-model analysis showed that the changes in SBP were closely related to gender, indicating that the SBP-lowering effect after Val/Aml treatment might be better in women. In addition, the changes in DBP were closely related to age. Gender might be a factor for consideration in the decision-making process of individualised antihypertensive therapy, in the future. © The Author(s) 2016.

Concurrent estimation of amlodipine besylate, hydrochlorothiazide and valsartan by RP-HPLC, HPTLC and UV-spectrophotometry.

PubMed

Sharma, Manish; Kothari, Charmy; Sherikar, Omkar; Mehta, Priti

2014-01-01

Accurate, sensitive and reproducible reversed-phase high-performance liquid chromatography (RP-HPLC), high-performance thin-layer chromatography (HPTLC) and ultraviolet (UV) spectrophopometric methods were developed for the concurrent estimation of amlodipine besylate (AMLO), hydrochlorothiazide (HCTZ) and valsartan (VALS) in bulk and combined tablet dosage forms. For the RP-HPLC method, separation was achieved on a C18 column using potassium dihydrogen orthophosphate buffer (50 mM, pH 3.7) with 0.2% triethylamine as the modifier and acetonitrile in the ratio of 56:44 (v/v) as the mobile phase. Quantification was achieved using a photodiode array detector at 232 nm over a concentration range of 2-25 µg/mL for AMLO, 5-45 µg/mL for HCTZ and 20-150 µg/mL for VALS. For the HPTLC method, the drugs were separated by using ethyl acetate-methanol-toluene-ammonia (7.5:3:2:0.8, v/v/v/v) as the mobile phase. Quantification was achieved using UV detection at 242 nm over a concentration range of 100-600 ng/spot for AMLO, 150-900 ng/spot for HCTZ and 1,200-3,200 ng/spot for VALS. The UV-spectrophotometric simultaneous equation method was based on the measurement of absorbance at three wavelengths; i.e., at 237.6 nm (λmax of AMLO), 270.2 nm (λmax of HCTZ) and 249.2 nm (λmax of VALS) in methanol. Quantification was achieved over the concentration range of 2-20 µg/mL for AMLO, 5-25 µg/mL HCTZ and 10-50 µg/mL for VALS. All methods were validated according to International Conference on Harmonization guidelines and successfully applied to marketed pharmaceutical formulations. Additionally, the three methods were compared statistically by an analysis of variance test, which revealed no significant difference between the proposed methods with respect to accuracy and precision.

Effects of Demographics on the Antihypertensive Efficacy of Triple Therapy With Amlodipine, Valsartan, and Hydrochlorothiazide for Moderate to Severe Hypertension

PubMed Central

Calhoun, David A.; Lacourci00E8;re, Yves; Crikelair, Nora; Jia, Yan; Glazer, Robert D.

2014-01-01

Objective To compare the antihypertensive efficacy and safety of once-daily triple therapy with amlodipine (Aml) 10 mg, valsartan (Val) 320 mg, and hydrochlorothiazide (HCTZ) 25 mg versus dual-therapy combinations of these components in patients with moderate to severe hypertension. Research design Subgroup analysis of a multinational, randomized, double-blind, parallel-group, active-controlled trial. Methods After antihypertensive washout and a placebo run-in of up to 4 weeks, 2271 patients were randomly allocated in a 1:1:1:1 ratio to receive Aml/Val/HCTZ triple therapy or dual therapy with Val/HCTZ, Aml/Val, or Aml/HCTZ for 8 weeks. Forced titration to the full dose was done over the first 2 weeks of treatment. Efficacy and safety parameters were determined by age group (<65 vs. ≥65 years), gender, race (White vs. Black), ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), and body mass index (BMI, <30 vs. ≥30 kg/m2). Main outcome measures Change from baseline to endpoint in mean sitting systolic blood pressure (MSSBP) and mean sitting diastolic blood pressure (MSDBP); blood pressure (BP) control rate <140/90 mmHg. Results Triple therapy was numerically superior and, for the majority of comparisons, statistically superior to each dual therapy in reducing MSSBP and MSDBP and in improving BP control rates in all subgroups. Across subgroups, triple therapy reduced MSSBP by 5.7–10.7 mmHg more than Val/HCTZ, 3.4–8.3 mmHg more than Aml/Val, and 4.4–9.4 mmHg more than Aml/HCTZ. Triple therapy was well tolerated across all subgroups. Limitations of our analysis included the lack of stratification of patients by subgroup at randomization and the small sample size of some subgroups (eg, Blacks, elderly). Conclusions Triple therapy with Aml/Val/HCTZ is effective and well tolerated in patients with moderate to severe hypertension regardless of age, gender, race, ethnicity, or BMI. PMID:23721363

Valsartan decreases platelet activity and arterial thrombotic events in elderly patients with hypertension.

PubMed

Wu, Fang; Wang, Hong-Yan; Cai, Fan; Wang, Ling-Jie; Zhang, Feng-Ru; Chen, Xiao-Nan; Yang, Qian; Jiang, Meng-Hui; Wang, Xue-Feng; Shen, Wei-Feng

2015-01-20

Angiotensin type 1 receptor (AT 1 R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT 1 R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension. Two-hundred and ten patients with hypertension and aged > 60 years were randomized to valsartan (n = 140) or amlodipine (n = 70) on admission. The primary endpoint was platelet aggregation rate (PAR) induced by arachidonic acid at discharge, and the secondary endpoint was the rate of thrombotic events including brain infarction and myocardial infarction during follow-up. Human aortic endothelial cells (HAECs) were stimulated by angiotensin II (Ang II, 100 nmol/L) with or without pretreatment of valsartan (100 nmol/L), and relative expression of cyclooxygenase-2 (COX-2) and thromboxane B 2 (TXB 2 ) and both p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) activities were assessed. Statistical analyses were performed by GraphPad Prism 5.0 software (GraphPad Software, Inc., California, USA). PAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001). Plasma COX-2 and TXB 2 levels correlated significantly with PAR in overall patients (r = 0.109, P < 0.001). During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002). Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L). AT 1 R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA 2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

Novel spectrophotometric methods for simultaneous determination of Amlodipine, Valsartan and Hydrochlorothiazide in their ternary mixture

NASA Astrophysics Data System (ADS)

Lotfy, Hayam M.; Hegazy, Maha A.; Mowaka, Shereen; Mohamed, Ekram Hany

2015-04-01

This work represents a comparative study of two smart spectrophotometric techniques namely; successive resolution and progressive resolution for the simultaneous determination of ternary mixtures of Amlodipine (AML), Hydrochlorothiazide (HCT) and Valsartan (VAL) without prior separation steps. These techniques consist of several consecutive steps utilizing zero and/or ratio and/or derivative spectra. By applying successive spectrum subtraction coupled with constant multiplication method, the proposed drugs were obtained in their zero order absorption spectra and determined at their maxima 237.6 nm, 270.5 nm and 250 nm for AML, HCT and VAL, respectively; while by applying successive derivative subtraction they were obtained in their first derivative spectra and determined at P230.8-246, P261.4-278.2, P233.7-246.8 for AML, HCT and VAL respectively. While in the progressive resolution, the concentrations of the components were determined progressively from the same zero order absorption spectrum using absorbance subtraction coupled with absorptivity factor methods or from the same ratio spectrum using only one divisor via amplitude modulation method can be used for the determination of ternary mixtures using only one divisor where the concentrations of the components are determined progressively. The proposed methods were checked using laboratory-prepared mixtures and were successfully applied for the analysis of pharmaceutical formulation containing the cited drugs. Moreover comparative study between spectrum addition technique as a novel enrichment technique and a well established one namely spiking technique was adopted for the analysis of pharmaceutical formulations containing low concentration of AML. The methods were validated as per ICH guidelines where accuracy, precision and specificity were found to be within their acceptable limits. The results obtained from the proposed methods were statistically compared with the reported one where no significant difference was observed.

Rationale for nebivolol/valsartan combination for hypertension: review of preclinical and clinical data.

PubMed

Giles, Thomas D; Cockcroft, John R; Pitt, Bertram; Jakate, Abhijeet; Wright, Harold M

2017-09-01

: To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin-angiotensin-aldosterone system inhibitors, when combined, have been deemed 'less effective' based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg - a vasodilatory β1-selective antagonist/β3 agonist - and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I-II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension.

Valsartan and Sacubitril

MedlinePlus

Entresto® (as a combination product containing Sacubitril, Valsartan) ... The combination of valsartan and sacubitril is usually used in combination with other medications to lower the risk of death and hospitalization with certain types of heart ...

Effects of Sacubitril/Valsartan Versus Olmesartan on Central Hemodynamics in the Elderly With Systolic Hypertension: The PARAMETER Study.

PubMed

Williams, Bryan; Cockcroft, John R; Kario, Kazuomi; Zappe, Dion H; Brunel, Patrick C; Wang, Qian; Guo, Weinong

2017-03-01

Effective treatment of systolic hypertension in elderly patients remains a major therapeutic challenge. A multicenter, double-blind, randomized controlled trial with sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, was conducted to determine its effects versus olmesartan (angiotensin receptor blocker) on central aortic pressures, in elderly patients (aged ≥60 years) with systolic hypertension and pulse pressure >60 mm Hg, indicative of arterial stiffness. Patients (n=454; mean age, 67.7 years; mean seated systolic blood pressure, 158.6 mm Hg; mean seated pulse pressure, 69.7 mm Hg) were randomized to receive once-daily sacubitril/valsartan 200 mg or olmesartan 20 mg, force titrated to double the initial doses after 4 weeks, before primary assessment at 12 weeks. The study extended double-blind treatment for 12 to 52 weeks, during which amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) were added-on for patients not achieving blood pressure target (<140/90). At week 12, sacubitril/valsartan reduced central aortic systolic pressure (primary assessment) greater than olmesartan by -3.7 mm Hg ( P =0.010), further corroborated by secondary assessments at week 12 (central aortic pulse pressure, -2.4 mm Hg, P <0.012; mean 24-hour ambulatory brachial systolic blood pressure and central aortic systolic pressure, -4.1 mm Hg and -3.6 mm Hg, respectively, both P <0.001). Differences in 24-hour ambulatory pressures were pronounced during sleep. After 52 weeks, blood pressure parameters were similar between treatments ( P <0.002); however, more patients required add-on antihypertensive therapy with olmesartan (47%) versus sacubitril/valsartan (32%; P <0.002). Both treatments were equally well tolerated. The PARAMETER study (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly), for the first time, demonstrated superiority of sacubitril/valsartan versus olmesartan in reducing clinic and ambulatory central aortic and brachial pressures in elderly patients with systolic hypertension and stiff arteries. © 2017 American Heart Association, Inc.

Rationale for nebivolol/valsartan combination for hypertension: review of preclinical and clinical data

PubMed Central

Giles, Thomas D.; Cockcroft, John R.; Pitt, Bertram; Jakate, Abhijeet; Wright, Harold M.

2017-01-01

To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin–angiotensin–aldosterone system inhibitors, when combined, have been deemed ‘less effective’ based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg – a vasodilatory β1-selective antagonist/β3 agonist – and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I–II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension. PMID:28509722

Valsartan and Hydrochlorothiazide

MedlinePlus

Diovan® HCT (as a combination product containing Valsartan, Hydrochlorothiazide) ... Combination productThis product contains two medications, valsartan and hydrochlorothiazide. Please see the individual monographs for information about each of the medications contained in this product.

Olmesartan/amlodipine: a review of its use in the management of hypertension

PubMed Central

Kreutz, R

2011-01-01

Combination therapy is an effective strategy to increase antihypertensive efficacy in those patients with poor blood pressure (BP) control. In order to achieve BP targets, at least 75% of patients may require combination therapy, and European guidelines advocate this approach, particularly in those patients with a high cardiovascular risk. Evidence from large, randomized controlled trials, and the European hypertension treatment guidelines is supportive of the use of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB). Fixed-dose combination formulations of olmesartan medoxomil, an ARB, and the CCB amlodipine are approved in several European countries for patients with essential hypertension. The olmesartan/amlodipine combination has demonstrated greater efficacy than its component monotherapies in reducing BP in patients with mild-to-severe hypertension. Significantly greater reductions in seated diastolic BP were observed between baseline and after eight weeks of treatment with olmesartan/amlodipine, compared with equivalent doses of olmesartan or amolodipine monotherapy (P < 0.001), in the factorial Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial. About 85% of the maximal BP reductions after the 8-week treatment period were already observed after two weeks. Uptitration as necessary, with or without hydrochlorothiazide, allowed the majority of patients to achieve BP control in a 44-week open-label extension treatment period to the COACH trial. The use of olmesartan/amlodipine allowed up to 54% of patients, with previously inadequate responses to amlodipine or olmesartan monotherapy, to achieve their BP goals. Data from post-registration studies using tight BP control and forced titration regimens have further demonstrated the high efficacy of olmesartan/amlodipine in achieving BP goal rates. Moreover, consistent reductions in BP were observed over the 24-hour dosing interval using ambulatory measurements. Olmesartan/amlodipine was generally well tolerated over the short- and long-term, with a lower frequency of peripheral edema with olmesartan/amlodipine 40/10 mg than with amlodipine 10 mg monotherapy. PMID:21490944

Amlodipine and atorvastatin improve ventricular hypertrophy and diastolic function via inhibiting TNF-α, IL-1β and NF-κB inflammatory cytokine networks in elderly spontaneously hypertensive rats.

PubMed

Lu, Jingchao; Liu, Fan; Chen, Fei; Jin, Yaqiong; Chen, Huiqiang; Liu, Demin; Cui, Wei

2016-10-01

This study aimed to examine the effects of amlodipine and atorvastatin alone or in combination on the regulation of inflammatory cytokines and the underlying mechanisms in elderly spontaneously hypertensive (SH) rats. The level of serum hs-CRP was detected with ELISA. The serum TNF-α and IL-1β levels were assessed by radioimmunity assay (RIA). Cardiac inflammatory cell infiltration was observed by HE staining. The protein levels of TNF-α, IL-1β, of NF-κB P65 and IκBα were detected by immunoblotting. The intracellular localization of NF-κB p65 was observed using immunohistochemistry. Amlodipine or atorvastatin obviously ameliorated the myocardial inflammatory cell infiltration in SH rats, which was further improved by combinatorial treatment with amlodipine and atorvastatin. Either amlodipine or atorvastatin decreased plasma IL-1β content in SH rats, but there was no significant difference when compared with untreated SH rats. However, the combination of amlodipine and atorvastatin significantly decreased plasma IL-1β level in SH rats. Moreover, amlodipine or atorvastatin intervention significantly reduced myocardial TNF-α and IL-1β protein levels in SH rats, which was further suppressed by the combination of amlodipine and atorvastatin. In addition, amlodipine or atorvastatin inhibited the activity of NF-κB signaling in SH rats, which was further suppressed by combinatorial treatment. Furthermore, amlodipine or atorvastatin restored the activity of IκB-α in SH rats, which was enhanced by combinatorial treatment. Our results demonstrated amlodipine and atorvastatin improved ventricular hypertrophy and diastolic function possibly through the intervention of TNF-α, IL-1β, NF-κB/IκB inflammatory cytokine network. Our study suggests that amlodipine combined with atorvastatin may have additive effect on inhibiting inflammatory response. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A Single-Center, Open-Label, 3-Way Crossover Trial to Determine the Pharmacokinetic and Pharmacodynamic Interaction Between Nebivolol and Valsartan in Healthy Volunteers at Steady State

PubMed Central

Chen, Chun Lin; Desai-Krieger, Daksha; Ortiz, Stephan; Kerolous, Majid; Wright, Harold M.; Ghahramani, Parviz

2015-01-01

Combining different classes of antihypertensives is more effective for reducing blood pressure (BP) than increasing the dose of monotherapies. The aims of this phase I study were to investigate pharmacokinetic and pharmacodynamic interactions between nebivolol, a vasodilatory β1-selective blocker, and valsartan, an angiotensin II receptor blocker, and to assess safety and tolerability of the combination. This was a single-center, randomized, open-label, multiple-dose, 3-way crossover trial in 30 healthy adults aged 18–45 years. Participants were randomized into 1 of 6 treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol (20 mg), valsartan (320 mg), and nebivolol–valsartan combination (20/320 mg). Outcomes included AUC0-τ,ss, Cmax,ss, Tmax,ss, changes in BP, pulse rate, plasma angiotensin II, plasma renin activity, 24-hour urinary aldosterone, and adverse events. Steady-state pharmacokinetic interactions were observed but deemed not clinically significant. Systolic and diastolic BP reduction was significantly greater with nebivolol–valsartan combination than with either monotherapy. The mean pulse rate associated with nebivolol and nebivolol–valsartan treatments was consistently lower than that associated with valsartan monotherapy. A sharp increase in mean day 7 plasma renin activity and plasma angiotensin II that occurred in valsartan-treated participants was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at day 7 was substantially decreased after combined treatment, as compared with either monotherapy. All treatments were safe and well tolerated. In conclusion, nebivolol and valsartan coadministration led to greater reductions in BP compared with either monotherapy; nebivolol and valsartan lower BP through complementary mechanisms. PMID:25853236

A Single-Center, Open-Label, 3-Way Crossover Trial to Determine the Pharmacokinetic and Pharmacodynamic Interaction Between Nebivolol and Valsartan in Healthy Volunteers at Steady State.

PubMed

Chen, Chun Lin; Desai-Krieger, Daksha; Ortiz, Stephan; Kerolous, Majid; Wright, Harold M; Ghahramani, Parviz

2015-01-01

Combining different classes of antihypertensives is more effective for reducing blood pressure (BP) than increasing the dose of monotherapies. The aims of this phase I study were to investigate pharmacokinetic and pharmacodynamic interactions between nebivolol, a vasodilatory β1-selective blocker, and valsartan, an angiotensin II receptor blocker, and to assess safety and tolerability of the combination. This was a single-center, randomized, open-label, multiple-dose, 3-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into 1 of 6 treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol (20 mg), valsartan (320 mg), and nebivolol-valsartan combination (20/320 mg). Outcomes included AUC0-τ,ss, Cmax,ss, Tmax,ss, changes in BP, pulse rate, plasma angiotensin II, plasma renin activity, 24-hour urinary aldosterone, and adverse events. Steady-state pharmacokinetic interactions were observed but deemed not clinically significant. Systolic and diastolic BP reduction was significantly greater with nebivolol-valsartan combination than with either monotherapy. The mean pulse rate associated with nebivolol and nebivolol-valsartan treatments was consistently lower than that associated with valsartan monotherapy. A sharp increase in mean day 7 plasma renin activity and plasma angiotensin II that occurred in valsartan-treated participants was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at day 7 was substantially decreased after combined treatment, as compared with either monotherapy. All treatments were safe and well tolerated. In conclusion, nebivolol and valsartan coadministration led to greater reductions in BP compared with either monotherapy; nebivolol and valsartan lower BP through complementary mechanisms.

Evaluation of amlodipine, lisinopril, and a combination in the treatment of essential hypertension

PubMed Central

Naidu, M; Usha, P; Rao, T; Shobha, J

2000-01-01

Angiotensin converting enzyme (ACE) inhibitors and dihydropyridine calcium antagonists are well established and widely used as monotherapy in patients with mild to moderate essential hypertension. Earlier studies combining short acting drugs from these classes require multiple dosing and were associated with poor compliance. Availability of longer acting compounds allows once daily administration to avoid the inconvenience of a multiple daily dose. It was decided to perform a randomised double blind, crossover study with the long acting calcium channel blocker amlodipine and the long acting ACE inhibitor lisinopril, given either alone or in combination in essential hypertension. Twenty four patients with diastolic blood pressure (DBP) between 95 and 104 mm Hg received amlodipine 2.5 mg and 5 mg, lisinopril 5 mg and 10 mg, and their combination as per a prior randomisation schedule. Supine and standing blood pressure and heart rate were recorded at weekly intervals. Higher doses of both the drugs individually or in combination were used if the target supine DBP below 90 mm Hg was not achieved. There was a significant additional blood pressure lowering effect with the combination when compared either with amlodipine or lisinopril alone. Five mg amlodipine and 10 mg lisinopril monotherapy achieved the target blood pressure in 71% and 72% patients respectively. The combination of 2.5 mg amlodipine with 5 mg lisinopril produced a much more significant lowering of blood pressure in a higher percentage of patients than that with an individual low dose.


Keywords: amlodipine; lisinopril; hypertension; combination therapy PMID:10824049

Comparisons of the pharmacokinetics and tolerability of fixed-dose combinations of amlodipine besylate/losartan and amlodipine camsylate/losartan in healthy subjects: a randomized, open-label, single-dose, two-period, two-sequence crossover study.

PubMed

Choi, YoonJung; Lee, SeungHwan; Cho, Sang-Min; Kang, Won-Ho; Nam, Kyu-Yeol; Jang, In-Jin; Yu, Kyung-Sang

2016-01-01

A fixed-dose combination (FDC) of amlodipine and losartan has been used to reduce blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The aim of this study was to evaluate the pharmacokinetic (PK) characteristics and tolerability of an FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium compared to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium in healthy subjects. A randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted on 46 healthy male subjects. Blood concentrations were measured by liquid chromatography-tandem mass spectrometry. Blood samples were collected up to 144 hours post dose for each period. PK parameters were calculated in each treatment group using a noncompartmental method. The 90% confidence intervals (CIs) of the geometric mean ratios of the two treatments for the maximum plasma concentration ( C max ) and the area under the concentration curve from time zero to the last quantifiable time point (AUC 0-t ) were estimated. Tolerability assessments were performed for all subjects who received the drug at least once. The PK profiles of the two treatments were similar. For amlodipine, the geometric mean ratios (90% CIs) of amlodipine besylate to amlodipine camsylate for the C max and AUC 0-t were 0.98 (0.94-1.01) and 0.97 (0.93-1.01), respectively. The corresponding values for losartan were 0.91 (0.81-1.02) and 1.05 (0.98-1.12), respectively. The incidence of adverse events was not significantly different between the two treatments, and both were well tolerated. An FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium produced similar results to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium treatment with respect to the PK parameters of amlodipine and losartan based on C max and AUC 0-t values. The amlodipine besylate/losartan potassium combination was well tolerated by healthy male subjects.

The Synergistic Effect of Valsartan and LAF237 [(S)-1-[(3-Hydroxy-1-Adamantyl)Ammo]acetyl-2-Cyanopyrrolidine] on Vascular Oxidative Stress and Inflammation in Type 2 Diabetic Mice

PubMed Central

Shen, Min; Sun, Dongdong; Li, Weijie; Liu, Bing; Wang, Shenxu; Zhang, Zheng; Cao, Feng

2012-01-01

Aim. To investigate the combination effects and mechanisms of valsartan (angiotensin II type 1 receptor blocker) and LAF237 (DPP-IV inhibitor) on prevention against oxidative stress and inflammation injury in db/db mice aorta. Methods. Db/db mice (n = 40) were randomized to receive valsartan, LAF237, valsartan plus LAF237, or saline. Oxidative stress and inflammatory reaction in diabetic mice aorta were examined. Results. Valsartan or LAF237 pretreatment significantly increased plasma GLP-1 expression, reduced apoptosis of endothelial cells isolated from diabetic mice aorta. The expression of NAD(P)H oxidase subunits also significantly decreased resulting in decreased superoxide production and ICAM-1 (fold change: valsartan : 7.5 ± 0.7, P < 0.05; LAF237: 10.2 ± 1.7, P < 0.05), VCAM-1 (fold change: valsartan : 5.2 ± 1.2, P < 0.05; LAF237: 4.8 ± 0.6, P < 0.05), and MCP-1 (fold change: valsartan: 3.2 ± 0.6, LAF237: 4.7 ± 0.8; P < 0.05) expression. Moreover, the combination treatment with valsartan and LAF237 resulted in a more significant increase of GLP-1 expression. The decrease of the vascular oxidative stress and inflammation reaction was also higher than monotherapy with valsartan or LAF237. Conclusion. These data indicated that combination treatment with LAF237 and valsartan acts in a synergistic manner on vascular oxidative stress and inflammation in type 2 diabetic mice. PMID:22474415

Correlations of plasma renin activity and aldosterone concentration with ambulatory blood pressure responses to nebivolol and valsartan, alone and in combination, in hypertension.

PubMed

Giles, Thomas D; Bakris, George; Oparil, Suzanne; Weber, Michael A; Li, Huiling; Mallick, Madhuja; Bharucha, David B; Chen, ChunLin; Ferguson, William G

2015-11-01

After demonstration of the antihypertensive efficacy of the combination of the beta-blocker nebivolol and the angiotensin receptor blocker valsartan in an 8-week, randomized, placebo-controlled trial (N = 4161), we now report the effects of this treatment on the renin-angiotensin-aldosterone system in a substudy (n = 805). Plasma renin activity increased with valsartan (54%-73%) and decreased with nebivolol (51%-65%) and the combination treatment (17%-39%). Plasma aldosterone decreased with individual treatments (valsartan, 11%-22%; nebivolol, 20%-26%), with the largest reduction (35%) observed with maximum combination dose (20 mg nebivolol/320 mg valsartan). Baseline ln(plasma renin activity) correlated with the 8-week reductions in 24-hour systolic and diastolic BP following treatments with the combination (all doses combined, P = .003 and P < .001) and nebivolol (both, P < .001), but not with valsartan. Baseline ln(aldosterone) correlated with 24-hour systolic and diastolic BP reductions following combination treatment only (P < .001 and P = .005). The implications of the renin-angiotensin-aldosterone system effects of this beta blocker-angiotensin receptor blocker combination should be explored further. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension.

PubMed

Weber, Michael A; White, William B; Sica, Domenic; Bakris, George L; Cao, Charlie; Roberts, Andrew; Kupfer, Stuart

2014-04-01

The aim of the study was to measure the effects on blood pressure (BP) of the angiotensin receptor blocker azilsartan medoxomil, in 40 and 80 mg doses, combined with 5 mg of the calcium channel blocker amlodipine and to compare these effects with placebo plus amlodipine 5 mg. This was a randomized, controlled, double-blind study of 6 weeks' duration in 566 patients with stage 2 hypertension. The primary endpoint was 24-h systolic BP by ambulatory monitoring. The mean age of the participants was 58 years; men and women were equally represented, and baseline 24-h BP (153-154/93 mmHg) and clinic BP (165-166/94-95 mmHg) were similar across the three treatment groups. After 6 weeks, 24-h BP decreased by 25/15 mmHg in both the azilsartan medoxomil/amlodipine 40/5 and 80/5 mg groups. These reductions were each greater than the 14/8 mmHg decrease with placebo plus amlodipine 5 mg (P≤0.001 for both comparisons). All treatments were well tolerated, and adverse events did not increase with the azilsartan medoxomil doses. Edema or fluid retention was less common in both combination groups (2.6 and 2.7%) than with placebo plus amlodipine (7.6%). Coadministration of azilsartan medoxomil with amlodipine was well tolerated and led to meaningful additional BP reductions compared with placebo plus amlodipine.

Evaluation of the dose-response relationship of amlodipine and losartan combination in patients with essential hypertension: an 8-week, randomized, double-blind, factorial, phase II, multicenter study.

PubMed

Park, Chang-Gyu; Youn, Ho-Joong; Chae, Shung-Chull; Yang, Joo-Young; Kim, Moo-Hyun; Hong, Taek-Jong; Kim, Cheol Ho; Kim, Jae Joong; Hong, Bum-Kee; Jeong, Jin-Won; Park, Si-Hoon; Kwan, Jun; Choi, Young-Jin; Cho, Seung-Yun

2012-02-01

Despite recommendations for more intensive treatment and the availability of several effective treatments, hypertension remains uncontrolled in many patients. The aim of this study was to determine the dose-response relationship and assess the efficacy and safety of amlodipine or losartan monotherapy and amlodipine camsylate/losartan combination therapy in patients with essential hypertension. This was an 8-week, randomized, double-blind, factorial design, phase II, multicenter study conducted in outpatient hospital clinics among adult patients aged 18-75 years with essential hypertension. At screening, patients received placebo for 2-4 weeks. Eligible patients (n=320) were randomized to one of eight treatment groups: amlodipine 5 mg or 10 mg, losartan 50 mg or 100 mg, amlodipine camsylate/losartan 5 mg/50 mg, 5 mg/100 mg, 10 mg/50 mg, or 10 mg/100 mg. The assumption of strict superiority was estimated using the mean change in sitting diastolic blood pressure (DBP) at 8 weeks. Safety was monitored through physical examinations, vital signs, laboratory test results, ECG, and adverse events. The reduction in DBP at 8 weeks was significantly greater in patients treated with the combination therapies compared with the respective monotherapies for all specified comparisons except amlodipine camsylate/losartan 10 mg/100 mg versus amlodipine 10 mg. The incidence of adverse events in the group of patients treated with the amlodipine camsylate/losartan 10 mg/50 mg combination tended to be higher than for any other group (27.9%, 12/43); however, the effect was not statistically significant. Combination amlodipine camsylate/losartan (5 mg/50 mg, 5 mg/100 mg and 10 mg/50 mg) resulted in significantly greater BP lowering compared with amlodipine or losartan monotherapy, and was determined to be generally safe and tolerable in patients with essential hypertension. Registered at clinicaltrials.gov: NCT00942344.

Nebivolol and valsartan as a fixed-dose combination for the treatment of hypertension.

PubMed

Sander, Gary E; Giles, Thomas D

2015-04-01

The fixed-dose combination of nebivolol and valsartan drug has been clinically evaluated and demonstrated to represent a unique combination of nebivolol, a selective β1-adrenoceptor antagonist and a β3-adrenoceptor agonist; β3 receptor activation increases endothelial nitric oxide and produces vasodilation. Valsartan is highly selective angiotensin AT1 receptor blocker and exerts its major pharmacological effect by decreasing angiotensin II-induced vasoconstriction and production of aldosterone. The addition of nebivolol counteracts the effects of increased angiotensin II concentrations resulting from potent AT1 blockade. This review describes a recently completed trial establishing the efficacy of the nebivolol/valsartan combination. This review provides a literature search of pertinent pharmacological and clinical data that describes the mechanisms of both drugs individually and the results of a clinical trial comparing fixed-dose combinations of nebivolol with valsartan as compared with each drug as monotherapy. Fixed-dose combination drugs are intended to improve patient compliance and reduce drug costs, as well as to reduce long-term cardiovascular event rates and block counter-regulatory effects due to monotherapy. The vast majority of hypertensive patients will require at least two medications. We believe that the clinical evidence suggests that the combination of nebivolol with valsartan offers a definite clinical benefit, combining β1-adrenoceptor and angiotensin AT1 receptor blockade with β3 receptor activation and resultant increase in nitric oxide and vasodilation.

Efficacy and Safety of Fixed-Dose Perindopril Arginine/Amlodipine in Hypertensive Patients Not Adequately Controlled with Amlodipine 5 mg or Perindopril tert-Butylamine 4 mg Monotherapy.

PubMed

Hu, Dayi; Sun, Yihong; Liao, Yuhua; Huang, Jing; Zhao, Ruiping; Yang, Kan

2016-01-01

To assess the blood pressure-lowering efficacy and tolerability of perindopril/amlodipine fixed-dose combinations in Chinese patients with mild-to-moderate essential hypertension not adequately controlled with monotherapy alone. In 2 separate double-blind studies, patients received a 4-week run-in monotherapy of amlodipine 5 mg or perindopril 4 mg, respectively. Those whose blood pressure was uncontrolled were then randomized to receive the fixed-dose combination of perindopril 5 mg/amlodipine 5 mg (Per/Amlo group) or remain on the monotherapy for 8 weeks. Patients who were uncontrolled at the week 8 (W8) visit were up-titrated for the Per/Amlo combination, or received additional treatment if on monotherapy, for a further 4 weeks. The main efficacy assessment was at 8 weeks. After 8 weeks, systolic blood pressure (SBP; primary criterion) was statistically significantly lower in the Per/Amlo group (vs. Amlo 5 mg, p = 0.0095; vs. Per 4 mg, p < 0.0001). Uncontrolled patients at W8 who received an up-titration of the Per/Amlo combination showed a further SBP reduction. These changes were mirrored by reassuring reductions in diastolic blood pressure. The fixed-dose combinations were well tolerated. Single-pill combinations of perindopril and amlodipine provide hypertensive patients with a convenient and effective method of reducing blood pressure. © 2016 S. Karger AG, Basel.

Comparisons of the pharmacokinetics and tolerability of fixed-dose combinations of amlodipine besylate/losartan and amlodipine camsylate/losartan in healthy subjects: a randomized, open-label, single-dose, two-period, two-sequence crossover study

PubMed Central

Choi, YoonJung; Lee, SeungHwan; Cho, Sang-Min; Kang, Won-Ho; Nam, Kyu-Yeol; Jang, In-Jin; Yu, Kyung-Sang

2016-01-01

Background A fixed-dose combination (FDC) of amlodipine and losartan has been used to reduce blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The aim of this study was to evaluate the pharmacokinetic (PK) characteristics and tolerability of an FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium compared to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium in healthy subjects. Subjects and methods A randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted on 46 healthy male subjects. Blood concentrations were measured by liquid chromatography–tandem mass spectrometry. Blood samples were collected up to 144 hours post dose for each period. PK parameters were calculated in each treatment group using a noncompartmental method. The 90% confidence intervals (CIs) of the geometric mean ratios of the two treatments for the maximum plasma concentration (Cmax) and the area under the concentration curve from time zero to the last quantifiable time point (AUC0–t) were estimated. Tolerability assessments were performed for all subjects who received the drug at least once. Results The PK profiles of the two treatments were similar. For amlodipine, the geometric mean ratios (90% CIs) of amlodipine besylate to amlodipine camsylate for the Cmax and AUC0–t were 0.98 (0.94−1.01) and 0.97 (0.93−1.01), respectively. The corresponding values for losartan were 0.91 (0.81−1.02) and 1.05 (0.98−1.12), respectively. The incidence of adverse events was not significantly different between the two treatments, and both were well tolerated. Conclusion An FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium produced similar results to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium treatment with respect to the PK parameters of amlodipine and losartan based on Cmax and AUC0–t values. The amlodipine besylate/losartan potassium combination was well tolerated by healthy male subjects. PMID:27703330

Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial.

PubMed

Halimi, Jean-Michel; Giraudeau, Bruno; Buchler, Matthias; Al-Najjar, Azmi; Etienne, Isabelle; Laouad, Inass; Bruyère, Franck; Lebranchu, Yvon

2007-01-01

Most hypertensive renal transplant recipients require two or more antihypertensive medications to achieve blood pressure control. However, which medications must be combined is still a matter of debate. A prospective randomized open-label blinded evaluation trial comparing the six-month effects of the amlodipine-enalapril combination (n = 32) vs. enalapril alone (n = 33) and vs. amlodipine alone (n = 34) on arterial pressure, renal function, albuminuria and tolerability. At six months, diastolic arterial pressure was more adequately controlled (i.e., <90 mmHg) in the combination group than in the amlodipine and enalapril groups (100% vs. 82.4% and 84.8%, respectively, p = 0.038). The same trend was observed for systolic arterial pressure (65.6% vs. 58.8% and 51.5%, NS). The six-month change in albuminuria was similar in the combination group and in the enalapril group (-64.7% vs. -59.5%); however, patients in the combination group exhibited a greater reduction in albuminuria than in the amlodipine group (-64.7% vs. -29.0%, p = 0.002). As compared with baseline values, serum creatinine and potassium remained unchanged in the combination group, whereas they increased by 9 +/- 12 micromol/L (p = 0.01) and by 0.2 +/- 0.4 mmol/L (p < 0.01), respectively, in the enalapril group. The cyclosporine trough levels remained unchanged in the combination group, but increased in the amlodipine group. Angiotensin-converting enzyme inhibitor (ACEI)-calcium-channel blocker (CCB) combination controls arterial pressure more adequately than ACEI alone or CCB alone, reduces albuminuria and may prevent the ACEI-induced initial rise in serum creatinine.

Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension

PubMed Central

White, William B.; Sica, Domenic; Bakris, George L.; Cao, Charlie; Roberts, Andrew; Kupfer, Stuart

2014-01-01

Objective The aim of the study was to measure the effects on blood pressure (BP) of the angiotensin receptor blocker azilsartan medoxomil, in 40 and 80 mg doses, combined with 5 mg of the calcium channel blocker amlodipine and to compare these effects with placebo plus amlodipine 5 mg. Methods This was a randomized, controlled, double-blind study of 6 weeks’ duration in 566 patients with stage 2 hypertension. The primary endpoint was 24-h systolic BP by ambulatory monitoring. Results The mean age of the participants was 58 years; men and women were equally represented, and baseline 24-h BP (153–154/93 mmHg) and clinic BP (165–166/94–95 mmHg) were similar across the three treatment groups. After 6 weeks, 24-h BP decreased by 25/15 mmHg in both the azilsartan medoxomil/amlodipine 40/5 and 80/5 mg groups. These reductions were each greater than the 14/8 mmHg decrease with placebo plus amlodipine 5 mg (P≤0.001 for both comparisons). All treatments were well tolerated, and adverse events did not increase with the azilsartan medoxomil doses. Edema or fluid retention was less common in both combination groups (2.6 and 2.7%) than with placebo plus amlodipine (7.6%). Conclusion Coadministration of azilsartan medoxomil with amlodipine was well tolerated and led to meaningful additional BP reductions compared with placebo plus amlodipine. PMID:24445723

Beneficial effects of the combination of amlodipine and losartan for lowering blood pressure in spontaneously hypertensive rats.

PubMed

Choi, Seul Min; Seo, Mi Jeong; Kang, Kyung Koo; Kim, Jeong Hoon; Ahn, Byoung Ok; Yoo, Moohi

2009-03-01

A combination of antihypertensive agents can better control blood pressure and reduce the number and severity of side effects than a monotherapy. Since both CCBs (calcium channel blockers) and ARBs (angiotensin II receptor type-1 blockers) are current and effective antihypertensive drugs, this study assessed the synergistic antihypertensive effects as well as the optimal combination ratio of these two drugs. Amlodipine (3 mg/kg) or losartan (30 mg/kg) alone or a combination of each drug at a ratio 1:10 and 1:20 was administered orally to spontaneously hypertensive rats (SHR). A four-week treatment of either 3 mg/kg amlodipine or 30 mg/kg losartan alone decreased the systolic blood pressure (SBP). However, their combination significantly lowered the SBP from the 3(rd) week, and there was a positive correlation between this reduction in blood pressure and the improvement in arterial endothelium-dependent relaxation. In addition, the combination therapy (1:20) decreased both the cardiac mass and left ventricular weight to a greater extent than with either amlodipine or losartan alone. The collagen content in the cardiac tissue was also significantly lower after the 4-week combination therapy (1:10). These results suggest that the combined use of amlodipine and losartan might be more effective in treating hypertension than a monotherapy.

Evaluation of safety and efficacy of a fixed olmesartan/amlodipine combination therapy compared to single monotherapies.

PubMed

Derosa, Giuseppe; Cicero, Arrigo Francesco Giuseppe; Carbone, Anna; Querci, Fabrizio; Fogari, Elena; D'Angelo, Angela; Maffioli, Pamela

2013-09-01

Hypertension is known to be one of the main risk factors for cardiovascular disease. To evaluate the safety and efficacy of a fixed olmesartan/amlodipine (Olme/Amlo) combination in improving blood pressure control, lipid profile, insulin sensitivity and some inflammatory and insulin resistance markers. Two hundred and seventy-six hypertensive patients were randomly assigned to olmesartan 20 mg, amlodipine 10 mg or a single pill containing an Olme/Amlo combination 20/5 mg for 12 months. We evaluated after 6 and 12 months: body weight, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP, respectively), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, vaspin, visfatin, interleukins 8 and 10 (IL-8 and IL-10, respectively). Patients also underwent an euglycemic, hyperinsulinemic clamp. Olme/Amlo combination was more effective in decreasing SBP, and DPB compared to single monotherapies after 12 months. Olme/Amlo combination, but not amlodipine, decreased FPG after 12 months. FPI and HOMA index were decreased, and M value increased by Olme/Amlo combination compared to olmesartan monotherapy, and to amlodipine monotherapy. Olme/Amlo significantly decreased IL-8 and IL-10 better than each monotherapy. Olme/Amlo single pill combination can be a safe and effective option to reduce blood pressure, improve insulin sensitivity and decrease inflammatory markers.

Efficacy and tolerability of combination therapy with valsartan/hydrochlorothiazide in the initial treatment of severe hypertension.

PubMed

Calhoun, David A; Glazer, Robert D; Pettyjohn, Frank S; Coenen, P D M; Zhao, Yanxing; Grosso, Amie

2008-08-01

Most patients with severe hypertension are at high risk for cardiovascular events and require prompt blood pressure (BP)-lowering and combination therapy to achieve BP goals. This study evaluated the therapeutic efficacy and tolerability of initial treatment with the combination of valsartan and hydrochlorothiazide (HCTZ) compared with valsartan monotherapy in patients with severe hypertension. This was a 6-week, randomized, double-blind, multicenter, forced titration study that compared initial therapy with the combination of valsartan/HCTZ 160/12.5 mg (force titrated to 160/25 mg after 2 weeks and to 320/25 mg after 4 weeks) to monotherapy with valsartan 160 mg (force titrated to 320 mg after 2 weeks and sham-titrated to 320 mg after 4 weeks). Eligible patients were 18-80 years old with severe essential hypertension (mean sitting diastolic BP > or = 110 mmHg and < 120 mmHg and mean sitting systolic BP > or = 140 mmHg and < 200 mmHg). The Clinical Trial Registry number was NCT00273299. The primary efficacy variable was the rate of BP control (mean sitting BP < 140/90 mmHg) at Week 4. Tolerability was evaluated by monitoring all adverse events, vital signs, and laboratory tests including hematology and biochemistry. A total of 608 patients were randomized to either valsartan/HCTZ (n = 307) or valsartan monotherapy (n = 301). Significantly more patients achieved overall BP control (< 140/90 mmHg) with valsartan/HCTZ compared to monotherapy at Week 4 (primary efficacy variable and timepoint) (39.6% vs. 21.8%; p < 0.0001) and Week 6 (48.2% vs. 27.2%; p < 0.0001). Mean reductions in BP at Week 4 were significantly greater for valsartan/HCTZ (30.8/22.7 mmHg vs. 21.7/17.5 mmHg; p < 0.0001), with further reductions at Week 6. BP control rates were greater with combination therapy as early as Week 2. The overall incidence of adverse events was comparable between the combination therapy (34.9%) and monotherapy (36.7%) treatment groups. A potential limitation of the forced-titration design is that some patients were titrated to higher doses despite having achieved goal BP. This may impact the interpretation of the incidence of dose-dependent adverse events. Initial therapy with valsartan/HCTZ is effective and well tolerated in patients with severe hypertension.

Efficacy and tolerability of a fixed-dose combination of metoprolol extended release/amlodipine in patients with mild-to-moderate hypertension: a randomized, parallel-group, multicentre comparison with losartan plus amlodipine.

PubMed

Pareek, Anil; Chandurkar, Nitin B; Sharma, Ravishankar; Tiwari, Dharmendra; Gupta, Bhagwan S

2010-01-01

Epidemiological studies and clinical trials have shown that prevention of cardiovascular disease, the ultimate goal of hypertension treatment, requires a sufficient reduction in blood pressure. The primary objective of this study was to compare the mean decrease in systolic (SBP) and diastolic (DBP) blood pressure between metoprolol extended release (XL)/amlodipine fixed-dose combination and losartan plus amlodipine combination in patients with mild-to-moderate essential hypertension. The secondary objectives of this study were to compare the proportion of responders in the two treatment groups and to evaluate the tolerability of the study medications. This was a randomized, parallel-group, multicentre comparative study conducted at the outpatient departments of three teaching hospitals in India. Patients with mild-to-moderate hypertension (defined as DBP 90-109 mmHg) aged between 18 and 75 years were enrolled in this study and followed up for 12 weeks. Response to study treatments was evaluated in terms of mean decrease in SBP and DBP and the response rate (reduction to SBP <140 mmHg and DBP <90 mmHg). Out of 152 patients who underwent a 1-week placebo washout, 148 eligible patients were randomized to receive either metoprolol XL 25 mg/amlodipine 2.5 mg fixed-dose combination (76 patients) or losartan 25 mg plus amlodipine 2.5 mg (72 patients). The two treatment groups were similar with respect to demographic and baseline characteristics. Non-responders after 4 weeks of therapy were escalated to metoprolol XL 50 mg/amlodipine 5 mg fixed-dose combination or losartan 50 mg plus amlodipine 5 mg, respectively. The study was completed by 66 patients in each group, of whom 43 patients in each group responded to the starting doses. After 4 weeks' therapy, both treatments were associated with significant decreases in SBP and DBP from baseline (p < 0.001) and were comparable with respect to mean decrease in SBP (p = 0.304), mean decrease in DBP (p = 0.630) and response rate (p = 1.0). Also, both the step-up therapies were comparable with respect to mean decrease in SBP (p = 0.484), mean decrease in DBP (p = 0.650) and response rate (p = 0.134) at week 12. Both treatments were well tolerated in the studied population. Metoprolol XL/amlodipine fixed-dose combination was found to be as effective and well tolerated as losartan plus amlodipine in the treatment of essential hypertension.

The evolution of systolic blood pressure as a strong predictor of cardiovascular risk and the effectiveness of fixed-dose ARB/CCB combinations in lowering levels of this preferential target

PubMed Central

Mourad, Jean-Jacques

2008-01-01

Elevated blood pressure is an important cardiovascular risk factor. Although targets for both diastolic blood pressure (DBP) and systolic blood pressure (SBP) are defined by current guidelines, DBP has historically taken precedence in hypertension management. However, there is strong evidence that SBP is superior to DBP as a predictor of cardiovascular events. Moreover, achieving control of SBP is assuming greater importance amongst an aging population. In spite of the growing recognition of the importance of SBP in reducing cardiovascular risk and the emphasis by current guidelines on SBP control, a substantial proportion of patients still fail to achieve SBP targets, and SBP control is achieved much less frequently than DBP control. Thus, new approaches to the management of hypertension are required in order to control SBP and minimize cardiovascular risk. Fixed-dose combination (FDC) therapy is an approach that offers the advantages of multiple drug administration and a reduction in regimen complexity that favors compliance. We have reviewed the latest evidence demonstrating the efficacy in targeting SBP of the most recent FDC products; combinations of the calcium channel blocker (CCB), amlodipine, with angiotensin receptor blockers (ARBs), valsartan or olmesartan. In addition, results from studies with new classes of agent are outlined. PMID:19337545

Effect of aliskiren and valsartan combination versus aliskiren monotherapy on hemostatic biomarkers in hypertensive diabetics: Aliskiren and Valsartan Impact in Diabetics pilot trial.

PubMed

Serebruany, Victor L; Pokov, Alex N; Aradi, Daniel; Can, Mehmet; DiNicolantonio, James; Kipshidze, Nodar; Atar, Dan

2014-01-01

Valsartan is known to inhibit platelet activity in both in vitro and ex vivo clinical setting, whereas aliskiren in vitro modulates antithrombin-III in plasma. The authors tested how aliskiren and valsartan combination versus aliskiren monotherapy will affect hemostatic biomarkers in mild-to-moderate hypertensive diabetics in the frame of the Aliskiren and Valsartan Impact in Diabetics (AVID) trial. A total of 52 patients with type 2 diabetes and mild-to-moderate hypertension were equally randomized to aliskiren (150-300 mg/d) and valsartan (160 mg/d) versus aliskiren (150-300 mg/d) alone for 4 weeks. A total of 25 biomarkers were serially measured, of which 16 are related to platelet function, 6 to coagulation, and 3 to fibrinolysis. Aliskiren monotherapy has no significant impact on any of the assessed biomarkers. In contrast, valsartan on top of aliskiren provided significant inhibition of ADP-induced platelet aggregation (P=0.032), decreased shear-induced activation measured with PFA-100 analyzer (P=0.041), and diminished expression of GP IIb/IIIa activity (P=0.027) measured by PAC-1 antibody, GP Ib (CD42b, P=0.033), vitronectin receptor (CD51/61, P=0.046), P-selectin (CD62p, P=0.026), lysosome-associated membrane protein (CD107a, P=0.042), and CD40-ligand (CD154, P=0.048). In AVID trial, valsartan in combination with aliskiren mildly but significantly inhibited platelets, confirming previous observations. In contrast, aliskiren monotherapy does not enhance antithrombin activity, suggesting that previous data probably represent a laboratory artifact. Importantly, these randomized data were generated on top of low-dose daily aspirin, supporting extra benefit for combination use of angiotensin receptor blockers and renin inhibitors in high-risk diabetic population.

REDUCTION OF ALDOSTERONE PRODUCTION IMPROVES RENAL OXIDATIVE STRESS AND FIBROSIS IN DIABETIC RATS

PubMed Central

Matavelli, Luis C.; Siragy, Helmy M.

2012-01-01

SUMMARY Aldosterone is increased in diabetes and contributes to the development of diabetic nephropathy. We hypothesized that reduction in aldosterone production in diabetes by amlodipine or aliskiren improves diabetic kidney disease by attenuating renal oxidative stress and fibrosis. Normoglycemic and streptozotocin-induced diabetes Sprague-Dawley rats were given vehicle, amlodipine or aliskiren individually and combined for six weeks. At the end of study, we evaluated BP, 24h urinary sodium (UNaV) and aldosterone excretion rates, renal interstitial fluid (RIF) levels of nitric oxide (NO), cGMP and 8-isoprostane, and renal morphology. BP was not significantly different between any of experimental groups. UNaV increased in diabetic animals and was not affected by different treatments. Urinary aldosterone excretion increased in diabetic rats receiving vehicle and decreased with amlodipine and aliskiren individually or combined. RIF NO and cGMP levels were reduced in vehicle treated diabetic rats and increased with amlodipine or aliskiren given individually and combined. RIF 8-isoprostane levels and renal immunostaining for PAS and fibronectin were increased in vehicle treated diabetic rats and decreased with aliskiren individually or combined with amlodipine. We conclude that inhibition of aldosterone by amlodipine or aliskiren ameliorates diabetes induced renal injury via improvement of NO-cGMP pathway, and reduction in oxidative stress and fibrosis, independent of BP changes. PMID:23011470

Efficacy and Safety of Crystalline Valsartan/Sacubitril (LCZ696) Compared With Placebo and Combinations of Free Valsartan and Sacubitril in Patients With Systolic Hypertension: The RATIO Study.

PubMed

Izzo, Joseph L; Zappe, Dion H; Jia, Yan; Hafeez, Kudsia; Zhang, Jack

2017-06-01

We compared the systolic blood pressure (SBP)-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 coadministered with placebo or increasing doses of free sacubitril (50, 100, 200, or 400 mg once daily) 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 SBP 150-179 mm Hg). Primary-dependent variable was change in office SBP from baseline to week 8. At entry (n = 907), mean age was 61.5 years, sitting office BP 160/90.2 mm Hg, and mean 24-hour ambulatory BP 142/82.1 mm Hg; 852 participants completed the study. At week 8, there were greater reductions in sitting office SBP and 24-hour ambulatory SBP with LCZ696 400 mg than with valsartan 320 mg (-5.7 and -3.4 mm Hg, respectively, P < 0.05 each). The SBP reduction with LCZ696 400 daily was similar to coadministered free valsartan 320 mg and sacubitril 200 mg. Effects were similar in those older and younger than 65 years, 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 SBP, (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.

The efficacy and safety of valsartan and combination of valsartan and hydrochlorothiazide in the treatment of patients with mild to moderate arterial hypertension - the VICTORY trial.

PubMed

Accetto, Rok; Chazova, Irina Yevgenyevna; Sirenko, Yuriy; Vincelj, Josip; Widimsky, Jiri; Barbič-Žagar, Breda

2017-01-01

The aim of the trial was to establish the efficacy and safety of Valsacor® (valsartan) and Valsacombi® (combination of valsartan and hydrochlorothiazide) in a wide variety of patient populations with mild to moderate arterial hypertension. We performed an international, multicentre, open-label, prospective trial. After one week of washout in previously treated patients, the patients were treated for 16 weeks according to the protocol. Naïve patients entered the treatment period immediately. During the active treatment, four visits were planned for each patient to obtain the data for the primary and secondary efficacy endpoints analysis. The principal methods were blood pressure (BP) measurement, additionally in a subgroup of patients, assessment of erectile function. The initial dosage of valsartan 80 mg/day was titrated up to 320 mg/day to achieve the BP goal, with the addition of hydrochlorothiazide (HCTZ) in a fixed-dose combination (FDC), if needed. Mean ± standard deviation changes from baseline at week 16 were -26.6 ± 10.4 mm Hg (systolic BP) and -14.8 ± 7.6 mm Hg (diastolic BP). A total of 91% of the patients treated with either valsartan or valsartan FDC achieved the BP goal. Adverse reactions were experienced by 7.1% of the patients, with the most common being headache (1.9%), palpitation (1.6%), dizziness (1.6%), and fatigue (1.6%), during the whole trial. The results of the VICTORY trial show that valsartan and valsartan FDC effectively reduce the BP in patients with mild to moderate arterial hypertension and have a good tolerability profile.

Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.

PubMed

Pfeffer, Marc A; McMurray, John J V; Velazquez, Eric J; Rouleau, Jean-Lucien; Køber, Lars; Maggioni, Aldo P; Solomon, Scott D; Swedberg, Karl; Van de Werf, Frans; White, Harvey; Leimberger, Jeffrey D; Henis, Marc; Edwards, Susan; Zelenkofske, Steven; Sellers, Mary Ann; Califf, Robert M

2003-11-13

Angiotensin-converting-enzyme (ACE) inhibitors such as captopril reduce mortality and cardiovascular morbidity among patients with myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both. In a double-blind trial, we compared the effect of the angiotensin-receptor blocker valsartan, the ACE inhibitor captopril, and the combination of the two on mortality in this population of patients. Patients receiving conventional therapy were randomly assigned, 0.5 to 10 days after acute myocardial infarction, to additional therapy with valsartan (4909 patients), valsartan plus captopril (4885 patients), or captopril (4909 patients). The primary end point was death from any cause. During a median follow-up of 24.7 months, 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group (hazard ratio in the valsartan group as compared with the captopril group, 1.00; 97.5 percent confidence interval, 0.90 to 1.11; P=0.98; hazard ratio in the valsartan-and-captopril group as compared with the captopril group, 0.98; 97.5 percent confidence interval, 0.89 to 1.09; P=0.73). The upper limit of the one-sided 97.5 percent confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality (P=0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (P<0.001). The valsartan-and-captopril group had the most drug-related adverse events. With monotherapy, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group. Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival. Copyright 2003 Massachusetts Medical Society

An 18-week, prospective, randomized, double-blind, multicenter study of amlodipine/ramipril combination versus amlodipine monotherapy in the treatment of hypertension: the assessment of combination therapy of amlodipine/ramipril (ATAR) study.

PubMed

Miranda, Roberto Dischinger; Mion, Décio; Rocha, Joăo Carlos; Kohlmann, Oswaldo; Gomes, Marco Antonio Mota; Saraiva, José Francisco Kerr; Amodeo, Celso; Filho, Bráulio Luna

2008-09-01

A combination of antihypertensive agents of different drug classes in a fixed-dose combination (FDC) may offer advantages in terms of efficacy, tolerability, and treatment compliance. Combination of a calcium channel blocker with an angiotensin-converting enzyme inhibitor may act synergistically to reduce blood pressure (BP). The aim of this study was to compare the efficacy and tolerability of an amlodipine/ramipril FDC with those of amlodipine monotherapy. This 18-week, prospective, randomized, double-blind study was conducted at 8 centers across Brazil. Patients with stage 1 or 2 essential hypertension were enrolled. After a 2-week placebo run-in phase, patients received amlodipine/ramipril 2.5/2.5 mg or amlodipine 2.5 mg, after which the doses were titrated, based on BP, to 5/5 then 10/10 mg (amlodipine/ramipril) and 5 then 10 mg (amlodipine). The primary end point was BP measured in the intent-to-treat (ITT) population. Hematology and serum biochemistry were assessed at baseline and study end. Tolerability was assessed using patient interview, laboratory analysis, and physical examination, including measurement of ankle circumference to assess peripheral edema. A total of 222 patients completed the study (age range, 40-79 years; FDC group, 117 patients [mean dose, 7.60/7.60 mg]; monotherapy, 105 patients [mean dose, 7.97 mg]). The mean (SD) changes in systolic BP (SBP) and diastolic BP (DBP), as measured using 24-hour ambulatory blood pressure monitoring (ABPM) and in the physician's office, were significantly greater with combination therapy than monotherapy, with the exception of office DBP (ABPM, -20.76 [1.25] vs -15.80 [1.18] mm Hg and -11.71 [0.78] vs -8.61 [0.74] mm Hg, respectively [both, P = 0.004]; office, -27.51 [1.40] vs -22.84 [1.33] mm Hg [P = 0.012] and -16.41 [0.79] vs -14.64 [0.75] mm Hg [P = NS], respectively). In the ITT analysis, the mean changes in ambulatory, but not office-based, BP were statistically significant (ABPM: SBP, -20.21 [1.14] vs -15.31 [1.12] mm Hg and DBP, -11.61 [0.72] vs -8.42 [0.70] mm Hg, respectively [both, P = 0.002]; office: SBP, -26.60 [1.34] vs -22.97 [1.30] mm Hg and DBP, -16.48 [0.78] vs -14.48 [0.75] mm Hg [both, P = NS]). Twenty-nine patients (22.1%) treated with combination therapy and 41 patients (30.6%) treated with monotherapy experienced > or =1 adverse event considered possibly related to study drug. The combination-therapy group had lower prevalence of edema (7.6% vs 18.7%; P = 0.011) and a similar prevalence of dry cough (3.8% vs 0.8%; P = NS). No clinically significant changes in laboratory values were found in either group. In this population of patients with essential hypertension, the amlodipine/ramipril FDC was associated with significantly reduced ambulatory and office-measured BP compared with amlodipine monotherapy, with the exception of office DBP. Both treatments were well tolerated.

Patient Adherence to Olmesartan/Amlodipine Combinations: Fixed Versus Extemporaneous Combinations.

PubMed

Levi, Miriam; Pasqua, Alessandro; Cricelli, Iacopo; Cricelli, Claudio; Piccinni, Carlo; Parretti, Damiano; Lapi, Francesco

2016-03-01

Lack of adherence to prescribed therapies is often a cause of suboptimal blood pressure control in patients with hypertension. To enhance patients' adherence to treatment, fixed-dose combinations of active substances with complementary mechanisms of action have been developed. An angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker (ARB) is often combined with a calcium channel blocker. Olmesartan is the most used ARB in combination therapy. In Italy, in September 2011, a fixed-dose combination of olmesartan/amlodipine (olmesartan/amlodipine 20/5 mg, 40/5 mg, or 40/10 mg) was introduced to treat patients with hypertension for whom control of blood pressure is not reached with either olmesartan or amlodipine alone. Prior research on adherence to olmesartan/amlodipine combinations was carried out in local contexts (e.g., claims databases of Italian regions or local health authorities), and/or it was limited by the fact that adherence was assessed against monotherapies already known for their low compliance profile, such as diuretics. To compare adherence with olmesartan/amlodipine fixed-dose combination (FDC) and extemporaneous combination in primary care in Italy. A nationwide, population-based study was conducted by using the Health Search IMS Health Longitudinal Patient Database. Patients aged > 17 years, affected by hypertension and treated with the FDC or extemporaneous combination of olmesartan/amlodipine, were identified. Adherence to these 2 therapeutic regimens was estimated by calculating the proportion of days covered (PDC). Patients were classified into 3 levels of adherence: high (PDC ≥ 80%), intermediate (PDC = 40%-79%), or low (PDC < 40%). In the 6-month follow-up, FDC showed higher adherence compared with an extemporaneous combination (55.1% vs. 15.9%, P < 0.001). This difference was confirmed in a multivariable logistic regression model clustered on patient identifier (odds ratio = 6.65; 95% CI = 3.10-14.26; P < 0.001). The proportion of patients adherent to FDC varied from 60.4% for the 40/5 mg formulation to 47.5% for the 40/10 mg formulation. These findings suggest that higher adherence may be achieved with FDCs than with extemporaneous combinations. To improve the degree of adherence, general practitioners may consider prescribing fixed combinations of antihypertensive agents as soon as monotherapies fail to achieve the expected therapeutic objective.

FIXED DOSE COMBINATIONS WITH SELECTIVE BETA-BLOCKERS: QUANTITATIVE DETERMINATION IN BIOLOGICAL FLUIDS.

PubMed

Mahu, Ştefania Corina; Hăncianu, Monica; Agoroaei, Luminiţa; Grigoriu, Ioana Cezara; Strugaru, Anca Monica; Butnaru, Elena

2015-01-01

Hypertension is one of the most common causes of death, a complex and incompletely controlled disease for millions of patients. Metoprolol, bisoprolol, nebivolol and atenolol are selective beta-blockers frequently used in the management of arterial hypertension, alone or in fixed combination with other substances. This study presents the most used analytical methods for simultaneous determination in biological fluids of fixed combinations containing selective beta-blockers. Articles in Pub-Med, Science Direct and Wiley Journals databases published between years 2004-2014 were reviewed. Methods such as liquid chromatography--mass spectrometry--mass spectrometry (LC-MS/MS), high performance liquid chromatography (HPLC) or high performance liquid chromatography--mass spectrometry (HPLC-MS) were used for determination of fixed combination with beta-blockers in human plasma, rat plasma and human breast milk. LC-MS/MS method was used for simultaneous determination of fixed combinations of metoprolol with simvastatin, hydrochlorothiazide or ramipril, combinations of nebivolol and valsartan, or atenolol and amlodipine. Biological samples were processed by protein precipitation techniques or by liquid-liquid extraction. For the determination of fixed dose combinations of felodipine and metoprolol in rat plasma liquid chromatography--electrospray ionization--mass spectrometry (LC-ESI-MS/MS) was applied, using phenacetin as internal standard. HPLC-MS method was applied for the determination of bisoprolol and hydrochlorothiazide in human plasma. For the determination of atenolol and chlorthalidone from human breast milk and human plasma the HPLC method was used. The analytical methods were validated according to the specialized guidelines, and were applied to biological samples, thing that confirms the permanent concern of researchers in this field.

Efficacy of nebivolol-valsartan single-pill combination in obese and nonobese patients with hypertension.

PubMed

Mende, Christian W; Giles, Thomas D; Bharucha, David B; Ferguson, William G; Mallick, Madhuja; Patel, Mehul D

2017-06-01

Antihypertensive efficacy of single-pill combinations (SPCs) consisting of a β 1 -selective adrenergic blocker with vasodilatory properties via β 3 -agonism (nebivolol) and an angiotensin II receptor blocker (valsartan) was demonstrated in an 8-week phase 3 trial (NCT01508026). In this post hoc analysis, seated blood pressure, heart rate, 24-hour ambulatory blood pressure monitoring, plasma aldosterone, estimated glomerular filtration rate, and safety measures were assessed in obese (body mass index >32 kg/m 2 ; n=1823) and nonobese (body mass index <27 kg/m 2 ; n=847) adults with hypertension (stage I or II) treated with nebivolol-valsartan SPCs, nebivolol or valsartan monotherapy, or placebo. At week 8, reductions from baseline in blood pressure and ambulatory blood pressure monitoring were greater with SPCs and most nebivolol and valsartan monotherapy doses vs placebo regardless of obesity status. Aldosterone declined with all active treatments and estimated glomerular filtration rate remained steady. The nebivolol-valsartan 5/80 mg/d SPC was efficacious regardless of degree of obesity. © 2017 The Authors. The Journal of Clinical Hypertension Published by Wiley Periodicals, Inc.

Comparative effects of valsartan plus either cilnidipine or hydrochlorothiazide on home morning blood pressure surge evaluated by information and communication technology-based nocturnal home blood pressure monitoring.

PubMed

Fujiwara, Takeshi; Tomitani, Naoko; Kanegae, Hiroshi; Kario, Kazuomi

2018-01-01

The authors tested the hypothesis that a valsartan/cilnidipine combination would suppress the home morning blood pressure (BP) surge (HMBPS) more effectively than a valsartan/hydrochlorothiazide combination in patients with morning hypertension, defined as systolic BP (SBP) ≥135 mm Hg or diastolic BP ≥85 mm Hg assessed by a self-measuring information and communication technology-based home BP monitoring device more than three times before either combination's administration. This was an 8-week prospective, multicenter, randomized, open-label clinical trial. The HMBPS, which is a new index, was defined as the mean morning SBP minus the mean nocturnal SBP, both measured on the same day. The authors randomly allocated 129 patients to the valsartan/cilnidipine (63 patients; mean 68.4 years) or valsartan/hydrochlorothiazide (66 patients; mean 67.3 years) combination groups, and the baseline HMBPS values were 17.4 mm Hg vs 16.9 mm Hg, respectively (P = .820). At the end of the treatment period, the changes in nocturnal SBP and morning SBP from baseline were significant in both the valsartan/cilnidipine and valsartan/hydrochlorothiazide groups (P < .001): -5.0 vs -10.0 mm Hg (P = .035) and -10.7 vs -13.6 mm Hg (P = .142), respectively. HMBPS was significantly decreased from baseline in both groups (P < .001), but there was no significant difference between the two groups: 14.4 mm Hg vs 14.0 mm Hg, respectively (P = .892). Valsartan/cilnidipine could not significantly suppress HMBPS compared with valsartan/hydrochlorothiazide. Large-scale randomized controlled studies are needed to assess how reducing HMBPS will affect future cardiovascular outcomes. The information and communication technology-based home BP monitoring device may become an alternative to ambulatory BP monitoring, which has been a gold standard to measure nocturnal BP and the morning BP surge. ©2018 Wiley Periodicals, Inc.

Prospective direct comparison of antihypertensive effect and safety between high-dose amlodipine or indapamide in hypertensive patients uncontrolled by standard doses of angiotensin receptor blockers and amlodipine.

PubMed

Okamura, Keisuke; Shirai, Kazuyuki; Totake, Nao; Okuda, Tetsu; Urata, Hidenori

2018-01-01

When hypertension is uncontrolled by routine treatment with an angiotensin II receptor blocker (ARB) and the calcium channel blocker amlodipine (5 mg), the dose of amlodipine can be increased or a diuretic can be added. We investigated the more effective option in a prospective multicenter open-label study. Hypertensive patients were recruited if the target blood pressure (BP) in The Japanese Society of Hypertension 2009 guideline could not be achieved with standard-dose ARB therapy and amlodipine (5 mg). Patients were divided into three groups. Group-1 was switched to a combination of irbesartan (100 mg) and amlodipine (10 mg). Group-2A was changed to a combination of irbesartan (100 mg), amlodipine (5 mg), and indapamide, while Group-2B received a standard-dose ARB and amlodipine (5 mg) plus indapamide. Patients were assigned by their attending physicians and were followed for 6 months. The primary endpoint was the antihypertensive effect of each regimen. Group-1 contained 85 patients, Group-2A had 49 patients, and Group-2B had 4 patients. We only analyzed Group-1 and Group-2A due to the small size of Group-2B. In both groups, systolic BP and diastolic BP were significantly decreased up to 6 months (all p < 0.001). Reduction of systolic BP was greater in Group-1 than Group-2A after 1 month and 6 months (both p < 0.05). Uric acid was increased in Group-2A after 3 months, but not at 6 months. Although both regimens were effective for reducing BP, increasing amlodipine to 10 mg daily controlled hypertension without elevation of serum uric acid.

Valsartan plus hydrochlorothiazide: a review of its use since its introduction.

PubMed

Bains, Jujhar; Smith, William B

2011-08-01

This review focuses on the role of the fixed-dose combination (FDC) drug valsartan/hydrochlorothiazide (HCTZ) in the treatment of hypertension. Effective blood pressure control often is not achieved with monotherapy and, instead, requires combinations of drugs with different mechanisms of action to produce additive or synergistic effects. FDC valsartan/HCTZ enhances not only efficacy for blood pressure control but also provides beneficial effects on target organs beyond that expected from arterial pressure reduction alone. Data describe key clinical trial experiences with the FDC, with particular attention to efficacy and tolerability. Literature searches of these various topics were conducted in January 2011. There is evidence of potential benefits with this combination associated with left ventricular hypertrophy, left ventricular dysfunction and renal disease. The FDC is an effective treatment for patients with hypertension and is superior to monotherapy than either drug alone. In addition to the benefits of each drug, valsartan/HCTZ's metabolic interactions reduce some of the negative effects of both compounds. With its increased simplicity, minimal side-effect profile and efficacy without a significant cost penalty, valsartan/HCTZ represents an excellent choice for antihypertensive therapy.

Pharmacokinetic interaction between scutellarin and valsartan in rats.

PubMed

Cui, Ming-Yu; Tian, Chong-Chong; Ju, Ai-Xia; Zhang, Chun-Ting; Li, Qiu-Hong

2013-04-01

Scutellarin is the main effective constituent of breviscapine, a flavonoid mixture isolated from the dried whole plant of Erigeron breviscapus (Vant.) Hand-Mazz, and valsartan is used as an antihypertensive drug. These two drugs have already been clinically used together to treat diabetic nephropathy (DN) in China, and the combined medications showed some enhanced protection against DN. The aim of this study is to investigate the potential pharmacokinetic interaction between scutellarin and valsartan in rats. Breviscapine injection (20 mg x kg(-1), i.v.) and valsartan (15 mg x kg-, i.g.), either alone or together were given to 18 male Sprague-Dawley rats. Concentrations of scutellarin and valsartan were quantified by HPLC, and pharmacokinetic parameters were calculated by non-compartmental methods. We found that the pharmacokinetic parameters of scutellarin altered significantly after co-administration of oral valsartan. The plasma clearance (CL(p)) and the bile clearance (CL(b)) of scutellarin were reduced significantly in the presence of valsartan. After oral administration of valsartan with or without intravenous scutellarin, however, the pharmacokinetic parameters of valsartan were comparable. In conclusion, our data suggests that the concurrent use of valsartan reduces the biliary excretion of scutellarin, and this may be due to the inhibitory effect of valsartan on the biliary excretion of scutellarin mediated by Mrp2 (Multidrug resistance-associated protein 2).

[Fixed drug combinations in hypertension: a budget impact analysis for the Spanish Health System on the marketing of a fixed combination of olmesartan/amlodipine].

PubMed

Belén Ferro-Rey, M; Roca-Cusachs, Alex; Sicras-Mainar, Antoni; Alvarez-Martín, Carlos; de Salas-Cansado, Marina

2011-07-01

To carry out a budget impact analysis (BIA) of olmesartan/amlodipine (20/5, 40/5 and 40/10mg) marketed as a fixed combination (FC) in its approved indication for the National Health System (NHS). We developed a decision tree model in order to estimate usual hypertension treatment algorithm in Spanish clinical practice. The BIA has been developed from the perspective of the NHS for a period of 3 years (years 2010-2012). Spanish hypertensive population ≥ 35 years old. Introduction into the market of a fixed combination (FC) olmesartan/amlodipine in Spain. Expected costs to be assumed by the Spanish NHS (RRP-VAT) for hypertensive population able to be treated with the FC versus currently assumed costs by the NHS with free combination olmesartan and amlodipine. Estimated pharmaceutical costs in hypertensive population treated with olmesartan and amlodipine (2 pills) would be €25.2M (1(st) year), €26.4M (2011), €27.6M (2012), with a total 3-year period of €79.2M. According to patient tree model, the population able to be treated with FC would be 71,283 patients (2010), with a growth rate of 4.8% in the successive years, which supposes an annual cost of €21.2M (2010), €21.8M (2011) and €22.4M (2012), with a total 3-year period of €65.4M. The BIA shows savings of €13.8M in a total 3-year period. The BIA of FC olmesartan/amlodipine could generate net savings of €13.8M for the NHS in the period ranging from years 2010 to 2012. Copyright © 2010 Elsevier España, S.L. All rights reserved.

Development of an HPLC-UV Method for the Analysis of Drugs Used for Combined Hypertension Therapy in Pharmaceutical Preparations and Human Plasma.

PubMed

Kepekci Tekkeli, Serife Evrim

2013-01-01

A simple, rapid, and selective HPLC-UV method was developed for the determination of antihypertensive drug substances: amlodipine besilat (AML), olmesartan medoxomil (OLM), valsartan (VAL), and hydrochlorothiazide (HCT) in pharmaceuticals and plasma. These substances are mostly used as combinations. The combinations are found in various forms, especially in current pharmaceuticals as threesome components: OLM, AML, and HCT (combination I) and AML, VAL, and HCT (combination II). The separation was achieved by using an RP-CN column, and acetonitrile-methanol-10 mmol orthophosphoric acid pH 2.5 (7 : 13 : 80, v/v/v) was used as a mobile phase; the detector wavelength was set at 235 nm. The linear ranges were found as 0.1-18.5  μ g/mL, 0.4-25.6  μ g/mL, 0.3-15.5  μ g/mL, and 0.3-22  μ g/mL for AML, OLM, VAL, and HCT, respectively. In order to check the selectivity of the method for pharmaceutical preparations, forced degradation studies were carried out. According to the validation studies, the developed method was found to be reproducible and accurate as shown by RSD ≤6.1%, 5.7%, 6.9%, and 4.6% and relative mean error (RME) ≤10.6%, 5.8%, 6.5%, and 6.8% for AML, OLM, VAL, and HCT, respectively. Consequently, the method was applied to the analysis of tablets and plasma of the patients using drugs including those substances.

S-Amlodipine: An Isomer with Difference—Time to Shift from Racemic Amlodipine

PubMed Central

Mohan, J. C.; Iyengar, S. S.; Hiremath, Jagdish; Sathyamurthy, Immaneni; Bansal, Sandeep; Kahali, Dhiman; Dasbiswas, Arup

2018-01-01

Calcium channel blockers are among the first-line drugs for treatment of hypertension (HTN). S-amlodipine (S-AM), an S-enantiomer of amlodipine, is available in India and in other countries like China, Korea, Russia, Ukraine, and Nepal. Being clinically researched for nearly two decades, we performed in-depth review of S-AM. This review discusses clinical evidence from total 42 studies (26 randomized controlled trials, 14 observational studies, and 2 meta-analyses) corroborating over 7400 patients treated with S-AM. Efficacy and safety of S-AM in HTN in comparison to racemic amlodipine, used as monotherapy and in combination with other antihypertensives, efficacy in angina, and pleiotropic benefits with S-AM, are discussed in this review. PMID:29887996

In Vivo and In Vitro Antimalarial Properties of Azithromycin-Chloroquine Combinations That Include the Resistance Reversal Agent Amlodipine ▿ †

PubMed Central

Pereira, Marcus R.; Henrich, Philipp P.; Sidhu, Amar bir Singh; Johnson, David; Hardink, Joel; Van Deusen, Jeffrey; Lin, Jian; Gore, Katrina; O'Brien, Connor; Wele, Mamadou; Djimde, Abdoulaye; Chandra, Richa; Fidock, David A.

2011-01-01

Evidence of emerging Plasmodium falciparum resistance to artemisinin-based combination therapies, documented in western Cambodia, underscores the continuing need to identify new antimalarial combinations. Given recent reports of the resurgence of chloroquine-sensitive P. falciparum parasites in Malawi, after the enforced and prolonged withdrawal of this drug, and indications of a possible synergistic interaction with the macrolide azithromycin, we sought to further characterize chloroquine-azithromycin combinations for their in vitro and in vivo antimalarial properties. In vitro 96-h susceptibility testing of chloroquine-azithromycin combinations showed mostly additive interactions against freshly cultured P. falciparum field isolates obtained from Mali. Some evidence of synergy, however, was apparent at the fractional 90% inhibitory concentration level. Additional in vitro testing highlighted the resistance reversal properties of amlodipine for both chloroquine and quinine. In vivo experiments, using the Peters 4-day suppressive test in a P. yoelii mouse model, revealed up to 99.9% suppression of parasitemia following treatment with chloroquine-azithromycin plus the R enantiomer of amlodipine. This enantiomer was chosen because it does not manifest the cardiac toxicities observed with the racemic mixture. Pharmacokinetic/pharmacodynamic analyses in this rodent model and subsequent extrapolation to a 65-kg adult led to the estimation that 1.8 g daily of R-amlodipine would be required to achieve similar efficacy in humans, for whom this is likely an unsafe dose. While these data discount amlodipine as an additional partner for chloroquine-based combination therapy, our studies continue to support azithromycin as a safe and effective addition to antimalarial combination therapies. PMID:21464242

Sub-therapeutic doses of fluvastatin and valsartan are more effective than therapeutic doses in providing beneficial cardiovascular pleiotropic effects in rats: A proof of concept study.

PubMed

Janić, Miodrag; Lunder, Mojca; France Štiglic, Alenka; Jerin, Aleš; Skitek, Milan; Černe, Darko; Marc, Janja; Drevenšek, Gorazd; Šabovič, Mišo

2017-12-01

Statins and sartans can, in therapeutic doses, induce pleiotropic cardiovascular effects. Similar has recently been shown also for sub-therapeutic doses. We thus explored and compared the cardiovascular pleiotropic efficacy of sub-therapeutic vs. therapeutic doses. Wistar rats were randomly divided into 7 groups receiving fluvastatin, valsartan and their combination in sub-therapeutic and therapeutic doses, or saline. After 6weeks, the animals were euthanised, their hearts and thoracic aortas isolated, and blood samples taken. Endothelium-dependent relaxation of the thoracic aortae and ischaemic-reperfusion injury of the isolated hearts were assessed along with the related serum parameters and genes expression. Fluvastatin and valsartan alone or in combination were significantly more effective in sub-therapeutic than therapeutic doses. The sub-therapeutic combination greatly increased thoracic aorta endothelium-dependent relaxation and maximally protected the isolated hearts against ischaemia-reperfusion injury and was thus most effective. Beneficial effects were accompanied by increased levels of nitric oxide (NO) and decreased levels of asymmetric dimethylarginine (ADMA) in the serum (again prominently induced by the sub-therapeutic combination). Furthermore, nitric oxide synthase 3 (NOS3) and endothelin receptor type A (EDNRA) genes expression increased, but only in both combination groups and without significant differences between them. In the therapeutic dose groups, fluvastatin and valsartan decreased cholesterol values and systolic blood pressure. Sub-therapeutic doses of fluvastatin and valsartan are more effective in expressing cardiovascular pleiotropic effects than therapeutic doses of fluvastatin and/or valsartan. These results could be of significant clinical relevance. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of combination treatment of S–amlodipine with peroxisome proliferator-activated receptor agonists on metabolic and cardiovascular parameters in Zucker fa/fa rats

PubMed Central

2014-01-01

Background Type 2 diabetes is a complex metabolic disorder characterized by hyperglycemia, impaired glucose tolerance and insulin resistance associated with dyslipidemia and hypertension. The available drugs are not sufficiently efficacious in reducing cardiovascular risk and restoring normal glucose metabolism associated with type 2 diabetes as a mono- or a combination therapy. The present study examined the combined effects of an antihypertensive (S-Amlodipine) and an insulin-sensitizing agent, peroxisome proliferator-activated receptor (PPAR) agonists (Pioglitazone and Ragaglitazar), on cardiovascular risk factors in aged diabetic and insulin-resistant Zucker fa/fa rats. Methods Following combination treatment for 14 days, blood pressure (BP), serum glucose, total cholesterol and triglycerides were measured. Aortic ring study was conducted to determine the effect of combination treatments on phenylephrine-induced vasoconstriction and acetylcholine (Ach)-induced vasorelaxation. Results In combination, S-Amlodipine and Pioglitazone significantly reduced blood glucose (115.1 ± 6.6 vs. 81.7 ± 4.2), BP (184.4 ± 5.0 vs. 155.1 ± 5.0), serum triglycerides (362.5 ± 47.5 vs. 211.1 ± 23.7) and glucose intolerance when compared with vehicle treated Zucker fa/fa rats. Similar results were observed with the combination of S-Amlodipine and Ragaglitazar (Triglycerides, 362.5 ± 47.5 vs. 252.34 ± 27.86; BP, 184.4 ± 5.0 vs. 159.0 ± 8.0) except for serum glucose. ACh-induced vasorelaxation in aortic rings was also superior with both of the combinations compared to individual treatment. Furthermore, there was less body weight gain and food intake with S-Amlodipine and Pioglitazone combination in Zucker fa/fa rats. S-Amlodipine itself caused significant reduction in glucose (115.1 ± 6.6 vs. 89.7 ± 2.7) and BP (184.4 ± 5.0 vs. 156.1 ± 4.0) with improvement in insulin sensitivity observed through oral glucose tolerance test. Conclusions The results suggest that a combination of PPAR agonists and S-Amlodipine has partial benefits in improving the cardiovascular risk factors such as reduction in triglyceride levels, associated with chronic type 2 diabetes, and therefore may be utilized as an approach for addressing some of these devastating metabolic syndrome complications. PMID:24673913

[Changes of twenty-four-hour profile blood pressure and its correction of patients with arterial hypertension on the background of combined antihypertensive therapy application].

PubMed

Solomennchuk, T M; Slaba, N A; Prots'ko, V V; Bedzaĭ, A O

2014-01-01

The aim of this research was the study of efficiency and endurance antihypertensive therapy on the basis of fixed combination of enalapril and hydrochlorothiazide (HCTZ) and enalapril and HCTZ in combination with amlodipine according to the twenty-four-hour (? day-and-night) monitoring of blood pressure (? 24H BPM) of patients with arterial hypertension (AH) 2-3 severity. The study included 33 patients with 2-3 grade of hypertension (average age--54,40 ± 3.45 years). All patients performed ? 24H BPM before treatment and after 12 weeks of therapy. The combination of enalapril and HCTZ allowed to achieve target levels of blood pressure in 79% of patients, amlodipine additional purpose--in 86% of patients. We found that this therapy has a corrective effect on daily blood pressure profile, significantly reducing the load pressure and blood pressure variability. During treatment with the combination of enalapril and HCTZ combination of enalapril, HCTZ with amlodipine optimal daily profile of blood pressure after 12 weeks of reaching respectively 63.1% and 71.4% of patients. The treatment with combination of enalapril and HCTZ and adding of amlodipine is characterized by good endurance and high adherence to treatment.

The safety of sacubitril-valsartan for the treatment of chronic heart failure.

PubMed

Tyler, Jeffrey M; Teerlink, John R

2017-02-01

Sacubitril-valsartan is a combination drug that contains the neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan. In 2015, the US Food and Drug Administration approved sacubitril-valsartan for treatment of heart failure patients with reduced ejection fraction and New York Heart Association class II-IV symptoms following a large, Phase III clinical trial (PARADIGM-HF) that demonstrated a 20% reduction in the combined primary end-point of death from cardiovascular cause or hospitalization for heart failure compared to enalapril. Areas covered: This review discusses the clinical efficacy and safety of angiotensin receptor neprilysin inhibitor sacubitril-valsartan in heart failure with reduced ejection fraction. Expert opinion: Based on the PARADIGM-HF trial, sacubitril-valsartan offers compelling reductions in meaningful clinical endpoints, independent of age or severity of disease. The rate of adverse events was comparable between the enalapril and sacubitril-valsartan groups, although the absolute rates are likely underestimated due to the entry criteria and run-in period. Future trials and post-market surveillance are critical to better understand the risk of angioedema in high risk populations, particularly African-Americans, as well as long-term theoretical risks including the potential for increased cerebral amyloid plaque deposition with possible development of neurocognitive disease. Current trials are underway to evaluate potential benefit in patients with heart failure with preserved ejection fraction.

Improvement in Hemodynamics After Methylene Blue Administration in Drug-Induced Vasodilatory Shock: A Case Report.

PubMed

Laes, JoAn R; Williams, David M; Cole, Jon B

2015-12-01

The purpose of this study is to describe a case where methylene blue improved hemodynamics in a poisoned patient. This is a single case report where a poisoned patient developed vasodilatory shock following ingestion of atenolol, amlodipine, and valsartan. Shock persisted after multiple therapies including vasopressors, high-dose insulin, hemodialysis, and 20% intravenous fat emulsion. Methylene blue (2 mg/kg IV over 30 min) was administered in the ICU with temporal improvement as measured by pulmonary artery catheter hemodynamic data pre- and post-methylene blue administration. Within 1 h of methylene blue administration, systemic vascular resistance improved (240 dyn s/cm5 increased to 1204 dyn s/cm5), and vasopressor requirements decreased with maintenance of mean arterial pressure 60 mmHg. Methylene blue may improve hemodynamics in drug-induced vasodilatory shock and should be considered in critically ill patients poisoned with vasodilatory medications refractory to standard therapies.

[Medication management: Simvastatin and Amlodipin - a clinically relevant drug-interaction?

PubMed

Schröder, Jane; Goltz, Lisa; Knoth, Holger

2016-10-01

The clinical relevance of the drug-drug interaction simvastatin and amlodipine is appraised controversially by german simvastatin Summary of Product Characteristics (SPCs) and different drug interaction databases. Results of clinical trials have shown that simultaneous administration of simvastatin and amlodipine can increase simvastatin bioavailability. However, it is unclear whether this increase is associated with a higher risk for adverse drug events. So far there is no evidence that the combination might increase cases of myopathy or rhabdomyolysis. Therefore combined treatment with amlodipine and up to 40 mg simvastatin daily seems clinically justifiable if the patient does not report adverse events. If myopathy or muscle weakness occur, simvastatin dose should be reduced to 20 mg daily or the patient should be switched to pravastatin, fluvastatin or rosuvastatin. The highest approved dose of simvastatin (80 mg) is generally not recommended in new patients because of increased risk of muscle damage. © Georg Thieme Verlag KG Stuttgart · New York.

Nebivolol/valsartan: Fixed-dose combination for treatment of hypertension.

PubMed

Paton, D M

2017-01-01

Clinical trials demonstrated that a fixed-dose combination (FDC) of the beta-blocker nebivolol (5 mg) and the angiotensin II antagonist valsartan (80 mg) produced a significant reduction of both diastolic and systolic blood pressure in patients with hypertension. Both nebivolol and valsartan contributed to this effect, partial additivity of 86.6% and 82.2% being observed for diastolic and systolic blood pressure, respectively. These values are very similar to the additivity ratios of other recently approved FDCs for hypertension. Use of the FDC nebivolol 5 mg/valsartan 80 mg formulation was associated with a low incidence of treatment-related adverse effects and of serious adverse effects. There was no evidence of adverse effects due to beta2-adrenoceptor blockade. The FDC (Byvalson) was approved and launched in 2016 in the U.S. for the treatment of hypertension. Copyright 2017 Clarivate Analytics.

Benefits and Harms of Sacubitril in Adults With Heart Failure and Reduced Left Ventricular Ejection Fraction.

PubMed

Aronow, Wilbert S; Shamliyan, Tatyana A

2017-10-01

The quality of evidence regarding patient-centered outcomes in adults with heart failure (HF) after sacubitril combined with valsartan has not been systematically appraised. We searched 4 databases in February 2017 and graded the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation working group approach. We reviewed 1 meta-analysis and multiple publications of 2 randomized controlled trials (RCT) and 1 unpublished RCT. In adults with HF and reduced ejection fraction, low-quality evidence from 1 RCT of 8,432 patients suggests that sacubitril combined with valsartan reduces all-cause (number needed to treat [NNT] to prevent 1 event [NNTp] = 35) and cardiovascular mortality (NNTp = 32), hospitalization (NNTp = 11), emergency visits (NNTp = 69), and serious adverse effects, leading to treatment discontinuation (NNTp = 63) and improves quality of life when compared with enalapril. In adults with HF and preserved ejection fraction, very low-quality evidence from 1 RCT of 301 patients suggests that there are no differences in mortality, morbidity, or adverse effects between sacubitril combined with valsartan and valsartan alone. In conclusion, in adults with HF and reduced ejection fraction, to reduce cardiovascular mortality and hospitalizations and improve quality of life, clinicians may recommend sacubitril combined with valsartan over angiotensin-converting enzyme inhibitors. Copyright © 2017 Elsevier Inc. All rights reserved.

Low-Dose Fluvastatin and Valsartan Rejuvenate the Arterial Wall Through Telomerase Activity Increase in Middle-Aged Men.

PubMed

Janić, Miodrag; Lunder, Mojca; Cerkovnik, Petra; Prosenc Zmrzljak, Uršula; Novaković, Srdjan; Šabovič, Mišo

2016-04-01

Previously, we have shown that slightly to moderately aged arteries in middle-aged males can be rejuvenated functionally by sub-therapeutic, low-dose fluvastatin and valsartan treatment. Here, we explore whether this treatment could also increase telomerase activity. We hypothesized that telomerase activity might be associated with (1) an improvement of arterial wall properties and (2) a reduction of inflammatory/oxidative stress parameters (both observed in our previous studies). The stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin and valsartan combination (10 and 20 mg), respectively, and placebo (control), were analyzed. The samples were taken before and after treatment lasting 30 days, and 5 months after treatment discontinuation. Telomerase activity was measured in blood leukocytes by a TaqMan Gene Expression Assay. Low-dose fluvastatin or valsartan increased telomerase activity (106.9% and 59.5% respectively; both p < 0.05, vs. control), whereas their combination was even more effective (an increase of 228.0%; p < 0.001, vs. control). No change was noted in the control group. Importantly, increased telomerase activity obtained in the combination group significantly correlated with arterial function, measured by flow-mediated dilation (FMD) (r = 0.79; p < 0.001) and C-reactive protein concentration (r = -0.54; p = 0.02) and total anti-oxidative status (r = 0.50; p = 0.03). We found that a low-dose combination of fluvastatin and valsartan substantially increased telomerase activity, which significantly correlated with an improvement of endothelial function and a decrease of inflammation/oxidative stress. These findings could lead to a new innovative approach to arterial rejuvenation.

Evaluation of the pharmacokinetic and pharmacodynamic drug interactions between cilnidipine and valsartan, in healthy volunteers

PubMed Central

Lee, Jieon; Lee, Howard; Jang, Kyungho; Lim, Kyoung Soo; Shin, Dongseong; Yu, Kyung-Sang

2014-01-01

Purpose Although cilnidipine and valsartan are widely coadministered to patients with hypertension, their drug–drug interaction potential has not been investigated. This study compared the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of cilnidipine and valsartan, both alone and in combination, in healthy male subjects. Patients and methods Fifty-four subjects, enrolled into an open-label, single-dose, three-treatment, three-period crossover study, randomly received cilnidipine (10 mg), valsartan (160 mg), or both according to one of six sequences. Blood samples were collected at baseline and up to 24 hours after drug administration in each period. Plasma concentrations of cilnidipine and valsartan were determined by liquid chromatography with tandem mass spectrometry. Maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to the last measurable time (AUClast) were estimated using a noncompartmental method. Tolerability was evaluated by assessing adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory tests. Blood pressure was also measured for PD assessment. Results A total of 51 subjects completed the study. The PK profile of cilnidipine was not significantly affected by coadministered valsartan; the geometric mean ratio and 90% confidence interval (90% CI) of AUClast for cilnidipine with and without valsartan was 1.04 (0.98–1.10). Likewise, cilnidipine did not affect the PK of valsartan; the geometric mean ratio (90% CI) of AUClast for valsartan with and without cilnidipine was 0.94 (0.83–1.07). Coadministration of cilnidipine and valsartan reduced blood pressure in an additive way. No serious AEs were reported, and both cilnidipine and valsartan were well tolerated. Conclusion Coadministered cilnidipine and valsartan do not cause a significant PK or PD interaction, and they are well tolerated. PMID:25336921

Cost-Effectiveness of Sacubitril-Valsartan Combination Therapy Compared With Enalapril for the Treatment of Heart Failure With Reduced Ejection Fraction.

PubMed

King, Jordan B; Shah, Rashmee U; Bress, Adam P; Nelson, Richard E; Bellows, Brandon K

2016-05-01

The objective of this study was to determine the cost-effectiveness and cost per quality-adjusted life year (QALY) gained of sacubitril-valsartan relative to enalapril for treatment of heart failure with reduced ejection fraction (HFrEF). Compared with enalapril, combination angiotensin receptor-neprilysin inhibition (ARNI), as is found in sacubitril-valsartan, reduces cardiovascular death and heart failure hospitalization rates in patients with HFrEF. Using a Markov model, costs, effects, and cost-effectiveness were estimated for sacubitril-valsartan and enalapril therapies for the treatment of HFrEF. Patients were 60 years of age at model entry and were modeled over a lifetime (40 years) from a third-party payer perspective. Clinical probabilities were derived predominantly from PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). All costs and effects were discounted at a 3% rate annually and are presented in 2015 U.S. dollars. In the base case, sacubitril-valsartan, compared with enalapril, was more costly ($60,391 vs. $21,758) and more effective (6.49 vs. 5.74 QALYs) over a lifetime. The cost-effectiveness of sacubitril-valsartan was highly dependent on duration of treatment, ranging from $249,411 per QALY at 3 years to $50,959 per QALY gained over a lifetime. Sacubitril-valsartan may be a cost-effective treatment option depending on the willingness-to-pay threshold. Future investigations should incorporate real-world evidence with sacubitril-valsartan to further inform decision making. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Simultaneous determination of metolazone and valsartan in plasma by on-line SPE coupled with liquid chromatography/tandem mass spectrometry.

PubMed

Zhou, Jiezhao; Chen, Meiling; Li, Ying; Yu, Fanglin; Cheng, Xiaohui; Yang, Yang; Liu, Yan; Xie, Xiangyang; Li, Zhiping; Zhang, Hui; Mei, Xingguo

2017-10-01

Combination of metolazone (0.5 mg) and valsartan (80 mg) has been verified as a promising therapy treatment for hypertension. In order to facilitate to pharmacokinetic research, it needs a method for the simultaneously determination of metolazone and valsartan in biological samples. However, there are no relative reports so far. In order to facilitate to pharmacokinetic research, an on-line solid phase extraction coupled with liquid chromatography-tandem mass spectrometry method for the simultaneous determination of metolazone and valsartan in beagle dog plasma was developed and validated in this study. An on-line solid phase extraction column Retain PEP Javelin (10 mm × 2.1 mm) was used to remove impurities in plasma samples. The metolazone, valsartan and internal standard (losartan) were separated on a Poroshell 120 SB-C18 column (4.6 mm × 50 mm × 2.7 µm) with a gradient elution procedure. Acidified acetonitrile/water mixture was used as a mobile phase. The selected multiple-reaction monitoring mode in positive ion was performed and the parent to the product transitions m/z 366/259, m/z 436.2/291 and m/z 423.4/207 were used to measure the metolazone, valsartan and losartan. The method was linear over the range of 0.1-100 ng/mL and 1-1000 ng/mL for metolazone and valsartan, respectively. This method was validated in terms of specificity, linearity, sensitivity, precision, accuracy, matrix effect, and stability and then successfully applied to pharmacokinetic studies of the metolazone and valsartan combination tablets in beagle dogs.

A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects

PubMed Central

Jung, Jin Ah; Lee, Soo-Yun; Kim, Jung-Ryul; Ko, Jae-Wook; Jang, Seong Bok; Nam, Su Youn; Huh, Wooseong

2015-01-01

Purpose Valsartan, an angiotensin-receptor blocker, and rosuvastatin, a competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are frequently coadministered to treat patients with hypertension and dyslipidemia. The study reported here sought to evaluate the pharmacokinetic and pharmacodynamic interactions between rosuvastatin and valsartan in healthy Korean subjects. Subjects and methods Thirty healthy male Korean subjects were administered with rosuvastatin (20 mg/day), valsartan (160 mg/day), and both drugs concomitantly for 4 days in a randomized, open-label, multiple-dose, three-treatment, three-period crossover study. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and valsartan were determined using validated high-performance liquid chromatography with tandem mass spectrometry. Lipid profiles and vital signs (systolic and diastolic blood pressure and pulse rate) were measured for the pharmacodynamic assessment. Results For rosuvastatin, the geometric mean ratios (90% confidence intervals [CIs]) of coadministration to mono-administration were 0.8809 (0.7873−0.9857) for maximum plasma concentration at steady state and 0.9151 (0.8632−0.9701) for area under the concentration–time curve (AUC) over a dosing interval at steady state. For valsartan, the geometric mean ratios (90% CIs) of those were 0.9300 (0.7946−1.0884) and 1.0072 (0.8893−1.1406), respectively. There were no significant differences in the metabolic ratio of N-desmethyl rosuvastatin AUC to rosuvastatin AUC between coadministration and rosuvastatin alone. No interaction was found in terms of systolic or diastolic blood pressure or lipid profiles. Combined treatment with valsartan and rosuvastatin was generally well tolerated without serious adverse events. Conclusion The pharmacokinetic profiles of rosuvastatin and valsartan in combination were comparable with those of rosuvastatin and valsartan administered individually, suggesting that their individual pharmacokinetics were not affected by their coadministration. No dose adjustment was required and the results are supportive of a study in a larger patient population. PMID:25767372

A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects.

PubMed

Jung, Jin Ah; Lee, Soo-Yun; Kim, Jung-Ryul; Ko, Jae-Wook; Jang, Seong Bok; Nam, Su Youn; Huh, Wooseong

2015-01-01

Valsartan, an angiotensin-receptor blocker, and rosuvastatin, a competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are frequently coadministered to treat patients with hypertension and dyslipidemia. The study reported here sought to evaluate the pharmacokinetic and pharmacodynamic interactions between rosuvastatin and valsartan in healthy Korean subjects. Thirty healthy male Korean subjects were administered with rosuvastatin (20 mg/day), valsartan (160 mg/day), and both drugs concomitantly for 4 days in a randomized, open-label, multiple-dose, three-treatment, three-period crossover study. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and valsartan were determined using validated high-performance liquid chromatography with tandem mass spectrometry. Lipid profiles and vital signs (systolic and diastolic blood pressure and pulse rate) were measured for the pharmacodynamic assessment. For rosuvastatin, the geometric mean ratios (90% confidence intervals [CIs]) of coadministration to mono-administration were 0.8809 (0.7873-0.9857) for maximum plasma concentration at steady state and 0.9151 (0.8632-0.9701) for area under the concentration-time curve (AUC) over a dosing interval at steady state. For valsartan, the geometric mean ratios (90% CIs) of those were 0.9300 (0.7946-1.0884) and 1.0072 (0.8893-1.1406), respectively. There were no significant differences in the metabolic ratio of N-desmethyl rosuvastatin AUC to rosuvastatin AUC between coadministration and rosuvastatin alone. No interaction was found in terms of systolic or diastolic blood pressure or lipid profiles. Combined treatment with valsartan and rosuvastatin was generally well tolerated without serious adverse events. The pharmacokinetic profiles of rosuvastatin and valsartan in combination were comparable with those of rosuvastatin and valsartan administered individually, suggesting that their individual pharmacokinetics were not affected by their coadministration. No dose adjustment was required and the results are supportive of a study in a larger patient population.

Safety of the Up-titration of Nifedipine GITS and Valsartan or Low-dose Combination in Uncontrolled Hypertension: the FOCUS Study.

PubMed

Park, Jeong Bae; Shin, Joon-Han; Kim, Dong-Soo; Youn, Ho-Joong; Park, Seung Woo; Shim, Wan Joo; Park, Chang Gyu; Kim, Dong-Woon; Lee, Hae-Young; Choi, Dong-Ju; Rim, Se-Joong; Lee, Sung-Yun; Kim, Ju-Han

2016-04-01

Doubling the dose of antihypertensive drugs is necessary to manage hypertension in patients whose disease is uncontrolled. However, this strategy can result in safety issues. This study compared the safety and efficacy of up-titration of the nifedipine gastrointestinal therapeutic system (GITS) with up-titration of valsartan monotherapy; these were also compared with low-dose combinations of the two therapies. This prospective, open-label, randomized, active-controlled, multicenter study lasted 8 weeks. If patients did not meet the target blood pressure (BP) after 4 weeks of treatment with low-dose monotherapy, they were randomized to up-titration of the nifedipine GITS dose from 30 mg (N30) to 60 mg or valsartan from 80 mg to 160 mg or they were randomized to receive a low-dose combination of N30 and valsartan 80 mg for another 4 weeks. BP variability was assessed by using the SD or the %CV of the short-term BP measured at clinic. Of the 391 patients (20~70 years with stage II or higher hypertension) screened for study inclusion, 362 patients who had 3 BP measurements were enrolled. The reduction in the mean systolic/diastolic BP from baseline to week 4 was similar in both low-dose monotherapy groups with either N30 or valsartan 80 mg. BP variability (SD) was unchanged with either therapy, but the %CV was slightly increased in the N30 group. There was no significant difference in BP variability either in SD or %CV between responders and nonresponders to each monotherapy despite the significant difference in the mean BP changes. The up-titration effect of nifedipine GTS from 30 to 60 mg exhibited an additional BP reduction, but this effect was not shown in the up-titration of valsartan from 80 to 160 mg. Although the difference in BP was obvious between high-dose nifedipine GTS and valsartan, the BP variability was unchanged between the 2 drugs and was similar to the low-dose combinations. There was a low rate of adverse events in all treatment groups. In addition, escalating the dose of either nifedipine GITS or valsartan revealed a similar occurrence of adverse effects with low-dose monotherapy or the low-dose combination. Compared with up-titration of the angiotensin receptor blocker valsartan, up-titration of the calcium channel blocker nifedipine GITS provided no additional increased safety concerns and revealed better mean reductions in BP without affecting short-term BP variability. ClinicalTrials.gov identifier: NCT01071122. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension.

PubMed

Sander, Gary E; Fernandez, Camilo; Giles, Thomas D

2016-01-01

Recent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact "lower is better," with blood pressure targets < 120/80 mm Hg appropriate for many hypertensive patients. Two drug combinations are often indicated as initial therapy if a 20/10 mm Hg or greater blood pressure reduction is necessary to reach target. Combinations consisting of β-blockers and renin-angiotensin-aldosterone system inhibitors have previously been deemed "less effective," based on partially overlapping mechanisms of action and limited clinical trial evidence. Nebivolol is a vasodilating β1-selective blocker and β3- adrenoceptor agonist; β3-adrenoceptor activation increases nitric oxide concentrations and thus explains the vasodilatory effect. A recent 8-week randomized trial (N=4,161) in individuals with stage 1-2 hypertension demonstrated that single-pill fixed dose combinations (FDC) of nebivolol and valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other β-blockers, and will further support the pharmacological advantages of this particular combination.

Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients.

PubMed

Jamerson, Kenneth; Weber, Michael A; Bakris, George L; Dahlöf, Björn; Pitt, Bertram; Shi, Victor; Hester, Allen; Gupte, Jitendra; Gatlin, Marjorie; Velazquez, Eric J

2008-12-04

The optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that treatment with the combination of an angiotensin-converting-enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic. In a randomized, double-blind trial, we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. The baseline characteristics of the two groups were similar. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group. There were 552 primary-outcome events in the benazepril-amlodipine group (9.6%) and 679 in the benazepril-hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; P<0.001). For the secondary end point of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, the hazard ratio was 0.79 (95% CI, 0.67 to 0.92; P=0.002). Rates of adverse events were consistent with those observed from clinical experience with the study drugs. The benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. (ClinicalTrials.gov number, NCT00170950.) 2008 Massachusetts Medical Society

An Economic Evaluation of Sacubitril/Valsartan for Heart Failure Patients in the Netherlands.

PubMed

van der Pol, Simon; Degener, Fabian; Postma, Maarten J; Vemer, Pepijn

2017-03-01

In September 2014, the PARADIGM-HF trial showed the heart failure drug combination sacubitril/valsartan to be superior to enalapril for patients with a reduced ejection fraction. To determine the incremental cost-effectiveness of sacubitril/valsartan compared with enalapril in the Netherlands using the clinical data from the PARADIGM-HF trial. To compare sacubitril/valsartan and enalapril in a cost-effectiveness study, a Markov model was developed using the effectiveness data from the PARADIGM-HF trial. A health care payer's perspective was applied in the economic evaluation. The developed model was used to evaluate the cost-effectiveness for sacubitril/valsartan at different per diem prices. The base-case analysis showed that sacubitril/valsartan can be cost-effective at maximum daily costs of €5.50 and €14.14 considering willingness-to-pay thresholds of €20,000 and €50,000 per quality-adjusted life-year (QALY), respectively. Sensitivity analysis demonstrated the robustness of the model, identifying only the price of sacubitril/valsartan and the mortality within the sacubitril/valsartan group as significant drivers of the cost-effectiveness ratio. Sacubitril/valsartan was cost-effective at a willingness-to-pay threshold of €20,000 per QALY (€50,000 per QALY) in more than 80% of the replications with certainty at the price point of €3 (€10). Sacubitril/valsartan can be considered a cost-effective treatment at a daily price of €5.25. Unless priced lower than enalapril (<€0.045 per day), sacubitril/valsartan is very unlikely to be cost-saving/dominant. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Valsartan Improves β-Cell Function and Insulin Sensitivity in Subjects With Impaired Glucose Metabolism

PubMed Central

van der Zijl, Nynke J.; Moors, Chantalle C.M.; Goossens, Gijs H.; Hermans, Marc M.H.; Blaak, Ellen E.; Diamant, Michaela

2011-01-01

OBJECTIVE Recently, the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research Trial demonstrated that treatment with the angiotensin receptor blocker (ARB) valsartan for 5 years resulted in a relative reduction of 14% in the incidence of type 2 diabetes in subjects with impaired glucose metabolism (IGM). We investigated whether improvements in β-cell function and/or insulin sensitivity underlie these preventive effects of the ARB valsartan in the onset of type 2 diabetes. RESEARCH DESIGN AND METHODS In this randomized controlled, double-blind, two-center study, the effects of 26 weeks of valsartan (320 mg daily; n = 40) or placebo (n = 39) on β-cell function and insulin sensitivity were assessed in subjects with impaired fasting glucose and/or impaired glucose tolerance, using a combined hyperinsulinemic-euglycemic and hyperglycemic clamp with subsequent arginine stimulation and a 2-h 75-g oral glucose tolerance test (OGTT). Treatment effects were analyzed using ANCOVA, adjusting for center, glucometabolic status, and sex. RESULTS Valsartan increased first-phase (P = 0.028) and second-phase (P = 0.002) glucose-stimulated insulin secretion compared with placebo, whereas the enhanced arginine-stimulated insulin secretion was comparable between groups (P = 0.25). In addition, valsartan increased the OGTT-derived insulinogenic index (representing first-phase insulin secretion after an oral glucose load; P = 0.027). Clamp-derived insulin sensitivity was significantly increased with valsartan compared with placebo (P = 0.049). Valsartan treatment significantly decreased systolic and diastolic blood pressure compared with placebo (P < 0.001). BMI remained unchanged in both treatment groups (P = 0.89). CONCLUSIONS Twenty-six weeks of valsartan treatment increased glucose-stimulated insulin release and insulin sensitivity in normotensive subjects with IGM. These findings may partly explain the beneficial effects of valsartan in the reduced incidence of type 2 diabetes. PMID:21330640

Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial.

PubMed

Bakris, George L; Sarafidis, Pantelis A; Weir, Matthew R; Dahlöf, Björn; Pitt, Bertram; Jamerson, Kenneth; Velazquez, Eric J; Staikos-Byrne, Linda; Kelly, Roxzana Y; Shi, Victor; Chiang, Yann-Tong; Weber, Michael A

2010-04-03

The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality. We assessed the effects of these drug combinations on progression of chronic kidney disease. ACCOMPLISH was a double-blind, randomised trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). 11 506 patients with hypertension who were at high risk for cardiovascular events were randomly assigned via a central, telephone-based interactive voice response system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or benazepril (20 mg) plus hydrochlorothiazide (12.5 mg; n=5762), orally once daily. Drug doses were force-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidney disease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate <15 mL/min/1.73 m(2) or need for dialysis). Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00170950. The trial was terminated early (mean follow-up 2.9 years [SD 0.4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All randomised patients were included in the ITT analysis. There were 113 (2.0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (HR 0.52, 0.41-0.65, p<0.0001). The most frequent adverse event in patients with chronic kidney disease was peripheral oedema (benazepril plus amlodipine, 189 of 561, 33.7%; benazepril plus hydrochlorothiazide, 85 of 532, 16.0%). In patients with chronic kidney disease, angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group. Initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent. Novartis. Copyright 2010 Elsevier Ltd. All rights reserved.

Sacubitril/Valsartan: A Novel Cardiovascular Combination Agent.

PubMed

Sible, Alexandra M; Nawarskas, James J; Alajajian, David; Anderson, Joe R

2016-01-01

Sacubitril/valsartan [LCZ696 (Entresto), Novartis Pharmaceuticals Corp.] is the first in a new class of drugs that combines neprilysin inhibition with angiotensin II receptor antagonism, the combination of which acts to increase endogenous natriuretic peptides while inhibiting the renin-angiotensin-aldosterone system. Sacubitril/valsartan has been studied in the treatment of hypertension, heart failure with reduced ejection fraction (HFrEF), and heart failure with preserved ejection fraction (HFpEF) and has demonstrated clinical efficacy in blood pressure reduction in hypertensive patients with and without HFpEF and a reduction in hospitalizations and mortality for patients with HFrEF. Research to evaluate clinical outcomes in HFpEF is ongoing. Sacubitril/valsartan is approved to reduce hospitalization and risk of cardiovascular death for patients with HFrEF in New York Heart Association (NYHA) functional class II-IV. The product is as well tolerated as an angiotensin-converting enzyme inhibitor, with the most common side effect being hypotension. Expectedly, it is much more costly than generic angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, which will be a factor in determining how widespread the use of this agent will be. In summary, although the number of published studies evaluating its use is limited, sacubitril/valsartan represents a promising new treatment option for patients with HFrEF. Ongoing studies will continue to refine the role of this agent in clinical practice.

Spectrophotometric method for simultaneous determination of valsartan and substances from the group of statins in binary mixtures.

PubMed

Stolarczyk, Mariusz; Apola, Anna; Maślanka, Anna; Kwiecień, Anna; Opoka, Włodzimierz

2017-12-20

Applicability of derivative spectrophotometry for the determination of valsartan in the presence of a substance from the group of statins was checked. The obtained results indicate that the proposed method may be effective by using appropriate derivatives: for valsartan and fluvastatin - D1, D2 and D3, for valsartan and pravastatin - D1 and D3, for valsartan and atorvastatin - D2 and D3. The method was characterized by high sensitivity and accuracy. Linearity was maintained in the following ranges: 9.28-32.48 mg mL-1 for valsartan, 8.16-28.56 mg mL-1 f or fluvastatin, 14.40-39.90 mg mL-1 for atorvastatin and 9.60-48.00 mg mL-1 for pravastatin. Determination coefficients were in the range of 0.989-0.999 depending on the analyte and the order of derivative. The precision of the method was high with RSD from 0.1 to 2.5 % and recovery of individual components was within the range of 100 ± 5 %. The developed method was successfully applied to the determination of valsartan combined with fluvastatin, atorvastatin and pravastatin in laboratory prepared mixtures and in pharmaceutical preparations.

Add-On Aliskiren Elicits Stronger Renoprotection Than High-Dose Valsartan in Type 2 Diabetic KKAy Mice That Do Not Respond to Low-Dose Valsartan

PubMed Central

Lei, Bai; Nakano, Daisuke; Fan, Yu-Yan; Kitada, Kento; Hitomi, Hirofumi; Kobori, Hiroyuki; Mori, Hirohito; Masaki, Tsutomu; Nishiyama, Akira

2012-01-01

We hypothesized that aliskiren provides renoprotection in diabetic animals that did not receive sufficient renoprotection by AT1-receptor antagonist treatment. Type 2 diabetic KKAy mice were treated with group 1: vehicle or group 2: valsartan (15 mg/kg per day) from 12 to 16 weeks of age. The mice were subsequently divided into 4 groups and treated with the following combinations of drugs for another 6 weeks: 1: group 1 kept receiving vehicle, 2: group 2 continuously received 15 mg/kg per day of valsartan (Val-Val15), 3: group 2 received 50 mg/kg per day of valsartan (Val-Val50), 4: group 2 continuously received 15 mg/kg per day of valsartan with 25 mg/kg per day of aliskiren (Val-Val+Ali). Aliskiren exerted significant anti-albuminuric effects, whereas valsartan failed to ameliorate the albuminuria in the first four weeks. Surprisingly, the increasing dosage of valsartan in the Val-Val50 group showed non-significant tendencies to attenuate the albuminuria compared with vehicle infusion. Val-Val+Ali significantly suppressed the development of albuminuria and podocyte injury. Val-Val50 and Val-Val+Ali showed similar suppression of angiotensin II contents in the kidney of KKAy mice. In conclusion, the anti-albuminuric effect that was observed in the type 2 diabetic mice showing no anti-albuminuric effect by valsartan can be attributed to the add-on aliskiren. PMID:22673148

Progress report on the first sub-Saharan Africa trial of newer versus older antihypertensive drugs in native black patients

PubMed Central

2012-01-01

Background The epidemic surge in hypertension in sub-Saharan Africa is not matched by clinical trials of antihypertensive agents in Black patients recruited in this area of the world. We mounted the Newer versus Older Antihypertensive agents in African Hypertensive patients (NOAAH) trial to compare, in native African patients, a single-pill combination of newer drugs, not involving a diuretic, with a combination of older drugs including a diuretic. Methods Patients aged 30 to 69 years with uncomplicated hypertension (140 to 179/90 to 109 mmHg) and ≤2 associated risk factors are eligible. After a four week run-in period off treatment, 180 patients have to be randomized to once daily bisoprolol/hydrochlorothiazide 5/6.25 mg (R) or amlodipine/valsartan 5/160 mg (E). To attain blood pressure <140/<90 mmHg during six months, the doses of bisoprolol and amlodipine should be increased to 10 mg/day with the possible addition of up to 2 g/day α-methyldopa. Results At the time of writing of this progress report, of 206 patients enrolled in the run-in period, 140 had been randomized. At randomization, the R and E groups were similar (P ≥ 0.11) with respect to mean age (50.7 years), body mass index (28.2 kg/m2), blood pressure (153.9/91.5 mmHg) and the proportions of women (53.6%) and treatment naïve patients (72.7%). After randomization, in the R and E groups combined, blood pressure dropped by 18.2/10.1 mmHg, 19.4/11.2 mmHg, 22.4/12.2 mmHg and 25.8/15.2 mmHg at weeks two (n = 122), four (n = 109), eight (n = 57), and 12 (n = 49), respectively. The control rate was >65% already at two weeks. At 12 weeks, 12 patients (24.5%) had progressed to the higher dose of R or E and/or had α-methyldopa added. Cohort analyses of 49 patients up to 12 weeks were confirmatory. Only two patients dropped out of the study. Conclusions NOAAH (NCT01030458) demonstrated that blood pressure control can be achieved fast in Black patients born and living in Africa with a simple regimen consisting of a single-pill combination of two antihypertensive agents. NOAAH proves that randomized clinical trials of cardiovascular drugs in the indigenous populations of sub-Saharan Africa are feasible. PMID:22594907

Impact of Statin Therapy on the Blood Pressure-Lowering Efficacy of a Single-Pill Perindopril/Amlodipine Combination in Hypertensive Patients with Hypercholesterolemia.

PubMed

Sirenko, Yuriy; Radchenko, Ganna

2017-03-01

Several lines of research indicate that statins can lower blood pressure (BP) independently of their lipid-lowering effects when used as monotherapy and in combination with antihypertensive agents. This short-term, open-label study examined whether statin therapy had a synergistic effect on the BP-lowering efficacy of perindopril/amlodipine in a subgroup of patients in the PERSPECTIVA study with concomitant hypertension and hypercholesterolemia, with or without statin at baseline. The PERSPECTIVA study recruited 732 adults with untreated or uncontrolled hypertension. This subgroup analysis of PERSPECTIVA included 587 patients with concomitant hypertension and hypercholesterolemia (mean age 56.7 years) of whom 226 were receiving a statin at baseline (statin [+] group) and 361 were not (statin [-] group). All patients received treatment with single-pill combination perindopril/amlodipine at a dose of 5/5, 10/5 or 10/10 mg/day. The study duration was 60 days with follow-up visits for BP monitoring at 7, 15, 30 and 60 days. At day 60, BP control (<140/90 mmHg) was significantly greater in the statin [+] vs statin [-] group: 73 vs 64% respectively (+14%, P < 0.05). In the statin [+] group, the single-pill perindopril/amlodipine combination significantly reduced BP in patients previously untreated (n = 18), or treated with monotherapy (n = 97), dual therapy (n = 93), or triple therapy (n = 18): -38.8/-20.0, -39.1/-20.1, -38.0/-19.4, -39.9/-18.3 mmHg respectively (P < 0.001 vs baseline BP). The greatest BP reductions were observed in the first 7 days. Treatment was well tolerated with a similar rate of adverse events in the statin [+] group (0.9%) vs the statin [-] group (2.5%). BP control rates in patients with uncontrolled hypertension and concomitant hypercholesterolemia are significantly improved with a treatment regimen that combines perindopril/amlodipine with statin therapy, regardless of previous antihypertensive therapy. This subanalysis of the PERSPECTIVA study supports the synergistic BP-lowering effect of statins and perindopril/amlodipine.

Cognitive performance of patients with chronic heart failure on sacubitril/valsartan : A retrospective cohort study.

PubMed

De Vecchis, R; Ariano, C; Di Biase, G; Noutsias, M

2018-02-15

Sacubitril, a neprilysin inhibitor in the combination molecule sacubitril/valsartan, slows down degradation of endogenous natriuretic peptides, thereby enhancing their beneficial cardiovascular effects. However, sacubitril might also promote neuronal dysfunction and cognitive impairment in patients with chronic heart failure (CHF) treated with sacubitril/valsartan, due to possible neprilysin inhibition at the level of Central Nervous System. A retrospective cohort study was undertaken to detect the effects exerted by sacubitril/valsartan on cognitive function in CHF patients. The patients' clinical data were examined for information provided in the Mini-Mental State Examination (MMSE), which was routinely administered during clinical visits at two centers from 15 March to 31 October 2017. Patients in the sacubitril/valsartan group had a clinical history of at least 3 months of continuous sacubitril/valsartan administration. The control group comprised CHF patients on conventional therapy not taking sacubitril/valsartan. In the between-group comparison, patients were matched for mean age, educational level, sex, NYHA class, and comorbidities. In the present retrospective study only patients in NYHA class II-III were enrolled. The mean MMSE score was 22.72 ± 2.68 (mean ± standard deviation [SD]) in the sacubitril/valsartan group (n = 51 patients) vs. 21.96 ± 2.73 (mean ± SD) in the control group (n = 51; p = 0.1572, independent samples t-test). Thus, a similar mild-to-moderate impairment in cognitive performance was found in the comparison between the two groups. In our study, we did not find any evidence of the alleged harmful influence of sacubitril/valsartan on cognitive function. Patients taking sacubitril/valsartan for at least 3 months had similar mean MMSE scores to control subjects.

Heart rate as a predictor of stroke in high-risk, hypertensive patients with previous stroke or transient ischemic attack.

PubMed

Sandset, Else Charlotte; Berge, Eivind; Kjeldsen, Sverre E; Julius, Stevo; Holzhauer, Björn; Krarup, Lars-Henrik; Hua, Tsushung A

2014-01-01

Risk factors for first stroke are well established, but less is known about risk factors for recurrent stroke. In the present analysis, we aimed to assess the effect of heart rate and other possible predictors of stroke in a hypertensive population with previous stroke or transient ischemic attack (TIA). The Valsartan Antihypertensive Long-Term Use Evaluation trial was a multicentre, double-masked, randomized controlled, parallel group trial comparing the effects of an angiotensin receptor blocker (valsartan) and a calcium channel blocker (amlodipine) in patients with hypertension and high cardiovascular risk. We used Cox proportional hazard models to investigate the effect of baseline variables on the risk of stroke. Quadratic terms of the continuous variables were entered in the models to test for linearity. Of 15,245 patients included in the trial, 3014 had a previous stroke or TIA at baseline and were included in the present analysis. Stroke recurrence occurred in 239 patients (7.9%) during a median of 4.5 years of follow-up. Resting heart rate (per 10 beats per minute; hazard ratio [HR], 2.78; 95% confidence interval [CI], 1.18-6.58) and diabetes mellitus at baseline (HR, 1.47; 95% CI, 1.03-2.10) were significantly associated with an increased risk of stroke recurrence in the multivariable analysis. In high-risk, hypertensive patients with previous stroke or TIA, resting heart rate was the strongest predictor of recurrent stroke. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Changing the treatment of heart failure with reduced ejection fraction: clinical use of sacubitril-valsartan combination

PubMed Central

Kaplinsky, Edgardo

2016-01-01

Despite significant therapeutic advances, patients with chronic heart failure (HF) remain at high risk of morbidity and mortality. Sacubitril valsartan (previously known as LCZ696) is a new oral agent approved for the treatment of symptomatic chronic heart failure in adults with reduced ejection fraction. It is described as the first in class angiotensin receptor neprilysin inhibitor (ARNI) since it incorporates the neprilysin inhibitor, sacubitril and the angiotensin II receptor antagonist, valsartan. Neprilysin is an endopeptidase that breaks down several vasoactive peptides including natriuretic peptides (NPs), bradykinin, endothelin and angiotensin II (Ang-II). Therefore, a natural consequence of its inhibition is an increase of plasmatic levels of both, NPs and Ang-II (with opposite biological actions). So, a combined inhibition of these both systems (Sacubitril / valsartan) may enhance the benefits of NPs effects in HF (natriuresis, diuresis, etc) while Ang-II receptor is inhibited (reducing vasoconstriction and aldosterone release). In a large clinical trial (PARADIGM-HF with 8442 patients), this new agent was found to significantly reduce cardiovascular and all cause mortality as well as hospitalizations due to HF (compared to enalapril). This manuscript reviews clinical evidence for sacubitril valsartan, dosing and cautions, future directions and its considered place in the therapy of HF with reduced ejection fraction. PMID:28133468

Effect of the Hepatitis C Virus Protease Inhibitor Telaprevir on the Pharmacokinetics of Amlodipine and Atorvastatin▿

PubMed Central

Lee, Jee Eun; van Heeswijk, Rolf; Alves, Katia; Smith, Frances; Garg, Varun

2011-01-01

Telaprevir is a hepatitis C virus protease inhibitor that is both a substrate and an inhibitor of CYP3A. Amlodipine and atorvastatin are both substrates of CYP3A and are among the drugs most frequently used by patients with hepatitis C. This study was conducted to examine the effect of telaprevir on atorvastatin and amlodipine pharmacokinetics (PK). This was an open-label, single sequence, nonrandomized study involving 21 healthy male and female volunteers. A coformulation of 5 mg amlodipine and 20 mg atorvastatin was administered on day 1. Telaprevir was taken with food as a 750-mg dose every 8 h from day 11 until day 26, and a single dose of the amlodipine-atorvastatin combination was readministered on day 17. Plasma samples were collected for determination of the PK of telaprevir, amlodipine, atorvastatin, ortho-hydroxy atorvastatin, and para-hydroxy atorvastatin. When administration with telaprevir was compared with administration without telaprevir, the least-square mean ratios (90% confidence limits) for amlodipine were 1.27 (1.21, 1.33) for the maximum drug concentration in serum (Cmax) and 2.79 (2.58, 3.01) for the area under the concentration-time curve from 0 h to infinity (AUC0-∞); for atorvastatin, they were 10.6 (8.74, 12.9) for the Cmax and 7.88 (6.84, 9.07) for the AUC0-∞. Telaprevir significantly increased exposure to amlodipine and atorvastatin, consistent with the inhibitory effect of telaprevir on the CYP3A-mediated metabolism of these agents. PMID:21825288

Synergistic anticonvulsant effects of pregabalin and amlodipine on acute seizure model of epilepsy in mice.

PubMed

Qureshi, Itefaq Hussain; Riaz, Azra; Khan, Rafeeq Alam; Siddiqui, Afaq Ahmed

2017-08-01

Status epilepticus is a life threatening neurological medical emergency. It may cause serious damage to the brain and even death in many cases if not treated properly. There is limited choice of drugs for the short term and long term management of status epilepticus and the dugs recommended for status epilepticus possess various side effects. The present study was designed to investigate synergistic anticonvulsant effects of pregabalin with amlodipine on acute seizure model of epilepsy in mice. Pentylenetetrazole was used to induce acute seizures which mimic status epilepticus. Pregabalin and amlodipine were used in combination to evaluate synergistic anti-seizure effects on acute seizure model of epilepsy in mice. Diazepam and valproate were used as reference dugs. The acute anti-convulsive activity of pregabalin with amlodipine was evaluated in vivo by the chemical induced seizures and their anti-seizure effects were compared with pentylenetetrazole, reference drugs and to their individual effects. The anti-seizure effects of tested drugs were recorded in seconds on seizure characteristics such as latency of onset of threshold seizures, rearing and fallings and Hind limbs tonic extensions. The seizure protection and mortality to the animals exhibited by the drugs were recorded in percentage. Combination regimen of pregabalin with amlodipine exhibited dose dependent significant synergistic anticonvulsant effects on acute seizures which were superior to their individual effects and equivalent to reference drugs.

Aliskiren/amlodipine as a single-pill combination in hypertensive patients: subgroup analysis of elderly patients, with metabolic risk factors or high body mass index

PubMed Central

Axthelm, Christoph; Sieder, Christian; Meister, Franziska; Pittrow, David; Kaiser, Edelgard

2013-01-01

Aims Blood pressure (BP) reduction in hypertensive patients is more difficult to achieve in the elderly or in the presence of comorbidities. We aimed to investigate the efficacy of the single-pill combination (SPC) aliskiren/amlodipine in hypertensive elderly patients, patients with high body mass index (BMI), with at least one metabolic risk factor, and/or type 2 diabetes mellitus (DM). Methods In an open-label non-randomized study, patients not adequately controlled by previous treatment with the SPC olmesarten 40/amlodipine 10 (phase 1) were switched to the SPC aliskiren 300/amlodipine 10 (phase 2). The present post-hoc analysis investigated BP reduction in phase 2 in the named subgroups. The EudraCT identifier was 2009-016693-33, ClinicalTrials.gov identifier NCT01113047. Results Of the 187 patients not adequately controlled in phase 1 and thus treated with the SPC aliskiren 300/amlodipine 10 in phase 2, 69 were of advanced age (≥65 years), 74 or 89 were overweight or obese (BMI 25.0–29.9 kg/m2 or ≥30 kg/m2, respectively), 91 had metabolic risk factors (without DM) and 41 had DM. At the beginning of phase 2, depending on the subgroup, baseline SBP was 168–169 mmHg and DBP 103–104 mmHg. After 4 weeks of treatment with aliskiren 300/amlodipine 10, SBP/DBP was lowered by −5.1/−4.8 mmHg in the total cohort, by −5.5/−5.1 mmHg in elderly patients, by −6.7/−5.5 in overweight and by −4.2/−4.5 mmHg in obese patients, by −6.4/−4.7 mmHg in patients with metabolic risk factors without DM, and by −3.3/−5.0 mmHg in DM patients. Limitations include low sample size, limited treatment duration and the fact that the post-hoc defined groups were not mutually exclusive. Conclusions In this study reflecting clinical practice, the aliskiren/amlodipine combination achieved effective BP reduction in elderly patients or with metabolic comorbidities, including DM that might be more difficult to treat. This consistent BP lowering pattern facilitates everyday care of patients who receive aliskiren/amlodipine. PMID:27536431

Dual Angiotensin Receptor and Neprilysin Inhibition with Sacubitril/Valsartan in Chronic Systolic Heart Failure: Understanding the New PARADIGM.

PubMed

Lillyblad, Matthew P

2015-11-01

To evaluate the clinical role of sacubitril/valsartan, a novel angiotensin-neprilysin inhibitor, for the treatment of chronic heart failure with a reduced ejection fraction (HFrEF). A search of PubMed was conducted using a combination of the search terms sacubitril, valsartan, LCZ696, neprilysin inhibition, natriuretic peptide system, renin-angiotensin system, and heart failure with reduced ejection fraction. Bibliographies of all retrieved articles were reviewed for relevant literature. All references included were published between 1980 and May 2015. All studies and review articles that contained data describing the use of sacubitril/valsartan in HFrEF were reviewed. HFrEF remains a disease of high morbidity and mortality. Natriuretic peptide (NP) augmentation has emerged as a most promising neurohormonal target in HFrEF. NPs provide vasodilatory, natriuretic, diuretic, and antiproliferative actions to help support the failing heart. Neprilysin, a neutral endopeptidase, is a primary pathway for NP metabolism. Combined inhibition of the renin angiotensin aldosterone system and neprilysin augments the beneficial natriuretic peptide pathway while providing direct antagonism to increases in angiotensin II. In the landmark PARADIGM HF trial, the neprilysin inhibitor sacubitril added to valsartan significantly improved morbidity and mortality over enalapril, a standard of care in HFrEF. Application of these results to clinical practice requires careful considerations of trial design, study patient population, and clinical monitoring. Sacubitril/valsartan significantly improved morbidity and mortality in patients with chronic HFrEF but will require careful application to "real-world" populations of HFrEF. © The Author(s) 2015.

Real-world effectiveness of valsartan on hypertension and total cardiovascular risk: review and implications of a translational research program

PubMed Central

Abraham, Ivo; MacDonald, Karen; Hermans, Christine; Aerts, Ann; Lee, Christopher; Brié, Heidi; Vancayzeele, Stefaan

2011-01-01

The pharmacological efficacy of various monotherapy, single pill, and combination therapies of the angiotensin II receptor blocker valsartan have been established, mainly through randomized controlled trials that used similar methodological and statistical platforms and thus enabled synthesis of evidence. The real world effectiveness of valsartan has been studied extensively, but the relative lack of scientific and technical congruence of these studies render synthesis virtually impossible. To date, all have focused on blood pressure outcomes, despite evidence-based calls to grade antihypertensive treatment to patients’ total cardiovascular risk. We review a T3 translational research program of seven studies involving valsartan monotherapy as well as single and separate pill combinations, and the determinants and effect on blood pressure and total cardiovascular risk outcomes. All seven studies examined not only the impact of valsartan-based regimens on blood pressure values and control, but also, within a statistical hierarchical approach, the physician- and patient-related determinants of these blood pressure outcomes. Two studies also investigated the determinants and outcomes of valsartan-based treatment on total cardiovascular risk – among the first studies to use this risk coefficient as an outcome rather than only a determinant. These seven studies included a total of 19,533 patients, contributed by 3434 physician-investigators in Belgium – a country particularly well-suited for observational effectiveness studies because of demographics and epidemiology. Each study used the same methodological and statistical platform. We summarize the impact of various valsartan regimens on such outcomes as blood pressure values and control, change in total cardiovascular risk, and reduction in risk by at least one category. We also review the results of statistical multilevel and logistic modeling of physician- and patient-related determinants on these outcomes, including the proportion of variance attributable to a physician class effect before patients enter the equation. In its different formulations, valsartan has major real-world benefits in lowering blood pressure and total cardiovascular risk within a 90-day period. It is essential to understand the physician- and patient-related determinants of blood pressure and total cardiovascular risk outcomes associated with valsartan treatment. Antihypertensive research should expand its historical focus on lowering blood pressure with an emphasis on lowering total cardiovascular research. PMID:21490947

Atorvastatin calcium plus amlodipine for the treatment of hypertension.

PubMed

Delgado-Montero, Antonia; Zamorano, Jose L

2012-12-01

Hypertension (HTN) and dyslipemia (DYL) are two of the major modifiable cardiovascular (CV) risk factors, determinants in the development of cerebrovascular and coronary heart disease (CHD). Many patients have both risk factors which increase their total CV risk compared with patients with only one risk factor. Treatment guideline recommendations are poorly implemented in real practice, in part due to numerous and complicated drug regimes which hamper patient´s adherence. In this article the authors describe the first combined fixed-dose pill of an antihypertensive and a lipid-lowering agent, the single-pill combination of amlodipine besylate and atorvastatin calcium (SPAA). They summarize the pharmacokinetic and pharmacodynamic properties of both compounds and the main randomized clinical studies, as well as real-world observational studies, made with the new combined formulation. The use of the single-pill amlodipine and atorvastatin is an adequate option for the clinician to treat hypertensive patients with DYL or high CV risk burden, with proven efficacy, tolerability, cost-effectiveness, and the advantage of improving patient treatment compliance.

Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

PubMed Central

Hubers, Scott A.; Brown, Nancy J.

2016-01-01

Heart failure affects approximately 5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the FDA approved the first of a new class of drugs for the treatment of heart failure; valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses two of the pathophysiologic mechanisms of heart failure - activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared to enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacologic properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension. PMID:26976916

Innovative spectrophotometric methods for simultaneous estimation of the novel two-drug combination: Sacubitril/Valsartan through two manipulation approaches and a comparative statistical study

NASA Astrophysics Data System (ADS)

Eissa, Maya S.; Abou Al Alamein, Amal M.

2018-03-01

Different innovative spectrophotometric methods were introduced for the first time for simultaneous quantification of sacubitril/valsartan in their binary mixture and in their combined dosage form without prior separation through two manipulation approaches. These approaches were developed and based either on two wavelength selection in zero-order absorption spectra namely; dual wavelength method (DWL) at 226 nm and 275 nm for valsartan, induced dual wavelength method (IDW) at 226 nm and 254 nm for sacubitril and advanced absorbance subtraction (AAS) based on their iso-absorptive point at 246 nm (λiso) and 261 nm (sacubitril shows equal absorbance values at the two selected wavelengths) or on ratio spectra using their normalized spectra namely; ratio difference spectrophotometric method (RD) at 225 nm and 264 nm for both of them in their ratio spectra, first derivative of ratio spectra (DR1) at 232 nm for valsartan and 239 nm for sacubitril and mean centering of ratio spectra (MCR) at 260 nm for both of them. Both sacubitril and valsartan showed linearity upon application of these methods in the range of 2.5-25.0 μg/mL. The developed spectrophotmetric methods were successfully applied to the analysis of their combined tablet dosage form ENTRESTO™. The adopted spectrophotometric methods were also validated according to ICH guidelines. The results obtained from the proposed methods were statistically compared to a reported HPLC method using Student t-test, F-test and a comparative study was also developed with one-way ANOVA, showing no statistical difference in accordance to precision and accuracy.

Randomized trial comparing the effects of a low-dose combination of nifedipine GITS and valsartan versus high-dose monotherapy on central hemodynamics in patients with inadequately controlled hypertension: FOCUS study.

PubMed

Park, Jeong Bae; Ha, Jong-Won; Jung, Hae-Ok; Rhee, Moo-Yong

2014-10-01

Measurement of central blood pressure provides prognostic information beyond conventional peripheral blood pressure (BP). However, few studies have directly compared the effects of antihypertensives on central hemodynamics. This study investigated the effects of a low-dose combination of nifedipine Gastrointestinal Therapeutic System (GITS) and valsartan versus high-dose monotherapy with either agent in reducing central BP in essential hypertension inadequately controlled by low-dose monotherapy. In this prospective, open-label, randomized, active-controlled, multicenter 8-week study, patients not meeting the target BP after 4 weeks of treatment with low-dose monotherapy were randomized to receive nifedipine GITS 30 mg plus valsartan 80 mg (N30+V80), nifedipine GITS 60 mg (N60), or valsartan 160 mg (V160) for a further 4 weeks. Central hemodynamics were measured by applanation tonometry. A total of 391 patients were enrolled. Reduction in central systolic BP from baseline to week 8, the primary efficacy variable, was significantly greater in the N30+V80 group (-27.2±14.7 mmHg) and the N60 group (-27.1±16.5 mmHg) compared with V160 group (-14.4±16.6 mmHg). Decrease in the augmentation index in the N60 group was significantly greater compared with V160 alone, without differences between combination therapy and either high-dose monotherapy. Decreases in brachial systolic BP were significantly greater in the N30+V80 and N60 groups than in the V160 group. By multiple regression analysis, most differences in drug effects on central hemodynamics disappeared after controlling for changes in peripheral BP. A low rate of adverse events occurred in all treatment groups. A low-dose combination of nifedipine GITS plus valsartan or high-dose nifedipine was more effective in improving central hemodynamics than high-dose valsartan in patients with hypertension, mostly because of the improvement in peripheral (brachial) hemodynamics.

Pharmacokinetic and bioequivalence study of a telmisartan/S-amlodipine fixed-dose combination (CKD-828) formulation and coadministered telmisartan and S-amlodipine in healthy subjects.

PubMed

Kang, Woo Youl; Seong, Sook Jin; Ohk, Boram; Gwon, Mi-Ri; Kim, Bo Kyung; La, Sookie; Kim, Hyun-Ju; Cho, Seungil; Yoon, Young-Ran; Yang, Dong Heon; Lee, Hae Won

2018-01-01

A new fixed-dose combination (FDC) formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828) has been developed to increase convenience (as only one tablet is required per day) and improve treatment compliance. The pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography-tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period. Forty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (C max ) and the area under the plasma concentration-time curve from time 0 to the last measurement (AUC 0-t ) values of telmisartan were 522.29 ng/mL and 2,475.16 ng·h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng·h/mL for the individual agents concomitantly administered, respectively. The mean C max and AUC 0-t values of S-amlodipine were 2.71 ng/mL and 130.69 ng·h/mL for the FDC, and 2.74 ng/mL and 129.81 ng·h/mL for the individual agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the telmisartan C max and AUC 0-t (FDC of telmisartan and S-amlodipine/concomitant administration) were 0.8509 (0.7353-0.9846) and 0.9431 (0.8698-1.0226), respectively. The GMR and 90% CI for the S-amlodipine C max and AUC 0-t (FDC/concomitant administration) were 0.9829 (0.9143-1.0567) and 0.9632 (0.8798-1.0546), respectively. As the intrasubject variability of the C max for telmisartan administered individually was 42.94%, all 90% CIs of the GMRs fell within the predetermined acceptance range. Both treatments were well tolerated in this study. CKD-828 FDC tablets were shown to be bioequivalent to coadministration of the individual agents with the respective strength, in healthy subjects under fasting conditions. There was no significant difference in safety profile between the two treatments.

The calcium channel blocker amlodipine promotes the unclamping of eNOS from caveolin in endothelial cells.

PubMed

Batova, Suzan; DeWever, Julie; Godfraind, Théophile; Balligand, Jean-Luc; Dessy, Chantal; Feron, Olivier

2006-08-01

Amlodipine is a calcium channel blocker (CCB) known to stimulate nitric oxide production from endothelial cells. Whether this ancillary property can be related to the capacity of amlodipine to concentrate and alter the structure of cholesterol-containing membrane bilayers is a matter of investigation. Here, we reasoned that since the endothelial nitric oxide synthase is, in part, expressed in cholesterol-rich plasmalemmal microdomains (e.g., caveolae and rafts), amlodipine could interfere with this specific locale of the enzyme and thereby modulate NO production in endothelial cells. Using a method combining lubrol-based extraction and subcellular fractionation on sucrose gradient, we found that amlodipine, but not verapamil or nifedipine, induced the segregation of endothelial NO synthase (eNOS) from caveolin-enriched low-density membranes (8+/-2% vs. 42+/-3% in untreated condition; P<0.01). We then performed co-immunoprecipitation experiments and found that amlodipine dose-dependently disrupted the caveolin/eNOS interaction contrary to other calcium channel blockers, and potentiated the stimulation of NO production by agonists such as bradykinin and vascular endothelial growth factor (VEGF) (+138+/-28% and +183+/-27% over values obtained with the agonist alone, respectively; P<0.01). Interestingly, we also documented that the dissociation of the caveolin/eNOS heterocomplex induced by amlodipine was not mediated by the traditional calcium-dependent calmodulin binding to eNOS and that recombinant caveolin expression could compete with the stimulatory effects of amlodipine on eNOS activity. Finally, we showed that the amlodipine-triggered, caveolin-dependent mechanism of eNOS activation was independent of other pleiotropic effects of the CCB such as superoxide anion scavenging and angiotensin-converting enzyme (ACE) inhibition. This study unravels the modulatory effects of amlodipine on caveolar integrity and the capacity of caveolin to maintain eNOS in its vicinity in the absence of any detectable changes in intracellular calcium levels. The resulting increase in caveolin-free eNOS potentiates the NO production in response to agonists including VEGF and bradykinin. More generally, this work opens new avenues of treatment for drugs able to structurally alter signaling pathways concentrated in caveolae.

Economic evaluation of single-pill combination of indapamide and amlodipine in the treatment of arterial hypertension in the Polish setting.

PubMed

Kawalec, Paweł; Holko, Przemysław; Stawowczyk, Ewa; Borowiec, Łukasz; Filipiak, Krzysztof J

2015-01-01

Arterial hypertension is a common disorder that affects around 9 million adults in Poland. Single-pill combinations (SPCs) for the treatment of arterial hypertension have significant advantages over the free combinations, resulting in lower risk of cardiovascular events and lower consumption of medical resources. The current ESC/ESH 2013 guidelines for the first time recommend treatment with a combination of thiazide-like diuretic with calcium channel blocker. Currently, no such combination is reimbursed from public funds in Poland. To assess the economic value of treatment with SPC of indapamide and amlodipine (Tertens-AM®) for hypertensive patients compared with free combination therapy (FC), in the Polish setting. As there are currently no published data directly estimating the additional effect of using indapamide + amlo-dipine SPC vs. FC, two extreme approaches are presented: with difference in effectiveness due to improved adherence to the treatment estimated from published studies on other molecules used in hypertension such as SPCs and FCs - the base-case approach (1); and assuming no difference of effectiveness or adherence between SPC and FC of indapamide and amlodipine - the conservative approach (2). Modelling was carried out based on the Markov process in lifetime horizon. In the base-case approach, with the difference in effectiveness between SPC and FC, it was assumed that the differences in compliance translate into the differences in systolic blood pressure. Patients' characteristics were correlated with the risk of events associated with cardiovascular disease, based on the prediction algorithms from the Framingham Heart Study. Costs were considered from a National Health Fund (NHF) perspective and NHF and patient's perspective, and therefore direct medical costs were only included. The treatment with SPC of indapamide and amlodipine in place of FC resulted in 7.6 additional days of life in full health and longer overall patient survival by 2.9 days. The replacement of FC with SPC would result in national savings from both NHF perspective and NHF and patient's perspective, irrespective of the assumption of the difference in adherence between SPC and FC. The savings would amount to 1.602-3.954 million PLN and 16.498-19.186 million PLN from NHF perspective and NHF and patient's perspective, respectively. The treatment with SPC of indapamide and amlodipine for hypertensive patients was found to be dominant over FC or at least less expensive than treatment with FC when the difference in effectiveness was neglected. The replacement of FC with SPC would result in savings from both NHF perspective and NHF and patient's perspective.

Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability.

PubMed

Dennison, Thomas J; Smith, Julian C; Badhan, Raj K; Mohammed, Afzal R

2017-01-01

Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (P app ) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (<30 s) while displaying a radial crushing strength in excess of 100 N and friability ≤1%. In vitro dissolution test was performed in fasted and fed-state simulated intestinal fluid (FeSSIF) and analyzed using high-performance liquid chromatography. Dissolution profiles for single and FDC ODTs were compared using US FDA recommended difference (f 1 ) and similarity (f 2 ) factor testing for bioequivalence. In all cases, there was no difference in active pharmaceutical ingredient dissolution between single or FDC ODTs, with the exception of amlodipine in FeSSIF. Pharmacokinetic clinical trial simulations were conducted using Simcyp (Version 14), incorporating P app and dissolution data. Simulated clinical trials in healthy volunteers showed no difference in bioavailability based on pharmacokinetic parameters between single and combination doses with either active pharmaceutical ingredient. An increase in C max and AUC for atorvastatin in fed subjects was attributed to extended transit along the gut lumen and reduced atorvastatin metabolism due to lower CYP3A4 expression at more distal small intestine absorption sites. The results demonstrated bioequivalence of an FDC ODT for amlodipine and atorvastatin, while highlighting several limitations of f 1 and f 2 bioequivalence testing and strengths of mechanistic pharmacokinetic modeling for oral drug absorption.

Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability

PubMed Central

Dennison, Thomas J; Smith, Julian C; Badhan, Raj K; Mohammed, Afzal R

2017-01-01

Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (Papp) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (<30 s) while displaying a radial crushing strength in excess of 100 N and friability ≤1%. In vitro dissolution test was performed in fasted and fed-state simulated intestinal fluid (FeSSIF) and analyzed using high-performance liquid chromatography. Dissolution profiles for single and FDC ODTs were compared using US FDA recommended difference (f1) and similarity (f2) factor testing for bioequivalence. In all cases, there was no difference in active pharmaceutical ingredient dissolution between single or FDC ODTs, with the exception of amlodipine in FeSSIF. Pharmacokinetic clinical trial simulations were conducted using Simcyp (Version 14), incorporating Papp and dissolution data. Simulated clinical trials in healthy volunteers showed no difference in bioavailability based on pharmacokinetic parameters between single and combination doses with either active pharmaceutical ingredient. An increase in Cmax and AUC for atorvastatin in fed subjects was attributed to extended transit along the gut lumen and reduced atorvastatin metabolism due to lower CYP3A4 expression at more distal small intestine absorption sites. The results demonstrated bioequivalence of an FDC ODT for amlodipine and atorvastatin, while highlighting several limitations of f1 and f2 bioequivalence testing and strengths of mechanistic pharmacokinetic modeling for oral drug absorption. PMID:28352156

Sacubitril/Valsartan: The Newest Addition to the Toolbox for Guideline-Directed Medical Therapy of Heart Failure.

PubMed

Rodgers, Jo E

2017-06-01

Sacubitril/valsartan combines a neprilysin inhibitor with an angiotensin receptor blocker. As an inhibitor of neprilysin, an enzyme that degrades biologically active natriuretic peptides, this first-in-class therapy increases levels of circulating natriuretic peptides, resulting in natriuretic, diuretic, and vasodilatory effects. In patients with chronic New York Heart Association class II-IV heart failure with reduced ejection fraction, the PARADIGM-HF trial demonstrated that sacubitril/valsartan significantly reduced the primary endpoint of cardiovascular mortality and heart failure hospitalization, compared with enalapril. The rate of all-cause mortality was also significantly reduced. Subsequently, the American College of Cardiology/American Heart Association/Heart Failure Society of America recently updated guideline recommendations for Stage C patients with heart failure with reduced ejection fraction to recommend angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril/valsartan in conjunction with other evidence-based therapies to reduce morbidity and mortality. Several analyses have suggested the cost-effectiveness of this new therapy. To ensure tolerability, initiating the lower dosage form of sacubitril/valsartan is warranted in patients with severe renal impairment, moderate hepatic impairment, and low blood pressure, and close monitoring is warranted in such patients. A 36-hour washout period is recommended when switching patients from an angiotensin-converting enzyme inhibitor to sacubitril/valsartan. Similarly, sacubitril/valsartan is contraindicated in patients receiving concomitant angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and those with a history of angioedema. Copyright © 2017 Elsevier Inc. All rights reserved.

Spectrophotometric and HPLC Methods for Simultaneous Estimation of Amlodipine Besilate, Losartan Potassium and Hydrochlorothiazide in Tablets

PubMed Central

Wankhede, S. B.; Raka, K. C.; Wadkar, S. B.; Chitlange, S. S.

2010-01-01

Two UV-spectrophotometric and one reverse phase high performance liquid chromatography methods have been developed for the simultaneous estimation of amlodipine besilate, losartan potassium and hydrochlorothiazide in tablet dosage form. The first UV spectrophotometric method was a determination using the simultaneous equation method at 236.5, 254 and 271 nm over the concentration range 5-25, 10-50 and 5-25 μg/ml for amlodipine besilate, losartan potassium and hydrochlorothiazide, respectively. The second UV method was a determination using the area under curve method at 231.5-241.5, 249-259 and 266-276 nm over the concentration range of 5-25, 5-25 and 10-50 μg/ml for amlodipine besilate, hydrochlorothiazide and losartan potassium, respectively. In reverse phase high performance liquid chromatography analysis is carried out using 0.025 M phosphate buffer (pH 3.7):acetonitrile (57:43 v/v) as the mobile phase and Kromasil C18 (4.6 mm i.d×250 mm) column as stationery phase with detection wavelength of 232 nm linearity was obtained in the concentration range of 2-14, 20-140 and 5-40 μg/ml for amlodipine besilate, losartan potassium and hydrochlorothiazide, respectively. Both UV-spectrophotometric and reverse phase high performance liquid chromatography methods were statistically validated and can be used for analysis of combined dose tablet formulation containing amlodipine besilate, losartan potassium and hydrochlorothiazide. PMID:20582208

Innovative spectrophotometric methods for simultaneous estimation of the novel two-drug combination: Sacubitril/Valsartan through two manipulation approaches and a comparative statistical study.

PubMed

Eissa, Maya S; Abou Al Alamein, Amal M

2018-03-15

Different innovative spectrophotometric methods were introduced for the first time for simultaneous quantification of sacubitril/valsartan in their binary mixture and in their combined dosage form without prior separation through two manipulation approaches. These approaches were developed and based either on two wavelength selection in zero-order absorption spectra namely; dual wavelength method (DWL) at 226nm and 275nm for valsartan, induced dual wavelength method (IDW) at 226nm and 254nm for sacubitril and advanced absorbance subtraction (AAS) based on their iso-absorptive point at 246nm (λ iso ) and 261nm (sacubitril shows equal absorbance values at the two selected wavelengths) or on ratio spectra using their normalized spectra namely; ratio difference spectrophotometric method (RD) at 225nm and 264nm for both of them in their ratio spectra, first derivative of ratio spectra (DR 1 ) at 232nm for valsartan and 239nm for sacubitril and mean centering of ratio spectra (MCR) at 260nm for both of them. Both sacubitril and valsartan showed linearity upon application of these methods in the range of 2.5-25.0μg/mL. The developed spectrophotmetric methods were successfully applied to the analysis of their combined tablet dosage form ENTRESTO™. The adopted spectrophotometric methods were also validated according to ICH guidelines. The results obtained from the proposed methods were statistically compared to a reported HPLC method using Student t-test, F-test and a comparative study was also developed with one-way ANOVA, showing no statistical difference in accordance to precision and accuracy. Copyright © 2017 Elsevier B.V. All rights reserved.

Anti-stress and nootropic activity of drugs affecting the renin-angiotensin system in rats based on indirect biochemical evidence.

PubMed

Anil Kumar, K V; Nagwar, Shrasti; Thyloor, Rama; Satyanarayana, Sreemantula

2015-12-01

Various stress hormones are responsible for bringing out stress-related changes and are implicated in learning and memory processes. The extensive clinical experience of angiotensin receptor blockers (ARBs) and direct renin inhibitor as antihypertensive agents provides anecdotal evidence of improvements in cognition. The neurochemical basis underlying the anti-stress and nootropic effects are unclear. This study was aimed to determine the effects of aliskiren, valsartan and their combination on the neuromediators of the central nervous system (CNS) and periphery as well as on cognitive function. Groups of rats were subjected to a forced swim stress for one hour after daily treatment with aliskiren, valsartan and their combination. The 24 h urinary excretion of vanillylmandellic acid (VMA), 5-hydroxyindoleacetic acid (5-HIAA), 6-β-hydroxycortisol (6-β-OH) cortisol and homovanillic acid (HVA) was determined in all groups under normal and stressed conditions. Nootropic activity was studied using cook's pole climbing apparatus and acetylcholinesterase (AChE) inhibitory activity by Ellman's method. Administration of aliskiren (10 mg/kg), valsartan (20 mg/kg) and their combination at a dose of 5 and 10 mg/kg respectively reduced the urinary metabolite levels. Further, all drugs showed significant improvement in scopolamine-impaired performance and produced inhibition of the AChE enzyme. The present study provides scientific support for the anti-stress and nootropic activities of aliskiren, valsartan and their combination. © The Author(s) 2014.

A randomized, controlled study evaluating effects of amlodipine addition to chelators to reduce iron loading in patients with thalassemia major.

PubMed

Eghbali, Aziz; Kazemi, Hamideh; Taherahmadi, Hassan; Ghandi, Yazdan; Rafiei, Mohammad; Bagheri, Bahador

2017-12-01

Cardiomyopathy due to iron overload can be fatal in patients with thalassemia major. Calcium channel blockers seem to be effective to reduce iron loading. Our goal was to study effects of amlodipine addition to chelators on iron loading in patients with thalassemia major. This randomized, controlled, and single-center trial was performed on 56 patients with thalassemia major. Patients were randomized 1:1 to combined group (iron chelator plus amlodipine) or control group (iron chelator) for 1 year. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. Serum ferritin was also measured. After 12 months of treatment, myocardial T2* values had significant improvement in combined group (21.9 ± 8.0 ms to 24.5 ± 7.6 ms; P < .05); Difference between two groups was significant (P = .02). Combined treatment had no effect on hepatic T2* value (9.6 ± 2.8 ms to 9.5 ± 3.6 ms); difference between two groups was not significant (P = .2). In addition, a significant reduction was seen in serum ferritin levels in two groups. Mild gastrointestinal upset was the most common untoward effect. Addition of amlodipine to iron chelators has beneficial effects for reduction of iron loading in patients with thalassemia major. This combination therapy seems safe. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pharmacokinetic Interaction Between Rosuvastatin, Telmisartan, and Amlodipine in Healthy Male Korean Subjects: A Randomized, Open-label, Multiple-dose, 2-period Crossover Study.

PubMed

Son, Mijeong; Guk, Jinju; Kim, Yukyung; Woo Chae, Dong; Heo, Young-A; Soh, Dongjun; Park, Kyungsoo

2016-08-01

Rosuvastatin, a hydroxy methylglutaryl coenzyme A reductase inhibitor; telmisartan, an angiotensin receptor blocker; and amlodipine, a calcium channel inhibitor, are commonly prescribed together for the treatment of hypertension nonresponsive to monotherapy and accompanied by dyslipidemia. However, the pharmacokinetic interactions among these 3 substances are not well understood. The aim of this study was to investigate the pharmacokinetic drug-drug interactions among rosuvastatin, telmisartan, and amlodipine in a healthy Korean male population. In both parts of this randomized, open-label, multiple-dose, 2-part, 2-period crossover study, subjects aged 19 to 55 years were enrolled. In part 1, each subject received rosuvastatin 20 mg with and without 2 fixed-dose combination (FDC) tablets of telmisartan/amlodipine 40/5 mg, once daily for 9 consecutive days. In part 2, each subject received 2 FDC tablets of telmisartan/amlodipine 40/5 mg with and without rosuvastatin 20 mg, once daily for 9 consecutive days. In both parts, there was a 13-day washout period between treatments. Pharmacokinetic samples were collected up to 72 hours after the last dose in subjects who received rosuvastatin only, and up to 144 hours after the last dose in subjects who received telmisartan/amlodipine with or without rosuvastatin. Adverse events (AEs) were assessed via interviews and physical examinations. Forty-eight subjects were enrolled, of whom 19 in part 1 and 22 in part 2 completed the study. In Part 1, the 90% CIs of the geometric mean ratios (GMRs) (coadministration of rosuvastatin and telmisartan/amlodipine to monotherapy with rosuvastatin) of the primary pharmacokinetic parameters (AUCτ and Cmax,ss) were: rosuvastatin, 1.1436 to 1.3059 and 1.8970 to 2.3514, respectively; and N-desmethyl rosuvastatin, 0.8441 to 1.0200 and 1.1971 to 1.5457. In part 2, the 90% CIs of the GMRs (coadministration to monotherapy with telmisartan/amlodipine) were: telmisartan, 1.1204 to 1.4228 and 0.9940 to 1.5940; amlodipine, 0.9705 to 1.0636 and 0.9813 to 1.0779. There were no significant differences in the prevalences of AEs between the treatments, and all reported AEs were mild or moderate. These results demonstrate that when rosuvastatin, telmisartan, and amlodipine are coadministered to healthy male subjects, pharmacokinetic exposure increases with respect to rosuvastatin and telmisartan, whereas no change occurs with respect to amlodipine. However, based on previous analyses, the degree of increase in the exposure observed was not regarded as clinically significant. All treatments were well-tolerated. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Valsartan combined with clopidogrel and/or leflunomide for the treatment of progressive immunoglobulin A nephropathy.

PubMed

Cheng, Genyang; Liu, Dongwei; Margetts, Peter; Liu, Limin; Zhao, Zhanzheng; Liu, Zhangsuo; Tang, Lin; Fang, Yudong; Li, Haijian; Guo, Yuanyuan; Chen, Fengmei; Liu, Fengxun

2015-02-01

The current standard treatment for IgA nephropathy relies on steroid and/or immunosuppressive therapy and angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB). This study examines the benefits and safety of combining valsartan with clopidogrel and leflunomide as a treatment for progressive IgA nephropathy. Patients with primary IgA nephropathy, confirmed by renal biopsy, were recruited for this study. Patients were separated into four groups (n = 42 each) after 2 months of run-in period of valsartan treatment. All patients were treated with valsartan alone (Group 1) or valsartan and either clopidogrel (Group 2) or leflunomide (Group 3) or both clopidogrel and leflunomide (Group 4). Each group was followed up for their next 24 months for 24 h urinary protein excretion, serum creatinine and estimated glomerular filtration rate (eGFR) to assess the effect of the treatment. Adverse effects were recorded concurrently to evaluate the safety of the treatment. Of all 168 patients, 107 were males and 61 were females, with an average age of 33.8 ± 8.79 years. Baseline characteristics were comparable among the four groups (P > 0.05) prior to the experimental treatment. There was a significant (P < 0.05) decrease in 24 h urinary protein excretion after 4 months of experimental treatment. At the end of the 24 months, groups 3 and 4 showed a respective 62.35% and 69.47% reduction in proteinuria. The serum creatinine was significantly higher (P < 0.05) in group 1 and 2 at the end of the follow-up, and their respective eGFR was significantly lower. The incidence of cardiovascular complication was 11.9% and 9.5% for group 1 and 3, respectively. The treatment with Valsartan combined with Clopidogrel and Leflunomide can reduce the urinary proteins loss and renal function deterioration for IgA nephropathy patients and cause minimal adverse reactions. Our study suggests a new clinical treatment option for IgA nephropathy. © 2014 Asian Pacific Society of Nephrology.

Is Time an Important Problem in Management of Hypertension and Hypercholesterolemia by Using an Amlodipine-Atorvastatin Single Pill Combination?

PubMed

Zeng, Rui; Wang, Mian; Zhang, Li

2016-07-26

BACKGROUND Is the timing of dosing for amlodipine and atorvastatin important with regard to therapeutic efficacy? To answer this question, we designed an outpatient, practice-based, case-control study lasting 8 weeks. MATERIAL AND METHODS Two hundred patients were divided into 2 groups: in Group I, patients were provided with a single pill containing amlodipine/atorvastatin (5/20 mg) to be taken each night at 10 pm, and in Group II, patients were taking amlodipine (5 mg) and atorvastatin (20 mg) each morning at 7 am. RESULTS Our results indicated no obvious difference in blood pressure control between the 2 groups. Taking amlodipine at night not only lowered blood pressure, but it also provided better control during the peak blood pressure in the morning. Hypercholesterolemia control in the 2 groups was also not significantly different, taking atorvastatin in the morning was as effective as dosing at night in patients with hypercholesterolemia. While the carotid IMT, hs-CRP, and LVMI were significantly lower after treatment, no differences were found between the 2 groups. Although no obvious difference was found in adverse drug reactions between the 2 groups, compliance was much better in the single-pill group than in patients taking the 2 medications separately. CONCLUSIONS In conclusion, single-pill amlodipine-atorvastatin taken at night can lower blood pressure and reduce the morning peak blood pressure levels the next day. Additionally, this dosing method could improve patient adherence to the therapy.

Effect of amlodipine, efonidipine, and trichlormethiazide on home blood pressure and upper-normal microalbuminuria assessed by casual spot urine test in essential hypertensive patients.

PubMed

Hosaka, Miki; Inoue, Ryusuke; Satoh, Michihiro; Watabe, Daisuke; Hanazawa, Tomohiro; Ohkubo, Takayoshi; Asayama, Kei; Obara, Taku; Imai, Yutaka

2018-01-01

The aim of this study was to assess the effects of irbesartan alone and combined with amlodipine, efonidipine, or trichlormethiazide on blood pressure (BP) and urinary albumin (UA) excretion in hypertensive patients with microalbuminuria (30≤UA/creatinine (Cr) ratio [UACR] <300 mg/g Cr) and upper-normal microalbuminuria (10≤UACR<30 mg/g Cr). This randomized controlled trial enrolled 175 newly diagnosed and untreated hypertensive patients (home systolic blood pressure [SBP]≥135 mmHg; 10≤UACR<300 mg/g Cr of casual spot urine at the first visit to clinic). All patients were treated with irbesartan (week 0). Patients who failed to achieve home SBP ≤125 mmHg on 8-week irbesartan monotherapy (nonresponders, n = 115) were randomized into three additional drug treatment groups: trichlormethiazide (n = 42), efonidipine (n = 39), or amlodipine (n = 34). Irbesartan monotherapy decreased home SBP and first morning urine samples (morning UACR) for 8 weeks (p < 0.0001). At 8 weeks after randomization, all three additional drugs decreased home SBP (p < 0.0002) and trichlormethiazide significantly decreased morning UACR (p = 0.03). Amlodipine decreased morning UACR in patients with microalbuminuria based on casual spot urine samples (p = 0.048). However, multivariate analysis showed that only higher home SBP and UACR at week 8, but not any additional treatments, were significantly associated with UACR reduction between week 8 and week 16. In conclusion, crucial points of the effects of combination therapy on UACR were basal UACR and SBP levels. The effect of trichlormethiazide or amlodipine treatment in combination with irbesartan treatment on microalbuminuria needs to be reexamined based on a larger sample size after considering basal UACR and SBP levels.

Practical considerations on the introduction of sacubitril/valsartan in clinical practice: Current evidence and early experience.

PubMed

Farmakis, Dimitrios; Bistola, Vassiliki; Karavidas, Apostolos; Parissis, John

2016-11-15

The combination of neprilysin inhibitor sacubitril with the angiotensin II receptor 1 blocker valsartan is the first agent from the angiotensin receptor neprilysin inhibitors (ARNI) class authorized for clinical use in heart failure (HF) patients with reduced ejection fraction (HFrEF). Sacubitril/valsartan resulted in 20% reduction in the incidence rate of death or HF hospitalization compared to enalapril in symptomatic HFrEF patients in the seminal PARADIGM-HF trial. As a result, the recently updated European and American HF guidelines granted this agent a class IB indication for the treatment of ambulatory/chronic symptomatic HFrEF patients. However, translating the positive results of trials into true clinical benefit is often challenging. This is particularly true in the case of sacubitril/valsartan, as HF is a heterogeneous syndrome including many severely ill patients who are prone to decompensation, while this new agent comes to replace a cornerstone of current evidence-based HF therapy. In the present paper, we address a number of practical issues regarding the introduction of sacubitril/valsartan and propose an algorithm based on available evidence and early clinical experience. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Mortality and morbidity during and after Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: results by sex.

PubMed

Oparil, Suzanne; Davis, Barry R; Cushman, William C; Ford, Charles E; Furberg, Curt D; Habib, Gabriel B; Haywood, L Julian; Margolis, Karen; Probstfield, Jeffrey L; Whelton, Paul K; Wright, Jackson T

2013-05-01

To determine whether an angiotensin-converting enzyme inhibitor (lisinopril) or calcium channel blocker (amlodipine) is superior to a diuretic (chlorthalidone) in reducing cardiovascular disease incidence in sex subgroups, we carried out a prespecified subgroup analysis of 15 638 women and 17 719 men in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Total follow-up (active treatment + passive surveillance using national administrative databases to ascertain deaths and hospitalizations) was 8 to 13 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease. In-trial rates of HF, stroke, and combined cardiovascular disease were significantly higher for lisinopril compared with chlorthalidone, and rates of HF were significantly higher for amlodipine compared with chlorthalidone in both men and women. There were no significant treatment sex interactions. These findings did not persist through the extension period with the exception of the HF result for amlodipine versus chlorthalidone, which did not differ significantly by sex. For both women and men, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary coronary heart disease outcome or any other cardiovascular disease outcome, and chlorthalidone-based treatment resulted in the lowest risk of HF. Neither lisinopril nor amlodipine is superior to chlorthalidone for initial treatment of hypertension in either women or men. Clinical Trial Registration- clinicaltrials.gov; Identifier: NCT00000542.

Combination Therapy with Atorvastatin and Amlodipine Suppresses Angiotensin II-Induced Aortic Aneurysm Formation

PubMed Central

Takahashi, Kikuyo; Matsumoto, Yasuharu; Do.e, Zhulanqiqige; Kanazawa, Masanori; Satoh, Kimio; Shimizu, Takuya; Sato, Akira; Fukumoto, Yoshihiro; Shimokawa, Hiroaki

2013-01-01

Background Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs. Methods and Results Experimental AAA was induced in Apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects. Conclusions Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved. PMID:23967318

Meta-analysis of the efficacy and safety of adding an angiotensin receptor blocker (ARB) to a calcium channel blocker (CCB) following ineffective CCB monotherapy.

PubMed

Ma, Jin; Wang, Xiao-Yan; Hu, Zhi-De; Zhou, Zhi-Rui; Schoenhagen, Paul; Wang, Hao

2015-12-01

We conducted this meta-analysis to systematically review and analyze the clinical benefits of angiotensin receptor blocker (ARB) combined with calcium channel blocker (CCB) following ineffective CCB monotherapy. PubMed was searched for articles published until August 2015. Randomized controlled trials (RCTs) evaluating the clinical benefits of ARB combined with CCB following ineffective CCB monotherapy were included. The primary efficacy endpoint of the studies was normal rate of blood pressure, the secondary efficacy endpoints were the response rate and change in blood pressure from baseline. The safety endpoint of the studies was incidence of adverse events. Differences are expressed as relative risks (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and weighted mean differences (WMDs) with 95% CIs for continuous outcomes. Heterogeneity across studies was tested by using the I(2) statistic. Seven RCTs were included and had sample sizes ranging from 185 to 1,183 subjects (total: 3,909 subjects). The pooled analysis showed that the on-target rate of hypertension treatment was significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group (RR =1.59; 95% CI, 1.31-1.91; P<0.01). The response rate of systolic blood pressure (SBP) (RR =1.28; 95% CI, 1.04-1.58; P<0.01) and diastolic blood pressure (DBP) (RR =1.27; 95% CI, 1.12-1.44; P=0.04) were significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group. The change in SBP (RR =-3.56; 95% CI, -7.76-0.63; P=0.10) and DBP (RR =-3.03; 95% CI, -6.51-0.45; P=0.09) were higher in hypertensive patients receiving amlodipine + ARB but the difference did not reach statistical significance. ARB + amlodipine treatment carried a lower risk of adverse events relative to amlodipine monotherapy (RR =0.88; 95% CI, 0.80-0.96; P<0.01). The results of our meta-analysis demonstrate that adding an ARB to CCB after initial ineffective CCB monotherapy, significantly improved blood pressure control and the percentage of on-target hypertension treatment with significantly reduced incidence of adverse events compared with continued CCB monotherapy.

Meta-analysis of the efficacy and safety of adding an angiotensin receptor blocker (ARB) to a calcium channel blocker (CCB) following ineffective CCB monotherapy

PubMed Central

Ma, Jin; Wang, Xiao-Yan; Hu, Zhi-De; Zhou, Zhi-Rui; Schoenhagen, Paul

2015-01-01

Background We conducted this meta-analysis to systematically review and analyze the clinical benefits of angiotensin receptor blocker (ARB) combined with calcium channel blocker (CCB) following ineffective CCB monotherapy. Methods PubMed was searched for articles published until August 2015. Randomized controlled trials (RCTs) evaluating the clinical benefits of ARB combined with CCB following ineffective CCB monotherapy were included. The primary efficacy endpoint of the studies was normal rate of blood pressure, the secondary efficacy endpoints were the response rate and change in blood pressure from baseline. The safety endpoint of the studies was incidence of adverse events. Differences are expressed as relative risks (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and weighted mean differences (WMDs) with 95% CIs for continuous outcomes. Heterogeneity across studies was tested by using the I2 statistic. Results Seven RCTs were included and had sample sizes ranging from 185 to 1,183 subjects (total: 3,909 subjects). The pooled analysis showed that the on-target rate of hypertension treatment was significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group (RR =1.59; 95% CI, 1.31–1.91; P<0.01). The response rate of systolic blood pressure (SBP) (RR =1.28; 95% CI, 1.04–1.58; P<0.01) and diastolic blood pressure (DBP) (RR =1.27; 95% CI, 1.12–1.44; P=0.04) were significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group. The change in SBP (RR =−3.56; 95% CI, −7.76–0.63; P=0.10) and DBP (RR =−3.03; 95% CI, −6.51–0.45; P=0.09) were higher in hypertensive patients receiving amlodipine + ARB but the difference did not reach statistical significance. ARB + amlodipine treatment carried a lower risk of adverse events relative to amlodipine monotherapy (RR =0.88; 95% CI, 0.80-0.96; P<0.01). Conclusions The results of our meta-analysis demonstrate that adding an ARB to CCB after initial ineffective CCB monotherapy, significantly improved blood pressure control and the percentage of on-target hypertension treatment with significantly reduced incidence of adverse events compared with continued CCB monotherapy. PMID:26793346

Cost-effectiveness Analysis of Sacubitril/Valsartan vs Enalapril in Patients With Heart Failure and Reduced Ejection Fraction.

PubMed

Gaziano, Thomas A; Fonarow, Gregg C; Claggett, Brian; Chan, Wing W; Deschaseaux-Voinet, Celine; Turner, Stuart J; Rouleau, Jean L; Zile, Michael R; McMurray, John J V; Solomon, Scott D

2016-09-01

The angiotensin receptor neprilysin inhibitor sacubitril/valsartan was associated with a reduction in cardiovascular mortality, all-cause mortality, and hospitalizations compared with enalapril. Sacubitril/valsartan has been approved for use in heart failure (HF) with reduced ejection fraction in the United States and cost has been suggested as 1 factor that will influence the use of this agent. To estimate the cost-effectiveness of sacubitril/valsartan vs enalapril in the United States. Data from US adults (mean [SD] age, 63.8 [11.5] years) with HF with reduced ejection fraction and characteristics similar to those in the PARADIGM-HF trial were used as inputs for a 2-state Markov model simulated HF. Risks of all-cause mortality and hospitalization from HF or other reasons were estimated with a 30-year time horizon. Quality of life was based on trial EQ-5D scores. Hospital costs combined Medicare and private insurance reimbursement rates; medication costs included the wholesale acquisition cost for sacubitril/valsartan and enalapril. A discount rate of 3% was used. Sensitivity analyses were performed on key inputs including: hospital costs, mortality benefit, hazard ratio for hospitalization reduction, drug costs, and quality-of-life estimates. Hospitalizations, quality-adjusted life-years (QALYs), costs, and incremental costs per QALY gained. The 2-state Markov model of US adult patients (mean age, 63.8 years) calculated that there would be 220 fewer hospital admissions per 1000 patients with HF treated with sacubitril/valsartan vs enalapril over 30 years. The incremental costs and QALYs gained with sacubitril/valsartan treatment were estimated at $35 512 and 0.78, respectively, compared with enalapril, equating to an incremental cost-effectiveness ratio (ICER) of $45 017 per QALY for the base-case. Sensitivity analyses demonstrated ICERs ranging from $35 357 to $75 301 per QALY. For eligible patients with HF with reduced ejection fraction, the Markov model calculated that sacubitril/valsartan would increase life expectancy at an ICER consistent with other high-value accepted cardiovascular interventions. Sensitivity analyses demonstrated sacubitril/valsartan would remain cost-effective vs enalapril.

Efficacy and safety of nebivolol and valsartan as fixed-dose combination in hypertension: a randomised, multicentre study.

PubMed

Giles, Thomas D; Weber, Michael A; Basile, Jan; Gradman, Alan H; Bharucha, David B; Chen, Wei; Pattathil, Manoj

2014-05-31

The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating β blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension. We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5-8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026. Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554-555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference -1·2 mm Hg, 95% CI -2·3 to -0·1; p=0·030) and valsartan 320 mg/day (-4·4 mm Hg, -5·4 to -3·3; p<0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p<0·0001). All systolic blood pressure comparisons were also significant (all p<0·01). At least one treatment-emergent adverse event was experienced by 30-36% of participants in each group. Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension. Forest Research Institute. Copyright © 2014 Elsevier Ltd. All rights reserved.

Automated office and home phone-transmitted blood pressure recordings in uncontrolled hypertension treated with valsartan and hydrochlorothiazide.

PubMed

Girerd, Xavier; Denolle, Thierry; Yau, Caroline; Fiquet, Béatrice; Brunel, Patrick; Moulin, Bruno; Herpin, Daniel

2004-12-01

The study objective was to evaluate, by means of automated office and phone-transmitted home blood pressure (OBP and HBP) recordings, the effects of a fixed combination of valsartan 160 mg and hydrochlorothiazide (HCTZ) 25 mg in hypertensive patients previously uncontrolled with the combination of an angiotensin receptor antagonist and HCTZ. From 241 selected patients, 171 (71%) had uncontrolled hypertension OBP and HBP [mean baseline OBP and HBP systolic and diastolic (SBP/DBP): 157/91 and 152/87 mmHg]. In this open-design study, patients were directly switched from other angiotensin receptor blocker combination products to valsartan/HCTZ for 6 weeks. The same validated automated device was used for OBP and HBP recordings. At baseline, mean HBP was 152 +/- 15/87 +/- 10 mmHg and mean OBP was 157 +/- 12/91 +/- 9 mmHg. After 6 weeks of treatment with valsartan 160 mg and HCTZ 25 mg, a significant decrease in BP was observed both at home (146 +/- 17/83 +/- 12 mmHg) and at the office (151 +/- 18/87 +/- 11 mmHg), with a difference from baseline of -4 mmHg, p < 0.001 for DBP and of -6 mmHg for SBP, p < 0.001. The percentage of patients with office and home control was 24% and 23% respectively, with a kappa index at 0.459. Elevated OBP only (office hypertension) was observed in 3.6% and elevated HBP only (masked hypertension) in 10% of patients. In conclusion, treatment with valsartan and HCTZ 25 mg in patients with confirmed uncontrolled hypertension induced a clinically relevant decrease in BP with approximately 23% of additional patients strictly controlled with a single tablet. The use of an automated oscillometric device at the office and at home allowed the detection of controlled subjects with good agreement.

Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of fimasartan, amlodipine, and rosuvastatin using partial replicated design in healthy adult subjects.

PubMed

Oh, Minkyung; Ghim, Jong-Lyul; Park, Sung-Eun; Kim, Eun-Young; Shin, Jae-Gook

2018-01-01

The aim of this study was to compare the pharmacokinetics (PK) and safety profiles of a fixed-dose combination (FDC) formulation of fimasartan, amlodipine, and rosuvastatin with the co-administration of the two products by using a replicated crossover study design in healthy male subjects. This was an open-label, randomized, three-sequence, three-period replicated crossover study in healthy male subjects. The replicated crossover design was done because of high coefficient of variation of PK parameter for fimasartan, that is, >30%. With a 14 days washout period, an FDC tablet containing 60 mg fimasartan, 10 mg amlodipine, and 20 mg rosuvastatin was administered only once, and separate formulations of fimasartan/amlodipine 60 mg/10 mg FDC tablet and 20 mg rosuvastatin tablet administered twice. Blood samples were collected up to 72 hours following drug administration. The plasma concentrations of fimasartan, amlodipine, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was assessed by evaluating vital signs, clinical laboratory parameters, physical examinations, and medical interviews. The geometric mean ratios and 90% confidence intervals (CIs) for the maximum plasma concentration (C max ) and area under the curve from time zero to the last measurable sampling time (AUC t ) were 1.0776 (0.9201-1.2622) and 0.9978 (0.9538-1.0439) for fimasartan, 1.0038 (0.9782-1.0301) and 1.0055 (0.9828-1.0288) for amlodipine, and 1.0006 (0.9290-1.0776) and 0.9986 (0.9532-1.0461) for rosuvastatin, respectively. A total of 22 adverse events (AEs) were reported by 60 subjects; there were no significant differences in the incidence of AEs between the two groups. The 90% CI of the C max of fimasartan was within the widened acceptance limit, ln(0.6984)-ln(1.4319). The 90% CIs of the other PK parameters for drugs were between ln(0.8) and ln(1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile, to the co-administration of its three constituent drugs.

Clinical study of double dose of valsartan combined with tacrolimus in treatment of diabetic nephropathy.

PubMed

Jin, H; Zhang, H-N; Hou, X-L; Zhang, B; Wu, J; Zhang, H-B

2016-01-01

To investigate the clinical effect of double dose of valsartan combined with tacrolimus in the treatment of diabetic nephropathy (DN). HA total of 86 cases diagnosed with DN were selected from October 2013 to October 2014 in Zaozhuang Municipal Hospital, China. The study was approved by our hospital Ethics Committee and written consent was obtained from patients and their family members. Patients were randomly divided into three groups according to the sequence of admission, group A (conventional dose of valsartan group, n = 28 cases), group B (double dose of valsartan group, n = 29 cases) and group C (double dose of valsartan combined with tacrolimus group, n = 29). Clinical effects were compared by analyzing the renal function tests after 8 weeks. 24h urine protein, serum creatinine level of patients in group B and group C were significantly lower than that of group A. Those in group C was much lower. The glomerular filtration rates were significantly higher for group B and C than that of group A, and those in group C were much higher. The difference is statistically significant (p < 0.05). High-sensitivity C-reactive protein (hs CRP) and adiponectin levels of patients in group B and C of were significantly lower than that of group A and those in group C were much lower. The difference is statistically significant (p < 0.05). The high mobility group protein 1 (HMGB1) and renal tubular and interstitial damage index (TDI) of patients in B and C groups were significantly lower than those in the A group, and those in C group were significantly lower. The difference was statistically significant p < 0.05). The clinical effective rates of patients in group B and C were significantly higher than that in group A, and those of group C were much higher. The difference is statistically significant (p < 0.05). The recurrence rates of patients in group B and group C were significantly lower than those of group A and those in group C were much lower. The difference is statistically significant (p < 0.05). Patients in three groups showed no obvious drug complications. Double dose of valsartan combined with tacrolimus treatment of DN patients can improve clinical symptoms, reducing inflammation, inhibiting or even reversing the interstitial fibrosis, which will improve the curative effect and reduce the recurrence, as to provide a new theoretical basis for the clinical treatment of the disease.

Very low-dose fluvastatin-valsartan combination decreases parameters of inflammation and oxidative stress in patients with type 1 diabetes mellitus.

PubMed

Lunder, Mojca; Janić, Miodrag; Savić, Vedran; Janež, Andrej; Kanc, Karin; Šabovič, Mišo

2017-05-01

Previously we revealed the effectiveness of a new therapeutic approach with a short-term, very-low dose fluvastatin-valsartan combination on the improvement of arterial function in type 1 diabetes mellitus patients (T1DM). In this study we explored whether this approach influences inflammation and oxidative stress and explored any association of these effects with arterial function improvement. This was a supplementary analysis of the two previous double blind randomized studies (included 44 T1DM patients). Treatment group received very-low dose fluvastatin-valsartan, the control group received placebo. Blood samples were collected and inflammation parameters: high-sensitivity CRP (hsCRP), interleukin 6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1) and oxidative stress parameter total antioxidant status (TAS) were measured. Treatment decreased hsCRP values (by 56.5%, P<0.05) and IL-6 values (by 33.6%, P<0.05) and increased TAS values (by 21.1%; P<0.05) after 30days of treatment. High sensitivity CRP and TAS remained decreased 3months after treatment discontinuation. Importantly, the anti-inflammatory and anti-oxidative action significantly correlated with arterial function improvement. The approach consisting of short-term (30days) treatment with a very low-dose fluvastatin-valsartan combination acts anti-inflammatory and anti-oxidative in T1DM patients. These observations along with the improvement of arterial function support the assumption that this approach could have an important clinical benefit in T1DM patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Improving blood pressure control: increase the dose of diuretic or switch to a fixed-dose angiotensin receptor blocker/diuretic? the valsartan hydrochlorothiazide diuretic for initial control and titration to achieve optimal therapeutic effect (Val-DICTATE) trial.

PubMed

White, William B; Calhoun, David A; Samuel, Rita; Taylor, Addison A; Zappe, Dion H; Purkayastha, Das

2008-06-01

To assess the strategy of increasing the dose of a diuretic compared with using an angiotensin receptor blocker in combination with a diuretic, the authors performed a multicenter, randomized, parallel group trial in hypertensive patients (baseline blood pressure [BP], 153/97 mm Hg) whose BP remained uncontrolled on initial low-dose diuretic monotherapy (hydrochlorothiazide [HCTZ] 12.5 mg Hg). Patients with stage 1 and 2 hypertension were randomized to treatment with valsartan/HCTZ (160/12.5 mg) or to doubling of the HCTZ dose (25 mg). The primary end point was the percentage of patients whose clinic BP values were <140/90 mm Hg following 4 weeks of double-blind therapy. A significantly higher proportion (P<.001) of hypertensive patients met BP control levels in the valsartan/HCTZ (160/12.5 mg) group compared with the HCTZ 25 mg group (37% vs 16%). Changes from baseline in BP were significantly greater (P<.001) for both systolic BP and diastolic BP in the combination therapy arm compared with the diuretic monotherapy arm (-12. 4/-7.5 mm Hg in valsartan/HCTZ 160/12.5 mg group vs -5.6/-2.1 mm Hg in HCTZ 25 mg group). Tolerability and adverse events were similar in the 2 treatment groups. This study suggests that in the management of hypertension, utilizing an angiotensin receptor blocker/diuretic combination was more effective in lowering BP and achieving BP goals when compared with increasing the dose of the diuretic.

Additive effects of cilnidipine, an L-/N-type calcium channel blocker, and an angiotensin II receptor blocker on reducing cardiorenal damage in Otsuka Long-Evans Tokushima Fatty rats with type 2 diabetes mellitus.

PubMed

Mori, Yutaka; Aritomi, Shizuka; Niinuma, Kazumi; Nakamura, Tarou; Matsuura, Kenichi; Yokoyama, Junichi; Utsunomiya, Kazunori

2014-01-01

Cilnidipine (Cil), which is an L-/N-type calcium channel blocker (CCB), has been known to provide renal protection by decreasing the activity of the sympathetic nervous system (SNS) and the renin-angiotensin system. In this study, we compared the effects of the combination of Cil and amlodipine (Aml), which is an L-type CCB, with an angiotensin (Ang) II receptor blocker on diabetic cardiorenal damage in spontaneously type 2 diabetic rats. Seventeen-week-old Otsuka Long-Evans Tokushima Fatty rats were randomly assigned to receive Cil, Aml, valsartan (Val), Cil + Val, Aml + Val, or a vehicle (eight rats per group) for 22 weeks. Antihypertensive potencies were nearly equal among the CCB monotherapy groups and the combination therapy groups. The lowering of blood pressure by either treatment did not significantly affect the glycemic variables. However, exacerbations of renal and heart failure were significantly suppressed in rats administered Cil or Val, and additional suppression was observed in those administered Cil + Val. Although Val increased the renin-Ang system, Aml + Val treatment resulted in additional increases in these parameters, while Cil + Val did not show such effects. Furthermore, Cil increased the ratio of Ang-(1-7) to Ang-I, despite the fact that Val and Aml + Val decreased the Ang-(1-7) levels. These actions of Cil + Val might be due to their synergistic inhibitory effect on the activity of the SNS, and on aldosterone secretion through N-type calcium channel antagonism and Ang II receptor type 1 antagonism. Thus, Cil may inhibit the progression of cardiorenal disease in type 2 diabetes patients by acting as an N-type CCB and inhibiting the aldosterone secretion and SNS activation when these drugs were administered in combination with an Ang II receptor blocker.

Angioedema Spotlight: A Closer Examination of Sacubitril/Valsartan Safety Results.

PubMed

Owens, Ryan E; Oliphant, Carrie S

2017-01-01

Incorporation of neprilysin inhibition into heart failure pharmacotherapy regimens has recently been recommended by U.S. guidelines, based on results from the PARADIGM-HF trial comparing sacubitril/valsartan to enalapril. While most of the discussion has focused on efficacy, a closer examination of the safety results, particularly the incidence of angioedema during the run-in and double-blind periods, is also warranted. Although no major safety concerns were identified, an angioedema risk comparable to enalapril was found, primarily in the black population. Therefore, despite combination with an angiotensin receptor blocker, which historically has a lower incidence of angioedema, the addition of neprilysin inhibition yields an angioedema risk profile comparable to angiotensin converting enzyme (ACE) inhibitors. Clinicians should recognize this safety risk when prescribing sacubitril/valsartan and remain vigilant in counseling patients regarding the signs and symptoms of angioedema. As recommended by the guidelines, avoiding sacubitril/valsartan use concurrently or within 36 hours of the last dose of an ACE inhibitor or in patients with a history of angioedema is also crucial to minimize angioedema risk and prevent patient harm. © Copyright 2017 by the American Board of Family Medicine.

Efficacy and safety of long-term treatment with the combination of amlodipine besylate and olmesartan medoxomil in patients with hypertension.

PubMed

Chrysant, Steven G; Oparil, Suzanne; Melino, Michael; Karki, Sulekha; Lee, James; Heyrman, Reinilde

2009-09-01

J Clin Hypertens (Greenwich). 2009;11:475-482. (c) 2009 Wiley Periodicals, Inc.The authors report on the 44-week open-label extension of the 8-week, double-blind Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial in 1684 patients. Initial therapy was amlodipine (AML) plus olmesartan medoxomil (OM) 5+40 mg/d, up-titrated to AML+OM 10+40 mg/d plus hydrochlorothiazide (HCTZ) 12.5 mg then 25 mg if patients did not achieve blood pressure (BP) goal (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes). Baseline mean BP decreased from 164/102 mm Hg to 131/82 mm Hg at end of study, with an overall 66.7% of patients, including those with diabetes, achieving BP goal. The BP goal achievement was 80% for AML+OM 5+40 mg/d, 70.6% for AML+OM 10+40 mg/d, 66.6% for AML+OM+HCTZ 10+40+12.5 mg/d, and 46.3% for AML+OM+HCTZ 10+40+25 mg/d. Study medication was safe and well tolerated. Combination antihypertensive therapy with AML+OM+/-HTCZ, up-titrated as necessary, allowed a majority of patients to achieve BP goal.

A validated RP-HPLC method for simultaneous determination of propranolol and valsartan in bulk drug and gel formulation

PubMed Central

Imam, Syed Sarim; Ahad, Abdul; Aqil, Mohammed; Sultana, Yasmin; Ali, Asgar

2013-01-01

Objective: A simple, precise, and stability indicating high performance liquid chromatography (HPLC) method was developed and validated for the simultaneous determination of propranolol hydrochloride and valsartan in pharmaceutical dosage form. Materials and Methods: The method involves the use of easily available inexpensive laboratory reagents. The separation was achieved on Hypersil ODS C-18 column (250*4.6 mm, i.d., 5 μm particle size) with isocratic flow with UV detector. The mobile phase at a flow rate of 1.0 mL/min consisted of acetonitrile, methanol, and 0.01 M disodium hydrogen phosphate (pH 3.5) in the ratio of 50:35:15 v/v. Results: A linear response was observed over the concentration range 5-50 μg/mL of propranolol and the concentration range 4-32 μg/mL of valsartan. Limit of detection and limit of quantitation for propranolol were 0.27 μg/mL and 0.85 μg/mL, and for valsartan were 0.45 μg/mL and 1.39 μg/mL, respectively. The method was successfully validated in accordance to ICH guidelines acceptance criteria for linearity, accuracy, precision, specificity, robustness. Conclusion: The analysis concluded that the method was selective for simultaneous estimation of propranolol and valsartan can be potentially used for the estimation of these drugs in combined dosage form. PMID:23559826

Sacubitril/valsartan for heart failure with reduced left ventricular ejection fraction : A retrospective cohort study.

PubMed

De Vecchis, R; Ariano, C; Di Biase, G; Noutsias, M

2018-01-19

The combination drug sacubitril/valsartan was reported to be superior to enalapril in reducing all-cause death, cardiovascular mortality, and heart failure (HF) hospitalizations in patients with cardiac insufficiency and reduced left ventricular ejection fraction (HFREF) with NYHA class II-IV. Our retrospective cohort study aimed to assess the effects of sacubitril/valsartan in addition to a beta-blocker and mineral receptor antagonist (MRA) in a group of HFREF patients with NYHA class II-III HF vs. conventional therapy (ACE inhibitor or angiotensin II receptor blocker added to a beta-blocker plus an MRA) administered to a control group of HFREF patients with comparable clinical features. In both groups, treatment was supplemented by a loop diuretic, usually furosemide, at variable doses. The primary outcomes were all-cause death and HF hospitalizations. Safety outcomes were symptomatic hypotension, angioedema, hyperkalemia, and worsening renal function. Mortality at 6 months was 6.8% in patients taking sacubitril/valsartan vs. 34% in those on conventional therapy (odds ratio [OR] = 0.14; 95% CI: 0.04-0.49). Moreover, there was a 4.5% rate of HF hospitalizations in the sacubitril/valsartan group vs. 59% in the control group (OR = 0.03; 95% CI: 0.01-0.14). Safety outcomes were comparable in the two groups, although hypotension (systolic blood pressure < 100 mm Hg) was found in 15.9% of patients in the sacubitril/valsartan group vs. 5.7% in the control group (OR = 3.14; 95% CI: 0.94-10.55). Sacubitril/valsartan offered strong protection against all-cause death and HF hospitalizations at 6 months without any significant side effects. To validate this efficacious molecule, further postmarketing observational studies, focusing mainly on hypotension and angioedema are warranted.

Combined Treatment with Amlodipine and Atorvastatin Calcium Reduces Circulating Levels of Intercellular Adhesion Molecule-1 and Tumor Necrosis Factor-α in Hypertensive Patients with Prediabetes.

PubMed

Huang, Zhouqing; Chen, Chen; Li, Sheng; Kong, Fanqi; Shan, Peiren; Huang, Weijian

2016-01-01

To assess the effect of amlodipine and atorvastatin on intercellular adhesion molecule (ICAM)-1 and tumor necrosis factor (TNF)-α expression, as endothelial function and inflammation indicators, respectively, in hypertensive patients with and without prediabetes. Forty-five consecutive patients with hypertension, diagnosed according to JNC7, were divided into two groups based on the presence (HD group, n = 23) or absence (H group, n = 22) of prediabetes, diagnosed according to 2010 ADA criteria, including impaired glucose tolerance (IGT) and fasting glucose tests. All patients simultaneously underwent 12-week treatment with daily single-pill amlodipine besylate/atorvastatin calcium combination (5/10 mg; Hisun-Pfizer Pharmaceuticals Co. Ltd). Serum isolated before and after treatment from overnight fasting blood samples was analyzed by ELISA. In the HD and H groups after vs. before 12-week amlodipine/atorvastatin treatment, there were significantly (all P < 0.01) lower levels of ICAM-1 (3.06 ± 0.34 vs. 4.07 ± 0.70 pg/ml; 3.26 ± 0.32 vs. 3.81 ± 0.60 pg/ml, respectively) and TNF-α (78.71 ± 9.19 vs. 110.94 ± 10.71 pg/ml; 80.95 ± 9.33 vs. 101.79 ± 11.72 pg/ml, respectively), with more pronounced reductions in HD vs. H group (ICAM-1Δ: 1.01 ± 0.80 vs. 0.55 ± 0.64 pg/ml, respectively, P = 0.037; TNF-αΔ: 32.23 ± 14.33 vs. 20.84 ± 14.89 pg/ml, respectively, P = 0.011), independent of the blood pressure (BP) and cholesterol level reduction. Amlodipine/atorvastatin improved endothelial function and inflammation, as reflected by lower circulating levels of ICAM-1 and TNF-α, more prominently in hypertensives with than without prediabetes. Starting statin treatment before overt diabetes in hypertensives might thus improve cardiovascular outcomes.

Efficacy and safety profiles of a new S(-)-amlodipine nicotinate formulation versus racemic amlodipine besylate in adult Korean patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, double-dummy, parallel-group, phase III, noninferiority clinical trial.

PubMed

Kim, Sung Ai; Park, Sungha; Chung, Namsik; Lim, Do-Sun; Yang, Joo-Young; Oh, Byung-Hee; Tahk, Seung-Jea; Ahn, Tae-Hoon

2008-05-01

"Chiral switching" from an existing racemate to a pure enantiomeric compound is a popular theme in drug development, especially when the enantiomer is found to have better efficacy and safety profiles. Amlodipine is a racemic mixture, composed of the S(-)-enantiomer, which is the pharmacologically active isomer, and the R(+)-enantiomer, which is 1000-fold less active. S(-)-amlodipine nicotinate, a chirally switched form of amlodipine nicotinate, has been developed and found to be bioequivalent to amlodipine besylate in Phase I clinical trials in Korea. The aim of this study was to compare the efficacy and safety profiles of S(-)-amlodipine nicotinate with those of amlodipine besylate in adult Korean patients with mild to moderate hypertension (diastolic blood pressure [DBP] >or=90 mm Hg and or=90 and or=90 mm Hg). The primary end point was noninferiority of the difference in mean SiDBP from baseline to week 8 for S(-)-amlodipine nicotinate compared with amlodipine besylate. Secondary end points were as follows: (1) noninferiority of the difference in mean sitting systolic blood pressure (SiSBP) from baseline to week 8 between the study groups; and (2) SiDBP response rate (defined as the proportion of patients whose SiDBP was <90 mm Hg or whose SiDBP reduction was >or=10 mm Hg from baseline) after the 8-week treatment. Also, the incidence and severity of adverse events (AEs) and adverse drug reactions (ADRs) were reported. Severe AEs/ADRs were defined as those associated with any of the following: death; an event associated with a high risk of mortality; an event requiring hospitalization; or development of a permanent disability or congenital malformation. One hundred fifty-seven patients were assessed for inclusion in the study. Of these, 124 patients were randomly allocated to receive S(-)-amlodipine nicotinate (42 men, 21 women; mean [SD] age, 52.4 [10.3] years [range, 23-70 years]; weight, 67.7 [10.8] kg [range, 44-92 kg]) or amlodipine besylate (45 men, 16 women; mean [SD] age, 54.5 [10.0] years [range, 30-73]; weight, 68.9 [9.8] kg [range, 49-95 kg]). One hundred sixteen patients completed the study, but 11 patients (8.9%) were dropped from the per-protocol analysis due to violations; therefore, 105 patients were included in the modified intent-to-treat population analysis (S[-]-amlodipine nicotinate, 55 patients; amlodipine besylate, 50 patients). There were no significant between-group differences in the baseline characteristics. Baseline mean (SD) SiSBP and SiDBP were 142.6 (11.3) and 94.9 (4.8) mm Hg in the S(-)-amlodipine nicotinate group, and 141.8 (8.3) and 96.1 (4.9) mm Hg in the amlodipine besylate group. Mean (SD) changes in SiSBP were 17.6 (11.2) mm Hg in the S(-)-amlodipine nicotinate group and 18.6 (12.3) mm Hg in the amlodipine besylate group. The SiDBP response rates were 92.7% in the S(-)-amlodipine nicotinate group and 88.0% in the amlodipine besylate group. There were no significant between-group differences in the prevalence of AEs and ADRs. In the S(-)-amlodipine nicotinate group, 15 patients (23.8%) reported a total of 28 AEs, and 19 patients (31.1%) reported a total of 27 AEs in the amlodipine besylate group. Six patients (9.5%) in the S(-)-amlodipine nicotinate group and 7 patients (11.4%) in the amlodipine besylate group experienced a total of 19 ADRs (11 and 8, respectively). The most common ADRs were liver enzyme elevation (3/63 [4.8%]) in the S(-)-amlodipine nicotinate group and facial flushing (3/61 [4.9%]) in the amlodipine besylate group. No cases of severe AEs or ADRs were reported in either group. The reduction of SiDBP after 8 weeks of treatment with S(-)-amlodipine nicotinate was noninferior compared with that of racemic amlodipine besylate in these adult Korean patients with mild to moderate hypertension. The SiDBP response rate and the reduction of SiSBP after 8 weeks of treatment with S(-)-amlodipine nicotinate were not significantly different from those with racemic amlodipine besylate. Both treatments were generally well tolerated.

The angiotensin II type 1 receptor-neprilysin inhibitor LCZ696 blocked aldosterone synthesis in a human adrenocortical cell line.

PubMed

Miura, Shin-Ichiro; Suematsu, Yasunori; Matsuo, Yoshino; Tomita, Sayo; Nakayama, Asuka; Goto, Masaki; Arimura, Tadaaki; Kuwano, Takashi; Yahiro, Eiji; Saku, Keijiro

2016-11-01

A recent clinical study indicated that an angiotensin II (Ang II) type 1 (AT 1 ) receptor-neprilysin inhibitor (ARNi) designated LCZ696 (sacubitril/valsartan, as combined sodium complex) was superior to enalapril at reducing the risks of death and hospitalization due to heart failure. Therefore, we investigated the possible mechanisms of the beneficial effect of LCZ696, in which the inhibition of neprilysin enhances atrial natriuretic peptide (NP) or brain NP (ANP or BNP)-evoked signals that can block Ang II/AT 1 receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT 1 receptor was greater than that of valsartan alone in an AT 1 receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT 1 receptor between valsartan+LBQ657 and valsartan alone. In Ang II-sensitized human adrenocortical cells, ANP or BNP alone, but not LBQ657 or valsartan alone, significantly decreased Ald synthesis. The level of suppression of Ald synthesis by ANP or BNP with LBQ657 was greater than that by ANP or BNP without LBQ657. The suppression of ANP was blocked by inhibitors of regulator of G-protein signaling proteins and cyclic GMP-dependent protein kinase. The inhibition of neprilysin did not change the mRNA levels of the AT 1 receptor, ANP receptor A, regulator of G-protein signaling protein, renin or 3β-hydroxysteroid dehydrogenases. In conclusion, the inhibition of neprilysin by LBQ657 enhances the NP-evoked signals that can block Ang II/AT 1 receptor-induced Ald synthesis in human adrenocortical cells.

Valsartan vs. other angiotensin II receptor blockers in the treatment of hypertension: a meta-analytical approach.

PubMed

Nixon, R M; Müller, E; Lowy, A; Falvey, H

2009-05-01

To compare the efficacy of valsartan in systolic (SBP) and diastolic blood pressure (DBP) reduction with other angiotensin II receptor blockers (ARBs) in essential hypertension. Systematic literature search of databases between October 1997 and May 2008. Meta-analysis of short-term, double-blind, parallel group, randomised controlled trials (RCTs) for treatment of adult hypertension (DBP: 90-115 mmHg). Random-effects meta-regression adjusting for baseline blood pressure (BP) was used to analyse the data. Mean change in SBP and DBP was estimated for each individual drug and dose combination. In all, 31 RCTs (n = 13,110 patients) were included in the analysis. Six studies include trial arms with candesartan, six irbesartan, 13 losartan, two olmesartan, five telmisartan and 12 valsartan. The weighted average reduction in mean SBP and DBP for valsartan 160 mg was -15.32 mmHg (95% CI: -17.09, -13.63) and -11.3 mmHg (95% CI: -12.15, -10.52) and for 320 mg was -15.85 mmHg (95% CI: -17.60, -14.12) and -11.97 mmHg (95% CI: -12.81, -11.16); these are statistically significantly greater reductions compared with losartan 100 mg, which was -12.01 mmHg (95% CI: -13.78, -10.25) and -9.37 mmHg (95% CI: -10.18, -8.54) for SBP and DBP respectively. There is evidence that valsartan 160 mg reduces SBP and DBP more than irbesartan 150 mg and reduced DBP more than candesartan 16 mg. No other statistically significant difference in efficacy is demonstrated. Valsartan administered at 160 or 320 mg is more effective at lowering BP than losartan 100 mg and shows comparable efficacy to other ARBs in patients with essential hypertension.

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

PubMed Central

Seferovic, Jelena P; Claggett, Brian; Seidelmann, Sara B; Seely, Ellen W; Packer, Milton; Zile, Michael R; Rouleau, Jean L; Swedberg, Karl; Lefkowitz, Martin; Shi, Victor C; Desai, Akshay S; McMurray, John J V; Solomon, Scott D

2017-01-01

Summary Background 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. Methods In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA1c≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA1c, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Times to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups. Findings There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05–0·22, p=0·0023). HbA1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06–0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0·71, 95% CI 0·56–0·90, p=0·0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0·77, 0·58–1·02, p=0·073) in the sacubitril/valsartan group. Interpretation Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF. PMID:28330649

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.

PubMed

Seferovic, Jelena P; Claggett, Brian; Seidelmann, Sara B; Seely, Ellen W; Packer, Milton; Zile, Michael R; Rouleau, Jean L; Swedberg, Karl; Lefkowitz, Martin; Shi, Victor C; Desai, Akshay S; McMurray, John J V; Solomon, Scott D

2017-05-01

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 HbA 1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA 1c ≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA 1c , triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups. There were no significant differences in HbA 1c concentrations between randomised groups at screening. During the first year of follow-up, HbA 1c concentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05-0·22, p=0·0023). HbA 1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06-0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0·71, 95% CI 0·56-0·90, p=0·0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0·77, 0·58-1·02, p=0·073) in the sacubitril/valsartan group. Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA 1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF. Novartis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of antihypertensive drug therapy on short-term heart rate variability in newly diagnosed essential hypertension.

PubMed

Pavithran, Purushothaman; Prakash, E Sankaranarayanan; Dutta, Tarun K; Madanmohan, Trakroo

2010-02-01

1. Abnormalities of cardiac autonomic regulation are a potential mechanism for morbidity despite blood pressure (BP) lowering in hypertension. Analysis of short-term (5 min) heart rate variability (HRV) provides a non-invasive probe of autonomic regulation of sino-atrial (SA) node automaticity. 2. We hypothesized that antihypertensive drug therapy would be associated with an increase in 5 min overall HRV, along with a decrease in blood pressure (BP), at 8 weeks follow up in subjects with newly diagnosed, never-treated essential hypertension. 3. One hundred and fifty patients (84 men and 66 women; mean (+/-SD) age 48 +/- 10 years) with newly diagnosed essential hypertension were divided to five groups of 30 patients each to receive one of the following antihypertensive drugs (or drug combinations): 5 mg/day amlodipine; 50 mg/day atenolol; 5 mg/day enalapril; 25 mg/day hydrochlorothiazide; or a combination of 5 mg/day amlodipine and 50 mg/day atenolol. 4. The only significant change in HRV indices was an increase in total variability of RR intervals and an increase in high-frequency (HF) RR interval spectral power in the amlodipine + atenolol-treated group (P < 0.05). 5. The results indicate that there is a dissociation between changes in short-term HRV and mean RR interval and BP lowering in patients with newly diagnosed hypertension. 6. We interpret the increase in HF RR interval spectral power in the amlodipine + atenolol-treated group as being due to an increase in vagal modulation of RR intervals and/or diminution in sympathetic restraint of respiratory sinus arrhythmia.

Treatment of essential hypertension with calcium channel blockers: what is the place of lercanidipine?

PubMed

Burnier, Michel; Pruijm, Menno; Wuerzner, Gregoire

2009-08-01

In all actual clinical guidelines, dihydropyridine calcium channel blockers (CCBs) belong to the recommended first line antihypertensive drugs to treat essential hypertension. Several recent large clinical trials have confirmed their efficacy not only in lowering blood pressure but also in reducing cardiovascular morbidity and mortality in hypertensive patients with a normal or high cardiovascular risk profile. In clinical trials such as ALLHAT, VALUE or ASCOT, an amlodipine-based therapy was at least as effective, when not slightly superior, in lowering blood pressure and sometimes more effective in preventing target organ damages than blood pressure lowering strategies based on the use of diuretics, beta-blockers and blockers of the renin-angiotensin system. One of the main clinical side effects of the first and second generation CCBs including amlodipine is the development of peripheral edema. The incidence of leg edema can be markedly reduced by combining the CCB with a blocker of the renin-angiotensin system. This strategy has now led to the development of several fixed-dose combinations of amlodipine and angiotensin II receptor antagonists. Another alternative to lower the incidence of edema is to use CCBs of the third generation such as lercanidipine. Indeed, although no major clinical trials have been conducted with this compound, clinical studies have shown that lercanidipine and amlodipine have a comparable antihypertensive efficacy but with significantly less peripheral edema in patients receiving lercanidipine. In some countries, lercanidipine is now available in a single-pill association with an ACE inhibitor thereby further improving its efficacy and tolerability profile.

Fixed-dose combinations in the management of hypertension: defining the place of angiotensin receptor antagonists and hydrochlorothiazide.

PubMed

Kjeldsen, Sverre E; Os, Ingrid; Høieggen, Aud; Beckey, Kim; Gleim, Gilbert W; Oparil, Suzanne

2005-01-01

We discuss combination therapy with angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics in light of the independent actions of both types of agents, and the adverse effects of both agents independently and in the context of the physiologic synergy achieved in using these agents together. ARBs counteract many of the adverse events associated with the use of thiazide diuretics and have been shown to reduce the occurrence of new-onset diabetes mellitus. We also review outcome trials in patients with hypertension (such as LIFE [Losartan Intervention For Endpoint reduction in hypertension], VALUE [Valsartan Antihypertensive Long-term Use Evaluation], and SCOPE [Study on COgnition and Prognosis in the Elderly]), in which losartan, valsartan, and candesartan cilexetil were used in combination with hydrochlorothiazide. Fixed combination ARB/hydrochlorothiazide agents make sense as initial therapy for patients in whom BP is >20/10 mm Hg above goal.

Potential Expanded Indications for Neprilysin Inhibitors

PubMed Central

Riddell, Elizabeth; Vader, Justin M.

2017-01-01

Purpose of review The goal of this article is to review potential expanded indications for neprilysin inhibitors. This article reviews the rationale and design for ongoing and future trials of sacubitril/valsartan in cardiovascular and non-cardiovascular disease. Recent findings Randomized trial data are lacking for use of sacubitril/valsartan in acute heart failure and advanced heart failure. Mechanistic data from animal studies suggest a role for neprilysin inhibition in the treatment of post-myocardial infarction systolic dysfunction and heart failure with preserved ejection fraction. Beyond the cardiovascular system, renal and neurological function may be impacted by neprilysin inhibition. Forthcoming randomized trials will address the clinical impact of sacubitril/valsartan on these conditions. Summary Neprolysin inhibition with sacubitril/valsartan offers a new therapeutic strategy with a broad range of potential therapeutic actions. In PARADIGM-HF, the combination of neprolysin and RAAS inhibition was proven to be superior to enalapril for patients with stable NYHA class II–III heart failure and reduced left ventricular ejection fraction. Preliminary data suggests it may also have a role in other cardiovascular and non-cardiovascular disease. Several ongoing and planned studies will determine the extent of its benefit for these other indications. PMID:28281174

Evaluation of Pharmacokinetic and Pharmacodynamic Drug–Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild‐to‐Moderate Hypertension

PubMed Central

Langenickel, TH; Petruck, J; Kode, K; Ayalasomayajula, S; Schuehly, U; Greeley, M; Pal, P; Zhou, W; Prescott, MF; Sunkara, G; Rajman, I

2017-01-01

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open‐label, three‐period, single sequence study, patients with mild‐to‐moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (–5/–4/–4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470. PMID:28599060

Alteration of the intravenous and oral pharmacokinetics of valsartan via the concurrent use of gemfibrozil in rats.

PubMed

Yang, Seung Jun; Kim, Bong Jin; Mo, Lingxuan; Han, Hyo-Kyung

2016-07-01

The present study aimed to examine the potential pharmacokinetic drug interaction between valsartan and gemfibrozil. Compared with the control given valsartan (10 mg/kg) alone, the concurrent use of gemfibrozil (10 mg/kg) significantly (p < 0.05) increased the oral exposure of valsartan in rats. In the presence of gemfibrozil, the Cmax and AUC of oral valsartan increased by 1.7- and 2.5-fold, respectively. Consequently, the oral bioavailability of valsartan was significantly higher (p < 0.05) in the presence of gemfibrozil compared with that of the control group. Furthermore, the intravenous pharmacokinetics of valsartan (1 mg/kg) was also altered by pretreatment with oral gemfibrozil (10 mg/kg). The plasma clearance of valsartan was decreased by two-fold in the presence of gemfibrozil, while the plasma half-life was not altered. In contrast, both the oral and intravenous pharmacokinetics of gemfibrozil were not affected by the concurrent use of valsartan. The cellular uptake of valsartan and gemfibrozil was also investigated by using cells overexpressing OATP1B1 or OATP1B3. Gemfibrozil and gemfibrozil 1-O-β glucuronide inhibited the cellular uptake of valsartan with IC50 values (µm) of 39.3 and 20.4, respectively, in MDCK/OATP1B1, while they were less interactive with OATP1B3. The cellular uptake of gemfibrozil was not affected by co-incubation with valsartan in both cells. Taken together, the present study suggests the potential drug interaction between valsartan and gemfibrozil, at least in part, via the OATP1B1-mediated transport pathways during hepatic uptake. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Adherence with single-pill amlodipine/atorvastatin vs a two-pill regimen

PubMed Central

Patel, Bimal V; Scott Leslie, R; Thiebaud, Patrick; Nichol, Michael B; Tang, Simon SK; Solomon, Henry; Honda, Dennis; Foody, JoAnne M

2008-01-01

While clinical trials demonstrate the benefits of blood pressure and cholesterol reduction, medication adherence in clinical practice is problematic. We hypothesized that a single-pill would be superior to a 2-pill regimen for achieving adherence. In this retrospective, cohort study based on pharmacy claims data, patients newly initiated on a calcium channel blocker (CCB) or statin simultaneously or within 30 days, regardless of sequence, were followed (N = 4703). Adherence was measured over 6 months as proportion of days covered (PDC). At baseline, mean age was 63.0 years, 51.6% were female, and mean number of other medications was 7.8. Overall, 16.9% of patients were on single-pill amlodipine/atorvastatin, 15.6% amlodipine + atorvastatin, 24.7% amlodipine + other statin, 13.9% other CCB + atorvastatin, 28.9% other CCB + other statin. Percentages of patients achieving adherence (PDC ≥ 80%) were: 67.7% amlodipine/atorvastatin; 49.9% amlodipine + atorvastatin; 40.4% amlodipine + other statin; 46.9% other CCB + atorvastatin; 37.4% other CCB +other statin. After adjusting for treatment selection and cohort differences, odds ratios for adherence with amlodipine/atorva-statin were 1.95 (95% confidence interval [CI], 1.80–2.13) vs amlodipine + atorvastatin, 3.10 (95% CI, 2.85–3.38) vs amlodipine + other statin, 2.06 (95% CI, 1.89–2.24) vs other CCB + atorvastatin, 2.85 (95% CI, 2.61–3.10) vs other CCB + other statin (all p <0.0001). Single-pill amlodipine/atorvastatin may provide clinical benefits through improving adherence, offering clinicians a practical solution for cardiovascular risk management. PMID:18827917

Antihypertensive drug Valsartan promotes dendritic spine density by altering AMPA receptor trafficking

PubMed Central

Sohn, Young In; Lee, Nathanael J.; Chung, Andrew; Saavedra, Juan M.; Turner, R. Scott; Pak, Daniel T. S.; Hoe, Hyang-Sook

2013-01-01

Recent studies demonstrated that the antihypertensive drug Valsartan improved spatial and episodic memory in mouse models of Alzheimer’s Disease (AD) and human subjects with hypertension. However, the molecular mechanism by which Valsartan can regulate cognitive function is still unknown. Here, we investigated the effect of Valsartan on dendritic spine formation in primary hippocampal neurons, which is correlated with learning and memory. Interestingly, we found that Valsartan promotes spinogenesis in developing and mature neurons. In addition, we found that Valsartan increases the puncta number of PSD-95 and trends toward an increase in the puncta number of synaptophysin. Moreover, Valsartan increased the cell surface levels of AMPA receptors and selectively altered the levels of spinogenesis-related proteins, including CaMKIIα and phospho-CDK5. These data suggest that Valsartan may promote spinogenesis by enhancing AMPA receptor trafficking and synaptic plasticity signaling. PMID:24012668

Adsorption of Amlodipine at the Surface of Tosyl─Carbon Nanoparticles for Electrochemical Sensing

PubMed Central

Amiri, Mandana; Imanzade, Hamideh

2016-01-01

The adsorption processes of amlodipine onto hydrophilic carbon nanoparticles (Emperor 2000TM) are investigated. The significant increase in voltammetric responses for pre-adsorbed amlodipine compared with those for solution confirms high affinity of amlodipine to carbon nanoparticles (possibly due to π-π stacking interaction between aromatic rings of amlodipine and surface-sulfonated carbon nanoparticles). To obtain the optimum of adsorption conditions, the effects of pH, agitation rate, and adsorption time are investigated. Under differential pulse voltammetry conditions, the peak current for the oxidation of amlodipine shows two linear relationships with concentration in the range from 1000 μM to 10.0 μM and 10.0 μM to 10.0 nM. The limit of detection is estimated to be 1.0 nM. Determination of amlodipine in real samples such as human serum and commercial tablets is demonstrated. PMID:27980564

Preparation and stability evaluation of extemporaneous oral suspension of valsartan using commercially available tablets.

PubMed

Zaid, Abdel Naser; Assali, Mohyeddin; Qaddomi, Aiman; Ghanem, Mashhour; Zaaror, Yara Abu

2014-01-01

The aim of this study was to develop an extemporaneous valsartan suspension (80 mg valsartan/5 mL) starting from commercial tablets (80-mg/ tablet). A high-performance liquid chromatographic system was used for the analysis and quantification of valsartan in the samples studied. Samples of valsartan suspension for analysis were prepared as reported by the validated high-performance liquid chromatographic method and the dissolution tests were performed according to the U.S. Food and Drug Administration's method. The high-performance liquid chromatographic assay indicated that the 80-mg/5-mL valsartan suspension was stable for 30 days when stored at long-term and accelerated storage conditions. Valsartan release profile showed that approximately 85% of valsartan dissolved after 10 minutes and, accordingly, the calculation of similarity factor was not necessary. It is possible for the pharmacist to crush valsartan 80-mg tablets and prepare a suspension which has dosage flexibility that can be calculated according to body-surface area, kidney, and liver functions, without affecting the chemical stability of the active ingredient nor its dissolution profile and also have a cost-effective dosage form.

Prehypertensive treatment with losartan, however not amlodipine, leads to long-term effects on blood pressure and reduces the risk of stroke in spontaneously hypertensive stroke-prone rats.

PubMed

Zhang, Liangmin; He, Dehua; Lin, Jinxiu

2016-02-01

The current study investigated the efficacy of losartan and amlodipine in protecting spontaneously hypertensive stroke-prone (SHRSP) rats against the risk of stroke. SHRSP rats were administered losartan, amlodipine or the vehicle for 6 weeks. There were no significant differences in systolic blood pressure (SBP) in rats treated with losartan or amlodipine, however, following drug withdrawal, rats treated with losartan maintained reduced SBP for a longer time compared with rats treated with amlodipine. In addition, rats treated with losartan exhibited thinner vascular walls and improved systolic and diastolic function. Clinical stroke scores in the losartan group were significantly reduced compared with those in the amlodipine and vehicle groups. However, rats treated with losartan exhibited higher levels of angiotensin II and lower levels of aldosterone in the serum and brain cortex compared with the vehicle and amlodipine-treated rats. Furthermore, losartan significantly reduced the abnormal expression of angiotensin II receptors type 1 and 2 in SHRSP rats, whilst amlodipine did not. These results suggest that losartan may be more efficacious than amlodipine in ameliorating blood pressure deterioration and reducing stroke risk in SHRSP rats via regulation of the renin angiotensin system.

Valsartan.

PubMed

Ardiana, Febry; Suciati; Indrayanto, Gunawan

2015-01-01

Valsartan is an antihypertensive drug which selectively inhibits angiotensin receptor type II. Generally, valsartan is available as film-coated tablets. This review summarizes thermal analysis, spectroscopy characteristics (UV, IR, MS, and NMR), polymorphism forms, impurities, and related compounds of valsartan. The methods of analysis of valsartan in pharmaceutical dosage forms and in biological fluids using spectrophotometer, CE, TLC, and HPLC methods are discussed in details. Both official and nonofficial methods are described. It is recommended to use LC-MS method for analyzing valsartan in complex matrices such as biological fluids and herbal preparations; in this case, MRM is preferred than SIM method. © 2015 Elsevier Inc. All rights reserved.

Evaluation of Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild-to-Moderate Hypertension.

PubMed

Hsiao, H-L; Langenickel, T H; Petruck, J; Kode, K; Ayalasomayajula, S; Schuehly, U; Greeley, M; Pal, P; Zhou, W; Prescott, M F; Sunkara, G; Rajman, I

2018-03-01

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open-label, three-period, single sequence study, patients with mild-to-moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and C max of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (-5/-4/-4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470. © 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Fixed-dose combination of losartan and hydrochlorothiazide significantly improves endothelial function in uncontrolled hypertension by low-dose amlodipine: a randomized study.

PubMed

Takase, Bonpei; Nagata, Masayoshi

2014-12-01

Flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) in the brachial artery are well-known indices for evaluating endothelial function (ECF). The blood pressure-lowering effects of the combination of losartan (ARB) and low-dose hydrochlorothiazide (H: ARB-H; ARB, 50 mg and H, 12.5 mg) are useful. The aim of the present study was to examine whether the combination of losartan and low-dose hydrochlorothiazide could improve ECF. To investigate the effect of ARB-H on ECF in patients with uncontrolled hypertension despite the use of amlodipine (2.5 mg daily), we performed a randomized controlled open-labeled study by using the envelope method and assigned 42 patients to either a control (CTRL) group or an ARB-H combination group, both of which received amlodipine 2.5 mg daily during the treatment period. In addition, both the CTRL (n=21, 69±7 years old) and ARB-H groups (n=21, 69±7 years old) received additional behavioral modification. Before and after 8 weeks of therapy, FMD and NMD were measured in both groups using novel FMD equipment (UNEXEF18G). Although baseline FMD was not different between the two groups, post-therapy FMD increased in the ARB-H group (2.97±1.56 to 3.95±1.86%, p<0.05) but did not change significantly in the CTRL group (2.95±1.43 to 3.11±1.27%, NS). No significant change was seen in NMD when comparing baseline and post-therapy values in either group. No treatment complications were observed. A fixed-dose combination of losartan and hydrochlorothiazide enhances ECF, suggesting that this combination might have both anti-hypertensive and anti-atherosclerotic effects in patients with hypertension.

Effects of Sacubitril/Valsartan (LCZ696) on Natriuresis, Diuresis, Blood Pressures, and NT-proBNP in Salt-Sensitive Hypertension.

PubMed

Wang, Tzung-Dau; Tan, Ru-San; Lee, Hae-Young; Ihm, Sang-Hyun; Rhee, Moo-Yong; Tomlinson, Brian; Pal, Parasar; Yang, Fan; Hirschhorn, Elizabeth; Prescott, Margaret F; Hinder, Markus; Langenickel, Thomas H

2017-01-01

Salt-sensitive hypertension (SSH) is characterized by impaired sodium excretion and subnormal vasodilatory response to salt loading. Sacubitril/valsartan (LCZ696) was hypothesized to increase natriuresis and diuresis and result in superior blood pressure control compared with valsartan in Asian patients with SSH. In this randomized, double-blind, crossover study, 72 patients with SSH received sacubitril/valsartan 400 mg and valsartan 320 mg once daily for 4 weeks each. SSH was diagnosed if the mean arterial pressure increased by ≥10% when patients switched from low (50 mmol/d) to high (320 mmol/d) sodium diet. The primary outcome was cumulative 6- and 24-hour sodium excretion after first dose administration. Compared with valsartan, sacubitril/valsartan was associated with a significant increase in natriuresis (adjusted treatment difference: 24.5 mmol/6 hours, 50.3 mmol/24 hours, both P<0.001) and diuresis (adjusted treatment difference: 291.2 mL/6 hours, P<0.001; 356.4 mL/24 hours, P=0.002) on day 1, but not on day 28, and greater reductions in office and ambulatory blood pressure on day 28. Despite morning dosing of both drugs, ambulatory blood pressure reductions were more pronounced at nighttime than at daytime or the 24-hour average. Compared with valsartan, sacubitril/valsartan significantly reduced N-terminal pro B-type natriuretic peptide levels on day 28 (adjusted treatment difference: -20%; P=0.001). Sacubitril/valsartan and valsartan were safe and well tolerated with no significant changes in body weight or serum sodium and potassium levels with either treatments. In conclusion, sacubitril/valsartan compared with valsartan was associated with short-term increases in natriuresis and diuresis, superior office and ambulatory blood pressure control, and significantly reduced N-terminal pro B-type natriuretic peptide levels in Asian patients with SSH. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01681576. © 2016 American Heart Association, Inc.

The antihypertensive effectiveness and safety of dual RAAS blockade with aliskiren and valsartan.

PubMed

Chrysant, Steven G

2010-03-01

The renin-angiotensin-aldosterone system (RAAS) is a major factor for the development and maintenance of hypertension and a major cause for cardiovascular remodeling and cardiovascular complications through its active peptide angiotensin (Ang) II. Blockade of RAAS with ACE inhibitors (ACEIs) results in suppression of Ang II levels, which eventually return to baseline levels after prolonged ACEI administration. This leads to an escape phenomenon through generation of Ang II from enzymes other than ACE and led to the hypothesis that dual blockade of RAAS with an ACEI/Ang receptor blocker (ARB) combination could lead to total blockade of RAAS, since ARBs block the action of Ang II at the AT1 receptor level, irrespective of the mechanism of Ang II generation and will have an additive blood pressure (BP)-lowering effect. However, this hypothesis has not materialized clinically, as the ACEI/ARB combination produces modest BP reductions that are not significantly greater than monotherapy with the component drugs, and is frequently associated with higher incidence of side effects. A new dual RAAS blockade with the direct renin inhibitor aliskiren and the ARB valsartan produces greater BP reductions than monotherapy with the component drugs and is safe and well tolerated. The combination of aliskiren with valsartan, and with other antihypertensive drugs is discussed. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Effects of Changes in Potassium With Valsartan Use on Diabetes Risk: Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial

PubMed Central

Thomas, Laine; Svetkey, Laura; Brancati, Frederick L.; Califf, Robert M.; Edelman, David

2013-01-01

BACKGROUND Low and low-normal serum potassium is associated with an increased risk of diabetes. We hypothesized that the protective effect of valsartan on diabetes risk could be mediated by its effect of raising serum potassium. METHODS We analyzed data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, which randomized participants at risk for diabetes to either valsartan (up to 160mg daily) or no valsartan. Using Cox models, we evaluated the effect of valsartan on diabetes risk over a median of 4 years of follow-up and calculated the mediation effect of serum potassium as the difference in treatment hazard ratios from models excluding and including 1-year change in serum potassium. The 95% confidence interval (CI) for the difference in log hazard ratios was computed by bootstrapping. RESULTS The hazard ratio for developing diabetes among those on valsartan vs. no valsartan was 0.866 (95% CI = 0.795–0.943) vs. 0.868 (95% CI = 0.797–0.945), after controlling for 1-year change in potassium. The bootstrap 95% CI for a difference in these log hazard ratios was not statistically significant (−0.003 to 0.009). CONCLUSIONS Serum potassium does not appear to significantly mediate the protective effect of valsartan on diabetes risk. PMID:23417031

Valsartan regulates the interaction of angiotensin II type 1 receptor and endothelial nitric oxide synthase via Src/PI3K/Akt signalling.

PubMed

Su, Kuo-Hui; Tsai, Jin-Yi; Kou, Yu Ru; Chiang, An-Na; Hsiao, Sheng-Huang; Wu, Yuh-Lin; Hou, Hsin-Han; Pan, Ching-Chian; Shyue, Song-Kun; Lee, Tzong-Shyuan

2009-06-01

Valsartan, a selective angiotensin II type 1 receptor (AT1R) blocker, has beneficial effects in the cardiovascular system in part by its increase of nitric oxide (NO) bioavailability, yet the mechanisms are unclear. We investigated the molecular mechanisms underlying this effect in endothelial cells (ECs). NO production was examined by Griess reagent assay, DAF-2 DA fluorescence staining and cGMP ELISA kits. Protein interaction was determined by western blotting and immunoprecipitation. Treating bovine or human aortic ECs with valsartan increased NO production, as evidenced by elevated level of stable NO metabolites and intracellular cGMP. Valsartan increased the phosphorylation but not the protein level of endothelial NO synthase (eNOS). Inhibition of phosphoinositide-3 kinase (PI3K)/Akt and Src pathways by specific inhibitors suppressed valsartan-induced NO release. In addition, valsartan increased the tyrosine residue phosphorylation of AT1R, which was attenuated by inhibition of Src but not PI3K activities. Valsartan also suppressed the interaction of eNOS and AT1R, which was blocked by Src or PI3K inhibition. Valsartan-induced NO production in ECs is mediated through Src/PI3K/Akt-dependent phosphorylation of eNOS. Valsartan-induced AT1R phosphorylation depends on Src but not PI3K, whereas valsartan-induced suppression of AT1R-eNOS interaction depends on Src/PI3K/Akt signalling. These results indicate a novel vasoprotective mechanism of valsartan in upregulating NO production in ECs.

Antioxidant and antiapoptotic effects of sea cucumber and valsartan against doxorubicin-induced cardiotoxicity in rats: The role of low dose gamma irradiation.

PubMed

Ibrahim, Doaa M; Radwan, Rasha R; Abdel Fattah, Salma M

2017-05-01

Doxorubicin (DOX) is a highly effective antineoplastic drug; however, the clinical use of DOX is limited by its dose dependent cardiotoxicity. This study was conducted to evaluate the cardioprotective effect of sea cucumber and valsartan against DOX-induced cardiotoxicity in rats. Also, the role of exposure to low dose γ radiation (LDR) on each of them was investigated, since LDR could suppress various reactive oxygen species-related diseases. Rats received DOX (2.5mg/kg, ip) in six equal injections over a period of 2weeks, sea cucumber (14.4mg/kg, p.o) and valsartan (30mg/kg, p.o) for 8 successive weeks. Exposure to LDR (0.5Gy) was performed one day prior to DOX. Results revealed that DOX administration elevated serum levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK-MB) and troponin-I as well as increased cardiac lipid peroxide content and myeloperoxidase (MPO) activity. Additionally, it increased cardiac expressions of iNOS and caspase-3, accompanied by reduction in cardiac total protein and glutathione (GSH) contents. Treatment with sea cucumber or valsartan improved the cardiotoxicity of DOX. Their adjuvant therapy with LDR offers an additional benefit to the cardioprotection of the therapeutic drugs. These results confirmed by histopathological examination. In conclusion, sea cucumber and valsartan alone or combined with LDR attenuated DOX-induced cardiotoxicity via their antioxidant and anti-apoptotic activities and thus might be useful in the treatment of human patients under doxorubicin chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Generalised peripheral oedema associated with amlodipine therapy in two dogs.

PubMed

Creevy, K E; Scuderi, M A; Ellis, A E

2013-11-01

This report details two cases of adverse drug reactions to amlodipine. The first case presented with diffuse peripheral oedema and a history of amlodipine therapy. Haematology, clinical chemistry, endocrine testing, thoracic, abdominal and cardiac imaging revealed no cause for oedema. Amlodipine therapy was discontinued and oedema diminished markedly within 72 hours. The second case presented for bilateral retinal detachments secondary to systemic hypertension. Haematology, clinical chemistry, thoracic and abdominal imaging were unremarkable and amlodipine therapy was begun. Within 72 hours, diffuse peripheral oedema developed that was unresponsive to therapy and the dog was euthanised. Veterinarians should be aware of the potential serious adverse events associated with commonly used drugs; severe, diffuse oedema is a possible adverse drug event in dogs treated with amlodipine. © 2013 British Small Animal Veterinary Association.

Effect of losartan combined with amlodipine or with a thiazide on uric acid levels in hypertensive patients.

PubMed

Rubio-Guerra, Alberto F; Garro-Almendaro, Ana K; Elizalde-Barrera, Cesar I; Suarez-Cuenca, Juan A; Duran-Salgado, Montserrat B

2017-02-01

Hyperuricemia leads to endothelial dysfunction and insulin resistance, and has been associated with diseases such as hypertension. Antihypertensive drugs modify serum uric acid levels, however, few data are available about their combinations on uricemia. In this study we evaluate the effect of two combinations of losartan, with amlodipine or with hydrochlorothiazide, on serum uric acid levels in hypertensive patients. A total of 60 hypertensive patients were randomized in two groups; group LA received losartan/amlodipine (100/5 mg) once a day, whereas LH group received losartan hydrochlorothiazide (100/12.5 mg) once a day for 3 months. In both groups serum uric acid levels were measured at the beginning and end of the study. Patients were evaluated monthly for blood pressure (BP) and adverse events. Statistical analysis was performed with a two-way analysis of variance (ANOVA) for repeated measures. All patients experienced a significant reduction of BP to the same extent (LA 155/94 to 123/79, LH 157/92 to 124/78 mmHg, p > 0.05). In the LA group, serum uric acid decreased from 6.5 ± 1.6 to 4.6 ± 1.3 mg/ml ( p = 0.0001), whereas in the LH group there was a nonsignificant increase from 5.82 ± 1.4 to 5.85 ± 1.5 mg/ml, ( p = 0.936). When both groups were compared, we found a significant reduction ( p < 0.00013) on serum uric acid levels in the LA group. Both combinations decrease BP values to the same extent, however, LA combination showed a reduction on serum uric acid levels, which may contribute to a reduction in the metabolic risk in hypertensive patients.

Simultaneous spectrophotometric determination of valsartan and hydrochlorothiazide by H-point standard addition method and partial least squares regression.

PubMed

Lakshmi, Karunanidhi Santhana; Lakshmi, Sivasubramanian

2011-03-01

Simultaneous determination of valsartan and hydrochlorothiazide by the H-point standard additions method (HPSAM) and partial least squares (PLS) calibration is described. Absorbances at a pair of wavelengths, 216 and 228 nm, were monitored with the addition of standard solutions of valsartan. Results of applying HPSAM showed that valsartan and hydrochlorothiazide can be determined simultaneously at concentration ratios varying from 20:1 to 1:15 in a mixed sample. The proposed PLS method does not require chemical separation and spectral graphical procedures for quantitative resolution of mixtures containing the titled compounds. The calibration model was based on absorption spectra in the 200-350 nm range for 25 different mixtures of valsartan and hydrochlorothiazide. Calibration matrices contained 0.5-3 μg mL-1 of both valsartan and hydrochlorothiazide. The standard error of prediction (SEP) for valsartan and hydrochlorothiazide was 0.020 and 0.038 μg mL-1, respectively. Both proposed methods were successfully applied to the determination of valsartan and hydrochlorothiazide in several synthetic and real matrix samples.

Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction.

PubMed

McCormack, Paul L

2016-03-01

Sacubitril/valsartan (Entresto™; LCZ696) is an orally administered supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, which was recently approved in the US and the EU for the treatment of chronic heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF). In the large, randomized, double-blind, PARADIGM-HF trial, sacubitril/valsartan reduced the incidence of death from cardiovascular causes or first hospitalization for worsening heart failure (composite primary endpoint) significantly more than the angiotensin converting enzyme (ACE) inhibitor enalapril. Sacubitril/valsartan was also superior to enalapril in reducing death from any cause and in limiting the progression of heart failure. Sacubitril/valsartan was generally well tolerated, with no increase in life-threatening adverse events. Symptomatic hypotension was significantly more common with sacubitril/valsartan than with enalapril; the incidence of angio-oedema was low. Therefore, sacubitril/valsartan is a more effective replacement for an ACE inhibitor or an ARB in the treatment of HFrEF, and is likely to influence the basic approach to treatment.

Efficacy and Safety of S-Amlodipine 2.5 and 5 mg/d in Hypertensive Patients Who Were Treatment-Naive or Previously Received Antihypertensive Monotherapy.

PubMed

Şen, Selçuk; Demir, Meral; Yiğit, Zerrin; Üresin, Ali Yağız

2018-07-01

The aim of the present study was to evaluate the efficacy and safety of S-amlodipine 2.5 and 5 mg/d in patients with hypertension who were treatment-naive or previously received antihypertensive monotherapy. During the 8-week treatment period, all patients received S-amlodipine 2.5 mg/d for the first 4 weeks, followed by S-amlodipine 5 mg/d for the second 4 weeks. For efficacy assessments, ambulatory and office blood pressure (BP) measurements were performed during the baseline, fourth-week, and eighth-week visits. For safety assessments, all adverse events and abnormal laboratory findings were recorded. This study is registered with ClinicalTrials.gov (NCT03038451). Of 43 patients evaluated at the screening visit, 33 were enrolled. In the treatment-naive arm, significant reductions in both office and ambulatory systolic BP (SBP) and diastolic BP (DBP) were observed with S-amlodipine 2.5 mg/d and additional significant reductions were achieved with dose titration (S-amlodipine 5 mg/d). At the end of the study, the rate of the treatment-naive patients with BP under control (SBP/DBP <140/90 mm Hg) was 53% with S-amlodipine 2.5 mg and increased to 78% with S-amlodipine 5 mg. For the noninferiority evaluation, S-amlodipine 2.5 and 5 mg/d treatments were generally noninferior to both office and ambulatory BP levels achieved with the medications that the patients received before participating in the study. Five nonserious adverse events likely to be associated with the study drug were observed. No serious adverse event was encountered. Consequently, S-amlodipine can be suggested as an effective and safe treatment option for patients with hypertension.

Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT).

PubMed

Latini, Roberto; Masson, Serge; Anand, Inder; Judd, Dianne; Maggioni, Aldo P; Chiang, Yann-Tong; Bevilacqua, Maurizio; Salio, Monica; Cardano, Paola; Dunselman, Peter H J M; Holwerda, Nicolaas J; Tognoni, Gianni; Cohn, Jay N

2002-11-05

Brain natriuretic peptide (BNP) and norepinephrine (NE) are strongly related to severity of and are independent predictors of outcome in heart failure. The long-term effects of angiotensin receptor blockers on BNP and NE in heart failure patients are not known. Both BNP and NE were measured in 4284 patients randomized to valsartan or placebo in the Valsartan Heart Failure Trial (Val-HeFT) at baseline and 4, 12, and 24 months after randomization. The effects of valsartan were tested by ANCOVA, controlling for baseline values and concomitant ACE inhibitors and/or beta-blockers. BNP and NE concentrations were similar at baseline in the 2 groups and were decreased by valsartan starting at 4 months and up to 24 months. BNP increased over time in the placebo group. At the end point, least-squares mean (+/-SEM) BNP increased from baseline by 23+/-5 pg/mL in the placebo group (n=1979) but decreased by 21+/-5 pg/mL (n=1940) in the valsartan group (P<0.0001). NE increased by 41+/-6 pg/mL (n=1979) and 12+/-6 pg/mL (n=1941) for placebo and valsartan, respectively (P=0.0003). Concomitant therapy with both ACE inhibitors and beta-blockers significantly reduced the effect of valsartan on BNP but not on NE (P for interaction=0.0223 and 0.2289, respectively). In Val-HeFT, the largest neurohormone study in patients with symptomatic chronic heart failure, BNP and NE rose over time in the placebo group. Valsartan caused sustained reduction in BNP and attenuated the increase in NE over the course of the study. These neurohormone effects of valsartan are consistent with the clinical benefits reported in Val-HeFT.

Pharmacokinetic interaction of fimasartan, a new angiotensin II receptor antagonist, with amlodipine in healthy volunteers.

PubMed

Yi, SoJeong; Kim, Tae-Eun; Yoon, Seo Hyun; Cho, Joo-Youn; Shin, Sang-Goo; Jang, In-Jin; Yu, Kyung-Sang

2011-06-01

Fimasartan (BR-A-657) is a new angiotensin II receptor antagonist used as antihypertensive agent. The objective of this study was to investigate the effect of the coadministration of fimasartan and amlodipine on the steady-state pharmacokinetics of each drug. This study comprised 2 separate parts, A and B; each was a multiple-dose, open-label, 2-period crossover study in healthy male volunteers. In part A, 20 subjects were administered 120 mg of fimasartan alone in period I and fimasartan with 10 mg of amlodipine in period II. In part B, 14 subjects were administered amlodipine alone, followed by coadministration with fimasartan. Blood samples for pharmacokinetics were collected up to 24 hours after the last dosing. The pharmacokinetics of the coadministration of fimasartan and amlodipine were compared with that of each drug alone. The geometric mean ratio and 90% confidence intervals for C(max,ss) and area under the plasma concentration-time curve (AUC)(τ,ss) of fimasartan (with/without amlodipine) were 1.096 (0.746-1.610) and 1.163 (1.001-1.351), respectively. The geometric mean ratios (90% confidence interval) for C(max,ss) and AUC(τ,ss) of amlodipine (with/without fimasartan) after coadministration with fimasartan were 1.037 (0.969-1.110) and 0.975 (0.920-1.033), respectively. Coadministration of fimasartan and amlodipine did not result in clinically relevant changes in the systemic exposure of fimasartan or amlodipine.

Formulation and optimization of spray-dried amlodipine solid dispersion for enhanced oral absorption.

PubMed

Jang, Dong-Jin; Sim, Taeyong; Oh, Euichaul

2013-07-01

To enhance the oral absorption of photosensitive amlodipine free base, which exhibits a slow dissolution rate and low permeability characteristics, an amorphous solid dispersion system was formulated and characterized. The solid dispersion was prepared by dispersing the amlodipine free base in excess dextrin (1:10 by weight) using a spray-drying technique in the presence of a minimum amount (0.9% w/w) of SLS as an absorption enhancer. The dextrin-based solid dispersion of amlodipine (Amlo-SD) was evaluated in term of formulation, characterization and in vivo absorption study, as well as the spray-drying process was also optimized. The Amlo-SD particles were spherical with a smooth surface and an average particle size of 12.9 μm. Amlodipine was dispersed in an amorphous state and its content remained uniform in the Amlo-SD. The physicochemical stability of the Amlo-SD was maintained at room temperature for 6 months and the photostability was considerably improved. The dissolution of the Amlo-SD was much faster than that of amlodipine at pH 1.2 and 6.8. Amlo-SD produced significantly higher plasma concentrations of amlodipine in rats than amlodipine alone. Amlo-SD with and without SLS provided 2.8- and 2.0-fold increase in AUC, respectively: the difference seems to be attributed to a permeability enhancement effect by SLS. The Amlo-SD with SLS system is a potential formulation option for amlodipine.

Development of Validated Bioanalytical HPLC-UV Method for Simultaneous Estimation of Amlodipine and Atorvastatin in Rat Plasma

PubMed Central

Talele, G. S.; Porwal, P. K.

2015-01-01

A simple, economical and robust analytical high-performance liquid chromatography-ultraviolet method was developed and validated for simultaneous chromatographic elution of two cardiovascular drugs viz. amlodipine and atorvastatin in biological fluid for the first time. Only two liquid chromatography–mass spectrometry/mass spectrometry methods are available in literature for quantitation of selected pair of analytes. The bioanalytical method was developed in rat plasma by using Thermo beta-basic C18 (100×4.6 mm, 5 μm) and mobile phase was composed of dibasic phosphate buffer (pH 3.0):acetonitrile in the ratio of 55:45 at a flow rate of 1 ml/min with ultraviolet detection monitored at 240 nm. The selected chromatographic conditions were found to effectively separate amlodipine (5.1 min) and atorvastatin (12.1 min). The parametric statistics,i.e. correlation coefficient of 0.999, was assessed for both the drugs having linearity over the tested concentration range (0.05 to 10.0 μg/ml) in rat plasma using an unweighted calibration curve. The mean recovery (%) was more than 92.8% for both the drugs using protein precipitation method. The accuracy of samples for six replicate measurements at lower limit of quantitation level was within limit. The method was validated and was successfully applied to the nonclinical pharmacokinetic study of combination tablets containing amlodipine and atorvastatin in six Sprague Dawley rats. PMID:26997703

Calcium channel blocker overdose: experience with amlodipine.

PubMed

Ghosh, Supradip; Sircar, Mrinal

2008-10-01

Amlodipine overdose is only scarcely reported from India. We report two cases of near fatal Amlodipine overdose managed in our ICU with fluid, vasopressors, calcium infusion and Glucagon. Literature is reviewed and other treatment modalities discussed.

Treatment efficacy of anti-hypertensive drugs in monotherapy or combination

PubMed Central

Paz, Marco A.; de-La-Sierra, Alejandro; Sáez, Marc; Barceló, María Antonia; Rodríguez, Juan José; Castro, Sonia; Lagarón, Cristina; Garrido, Josep M; Vera, Pilar; Coll-de-Tuero, Gabriel

2016-01-01

Abstract Background: The relative efficacy of antihypertensive drugs/combinations is not well known. Identifying the most effective ones and the patients’ characteristics associated with best performance of the drugs will improve management of hypertensive patients. Objective: To assess the blood pressure (BP) reduction attributed to antihypertensive drugs and identify characteristics associated with BP decrease. Data sources: MEDLINE, Cochrane Central Register of Controlled Trials from inception through July 2012 and selected papers. Study eligibility criteria: Double-blind, randomized clinical trials whose main result was the reduction in BP by antihypertensive treatment, with study population ≥50 or ≥25 if the study was a crossover, follow-up of at least 8 weeks, and available required data. Study appraisal and synthesis methods: Study data were independently extracted by multiple observers and introduced in an electronic database. Inconsistencies were resolved by discussion and referral back to the original articles. Meta-analysis was performed according to PRISMA statement and using a Bayesian framework. Main Outcome(s) and Measure(s): Mean decrease in systolic (SBP) and diastolic blood pressure (DBP) achieved by each drug or combination. Results: Two hundred eight trials including 94,305 patients were identified. In monotherapy, most drugs achieved 10 to 15 mm Hg SBP and 8 to 10 mm Hg DBP decreases. Olmesartan/amlodipine, olmesartan/hydrochlorothiazide, felodipine/metoprolol, and valsartan/hydrochlorothiazide were the combinations leading to the greatest mean SBP reductions (>20 mm Hg). Female sex and body mass index >25 kg/m2 were associated with more pronounced SBP and DBP reductions, whereas Afro-American ethnicity was associated with BP reductions smaller than the median. Results were adjusted by study duration, cardiovascular disease, and diabetes mellitus. Still, the estimation was performed using the mean administered doses, which do not exactly match those of the available drug formats. Limitations: Data corresponded to those obtained in each of the included trials; the analysis of the combinations was limited to the most recent ones; estimations were performed using the mean administered doses. Conclusions and implications: Certain drug combinations achieve BP reductions ranging from 20 to 25/10 to 15 mm Hg. Sex, ethnicity, and obesity are associated with antihypertensive response. This information can contribute to better selection of the antihypertensive drug, depending on the magnitude of pretreatment BP elevation. Guidelines should be revised. PMID:27472680

Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy.

PubMed

Bomback, Andrew S; Rekhtman, Yelena; Klemmer, Philip J; Canetta, Pietro A; Radhakrishnan, Jai; Appel, Gerald B

2012-01-01

Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension and proteinuria compared with conventional RAAS blockade. Copyright © 2012 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Statins: Are These Cholesterol-Lowering Drugs Right for You?

MedlinePlus

... for use in the United States. They include: atorvastatin (Lipitor) lovastatin (Altoprev) pitavastatin (Livalo) pravastatin (Pravachol) rosuvastatin ( ... combined with another heart health medication. Examples are atorvastatin/amlodipine (Caduet) and simvastatin/ezetimibe (Vytorin). Increasing evidence ...

[Troubleshooting of bioinequivalence of compound valsartan tablets].

PubMed

Shao, Da; Zhang, Yi-Fan; Zhan, Yan; Chen, Xiao-Yan; Zhong, Da-Fang

2014-04-01

The study aims to evaluate the bioequivalence of valsartan hydrochlorothiazide tablets, and to investigate the potential cause of bioinequivalence. This was a single-center study with an open, randomized double-way crossover design. Test and reference preparations containing 160 mg of valsartan and 25 mg of hydrochlorothiazide were given to 36 healthy male volunteers. Plasma concentrations of valsartan and hydrochlorothiazide were determined simultaneously by LC-MS/MS. The pharmacokinetic parameters and relative bioavailability were calculated, while the bioequivalence between test and reference preparations were evaluated. The dissolution profiles of test and reference preparations in four different mediums were determined via dissolution test and HPLC. The similarity was investigated according to the similarity factors (f2). The F(o-t) and F(0-infinity) were (139.4 +/- 65.2)% and (137.5 +/- 61.2)% for valsartan of test preparations. It led to get the conclusion that test and reference preparations were not bioequivalent for valsartan. A significant difference was observed between test and reference tablets in the valsartan dissolution test of pH 1.2 hydrochloric acid solution. The key factor of the bioinequivalence might be that dissolution of valsartan in acid medium has marked difference between two preparations.

Determination of the R-enantiomer of valsartan in pharmaceutical formulation by capillary electrophoresis.

PubMed

Lee, Kyung Ran; Nguyen, NgocVan Thi; Lee, Yong Jae; Choi, Seungho; Kang, Jong Seong; Mar, Woongchon; Kim, Kyeong Ho

2015-01-01

Capillary zone electrophoresis was successfully applied to the enantiomeric purity determination of valsartan using acetyl-β-cyclodextrin (A-β-CD) as a chiral selector. Separations were carried out in a 50 µm, 64/56 cm fused-silica capillary. The optimized conditions included 25 mM phosphate buffer, pH 8.0, containing 10 mM A-β-CD as background electrolyte, an applied voltage of +30 kV and a temperature of 30 °C. Ibuprofen was used as an internal standard. The assay was validated for the R-enantiomer of valsartan in the range of 0.05-3.0%. The limit of detection was 0.01%, the limit of quantitation was 0.05%, relative to a concentration of valsartan of 1 mg/ml. Intra-day precision varied between 2.57 and 5.60%. Relative standard deviations of inter-day precision ranged between 4.46 and 6.76% for peak area ratio. The percentage recovery of the R-enantiomer of valsartan ranged between 97.0 and 99.6% in valsartan product. The assay was applied to the determination of the chiral purity of valsartan tablets and R-enantiomer of valsartan was found as an impurity.

Effects of combination therapy with vildagliptin and valsartan in a mouse model of type 2 diabetes

PubMed Central

2013-01-01

Background Dipeptidyl peptidase-4 (DPP-4) inhibitors modulate incretin hormones and exert anti-diabetic effects in type 2 diabetes mellitus. Treatment with angiotensin II type 1 receptor blockers (ARB) is a proven successful intervention for hypertension with type 2 diabetes. The present study investigated the combined effects of the DPP-4 inhibitor vildagliptin and the ARB valsartan in a mouse model of type 2 diabetes. Methods C57BL/6 J mice fed with high-fat diet (HFD) or db/db mice were treated with placebo, phloridzin (PHZ), vildagliptin alone (ViL), valsartan alone (VaL) or ViL with VaL (ViLVaL) for 8 weeks. Results Glucose metabolism was improved in response to PHZ, ViL and ViLVaL in both HFD and db/db mice. Upon glucose challenge, ViLVaL showed the greatest suppression of blood glucose excursions, with increased insulin secretion, in db/db mice. ViLVaL treatment also showed an improvement of insulin sensitivity in db/db mice. Serum inflammatory cytokines were significantly decreased, and adiponectin was highest, in the ViLVaL group. ViLVaL improved insulin signaling and attenuated stress signaling in liver with amelioration of hepatic steatosis due to activated fatty acid oxidation in db/db mice. Furthermore, immunohistochemical analysis of the pancreas revealed that the combination treatment resulted in an increased expression of insulin and PDX-1, and increased insulin content. Conclusions The combination therapy of ViL and VaL improves both pancreatic beta-cell function and insulin sensitivity, with a reduction of the inflammatory and cell stress milieu in mouse models of T2DM. Our results suggest that this combination therapy exerts additive or even synergistic benefits to treat T2DM. PMID:24188631

Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck.

PubMed

Ansara, A J; Kolanczyk, D M; Koehler, J M

2016-04-01

Heart failure remains a leading cause of morbidity and mortality worldwide. Advanced therapies have prolonged survival in patients with advanced heart failure, but pharmacotherapeutic optimization remains the mainstay of treatment. It has been over 10 years since the last mortality-reducing medication has been approved by the Food and Drug Administration. This article reviews the background, current knowledge and data supporting the use of sacubitril/valsartan (Entresto(®) ), the newly FDA-approved medication that dually inhibits angiotensin and neprilysin, in the treatment of heart failure. A literature search was performed (January 1980 to August 2015) using PubMed and the search terms were as follows: neprilysin inhibitor, heart failure, endopeptidase, natriuretic peptides, angiotensin, omapatrilat, LCZ696, valsartan and sacubitril. Peer-reviewed, published clinical trials, review articles, relevant treatment guidelines and prescribing information documents were identified and reviewed for relevance. Additionally, reference citations from publications identified were reviewed. The inhibition of endopeptidases has been an area of extensive study for the treatment of heart failure. Previously published literature with the endopeptidase inhibitor omapatrilat failed to demonstrate a sufficient balance between clinical efficacy and safety to justify its approval. Omapatrilat blocked three pathways that break down bradykinin, leading to high rates of angioedema. Sacubitril, on the other hand, is metabolized to a form that is highly selective for neprilysin without possessing activity for the other two peptidases, ACE and APP. The combination of sacubitril with valsartan in a single formulation offers the benefit of concurrent blockade of the renin angiotensin aldosterone system and the inhibition of neprilysin while minimizing angioedema risk. When compared to ACE inhibitor therapy in systolic heart failure patients, sacubitril/valsartan demonstrated reductions in all-cause mortality and hospitalization due to heart failure while maintaining a similar safety profile. A formulation that contains both sacubitril and valsartan was manufactured and approved by the FDA in July 2015 for the reduction of mortality and hospitalization in systolic heart failure patients. The new medication offers a potentially superior alternative to ACE inhibitor therapy in the management of systolic heart failure. The effects of treatment with sacubitril/valsartan in the setting of diastolic heart failure are currently under investigation in clinical trials. © 2016 John Wiley & Sons Ltd.

Impact of sacubitril–valsartan combination in patients with chronic heart failure and sleep apnoea syndrome: the ENTRESTO‐SAS study design

PubMed Central

Jaffuel, Dany; Molinari, Nicolas; Berdague, Philippe; Pathak, Atul; Galinier, Michel; Dupuis, Marion; Ricci, Jean‐Etienne; Mallet, Jean‐Pierre; Bourdin, Arnaud

2018-01-01

Abstract Aims Sleep‐disordered breathing (SDB) is a highly prevalent co‐morbidity in patients with chronic heart failure (CHF) and can play a detrimental role in the pathophysiology course of CHF. However, the best way to manage SDB in CHF remains a matter of debate. Sacubitril–valsartan has been included in the 2016 European Society of Cardiology guidelines as an alternative to angiotensin‐converting enzyme inhibitors to further reduce the risk of progression of CHF, CHF hospitalization, and death in ambulatory patients. Sacubitril and valsartan are good candidates for correcting SDB of CHF patients because their known mechanisms of action are likely to counteract the pathophysiology of SDB in CHF. Methods and results The ENTRESTO‐SAS trial is a 3‐month, multicentric, prospective, open‐label real‐life cohort study. Patients eligible for sacubitril–valsartan treatment (i.e. adults with left ventricular ejection fraction ≤35%, who remain symptomatic despite optimal treatment with an angiotensin‐converting enzyme inhibitor, a beta‐blocker, and a mineralocorticoid receptor antagonist) will be evaluated before and after 3 months of treatment (nocturnal ventilatory polygraphy, echocardiography, laboratory testing, and quality‐of‐life and SDB questionnaires). The primary outcome is the change in the Apnoea–Hypopnoea Index, before and after 3 months of treatment. One hundred twenty patients are required to detect a significant 20% improvement of the Apnoea–Hypopnoea Index with a power of 90% at an alpha risk of 5%. Conclusions In the context of the SERVE‐HF study, physicians are waiting for new trials and alternative therapies. We sought to assess in the ENTRESTO‐SAS trial whether sacubitril–valsartan could improve the outcome of SDB in CHF patients. PMID:29469206

Impact of sacubitril-valsartan combination in patients with chronic heart failure and sleep apnoea syndrome: the ENTRESTO-SAS study design.

PubMed

Jaffuel, Dany; Molinari, Nicolas; Berdague, Philippe; Pathak, Atul; Galinier, Michel; Dupuis, Marion; Ricci, Jean-Etienne; Mallet, Jean-Pierre; Bourdin, Arnaud; Roubille, François

2018-06-01

Sleep-disordered breathing (SDB) is a highly prevalent co-morbidity in patients with chronic heart failure (CHF) and can play a detrimental role in the pathophysiology course of CHF. However, the best way to manage SDB in CHF remains a matter of debate. Sacubitril-valsartan has been included in the 2016 European Society of Cardiology guidelines as an alternative to angiotensin-converting enzyme inhibitors to further reduce the risk of progression of CHF, CHF hospitalization, and death in ambulatory patients. Sacubitril and valsartan are good candidates for correcting SDB of CHF patients because their known mechanisms of action are likely to counteract the pathophysiology of SDB in CHF. The ENTRESTO-SAS trial is a 3-month, multicentric, prospective, open-label real-life cohort study. Patients eligible for sacubitril-valsartan treatment (i.e. adults with left ventricular ejection fraction ≤35%, who remain symptomatic despite optimal treatment with an angiotensin-converting enzyme inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist) will be evaluated before and after 3 months of treatment (nocturnal ventilatory polygraphy, echocardiography, laboratory testing, and quality-of-life and SDB questionnaires). The primary outcome is the change in the Apnoea-Hypopnoea Index, before and after 3 months of treatment. One hundred twenty patients are required to detect a significant 20% improvement of the Apnoea-Hypopnoea Index with a power of 90% at an alpha risk of 5%. In the context of the SERVE-HF study, physicians are waiting for new trials and alternative therapies. We sought to assess in the ENTRESTO-SAS trial whether sacubitril-valsartan could improve the outcome of SDB in CHF patients. © 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Amlodipine Inhibits Vascular Cell Senescence and Protects Against Atherogenesis Through the Mechanism Independent of Calcium Channel Blockade.

PubMed

Kayamori, Hiromi; Shimizu, Ippei; Yoshida, Yohko; Hayashi, Yuka; Suda, Masayoshi; Ikegami, Ryutaro; Katsuumi, Goro; Wakasugi, Takayuki; Minamino, Tohru

2018-05-30

Vascular cells have a finite lifespan and eventually enter irreversible growth arrest called cellular senescence. We have previously suggested that vascular cell senescence contributes to the pathogenesis of human atherosclerosis. Amlodipine is a mixture of two enantiomers, one of which (S- enantiomer) has L-type channel blocking activity, while the other (R+ enantiomer) shows ~1000-fold weaker channel blocking activity than S- enantiomer and has other unknown effects. It has been reported that amlodipine inhibits the progression of atherosclerosis in humans, but the molecular mechanism of this beneficial effect remains unknown. Apolipoprotein E-deficient mice on a high-fat diet were treated with amlodipine, its R+ enantiomer or vehicle for eight weeks. Compared with vehicle treatment, both amlodipine and the R+ enantiomer significantly reduced the number of senescent vascular cells and inhibited plaque formation to a similar extent. Expression of the pro-inflammatory molecule interleukin-1β was markedly upregulated in vehicle-treated mice, but was inhibited to a similar extent by treatment with amlodipine or the R+ enantiomer. Likewise, activation of p53 (a critical inducer of senescence) was markedly suppressed by treatment with amlodipine or the R+ enantiomer. These results suggest that amlodipine inhibits vascular cell senescence and protects against atherogenesis at least partly by a mechanism that is independent of calcium channel blockade.

Comparative effects of amlodipine and benazepril on left atrial pressure in dogs with experimentally-induced mitral valve regurgitation.

PubMed

Suzuki, Shuji; Fukushima, Ryuji; Ishikawa, Taisuke; Yamamoto, Yuta; Hamabe, Lina; Kim, Soomin; Yoshiyuki, Rieko; Machida, Noboru; Tanaka, Ryou

2012-09-18

One of the purposes of treatment for dogs with mitral regurgitation (MR) is lowering left atrial pressure (LAP). There has been few study of the amlodipine in dogs with MR and amlodipine's effect on LAP has not been fully evaluated in a quantitative manner because of difficulties in directly measuring LAP. The objective of our study was to compare the short-term effects of amlodipine (0.2 mg/kg PO q12h) vs benazepril (0.5 mg/kg PO q12h), on LAP and echocardiographic parameters in five beagle dogs with experimentally-induced MR. LAP of eight dogs that has own control were measured using radiotelemetry system at baseline and again on days 1, 2, 3, 4, 5, 6, 7 of the drug administration. Mean LAP decreased significantly after amlodipine (11.20 ± 4.19 mmHg vs 14.61 ± 3.81 mmHg at baseline, p < .01) but not after benazepril treatment (13.19 ± 3.47 mmHg, p > .05). LAP was lower after 7 days of amlodipine treatment than after 7 days of benazepril treatment. Significant reduction was seen for the first time 4 days after the administration amlodipine. The rate of the maximal area of the regurgitant jet signals to the left atrium area (ARJ/LAA) of the amlodipine treatment was significantly lower (p < .05) after 7 days compared to baseline. Other echocardiographic parameters did not change significantly. LAP was significantly decreased after amlodipine treatment in dogs with surgically-induced MR but not after benazepril treatment. Although this study did not focus on adverse effects, amlodipine may be an effective drug for helping the patients with acute onset of severe MR, such as rupture of chordae tendinae or end stage patients were the LAP is likely to be elevated. Additional studies in clinical patients with degenerative mitral valve disease and acute chordal rupture are warranted because the blood-pressure lowering effects of amlodipine can decrease renal perfusion and this can further activate the RAAS.

Formulations of Amlodipine: A Review

PubMed Central

Ahsan, Syed Furqan; Khan, Marium Fatima

2016-01-01

Amlodipine (AD) is a calcium channel blocker that is mainly used in the treatment of hypertension and angina. However, latest findings have revealed that its efficacy is not only limited to the treatment of cardiovascular diseases as it has shown to possess antioxidant activity and plays an important role in apoptosis. Therefore, it is also employed in the treatment of cerebrovascular stroke, neurodegenerative diseases, leukemia, breast cancer, and so forth either alone or in combination with other drugs. AD is a photosensitive drug and requires protection from light. A number of workers have tried to formulate various conventional and nonconventional dosage forms of AD. This review highlights all the formulations that have been developed to achieve maximum stability with the desired therapeutic action for the delivery of AD such as fast dissolving tablets, floating tablets, layered tablets, single-pill combinations, capsules, oral and transdermal films, suspensions, emulsions, mucoadhesive microspheres, gels, transdermal patches, and liposomal formulations. PMID:27822402

Valsartan independent of AT₁ receptor inhibits tissue factor, TLR-2 and -4 expression by regulation of Egr-1 through activation of AMPK in diabetic conditions.

PubMed

Ha, Yu Mi; Park, Eun Jung; Kang, Young Jin; Park, Sang Won; Kim, Hye Jung; Chang, Ki Churl

2014-10-01

Patients suffering from diabetes mellitus (DM) are at a severe risk of atherothrombosis. Early growth response (Egr)-1 is well characterized as a central mediator in vascular pathophysiology. We tested whether valsartan independent of Ang II type 1 receptor (AT1R) can reduce tissue factor (TF) and toll-like receptor (TLR)-2 and -4 by regulating Egr-1 in THP-1 cells and aorta in streptozotocin-induced diabetic mice. High glucose (HG, 15 mM) increased expressions of Egr-1, TF, TLR-2 and -4 which were significantly reduced by valsartan. HG increased Egr-1 expression by activation of PKC and ERK1/2 in THP-1 cells. Valsartan increased AMPK phosphorylation in a concentration and time-dependent manner via activation of LKB1. Valsartan inhibited Egr-1 without activation of PKC or ERK1/2. The reduced expression of Egr-1 by valsartan was reversed by either silencing Egr-1, or compound C, or DN-AMPK-transfected cells. Valsartan inhibited binding of NF-κB and Egr-1 to TF promoter in HG condition. Furthermore, valsartan reduced inflammatory cytokine (TNF-α, IL-6 and IL-1β) production and NF-κB activity in HG-activated THP-1 cells. Interestingly, these effects of valsartan were not affected by either silencing AT1R in THP-1 cells or CHO cells, which were devoid of AT1R. Importantly, administration of valsartan (20 mg/kg, i.p) for 8 weeks significantly reduced plasma TF activity, expression of Egr-1, TLR-2, -4 and TF in thoracic aorta and improved glucose tolerance of streptozotocin-induced diabetic mice. Taken together, we concluded that valsartan may reduce atherothrombosis in diabetic conditions through AMPK/Egr-1 regulation. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Valsartan independent of AT1 receptor inhibits tissue factor, TLR-2 and-4 expression by regulation of Egr-1 through activation of AMPK in diabetic conditions

PubMed Central

Ha, Yu Mi; Park, Eun Jung; Kang, Young Jin; Park, Sang Won; Kim, Hye Jung; Chang, Ki Churl

2014-01-01

Patients suffering from diabetes mellitus (DM) are at a severe risk of atherothrombosis. Early growth response (Egr)-1 is well characterized as a central mediator in vascular pathophysiology. We tested whether valsartan independent of Ang II type 1 receptor (AT1R) can reduce tissue factor (TF) and toll-like receptor (TLR)-2 and-4 by regulating Egr-1 in THP-1 cells and aorta in streptozotocin-induced diabetic mice. High glucose (HG, 15 mM) increased expressions of Egr-1, TF, TLR-2 and-4 which were significantly reduced by valsartan. HG increased Egr-1 expression by activation of PKC and ERK1/2 in THP-1 cells. Valsartan increased AMPK phosphorylation in a concentration and time-dependent manner via activation of LKB1. Valsartan inhibited Egr-1 without activation of PKC or ERK1/2. The reduced expression of Egr-1 by valsartan was reversed by either silencing Egr-1, or compound C, or DN-AMPK-transfected cells. Valsartan inhibited binding of NF-κB and Egr-1 to TF promoter in HG condition. Furthermore, valsartan reduced inflammatory cytokine (TNF-α, IL-6 and IL-1β) production and NF-κB activity in HG-activated THP-1 cells. Interestingly, these effects of valsartan were not affected by either silencing AT1R in THP-1 cells or CHO cells, which were devoid of AT1R. Importantly, administration of valsartan (20 mg/kg, i.p) for 8 weeks significantly reduced plasma TF activity, expression of Egr-1, TLR-2,-4 and TF in thoracic aorta and improved glucose tolerance of streptozotocin-induced diabetic mice. Taken together, we concluded that valsartan may reduce atherothrombosis in diabetic conditions through AMPK/Egr-1 regulation. PMID:25109475

Blood pressure control with amlodipine add-on therapy in patients with hypertension and diabetes: results of the Amlodipine Diabetic Hypertension Efficacy Response Evaluation Trial.

PubMed

Kloner, Robert A; Neutel, Joel; Roth, Eli M; Weiss, Robert; Weinberger, Myron H; Thakker, Kamlesh M; Schwartz, Brian; Shi, Harry; Gregg, Anne-Marie

2008-11-01

Attainment of blood pressure (BP) goals in patients with diabetes is critical both to reduce the risk of cardiovascular events and to delay the progression of renal disease. While therapeutic guidelines advise initial therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, monotherapy with these agents may not be sufficient to attain target BP. The ADHT (Amlodipine Diabetic Hypertension Efficacy Response Evaluation Trial) evaluated the efficacy and safety of adding amlodipine to the treatment regimen of patients with hypertension and diabetes who were already receiving either quinapril or losartan as monotherapy. ADHT was a double-blind, double-dummy, 22-week trial conducted in the US. After a washout period of 7-13 days, patients (aged 30-75 y) with hypertension and diabetes were randomized to receive quinapril 20 mg/day plus placebo or losartan 50 mg/day plus placebo for 4 weeks, titrated to 40 mg or 100 mg (if required), respectively, for an additional 4 weeks to achieve their BP goals (<130/80 mm Hg). At week 8, either amlodipine 5 mg/day or placebo was added for an additional 12 weeks, with titration to 10 mg at week 14 if the BP goal was not achieved. Efficacy of add-on therapy was evaluated in 411 patients (amlodipine 211, placebo 200). BP goal was reached by 27.5% of patients when amlodipine was added to quinapril or losartan monotherapy, compared with 12.5% when placebo was added (OR 2.73; 95% CI 1.61 to 4.64; p < 0.001). When added to quinapril or losartan monotherapy, amlodipine reduced BP by 8.1/5.4 mm Hg, compared with a 1.6/0.7 mm Hg decrease with add-on placebo (p < 0.001). Amlodipine, quinapril, and losartan were well tolerated. Amlodipine is safe and effective when added to quinapril or losartan monotherapy to help lower BP toward therapeutic targets in patients with hypertension and diabetes.

Transfer Behavior of the Weakly Acidic BCS Class II Drug Valsartan from the Stomach to the Small Intestine During Fasted and Fed States.

PubMed

Hamed, Rania; Alnadi, Sabreen Hasan

2018-05-07

The objective of this study was to investigate the transfer behavior of the weakly acidic BCS class II drug valsartan from the stomach to the small intestine during fasted and fed states. An in vitro transfer model previously introduced by Kostewicz et al. (J Pharm Pharmacol 56(1):43-51, 2004) based on a syringe pump and a USP paddle apparatus was used to determine the concentration profiles of valsartan in the small intestine. Donor phases of simulated gastric fluid during fasted (FaSSGF) and fed (FeSSGF) states were used to predisperse Diovan® tablets (160 mg valsartan). The initial concentrations of valsartan in FaSSGF and FeSSGF were 6.2 and 91.8%, respectively. Valsartan dispersions were then transferred to acceptor phases that simulate intestinal fluid and cover the physiological properties (pH, buffer capacity, and ionic strength) of the gastrointestinal fluid at a flow rate of 2 mL/min. The pH measurements were reported at time intervals corresponded to those of the transfer experiments to investigate the effect of percent dissolved of valsartan in the donor phase on lowering the pH of the acceptor phases. The f2 similarity test was used to compare the concentration profiles in the acceptor phases. In fasted state, the concentration of valsartan in the acceptor phases ranged between 33.1 and 89.4% after 240 min. Whereas in fed state, valsartan was fully dissolved in all acceptor phases within a range of 94.5-104.9% after 240 min. Therefore, the transfer model provides a useful screen for the concentrations of valsartan in the small intestine during fasted and fed states.

Adoption of Sacubitril/Valsartan for the Management of Patients With Heart Failure.

PubMed

Sangaralingham, Lindsey R; Sangaralingham, S Jeson; Shah, Nilay D; Yao, Xiaoxi; Dunlay, Shannon M

2018-02-01

The US Food and Drug Administration approved the use of sacubitril/valsartan in patients with heart failure with reduced ejection fraction in July 2015. We aimed to assess the adoption and prescription drug costs of sacubitril/valsartan in its first 18 months after Food and Drug Administration approval. Using a large US insurance database, we identified privately insured and Medicare Advantage beneficiaries who filled a first prescription for sacubitril/valsartan between July 1, 2015, and December 31, 2016. We compared them to patients treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Outcomes included adoption, prescription drug costs, and 180-day adherence, defined as a proportion of days covered ≥80%. A total of 2244 patients initiated sacubitril/valsartan. Although the number of users increased over time, the proportion of heart failure with reduced ejection fraction patients taking sacubitril/valsartan remained low (<3%). Patients prescribed sacubitril/valsartan were younger, more often male, with less comorbidity than those taking an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Although a majority of prescription costs were covered by the health plan (mean, $328.37; median, $362.44 per 30-day prescription), out-of-pocket costs were still high (mean, $71.16; median, $40.27). By comparison, median out-of-pocket costs were $2 to $3 for lisinopril, losartan, carvedilol, and spironolactone. Overall, 59.1% of patients were adherent to sacubitril/valsartan. Refill patterns suggested that nearly half of nonadherent patients discontinued sacubitril/valsartan within 180 days of starting. Adoption of sacubitril/valsartan after Food and Drug Administration approval has been slow and may be associated with the high cost. © 2018 American Heart Association, Inc.

Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment
.

PubMed

Kulmatycki, Kenneth M; Langenickel, Thomas; Ng, Wai Hong; Pal, Parasar; Zhou, Wei; Lin, Tsu-Han; Rajman, Iris; Chandra, Priyamvada; Sunkara, Gangadhar

2017-09-01

To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril C_max increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, C_max was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 - 109%, respectively. The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups.
.

Chronotherapeutically Modulated Pulsatile System of Valsartan Nanocrystals-an In Vitro and In Vivo Evaluation.

PubMed

Biswas, Nikhil; Kuotsu, Ketousetuo

2017-02-01

The objective was to improve the dissolution of valsartan by developing valsartan nanocrystals and design a pulsed release system for the chronotherapy of hypertension. Valsartan nanocrystals were prepared by sonication-anti-solvent precipitation method and lyophilized to obtain dry powder. Nanocrystals were directly compressed to minitablets and coated to achieve pulsatile valsartan release. Pharmacokinetic profiles of optimized and commercial formulations were compared in rabbit model. The mean particle size and PDI of the optimized nanocrystal batch V4 was reported as 211 nm and 0.117, respectively. DSC and PXRD analysis confirmed the crystalline nature of valsartan in nanocrystals. The dissolution extent of valsartan was markedly enhanced with both nanocrystals and minitablets as compared to pure valsartan irrespective of pH of the medium. Core minitablet V4F containing 5% w/w polyplasdone XL showed quickest release of valsartan, over 90% within 15 min. Coated formulation CV4F showed two spikes in release profile after successive lag times of 235 and 390 min. The pharmacokinetic study revealed that the bioavailability of optimized formulation (72.90%) was significantly higher than the commercial Diovan tablet (30.18%). The accelerated stability studies showed no significant changes in physicochemical properties, release behavior, and bioavialability of CV4F formulation. The formulation was successfully designed to achieve enhanced bioavailability and dual pulsatile release. Bedtime dosing will more efficiently control the circadian spikes of hypertension in the morning.

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

PubMed

Ushijima, Kentaro; Nakashima, Hajime; Shiga, Tsuyoshi; Harada, Kazuhiro; Ishikawa, Shizukiyo; Ioka, Takashi; Ando, Hitoshi; Fujimura, Akio

2015-01-01

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. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

In vitro interaction study of retinoic acid isomers with telmisartan and amlodipine by equilibrium dialysis method using UV spectroscopy

NASA Astrophysics Data System (ADS)

Varghese, Susheel John; Johny, Sojimol K.; Paul, David; Ravi, Thengungal Kochupappy

2011-07-01

The in vitro protein binding of retinoic acid isomers (isotretinoin and tretinoin) and the antihypertensive drugs (amlodipine and telmisartan) was studied by equilibrium dialysis method. In this study, free fraction of drugs and the % of binding of drugs in the mixture to bovine serum albumin (BSA) were calculated. The influence of retinoic acid isomers on the % of protein binding of telmisartan and amlodipine at physiological pH (7.4) and temperature (37 ± 0.5 °C) was also evaluated. The in vitro displacement interaction study of drugs telmisartan and amlodipine on retinoic acid isomers and also interaction of retinoic acid isomers on telmisartan and amlodipine were carried out.

Blood pressure variability and risk of cardiovascular events and death in patients with hypertension and different baseline risks.

PubMed

Mehlum, Maria H; Liestøl, Knut; Kjeldsen, Sverre E; Julius, Stevo; Hua, Tsushung A; Rothwell, Peter M; Mancia, Giuseppe; Parati, Gianfranco; Weber, Michael A; Berge, Eivind

2018-01-20

Blood pressure variability is associated with increased risk of cardiovascular events, particularly in high-risk patients. We assessed if variability was associated with increased risk of cardiovascular events and death in hypertensive patients at different risk levels. The Valsartan Antihypertensive Long-term Use Evaluation trial was a randomized controlled trial of valsartan vs. amlodipine in patients with hypertension and different risks of cardiovascular events, followed for a mean of 4.2 years. We calculated standard deviation (SD) of mean systolic blood pressure from visits from 6 months onward in patients with ≥3 visits and no events during the first 6 months. We compared the risk of cardiovascular events in the highest and lowest quintile of visit-to-visit blood pressure variability, using Cox regression. For analysis of death, variability was analysed as a continuous variable. Of 13 803 patients included, 1557 (11.3%) had a cardiovascular event and 1089 (7.9%) died. Patients in the highest quintile of SD had an increased risk of cardiovascular events [hazard ratio (HR) 2.1, 95% confidence interval (95% CI) 1.7-2.4; P < 0.0001], and a 5 mmHg increase in SD of systolic blood pressure was associated with a 10% increase in the risk of death (HR 1.10, 95% CI 1.04-1.17; P = 0.002). Associations were stronger among younger patients and patients with lower systolic blood pressure, and similar between patients with different baseline risks, except for higher risk of death among patients with established cardiovascular disease. Higher visit-to-visit systolic blood pressure variability is associated with increased risk of cardiovascular events in patients with hypertension, irrespective of baseline risk of cardiovascular events. Associations were stronger in younger patients and in those with lower mean systolic blood pressure. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.

A comparative assessment of the duration of action of amlodipine and nifedipine GITS in normotensive subjects.

PubMed

Ueda, S; Meredith, P A; Howie, C A; Elliott, H L

1993-12-01

1 This study in normotensive subjects compared the duration and consistency of action of amlodipine (5 mg) and nifedipine GITS (60 mg) by assessment of the attenuation of pressor responses to noradrenaline and angiotensin II. 2 Both drugs significantly attenuated pressor responses to both vasoconstrictors at 6 and 24 h post-dose with rightward shifts of up to 2.3-fold in the dose-response curves. 3 There was significantly less pharmacokinetic variability with amlodipine: for example, intra-subject variability was 33% with amlodipine and 59% with nifedipine GITS. 4 There were no significant differences in the pressor dose ratios up to 48 h post-dose with amlodipine whereas there was a significant and progressive reduction in the pressor dose ratios with nifedipine. 5 These results suggest that both drugs are broadly comparable as once daily treatments but amlodipine displayed less intra- and inter-subject variability and provided a significantly more sustained effect with a reserve of pharmacological activity up to 48 h post-dose.

Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease

PubMed Central

Assy, Nimer; Grozovski, Masha; Bersudsky, Ilana; Szvalb, Sergio; Hussein, Osamah

2006-01-01

AIM: To assess whether treatment with insulin-sensitizing agents (ISAs) in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the methionine choline-deficient diet (MCDD) rat model of non-alcoholic fatty liver disease (NAFLD). METHODS: Rats (n = 6 per group) were treated with different drugs, including MCDD only, MCDD diet with either metformin (200 mg/kg), rosiglitazone (3 mg/kg), metformin plus rosiglitazone (M+R), ezetimibe (2 mg/kg), valsartan (2 mg/kg), or combination of all drugs for a total of 15 wk. Liver histology, lipids, parameters of oxidative stress and TNF-alpha were measured. RESULTS: Fatty liver (FL) rats demonstrated severe hepatic fatty infiltration (> 91% fat), with an increase in hepatic TG (+1263%, P < 0.001), hepatic cholesterol (+245%, P < 0.03), hepatic MDA levels (+225%, P < 0.001), serum TNF-alpha (17.8 ± 10 vs 7.8 ± 0.0, P < 0.001), but a decrease in hepatic alpha tocopherol (-74%, P < 0.001) as compared to the control rats. Combination therapy with all drugs produced a significant decrease in liver steatosis (-54%), hepatic TG (-64%), hepatic cholesterol (-31%) and hepatic MDA (-70%), but increased hepatic alpha tocopherol (+443%) as compared to FL rats. Combination therapy with ISA alone produced a smaller decrease in liver steatosis (-32% vs -54%, P < 0.001) and in hepatic MDA levels (-55% vs -70%, P < 0.01), but a similar decrease in hepatic lipids when compared with the all drugs combination. TNF-alpha levels decreased significantly in all treatment groups except in ISA group. CONCLUSION: Combination therapies have a greater effect on liver fat content as compared to monotherapy. Rosiglitazone appears to improve hepatic steatosis to a greater extent than metformin. PMID:16865780

[Sacubitril / Valsartan in patients with diabetes and heart failure].

PubMed

Brandenburg, Vincent Matthias; Rocca, Hans-Peter Brunner-La; Marx, Nikolaus

2016-10-01

Sacubitril / Valsartan proofed to be an effective treatment compared to enalapril in reducing heart failure hospitalisations and mortality in patients with severe "Heart failure with reduced ejection fraction" (HFREF). Recent European cardiology guidelines attributed a class IB recommendation for Sacubitril / Valsartan in HFREF patients who remain symptomatic despite optimal treatment with ACE-I, a beta-blocker, and a mineralocorticoid receptor antagonist. There is a significant overlap between diabetic and HFREF patients and thus, efficacy assessment of Sacubitril / Valsartan is a clinically meaningful issue in the large subgroup of HFREF patients with diabetes. We discuss the present evidence why local authorities speculated about a potential interaction between the two diseases decreasing the efficacy of sacubitril/valsartan in terms of reducing relevant end-points in this cohort. Overall, Sacubitril / Valsartan is obviously a treatment option in diabetics with HFREF. However, diabetic cardiomyopathy needs to be recognised as a specific disease condition. © Georg Thieme Verlag KG Stuttgart · New York.

In vitro interaction study of retinoic acid isomers with telmisartan and amlodipine by equilibrium dialysis method using UV spectroscopy.

PubMed

Varghese, Susheel John; Johny, Sojimol K; Paul, David; Ravi, Thengungal Kochupappy

2011-07-01

The in vitro protein binding of retinoic acid isomers (isotretinoin and tretinoin) and the antihypertensive drugs (amlodipine and telmisartan) was studied by equilibrium dialysis method. In this study, free fraction of drugs and the % of binding of drugs in the mixture to bovine serum albumin (BSA) were calculated. The influence of retinoic acid isomers on the % of protein binding of telmisartan and amlodipine at physiological pH (7.4) and temperature (37±0.5°C) was also evaluated. The in vitro displacement interaction study of drugs telmisartan and amlodipine on retinoic acid isomers and also interaction of retinoic acid isomers on telmisartan and amlodipine were carried out. Copyright © 2011 Elsevier B.V. All rights reserved.

Ventricular Arrhythmic Storm after Initiating Sacubitril/Valsartan.

PubMed

Vicent, Lourdes; Juárez, Miriam; Martín, Irene; García, Jorge; González-Saldívar, Hugo; Bruña, Vanesa; Devesa, Carolina; Sousa-Casasnovas, Iago; Fernández-Avilés, Francisco; Martínez-Sellés, Manuel

Sacubitril/valsartan was approved recently for the treatment of patients with heart failure and reduced ejection fraction. We present 6 cases of ventricular arrhythmia, that occurred shortly after sacubitril/valsartan initiation, that required drug withdrawal. Other potential triggering factors of electrical storm were ruled out and, from the arrhythmic perspective, all of the patients were stable in the previous year. Our aim is to describe the possible association of sacubitril/valsartan with arrhythmic storm. This was an observational monocentric study performed in the first 7 months of sacubitril/valsartan commercialization in Spain (October 2016). All patients were included in the SUMA (Sacubitril/Varsartan Usado Ambulatoriamente en Madrid [Sacubitril/Valsartan Used in Outpatients in Madrid]) registry. Patients were consecutively enrolled on the day they started the drug. Ventricular arrhythmic storm was defined as ≥2 episodes of sustained ventricular arrhythmia or defibrillator therapy application in 24 h. From 108 patients who received the drug, 6 presented with ventricular arrhythmic storm (5.6%). Baseline characteristics were similar in the patients with and without ventricular arrhythmic storm. The total number of days that sacubitril/valsartan was administered to each patient was 5, 6, 44 (8 since titration), 84, 93, and 136 (105 since titration), respectively. Our data are not enough to infer a cause-and-effect relationship. Further investigations regarding a potential proarrhythmic effect of sacubitril/valsartan are probably needed. © 2018 S. Karger AG, Basel.

Effect of valsartan on cardiac senescence and apoptosis in a rat model of cardiotoxicity.

PubMed

Sakr, Hussein F; Abbas, Amr M; Elsamanoudy, Ayman Z

2016-06-01

The clinical application of doxorubicin is limited by its cardiotoxicity. The present study investigated the effect of valsartan on doxorubicin-induced cardiotoxicity in rats. Rats were divided into 6 groups: control, control + valsartan (10 mg/kg, for 14 days, orally), doxorubicin-treated (2.5 mg/kg, 3 times/week for 2 weeks, intraperitoneally), valsartan then doxorubicin, valsartan + doxorubicin, and doxorubicin then valsartan. ECG, isolated heart, lipid peroxidation (thiobaribituric acid reactive substances (TBARS)), total antioxidant capacity (TAC), and Bax, Bcl-2, and senescence marker protein 30 (SMP30) gene expression were measured in cardiac tissue. Blood samples were collected to measure lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB). Doxorubicin significantly increased LDH, CK-MB, TBARS, heart rate (HR), Bax gene expression, and -dP/dtmax and decreased TAC, Bcl-2 and SMP30 gene expression, left ventricular developed pressure (LVDP), and +dP/dtmax. Also, doxorubicin lengthened ST, QT, and QTc intervals. Concurrent or post- but not pre-treatment of doxorubicin-treated rats with valsartan reduced LDH, CK-MB, TBARS, HR, Bax gene expression, -dP/dtmax, and ST, QT, and QTc intervals and increased TAC, Bcl-2 and SMP30 gene expression, LVDP, and +dP/dtmax. Therefore, we conclude that concurrent or post- but not pre-treatment of doxorubicin-induced rats with valsartan attenuated doxorubicin-induced cardiotoxicity through inhibiting oxidative stress, apoptosis, and senescence.

Design, formulation and optimization of valsartan transdermal gel containing iso-eucalyptol as novel permeation enhancer: preclinical assessment of pharmacokinetics in Wistar albino rats.

PubMed

Ahad, Abdul; Aqil, Mohd; Kohli, Kanchan; Sultana, Yasmin; Mujeeb, Mohd

2014-08-01

The aim of this study was to develop and optimize a transdermal gel formulation of valsartan using Box-Behnken design and to evaluate it for pharmacokinetic study. The independent variables were Carbopol 940 (X1), PEG 400 (X2) and ethanol (X3) while valsartan flux (Y1), Tlag (Y2) and gel viscosity (Y3) were the dependent variables. Iso-eucalyptol was added in all gel formulations as permeation enhancer except for control gel. It was observed that the permeation rate of valsartan significantly increased in direct proportion to the ethanol concentration, but significantly decreased in direct proportion to polymer concentration. Lag time and viscosity decreased in reverse proportion to ethanol concentration. The optimized valsartan gel formulation (VGF-OPT) yielded flux of 143.27 ± 7.11 µg/cm(2)/h and 27.55 ± 2.51 µg/cm(2)/h across rat and human cadaver skin, respectively. In vivo pharmacokinetic study of VGF-OPT-transdermal therapeutic system containing iso-eucalyptol showed a significant increase in the bioavailability (2.52 times) compared with oral formulation of valsartan by virtue of better permeation through Wistar rat skin. It was concluded that the developed transdermal gel accentuates the flux of valsartan and could be used as an antihypertensive dosage form for effective transdermal delivery of valsartan.

Comparative effects of amlodipine and benazepril on Left Atrial Pressure in Dogs with experimentally-induced Mitral Valve Regurgitation

PubMed Central

2012-01-01

Background One of the purposes of treatment for dogs with mitral regurgitation (MR) is lowering left atrial pressure (LAP). There has been few study of the amlodipine in dogs with MR and amlodipine’s effect on LAP has not been fully evaluated in a quantitative manner because of difficulties in directly measuring LAP. The objective of our study was to compare the short-term effects of amlodipine (0.2 mg/kg PO q12h) vs benazepril (0.5 mg/kg PO q12h), on LAP and echocardiographic parameters in five beagle dogs with experimentally-induced MR. LAP of eight dogs that has own control were measured using radiotelemetry system at baseline and again on days 1, 2, 3, 4, 5, 6, 7 of the drug administration. Results Mean LAP decreased significantly after amlodipine (11.20 ± 4.19 mmHg vs 14.61 ± 3.81 mmHg at baseline, p < .01) but not after benazepril treatment (13.19 ± 3.47 mmHg, p > .05). LAP was lower after 7 days of amlodipine treatment than after 7 days of benazepril treatment. Significant reduction was seen for the first time 4 days after the administration amlodipine. The rate of the maximal area of the regurgitant jet signals to the left atrium area (ARJ/LAA) of the amlodipine treatment was significantly lower (p < .05) after 7 days compared to baseline. Other echocardiographic parameters did not change significantly. Conclusions LAP was significantly decreased after amlodipine treatment in dogs with surgically-induced MR but not after benazepril treatment. Although this study did not focus on adverse effects, amlodipine may be an effective drug for helping the patients with acute onset of severe MR, such as rupture of chordae tendinae or end stage patients were the LAP is likely to be elevated. Additional studies in clinical patients with degenerative mitral valve disease and acute chordal rupture are warranted because the blood-pressure lowering effects of amlodipine can decrease renal perfusion and this can further activate the RAAS. PMID:22989022

Stability of amlodipine besylate in two liquid dosage forms.

PubMed

Nahata, M C; Morosco, R S; Hipple, T F

1999-01-01

To determine the stability of amlodipine besylate in two liquid dosage forms under refrigeration and at room temperature. Commercially available amlodipine tablets (Norvasc-Pfizer) were used to prepare two suspensions: one in extemporaneously prepared 1% methylcellulose in syrup (1:1), and another in equal volumes of commercially available OraPlus/OraSweet. Each suspension containing amlodipine 1 mg/mL was stored in 10 plastic prescription bottles; 5 were stored at 4 degrees C and 5 at 25 degrees C. Samples were collected immediately after preparation (day 0) and on days 7, 14, 28, 42, 56, 70, and 91. Amlodipine concentration was measured by stability-indicating HPLC method (n = 15). Research laboratory at Children's Hospital. Physical and chemical stability (> 90% of the initial concentration) of amlodipine in the two extemporaneously prepared suspensions during storage in plastic prescription bottles at 4 degrees C and 25 degrees C. Observed mean concentrations exceeded 90% of the initial concentrations in both suspensions for 91 days at 4 degrees C and 56 days at 25 degrees C. No noticeable change in physical appearance or odor was observed; pH changed slightly in the methylcellulose-containing formulation stored at 25 degrees C. Amlodipine was stable in two suspensions when stored in plastic prescription bottles for 91 days at 4 degrees C or 56 days at 25 degrees C. These formulations may be considered for pediatric or elderly patients who are unable to swallow tablets. The liquid dosage form would also permit accurate administration of amlodipine doses to infants and young children based on their body weight.

CYP3A activity based on plasma 4β-hydroxycholesterol during the early postpartum period has an effect on the plasma disposition of amlodipine.

PubMed

Naito, Takafumi; Kubono, Naoko; Ishida, Takuya; Deguchi, Shuhei; Sugihara, Masahisa; Itoh, Hiroaki; Kanayama, Naohiro; Kawakami, Junichi

2015-12-01

This study aimed to evaluate plasma 4β-hydroxycholesterol as an endogenous marker of CYP3A4/5 activity in early postpartum women and its impact on the plasma disposition of amlodipine. Twenty-seven early postpartum women treated with amlodipine for pregnancy-induced hypertension were enrolled. The plasma concentration of 4β-hydroxycholesterol and its ratio to cholesterol in postpartum and in non-perinatal women were evaluated. The predose plasma concentration of amlodipine was determined at steady state. The medians of the plasma 4β-hydroxycholesterol concentration at day 0-3 and 8-21 after delivery were 146 and 161 ng/mL, respectively. No significant difference was observed in the plasma concentration of 4β-hydroxycholesterol between the postpartum periods. The plasma concentration of 4β-hydroxycholesterol and its ratio to cholesterol in postpartum women were significantly higher than those in non-perinatal women. A large individual variability was observed in the dose-normalized plasma concentration of amlodipine in early postpartum women. A weak negative correlation was observed between the dose-normalized plasma concentration of amlodipine and the plasma concentration of 4β-hydroxycholesterol. In conclusion, early postpartum women possessed higher CYP3A activity based on plasma 4β-hydroxycholesterol and had a large pharmacokinetic variability in amlodipine. CYP3A activity during the early postpartum period had an effect on the plasma disposition of amlodipine. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Cardioprotective effects of amlodipine on ischemia and reperfusion in two experimental models.

PubMed

Hoff, P T; Tamura, Y; Lucchesi, B R

1990-11-20

The cardioprotective effect of amlodipine, a long-acting dihydropyridine derivative, was studied in 2 experimental models of ischemia and reperfusion. Isolated and blood-perfused feline hearts were made globally ischemic for 60 minutes and then reperfused for 60 minutes. Alterations of left ventricular developed pressure and compliance were monitored in both amlodipine-treated hearts and saline-treated control animals. Changes in perfusion pressure indicated that amlodipine significantly reduced myocardial oxygen consumption and coronary vascular resistance. Furthermore, a progressive increase in resting left ventricular diastolic pressure indicated that amlodipine, administered before the onset of global ischemia, attenuated the development of ischemic contracture. Return of contractile function 60 minutes after reperfusion and maintenance of tissue concentrations of electrolytes were significantly better in the amlodipine-treated group than in the control animals. In intact canine hearts, regional myocardial ischemia was induced for 90 minutes, followed by 6 hours of reperfusion. Although the hemodynamic variables and the size of the region of risk did not differ significantly between treated animals and control animals, the infarct size was significantly smaller in the amlodipine-treated group than in the control animals, and a gradual reduction in coronary blood flow was observed in the control group that was prevented in the amlodipine group. A comparison of these findings with those observed with oxygen radical scavengers also is discussed. A detailed report of these studies was published in The American Journal of Cardiology (1989;64:101I-116I). This review is included here to maintain continuity of the symposium for the convenience of the reader.

Cost-effectiveness analysis of valsartan versus losartan and the effect of switching.

PubMed

Baker, Timothy M; Goh, Jowern; Johnston, Atholl; Falvey, Heather; Brede, Yvonne; Brown, Ruth E

2012-01-01

Losartan will shortly become generic, and this may encourage switching to the generic drug. However, valsartan was shown in a meta-analysis to be statistically superior in lowering blood pressure (BP) to losartan. This paper examines the costs of treatment with these two drugs and the potential consequences of switching established valsartan patients to generic losartan. A US payer cost-effectiveness model was developed incorporating the risk of cardiovascular disease (CVD) events related to systolic blood pressure (SBP) control comparing valsartan to continual losartan and switching from valsartan to generic losartan. The model, based upon a meta-analysis by Nixon et al. and Framingham equations, included first CVD event costs calculated from US administrative data sets and utility values from published sources. The modeled outcomes were number of CVD events, costs and incremental cost per quality-adjusted life-year (QALY) and life-year (LY). Fewer patients had fatal and non-fatal CVD events with valsartan therapy compared with continual losartan and with patients switched from valsartan to generic losartan. The base-case model results indicated that continued treatment with valsartan had an incremental cost-effectiveness ratio of $27,268 and $25,460 per life year gained, and $32,313 and $30,170 per QALY gained, relative to continual losartan and switching treatments, respectively. Sensitivity analyses found that patient discontinuation post-switching was a sensitive parameter. Including efficacy offsets with lowered adherence or discontinuation resulted in more favorable ratios for valsartan compared to switching therapy. The model does not evaluate post-primary CVD events and considers change in SBP from baseline level as the sole predictor of CVD risk. Valsartan appears to be cost-effective compared to switching to generic losartan and switching to the generic drug does not support a cost offset argument over the longer term. Physicians should continue to consider the needs of individual patient and not cost offsets.

Cost-effectiveness of sacubitril/valsartan versus enalapril in patients with heart failure and reduced ejection fraction.

PubMed

Liang, Lin; Bin-Chia Wu, David; Aziz, Mohamed Ismail Abdul; Wong, Raymond; Sim, David; Leong, Kui Toh Gerard; Wei, Yong Quek; Tan, Doreen; Ng, Kwong

2018-02-01

Sacubitril/valsartan reduces cardiovascular death and hospitalizations for heart failure (HF). However, decision-makers need to determine whether its benefits are worth the additional costs, given the low-cost generic status of traditional standard of care. To evaluate the cost-effectiveness of sacubitril/valsartan compared to enalapril in patients with HF and reduced ejection fraction, from the Singapore healthcare payer perspective. A Markov model was developed to project clinical and economic outcomes of sacubitril/valsartan vs enalapril for 66-year-old patients with HF over 10 years. Key health states included New York Heart Association classes I-IV and deaths; patients in each state incurred a monthly risk of hospitalization for HF and cardiovascular death. Sacubitril/valsartan benefits were modeled by applying the hazard ratios (HRs) in PARADIGM-HF trial to baseline probabilities. Primary model outcomes were total and incremental costs and quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) for sacubitril/valsartan relative to enalapril Results: Compared to enalapril, sacubitril/valsartan was associated with an ICER of SGD 74,592 (USD 55,198) per QALY gained. A major driver of cost-effectiveness was the cardiovascular mortality benefit of sacubitril/valsartan. The uncertainty of this treatment benefit in the Asian sub-group was tested in sensitivity analyses using a HR of 1 as an upper limit, where the ICERs ranged from SGD 41,019 (USD 30,354) to SGD 1,447,103 (USD 1,070,856) per QALY gained. Probabilistic sensitivity analyses showed the probability of sacubitril/valsartan being cost-effective was below 1%, 12%, and 71% at SGD 20,000, SGD 50,000, and SGD 100,000 per QALY gained, respectively. At the current daily price sacubitril/valsartan may not represent good value for limited healthcare dollars compared to enalapril in reducing cardiovascular morbidity and mortality in HF in the Singapore healthcare setting. This study highlights the cost-benefit trade-off that healthcare professionals and patients face when considering therapy.

Efficacy and Safety of Sacubitril/Valsartan (LCZ696) Compared With Olmesartan in Elderly Asian Patients (≥65 Years) With Systolic Hypertension.

PubMed

Supasyndh, Ouppatham; Wang, Jian'an; Hafeez, Kudsia; Zhang, Ying; Zhang, Jack; Rakugi, Hiromi

2017-11-06

Systolic hypertension is common in elderly patients and remains a challenge to treat effectively. The efficacy and safety of sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, vs. olmesartan was evaluated in elderly Asian patients (≥65 years) with systolic hypertension. In this randomized, double-blind, 14-week study, patients initially received once-daily sacubitril/valsartan 100 mg or olmesartan 10 mg, increased to sacubitril/valsartan 200 mg or olmesartan 20 mg at week 4. At week 10, for patients with blood pressure (BP) >140/90 mm Hg, the doses were up-titrated to sacubitril/valsartan 400 mg or olmesartan 40 mg. The primary assessment was superiority of sacubitril/valsartan vs. olmesartan in reducing office mean sitting (ms) systolic BP (msSBP) from baseline at week 10. Secondary efficacy assessments included changes from baseline in ms diastolic BP (msDBP), ms pulse pressure (msPP), 24-hour mean ambulatory (ma) BP (maBP), and maPP at week 10; msBP and msPP at weeks 4 and 14. Overall, 588 patients were randomized (mean age, 70.7 years; baseline msBP, 160.3/84.9 mm Hg; msPP, 75.4 mm Hg). At week 10, sacubitril/valsartan provided superior msSBP reductions vs. olmesartan (22.71 vs. 16.11 mm Hg, respectively; P < 0.001); similarly, reductions from baseline in other BP and PP assessments were significantly greater with sacubitril/valsartan. At week 14, despite more patients requiring up-titration in the olmesartan group, msBP and msPP reductions from baseline were significantly greater with sacubitril/valsartan. Both treatments were generally well-tolerated. Sacubitril/valsartan is more effective than olmesartan in reducing BP in elderly Asian patients with systolic hypertension. © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Effect of valsartan on kidney outcomes in people with impaired glucose tolerance.

PubMed

Currie, Gemma; Bethel, M Angelyn; Holzhauer, Björn; Haffner, Steven M; Holman, Rury R; McMurray, John J V

2017-06-01

To examine the effect of valsartan on kidney outcomes in patients with impaired glucose tolerance (IGT). In a double-blind randomized trial, 9306 patients with IGT were assigned to valsartan (160 mg daily) or placebo. The co-primary endpoints were the development of diabetes and two composite cardiovascular outcomes. Prespecified renal endpoints included: the composite of renal death, end-stage renal disease (ESRD) or doubling of serum creatinine; estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m 2 ; hospitalization for renal failure; and progression from normoalbuminuria to microalbuminuria, microalbuminuria to macroalbuminuria, and normoalbuminuria to macroalbuminuria. The median follow-up was 6.2 years. Valsartan reduced the incidence of diabetes but not cardiovascular events. In the valsartan group, 25/4631 patients (0.5%), vs 26/4675 (0.6%) patients in the placebo group, developed ESRD or experienced doubling of serum creatinine (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.55-1.66; P  = .87). Few patients in either group developed an eGFR of ≤30 mL/min/1.73 m 2 or had a renal hospitalization. Fewer patients on valsartan (237/4084 [5.8%]) than on placebo (342/4092 [8.4%]) developed microalbuminuria (HR 0.68, 95% CI 0.57-0.80; P  < .0001), and fewer valsartan-treated patients developed macroalbuminuria. Overall, urinary albumin-to-creatinine ratio (UACR) was 11% lower with valsartan (95% CI 8-13; P  < .0001) and 9% lower (95% CI 6-11; P  < .0001) after adjusting for both glucose and blood pressure. The effect of valsartan on UACR was not wholly explained by change in blood pressure or glucose. Valsartan reduced the incidence of microalbuminuria in IGT without increasing the incidence of hyperkalaemia or renal dysfunction compared with placebo. © 2017 John Wiley & Sons Ltd.

LCZ696 (Valsartan/Sacubitril)--A Possible New Treatment for Hypertension and Heart Failure.

PubMed

Andersen, Mathilde Borring; Simonsen, Ulf; Wehland, Markus; Pietsch, Jessica; Grimm, Daniela

2016-01-01

The aim of this MiniReview was to introduce the newly invented dual-acting drug valsartan/sacubitril (LCZ696), which combines an angiotensin receptor blocker (valsartan) with sacubitril, a specific inhibitor of the neutral endopeptidase (NEP) that degrades vasoactive peptides, including natriuretic peptides ANP and BNP, but also glucagon, enkephalins and bradykinin, among others. The MiniReview presents the data of four available trials NCT01193101, NCT00549770, NCT00887588 and NCT01035255 and provides the current knowledge about LCZ696 effects in patients with hypertension and heart failure. Presently, patients suffering from hypertension and heart failure are treated with ACE inhibitors or angiotensin receptor antagonists often in combination with other drugs. These current medications lead to a reduction in blood pressure in hypertensive patients and a decreased mortality and morbidity in patients with heart failure with reduced ejection fraction, but not in patients with heart failure with preserved ejection fraction. LCZ696 had been tested to utilize the beneficial properties of natriuretic peptides in combination with angiotensin receptor antagonism. It induces even greater blood pressure reductions and decreased mortality and morbidity in patients with heart failure with reduced ejection fraction, while patients with heart failure with preserved ejection fraction show lowered blood pressure and decreased NT-pro-BNP levels. Although long-term studies remain to be performed, these initial data suggest that there is a potential clinical benefit of LCZ696 in the treatment of hypertension and heart failure. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

[Protective effect of amlodipine on the cytotoxicity induced by contrast media in human kidney cells].

PubMed

Zhou, Xiao-rong; Duan, Shao-bin; Peng, You-ming; Liu, Fu-you; Ye, Yun; Liu, Rui-hong; Li, Gui-yuan

2007-10-01

To explore the protective effect of amlodipine on the cytotoxicity induced by contrast media (meglumine diatrizoate) in human kidney cells (HKC). An HKC line was used. The experiment was divided into 4 groups: a model group (diatrizoate 111g/L), a prevention group (diatrizoate 111g/L+amlodipine 10(-5)mol/L), an amlodipine control group (amlodipine 10(-5)mol/L), and a culture medium control group (simple none blood serum DMEM-F12 medium). Cytotoxicity induced by meglumine diatrizoate was analysed by methyl thiazolyl tetrazolium (MTT) test, lactate dehydrogenase (LDH) assay, Hochest33258 fluorescence stained cytospins, and flow cytometric DNA analysis. The protein expression of Bax was determined by Western blot, and caspase-3 activity was examined by fluorometric method. In the prevention group, the cell viability increased significantly (P<0.05), LDH levels decreased (P<0.05), and the apoptosis was lower than that of the model group (P<0.05) .Bax protein expression and caspase 3 activity decreased (P<0.05). Amlodipine can inhibit the HKC apoptosis and protect the renal tubule cell from injury induced by meglumine diatrizoate.

Valsartan attenuates bleomycin-induced pulmonary fibrosis by inhibition of NF-κB expression and regulation of Th1/Th2 cytokines.

PubMed

Mojiri-Forushani, Hoda; Hemmati, Ali Asghar; Khodadadi, Ali; Rashno, Mohammad

2018-06-01

Pulmonary fibrosis (PF) is a chronic respiratory system disease. The role of inflammation and angiotensin in the development and progression of PF has previously been demonstrated. Alternation in antifibrotic/profibrotic mediators and NF-κB activation have important roles in PF development. NF-κB, a nuclear factor, induces the transcription of inflammatory and pro-inflammatory cytokines. The aim of this study was to evaluate the effect of valsartan as an angiotensin receptor blocker on IL-4, INF-γ, and NF-κB expression in the treatment of PF. Rats were divided into five groups: groups I (bleomycin) and II (control) received a single injection of bleomycin (7.5 IU/kg) or vehicle, respectively. Groups III-V received valsartan (20, 40, and 80 mg/kg, respectively) orally a week before and for 3 weeks after the bleomycin injection. Serum levels of IL-4 and INF- γ were then measured. Relative NF-κB expression was investigated by real-time PCR. Histopathological examination showed the anti-inflammation effect of valsartan. Bleomycin significantly increased IL-4 serum level and decreased that of INF-γ in the serum. Valsartan could restore their levels to normal. Valsartan raised the decreased ratio of INF-γ/IL-4. Exposure to bleomycin elevated NF-κB expression; and valsartan decreased the increased gene expression. Valsartan as an angiotensin receptor antagonist presumably by blocking angiotensin receptor causes to ameliorated PF, which was at least partly due to antifibrotic/profibrotic cytokine regulation and reduced NF-κB expression. Valsartan showed a significant protective effect against bleomycin-induced PF.

Sacubitril/valsartan: An important piece in the therapeutic puzzle of heart failure.

PubMed

Marques da Silva, Pedro; Aguiar, Carlos

2017-09-01

Sacubitril/valsartan (LCZ696), a supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, was recently approved in the EU and the USA for the treatment of chronic heart failure (HF) with reduced ejection fraction (HFrEF) (NYHA class II-IV). Inhibition of chronically activated neurohormonal pathways (the renin-angiotensin-aldosterone system [RAAS] and sympathetic nervous system [SNS]) is central to the treatment of chronic HFrEF. Furthermore, enhancement of the natriuretic peptide (NP) system, with favorable cardiovascular (CV) and renal effects in HF, is a desirable therapeutic goal to complement RAAS and SNS blockade. Sacubitril/valsartan represents a novel pharmacological approach that acts by enhancing the NP system via inhibition of neprilysin (an enzyme that degrades NPs) and by suppressing the RAAS via AT1 receptor blockade, thereby producing more effective neurohormonal modulation than can be achieved with RAAS inhibition alone. In the large, randomized, double-blind PARADIGM-HF trial, replacement of an angiotensin-converting enzyme inhibitor (ACEI) (enalapril) with sacubitril/valsartan resulted in a significant improvement in morbidity and mortality in patients with HFrEF. Sacubitril/valsartan was superior to enalapril in reducing the risk of CV death or HF hospitalization (composite primary endpoint) and all-cause death, and in limiting progression of HF. Sacubitril/valsartan was generally well tolerated, with a comparable safety profile to enalapril; symptomatic hypotension was more common with sacubitril/valsartan, whereas renal dysfunction, hyperkalemia and cough were less common compared with enalapril. In summary, sacubitril/valsartan is a superior alternative to ACEIs/ARBs in the treatment of HFrEF, a recommendation that is reflected in many HF guidelines. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Valsartan reduces AT1-AA-induced apoptosis through suppression oxidative stress mediated ER stress in endothelial progenitor cells.

PubMed

Wang, Z-C; Qi, J; Liu, L-M; Li, J; Xu, H-Y; Liang, B; Li, B

2017-03-01

Valsartan has been reported to have the function of treating hypertension and improving the prognosis of patients. Many studies indicated that valsartan can also increase angiotensin II, andosterone and plasma renin activity (PRA). Autoantibodies against the angiotensin II type 1 receptor (AT1-AA) have been showed to increase reactive oxygen species (ROS) and calcium (Ca2+) and result in apoptosis in vascular smooth muscle cells. In this study, we attempted to explore the effect of valsartan on AT1-AA-induced apoptosis in endothelial progenitor cells. Endothelial progenitor cells (EPCs) were cultured. The cytotoxicity was determined by MTT assay. EPCs apoptosis was determined by DAPI staining and flow cytometry. Reactive oxygen species, intracellular calcium concentration and calpain activity were measured using Fluostar Omega Spectrofluorimeter. The expression of p-ERK, p-eIF-2a, CHOP, Bcl-2 and caspase-3 were detected by Western blot. MTT assays showed valsartan significantly inhibited AT1-AA- induced decline of the viability of EPCs. DAPI staining and flow cytometry results indicated valsartan inhibited AT1-AA-induced decline of the viability of EPCs via inhibiting AT1-AA-induced apoptosis. Furthermore, the increasing of reactive oxygen species, intracellular calcium and calpain activity induced by AT1-AA in EPCs were also recovered after pre-treated with valsartan. Meanwhile, the upregulation of p-ERK, p-eIF-2a and CHOP, downregulation of Bcl-2, and activation of Caspase-3 caused by AT1-AA were reversed after pre-incubated with valsartan. Valsartan could inhibit AT1-AA-induced apoptosis through inhibiting oxidative stress mediated ER stress in EPCs.

The effect of losartan and amlodipine on left ventricular diastolic function and atherosclerosis in Japanese patients with mild-to-moderate hypertension (J-ELAN) study.

PubMed

Yamamoto, Kazuhiro; Ozaki, Hitoshi; Takayasu, Ken; Akehi, Noriyuki; Fukui, Sugao; Sakai, Akihiko; Kodama, Mineo; Shimonagata, Tsuyoshi; Kobayashi, Keiji; Ota, Mitsushige; Horiguchi, Yasunori; Ebisuno, Shoji; Katsube, Yoshiki; Yamazaki, Tsutomu; Ohtsu, Hiroshi; Hori, Masatsugu

2011-03-01

This study was a prospective, randomized, open, blinded endpoint study to assess the effects of angiotensin II type 1 receptor blocker, losartan, compared with calcium channel blocker, amlodipine, on left ventricular (LV) diastolic function and atherosclerosis of the carotid artery in Japanese patients with mild-to-moderate hypertension, LV hypertrophy, diastolic dysfunction and preserved systolic function. Fifty-seven patients were randomly assigned to losartan- or amlodipine-based treatment groups and were followed up for 18 months. Blood pressure was similarly reduced by both regimens. Losartan shortened the transmitral E-wave deceleration time, and amlodipine reduced LV mass index; however, there was no significant difference in the percent changes of these indices between the two groups. Mean carotid intima-media thickness (mean IMT) as well as plaque score significantly increased in the amlodipine-based regimen (pre: 1.05±0.26 mm, follow-up: 1.23±0.33 mm, P=0.0015), but not in the losartan-based regimen (pre: 1.08±0.35 mm, follow-up: 1.16±0.52 mm, P=non-significant). The percent increase in mean IMT in the amlodipine-based regimen tended to be large compared with the losartan-based regimen (amlodipine: 19.8±23.7%, losartan: 6.9±23.3%, P=0.06). Under similar reduction of blood pressure, losartan is likely effective in protecting the progression of atherosclerosis of the carotid artery compared with amlodipine. Losartan may improve LV diastolic function, and amlodipine may attenuate LV hypertrophy; however, this study cannot make consecutive remarks about the superiority of either treatment regimen in the effects on cardiac function and geometry. This study has been registered at http://www.umin.ac.jp/ctr/listj/ (identifier C000000319). © 2011 The Japanese Society of Hypertension All rights reserved

Valsartan-induced acute pancreatitis.

PubMed

Can, Burak; Sali, Mursel; Batman, Adnan; Yilmaz, Hasan; Korkmaz, Ugur; Celebi, Altay; Senturk, Omer; Hulagu, Sadettin

2014-01-01

Gastrointestinal toxicity is uncommon among patients treated with angiotensin II receptor antagonists. A 58-year-old man presented with nausea, vomiting and constant pain in the epigastrium that radiated to the flanks. He received treatment with valsartan (160 mg daily) for hypertension. The clinical, biochemical and radiological findings were compatible with a diagnosis of acute pancreatitis. After the patient achieved a clinical and biochemical recovery, the valsartan therapy was started again. Six weeks later, he returned to the hospital with an attack of pancreatitis. Subsequently, he returned with repeated attacks of pancreatitis twice, and the valsartan was discontinued. Ten months after the treatment, the patient had no complaints. When severe abdominal symptoms occur for no apparent reason during treatment with valsartan, a diagnosis of pancreatitis should be considered.

Surface-imprinted microspheres prepared by a template-oriented method for the chiral separation of amlodipine.

PubMed

Lai, Shenzhi; Ouyang, Xiaoli; Cai, Changqun; Xu, Wensheng; Chen, Chunyan; Chen, Xiaoming

2017-05-01

The surface imprinting technique has been developed to overcome the mass-transfer difficulty, but the utilization ratio of template molecules in the imprinting procedure still remains a challengeable task to be improved. In this work, specifically designed surface-imprinted microspheres were prepared by a template-oriented method for enantioseparation of amlodipine besylate. Submicron mesoporous silica microspheres were surface-modified with double bonds, followed by polymerizing methacrylic acid to generate carboxyl modified mesoporous silica microspheres (PMAA@SiO 2 ). Afterwards, PMAA@SiO 2 was densely adsorbed with (S)-amlodipine molecules to immobilize template molecules through multiple hydrogen bonding interactions. Then surface molecular imprinting was carried out by cross-linking the carboxyl group of PMAA@SiO 2 with ethylene glycol diglycidyl ether. The surface-imprinted microspheres showed fast binding kinetics of only 20 min for equilibrium adsorption, and the saturation adsorption capacity reached 137 mg/g. The imprinted materials displayed appreciable chiral separation ability when used as column chromatography for enantioseparation of amlodipine from amlodipine besylate, and the enantiomeric excess of (S)-amlodipine reached 13.8% with only 2.3 cm column length by no extra chiral additives. Besides, the imprinted materials exhibited excellent reusability, and this allows the potential application for amplification production of amlodipine enantiomer. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The effects of missed doses of amlodipine and losartan on blood pressure in older hypertensive patients.

PubMed

de Leeuw, Peter W; Fagard, Robert; Kroon, Abraham A

2017-06-01

This randomized, double-blind, parallel-group, multicenter study compared the efficacy of amlodipine and losartan in an older hypertensive population, focusing on therapeutic coverage in the case of missed doses. Following a 4-week, single-blind, placebo washout period, 211 patients were randomly assigned to receive either 5 mg of amlodipine once daily or 50 mg of losartan once daily. Doses were doubled after 6 weeks of treatment if the diastolic blood pressure exceeded 90 mm Hg. After the 12-week treatment period, patients received the placebo for 2 days (drug holiday) to simulate two missed doses of antihypertensive medication. Twenty-four-hour ambulatory blood pressure monitoring was conducted at the end of the placebo washout period (baseline), upon completion of the 12-week treatment period (steady state), and after the 2-day drug holiday. Amlodipine was more effective than losartan in reducing patients' 24-h ambulatory blood pressure at the steady-state sampling time. The increases in 24-h blood pressure during the drug holiday averaged 6±2/2±1 mm Hg (P<0.0001) in the amlodipine group and 3±2/2±1 mm Hg (P<0.0001) in the losartan group. The rise in systolic pressure was greater in patients on amlodipine than in those on losartan (P<0.0001). For diastolic pressure, the changes did not differ. Owing to the lower pressure during treatment, patients in the amlodipine group remained at a significantly lower blood pressure level after the 2-day drug holiday. Amlodipine was more effective than losartan in lowering blood pressure and in maintaining blood pressure control after two missed doses, and the difference was most significant for systolic blood pressure.

Evaluation of the Efficacy and Safety of the Lercanidipine/Valsartan Combination in Korean Patients With Essential Hypertension Not Adequately Controlled With Lercanidipine Monotherapy: A Randomized, Multicenter, Parallel Design, Phase III Clinical Trial.

PubMed

Na, Sang-Hoon; Lee, Hae-Young; Hong Baek, Sang; Jeon, Hui-Kyung; Kang, Jin-Ho; Kim, Yoon-Nyun; Park, Chang-Gyu; Ryu, Jae-Kean; Rhee, Moo-Yong; Kim, Moo-Hyun; Hong, Taek-Jong; Choi, Dong-Ju; Cho, Seong-Wook; Cha, Dong-Hun; Jeon, Eun-Seok; Kim, Jae-Joong; Shin, Joon-Han; Park, Sung-Ha; Lee, Seung-Hwan; John, Sung-Hee; Shin, Eun-Seok; Kim, Nam-Ho; Lee, Sung-Yun; Kwan, Jun; Jeong, Myung-Ho; Kim, Sang-Wook; Jeong, Jin-Ok; Kim, Dong-Woon; Lee, Nam-Ho; Park, Woo-Jung; Ahn, Jeong-Cheon; Won, Kyung-Heon; Uk Lee, Seung; Cho, Jang-Hyun; Kim, Soon-Kil; Ahn, Taehoon; Hong, Sukkeun; Yoo, Sang-Yong; Kim, Song-Yi; Kim, Byung-Soo; Juhn, Jae-Hyeon; Kim, Sun-Young; Lee, Yu-Jeong; Oh, Byung-Hee

2015-08-01

The objective of this study was to evaluate the efficacy and safety of the lercanidipine/valsartan combination compared with lercanidipine monotherapy in patients with hypertension. Part 1 of this study was the randomized, multicenter, double-blind, parallel group, Phase III, 8-week clinical trial to compare superiority of lercanidipine 10 mg/valsartan 80 mg (L10/V80) and lercanidipine 10 mg/valsartan 160 mg (L10/V160) combinations with lercanidipine 10 mg (L10) monotherapy. At screening, hypertensive patients, whose diastolic blood pressure (DBP) was >90 mm Hg after 4 weeks with L10, were randomized to 3 groups of L10, L10/V80, and L10/V160. The primary end point was the change in the mean sitting DBP from baseline (week 0) after 8 weeks of therapy. Patients who were randomly assigned to L10/V160 and whose mean DBP was still ≥ 90 mm Hg in part 1 were enrolled to the up-titration extension study with lercanidipine 20 mg/valsartan 160 mg (L20/V160) (part 2). Of 772 patients screened, 497 were randomized to 3 groups (166 in the L10 group, 168 in the L10/V80 group, and 163 in the L10/V160 group). Mean (SD) age was 55 (9.9) years, and male patients comprised 69%. The mean (SD) baseline systolic blood pressure (SBP)/DBP were 148.4 (15.1)/94.3 (9.5) mm Hg. No significant differences were found between groups in baseline characteristics except the percentages of previous history of antihypertensive medication. The primary end points, the changes of mean (SD) DBP at week 8 from the baseline were -2.0 (8.8) mm Hg in the L10 group, -6.7 (8.5) mm Hg in L10/V80 group, and -8.1 (8.4) mm Hg in L10/V160 group. The adjusted mean difference between the combination groups and the L10 monotherapy group was -4.6 mm Hg (95% CI, -6.5 to -2.6; P < 0.001) in the L10/V80 group and -5.9 mm Hg (95% CI, -7.9 to -4.0, P < 0.001) in the L10/V160 group, which had significantly greater efficacy in BP lowering. A total of 74 patients were enrolled in the part 2 extension study. Changes of mean (SD) DBP and SBP from week 8 to week 12 and week 16 were -5.6 (7.9)/-8.0 (12.0) mm Hg and -5.5 (7.0)/-8.5 (11.3) mm Hg, respectively. For evaluation of the safety profile, the frequencies of adverse events between groups were also not significantly different. The most frequently reported adverse events were headache (6 cases, 20.7%) in the L10 group, dizziness (8 cases, 16.3%) in L10/V80 group, and nasopharyngitis (3 cases, 9.4%) in L10/V160 group, and the incidences of adverse events were not different between groups. Treatment of L10/V80 or L10/V160 combination therapy resulted in significantly greater BP lowering compared with L10 monotherapy. Moreover, the L20/V160 high dose combination had additional BP lowering effect compared with nonresponders with the L10/V160 combination. ClinicalTrials.gov: NCT01928628. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Gateways to Clinical Trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2002-09-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Adalimumab, aeroDose insulin inhaler, agomelatine, alendronic acid sodium salt, aliskiren fumarate, alteplase, amlodipine, aspirin, atazanavir; Bacillus Calmette-Guérin, basiliximab, BQ-788, bupropion hydrochloride; Cabergoline, caffeine citrate, carbamazepine, carvedilol, celecoxib, cyclosporine, clopidogrel hydrogensulfate, colestyramine; Dexamethasone, diclofenac sodium, digoxin, dipyridamole, docetaxel, dutasteride; Eletriptan, enfuvirtidie, eplerenone, ergotamine tartrate, esomeprazole magnesium, estramustine phosphate sodium; Finasteride, fluticasone propionate, fosinopril sodium; Ganciclovir, GBE-761-ONC, glatiramer acetate, gliclazide, granulocyte-CSF; Heparin sodium, human isophane insulin (pyr), Hydrochlorothiazide; Ibuprofen, inhaled insulin, interferon alfa, interferon beta-1a; Laminvudine, lansoprazole, lisinopril, lonafarnib, losartan potassium, lumiracoxib; MAb G250, meloxicam methotrexate, methylprednisolone aceponate, mitomycin, mycophenolate mofetil; Naproxen sodium, natalizumab, nelfinavir mesilate, nemifitide ditriflutate, nimesulide; Omalizumab, omapatrilat, omeprazole, oxybutynin chloride; Pantoprazole sodium, paracetamol, paroxetine, pentoxifylline, pergolide mesylate, permixon, phVEGF-A165, pramipexole hydrochloride, prasterone, prednisone, probucol, propiverine hydrochloride; Rabeprazole sodium, resiniferatoxin, risedronate sodium, risperidone, rofecoxib rosiglitazone maleate, ruboxistaurin mesilate hydrate; Selegiline transdermal system, sertraline, sildenafil citrate, streptokinase; Tadalafil, tamsulosin hydrochloride, technosphere/Insulin, tegaserod maleate, tenofovir disoproxil fumarate, testosterone heptanoate, testosterone undecanoate, tipifarnib, tolterodine tartrate, topiramate, troglitazone; Ursodeoxycholic acid; Valdecoxib, valsartan, vardenafil, venlafaxine hydrochloride, VX-745.

Sacubitril/Valsartan in Clinical Practice: A Report of 2 Cases.

PubMed

Cosentino, Eugenio

Following the results of the PARADIGM-HF trial, the European Society of Cardiology (ESC) guidelines recommend sacubitril/valsartan to replace ACE inhibitors in ambulatory patients with heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal therapy and who fit trial criteria. However, the optimal use of sacubitril/valsartan in clinical practice needs further investigation. We report here the cases of 2 patients with HFrEH successfully treated with sacubitril/valsartan in our daily practice. Both subjects presented multiple comorbidities and received an implantable cardioverter defibrillator in primary prevention. In both patients, therapy with sacubitril/valsartan led to prompt (30 days) amelioration of heart function, with a corresponding decrease in NHYA class and without any relevant safety issue. © 2017 S. Karger AG, Basel.

Efficacy and safety of sacubitril/valsartan in patients with essential hypertension uncontrolled by olmesartan: A randomized, double-blind, 8-week study.

PubMed

Cheung, Deanna G; Aizenberg, Diego; Gorbunov, Vladimir; Hafeez, Kudsia; Chen, Chien-Wei; Zhang, Jack

2018-01-01

A majority of patients with hypertension fail to achieve blood pressure (BP) control despite treatment with commonly prescribed drugs. This randomized, double-blind phase III trial assessed the superiority of sacubitril/valsartan 200 mg (97/103 mg) to continued olmesartan 20 mg in reducing ambulatory systolic BP after 8-week treatment in patients with mild to moderate essential hypertension uncontrolled with olmesartan 20 mg alone. A total of 376 patients were randomized to receive either sacubitril/valsartan (n = 188) or olmesartan (n = 188). Superior reductions in 24-hour mean ambulatory systolic BP were observed in the sacubitril/valsartan group vs the olmesartan group (-4.3 mm Hg vs -1.1 mm Hg, P < .001). Reductions in 24-hour mean ambulatory diastolic BP and pulse pressure and office systolic BP and diastolic BP were significantly greater with sacubitril/valsartan vs olmesartan (P < .014). A greater proportion of patients achieved BP control with sacubitril/valsartan vs olmesartan. The overall incidence of adverse events was comparable between the groups. Compared with continued olmesartan, sacubitril/valsartan was more effective and generally safe in patients with hypertension uncontrolled with olmesartan 20 mg. ©2018 Wiley Periodicals, Inc.

Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents.

PubMed

Lu, Yuyan; Guo, Haipeng; Sun, Yuxi; Pan, Xin; Dong, Jia; Gao, Di; Chen, Wei; Xu, Yawei; Xu, Dachun

2017-08-01

It has previously been demonstrated that the renin-angiotensin system is involved in the pathogenesis and development of pulmonary hypertension (PH). However, the efficacy of angiotensin II type I (AT1) receptor blockers in the treatment of PH is variable. The present study examined the effects of the AT1 receptor blocker valsartan on monocrotaline (MCT)‑induced PH in rats and chronic hypoxia‑induced PH in mice. The results demonstrated that valsartan markedly attenuated development of PH in rats and mice, as indicated by reduced right ventricular systolic pressure, diminished lung vascular remodeling and decreased right ventricular hypertrophy, compared with vehicle treated animals. Immunohistochemical analyses of proliferating cell nuclear antigen expression revealed that valsartan suppressed smooth muscle cell proliferation. Western blot analysis demonstrated that valsartan limited activation of p38, c‑Jun N‑terminal kinase 1/2 and extracellular signal‑regulated kinase 1/2 signaling pathways and significantly reduced MCT‑induced upregulation of pulmonary matrix metalloproteinases‑2 and ‑9, and transforming growth factor‑β1 expression. The results suggested that valsartan attenuates development of PH in rodents by reducing expression of extracellular matrix remodeling factors and limiting smooth muscle cell proliferation to decrease pathological vascular remodeling. Therefore, valsartan may be a valuable future therapeutic approach for the treatment of PH.

Results of a Markov model analysis to assess the cost-effectiveness of a single tablet of fixed-dose amlodipine and atorvastatin for the primary prevention of cardiovascular disease in Korea.

PubMed

Liew, Danny; Park, Hye-Jin; Ko, Su-Kyoung

2009-10-01

In Korea, the treatment of hypertension and dyslipidemia constitutes an important strategy for the prevention of cardiovascular disease (CVD). This study sought to investigate the cost-effectiveness (from the Korean health care system perspective) of prescribing a proprietary formulation single-tablet fixed-dose combination of amlodipine and atorvastatin (at weighted mean doses of 5 mg and 10.25 mg, respectively) to all eligible patients aged > or = 45 years for the primary prevention of CVD (ie, coronary heart disease and ischemic stroke) in Korea, compared with currently observed patterns of blood-pressure and lipid-lowering medication prescription and use. A Markov model was developed with 4 health states: alive without CVD, alive with CVD, dead from CVD, and dead from non-CVD causes. The model population comprised 244 Koreans aged >/=45 years from the 2005 Korean National Health and Nutrition Examination Survey (KNHNES) without a history of myocardial infarction (MI) or stroke who met current criteria for both blood-pressure and lipid-lowering treatment. From a 2008 baseline, follow-up was simulated for 40 years. Cardiovascular risk was estimated for each subject individually using a multivariate, Asian population-specific equation, and updated with ongoing cycles. Decision analysis compared the effects of prescribing the fixed-dose combination to all subjects versus currently observed patterns of treatment. Data regarding the blood-pressure and lipid-lowering efficacies of combination therapy were drawn from the Respond trial. Costs of the fixed-dose combination tablet and CVD were sourced from pharmaceutical pricing lists and Korean Health Insurance Review and Assessment Services estimates, respectively. Utility values for CVD were obtained from a large Korean utility study. In the model, of the 244 treatment-eligible subjects, 126 (51.6%) and 13 (5.3%) were taking blood-pressure and lipid-lowering therapy, respectively. Use of single-tablet fixed-dose combination amlodipine and atorvastatin by all subjects was associated with estimated incremental cost-effectiveness ratios of 7,773,063 Korean won (KRW) per quality-adjusted life-year gained and 10,378,230 KRW per overall life-year gained (1300 KRW approximately US $1). Sensitivity and uncertainty analyses indicated these results to be robust. In this model, based on data from the 2005 KNHNES, hypertension and dyslipidemia were undertreated among Koreans aged > or = 45 years without a history of MI or stroke. The administration of single-tablet fixed-dose combination amlodipine and atorvastatin to all such individuals was likely to represent a cost-effective means of preventing first-onset CVD (ie, coronary heart disease and ischemic stroke) in this subgroup, compared with current patterns of treatment.

COMBINED ALISKIREN AND AMLODIPINE REDUCE ALBUMINURIA VIA REDUCTION IN RENAL INFLAMMATION IN DIABETIC RATS

PubMed Central

Matavelli, Luis C.; Huang, Jiqian; Siragy, Helmy M.

2011-01-01

SUMMARY We hypothesized that compared to hydrochlorothiazide (HCTZ), the renin inhibitor aliskiren (ALISK) or amlodipine (AMLO) and their combination reduce albuminuria via reduction in renal inflammation, independent of BP changes. We studied normal and streptozotocin induced diabetic (DM) Sprague-Dawley rats treated for 6 weeks with vehicle, ALISK, HCTZ or AMLO individually and combined and evaluated effects of treatments on BP, urine albumin to creatinine ratio (UACR), renal interstitial fluid (RIF) levels of angiotensin II (Ang II), tumor necrosis factor-alpha (TNFα) and interleukin-6 (IL-6), and renal expression of TNFα, IL-6, transforming growth factor-beta1 (TGF-β1) and nuclear factor-kappa B (NF-κB). There were no differences in BP between treatments. Only ALISK and its combinations reduced RIF Ang II. UACR increased in DM rats and decreased with ALISK alone or combined with HCTZ or AMLO. HCTZ or AMLO individually and combined did not influence UACR. RIF TNFα and IL-6, and the renal expression of TNFα, IL-6, TGF-β1 and NF-κB were increased in DM rats. These renal inflammatory markers were reduced only with ALISK or AMLO individually or combined with other treatments. We conclude that ALISK alone and combined with HCTZ or AMLO reduced albuminuria in diabetes via reduction in renal inflammation, independent of BP changes. PMID:22075749

Combined aliskiren and amlodipine reduce albuminuria via reduction in renal inflammation in diabetic rats.

PubMed

Matavelli, Luis C; Huang, Jiqian; Siragy, Helmy M

2012-03-01

We hypothesized that compared with hydrochlorothiazide (HCTZ), the renin inhibitor aliskiren (ALISK) or amlodipine (AMLO) and their combination reduce albuminuria via reduction in renal inflammation, independent of blood pressure (BP) changes. We studied normal and streptozotocin-induced diabetic (DM) Sprague-Dawley rats treated for 6 weeks with vehicle, ALISK, HCTZ, or AMLO individually and combined and evaluated the effects of treatments on BP, urine albumin to creatinine ratio, renal interstitial fluid levels of angiotensin II, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) and renal expression of TNF-α, IL-6, transforming growth factor beta 1, and nuclear factor kappa B. There were no differences in BP between treatments. Only ALISK and its combinations reduced renal interstitial fluid angiotensin II. Urine albumin to creatinine ratio increased in DM rats and decreased with ALISK alone or combined with HCTZ or AMLO. HCTZ or AMLO individually and combined did not influence urine albumin to creatinine ratio. Renal interstitial fluid TNF-α and IL-6, and the renal expression of TNF-α, IL-6, transforming growth factor beta 1, and nuclear factor kappa B were increased in DM rats. These renal inflammatory markers were reduced only with ALISK or AMLO individually or combined with other treatments. We conclude that ALISK alone and combined with HCTZ or AMLO reduced albuminuria in diabetes via reduction in renal inflammation, independent of BP changes.

Manidipine in hypertensive patients with metabolic syndrome: the MARIMBA study.

PubMed

Martínez Martín, Francisco Javier

2009-07-01

To evaluate the effects of manidipine versus amlodipine on blood pressure, albuminuria, insulin sensitivity, adiponectin, TNF-alpha and C-reactive protein in nondiabetic subjects with metabolic syndrome (ATP-III definition), including impaired fasting glucose (>5.6 mmol/l) and hypertension. In total, 64 patients were recruited and randomly assigned to manidipine 20 mg versus amlodipine 10 mg (for 12 +/- 2 weeks). Blood pressure was reduced to a similar extent (p < 0.001) by both treatments. Albuminuria was significantly reduced by manidipine (-37.3%; p = 0.003), but not by amlodipine. C-reactive protein was reduced similarly (p < 0.01) by both treatments. Plasma adiponectin was increased (32.9%; p = 0.011) and plasma TNF-alpha was reduced by manidipine (-37.1%; p = 0.019), but neither was significantly changed by amlodipine. The HOMA insulin resistance index was significantly reduced by manidipine (-21.3%; p = 0.007), but not by amlodipine (-8.3%; p = 0.062). Tolerability with manidipine was superior to that with amlodipine (p = 0.04). These data support the added value of manidipine in renal and metabolic protection beyond blood pressure reduction in the treatment of hypertensive patients with metabolic syndrome.

Effect of the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of a single dose of furosemide

PubMed Central

Ayalasomayajula, Surya; Schuehly, Uwe; Pal, Parasar; Chen, Fabian; Zhou, Wei; Sunkara, Gangadhar

2018-01-01

Aims Sacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be coadministered with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two‐period, single‐sequence study in healthy subjects. Methods All subjects (n = 28) received 40 mg oral single‐dose furosemide during period 1, followed by a washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) was administered twice daily for 5 days and a single dose of 40 mg furosemide was coadministered on day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and the pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated. Results Coadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (Cmax) [estimated geometric mean ratio (90% confidence interval): 0.50 (0.44, 0.56)], area under the plasma concentration–time curve (AUC) from time 0 to infinity [0.72 (0.67, 0.77)] and 24‐h urinary excretion of furosemide [0.74 (0.69, 0.79)]. When coadministered with sacubitril/valsartan, 0–4‐h, 4–8‐h and 0–24‐h diuresis in response to furosemide was reduced by ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 28.5%, 7% and 15%, respectively. Post hoc analysis of the pivotal phase III Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF) indicated that the median furosemide dose was similar at baseline and at the end of the study in the sacubitril/valsartan group. Conclusions Sacubitril/valsartan reduced plasma Cmax and AUC and 24‐h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects. PMID:29318651

Effect of the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of a single dose of furosemide.

PubMed

Ayalasomayajula, Surya; Schuehly, Uwe; Pal, Parasar; Chen, Fabian; Zhou, Wei; Sunkara, Gangadhar; Langenickel, Thomas H

2018-05-01

Sacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be coadministered with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two-period, single-sequence study in healthy subjects. All subjects (n = 28) received 40 mg oral single-dose furosemide during period 1, followed by a washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) was administered twice daily for 5 days and a single dose of 40 mg furosemide was coadministered on day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and the pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated. Coadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (C max ) [estimated geometric mean ratio (90% confidence interval): 0.50 (0.44, 0.56)], area under the plasma concentration-time curve (AUC) from time 0 to infinity [0.72 (0.67, 0.77)] and 24-h urinary excretion of furosemide [0.74 (0.69, 0.79)]. When coadministered with sacubitril/valsartan, 0-4-h, 4-8-h and 0-24-h diuresis in response to furosemide was reduced by ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 28.5%, 7% and 15%, respectively. Post hoc analysis of the pivotal phase III Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) indicated that the median furosemide dose was similar at baseline and at the end of the study in the sacubitril/valsartan group. Sacubitril/valsartan reduced plasma C max and AUC and 24-h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects. © 2018 Crown copyright. British Journal of Clinical Pharmacology © 2018 British Pharmacological Society.

Incidence, Predictors, and Outcomes Associated With Hypotensive Episodes Among Heart Failure Patients Receiving Sacubitril/Valsartan or Enalapril: The PARADIGM-HF Trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure).

PubMed

Vardeny, Orly; Claggett, Brian; Kachadourian, Jessica; Pearson, Scott M; Desai, Akshay S; Packer, Milton; Rouleau, Jean; Zile, Michael R; Swedberg, Karl; Lefkowitz, Martin; Shi, Victor; McMurray, John J V; Solomon, Scott D

2018-04-01

In PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure), heart failure treatment with sacubitril/valsartan reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared with enalapril but resulted in more symptomatic hypotension. Concern on hypotension may be limiting use of sacubitril/valsartan in appropriate patients. We characterized patients in PARADIGM-HF by whether they reported hypotension during study run-in periods (enalapril, followed by sacubitril/valsartan) and after randomization and assessed whether hypotension modified the efficacy of sacubitril/valsartan. Of the 10 513 patients entering the enalapril run-in, 136 (1.3%) experienced hypotension and 93 (68%) were unable to continue to the next phase; of 9419 patients entering the sacubitril/valsartan run-in period, 228 (2.4%) patients experienced hypotension and 51% were unable to successfully complete the run-in. After randomization, 388 (9.2%) participants had 501 hypotensive events with enalapril, and 588 (14.0%) participants had 803 hypotensive events with sacubitril/valsartan ( P <0.001). There was no difference between randomized treatment groups in the number of participants who discontinued therapy because of hypotension. Individuals with a hypotensive event in either group were older, had lower blood pressure at randomization, and were more likely to have an implantable cardioverter defibrillator. Participants with hypotensive events during run-in who were ultimately randomized derived similar efficacy from sacubitril/valsartan compared with enalapril as those without hypotensive events ( P interaction>0.90). Hypotension was more common with sacubitril/valsartan relative to enalapril in PARADIGM-HF but did not differentially affect permanent discontinuations. Patients with hypotension during run-in derived similar benefit from sacubitril/valsartan compared with enalapril as those who did not experience hypotension. © 2018 American Heart Association, Inc.

In HFREF patients, sacubitril/valsartan, given at relatively low doses, does not lead to increased mortality or hospitalization : A retrospective cohort study.

PubMed

De Vecchis, R; Ariano, C; Di Biase, G; Noutsias, M

2018-03-08

In heart failure with reduced left ventricular ejection fraction (HFREF) patients, the dosage of sacubitril/valsartan is modulated according to a gradual increase regimen. Nevertheless, if patients exhibit tolerability problems, a provisional reduction of the dose of sacubitril/valsartan or even its interruption are recommended. This study provides estimates of respective proportions of patients receiving minimum or intermediate doses of sacubitril/valsartan. In addition, a comparison was made to detect possible differences regarding all-cause mortality and heart failure hospitalization in patients treated with the recommended optimum dose compared to those receiving submaximum maintenance doses of sacubitril/valsartan. Patients treated with sacubitril/valsartan in addition to beta-blocker and mineralocorticoid receptor blocker were 68. Among them, 20 patients (29.4%), were identified as having clinical features that were contraindications to the administration of sacubitril/valsartan at full dose. The subsequent decision was to maintain an intermediate dose in 11 patients and to reduce the dose to the minimum level allowed, i.e., 24 mg/26 mg twice daily in nine patients. After a median follow-up of 5.25 months, no differences were found concerning the risk of all-cause death by comparing patients treated with reduced versus those subjected to target doses of sacubitril/valsartan (odds ratio [OR] = 1.666; 95% confidence interval [CI] = 0.256-10.823; p = 0.6266). Patients taking reduced doses had a similar risk of heart failure hospitalizations when compared to patients treated with the target dose (OR = 0.789; 95% CI: 0.077-8.0808; p = 1.00). During a median follow-up of 5.25 months, in the group of patients who had proven to be intolerant to the maximum dose of sacubitril/valsartan, use of reduced doses of the drug did not result in increased all-cause mortality or heart failure hospitalization compared to patients treated with sacubitril/valsartan at the target dose.

Effects of angiotensin-converting enzyme inhibitor versus valsartan on cellular signaling events in heart transplant.

PubMed

White, Michel; Ross, Heather; Levesque, Sylvie; Whittom, Lucette; Pelletier, Guy B; Racine, Normand; Meloche, Sylvain; Voisin, Laure

2009-05-01

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) provide similar biologic effects in model systems and similar clinical impacts in humans. The changes in the cardiac angiotensin system signaling pathways in the human heart in response to ACE inhibitors versus ARBs have been incompletely studied. To investigate the effects of ACE inhibitors versus valsartan on the angiotensin II signal transduction pathways in the transplanted human heart. Twenty-seven stable cardiac transplant recipients were randomized to remain on ACE inhibitor therapy (n = 8) or to receive valsartan (n = 19). Two additional endomyocardial biopsy samples were obtained at baseline and after 9 months of therapy. The expression of cardiac angiotensin type I and II receptors and atrial natriuretic factor (ANF) was measured by quantitative polymerase chain reaction. The expression and phosphorylation levels of selected signal transduction pathways were analyzed by immunoblotting. The mean dose of valsartan was 114 +/- 41 mg/day. The use of valsartan resulted in a similar impact on blood pressure and biochemistry profile. There were no significant changes in the expression of angiotensin type I and II receptors and ANF with valsartan. Similarly, no significant changes in the expression and phosphorylation of Jun N-terminal kinase, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinases or AKT, and mammalian target of rapamycin was observed in the valsartan-treated group. Valsartan use is associated with similar clinical and molecular cardiac effects as ACE inhibitor therapy in stable long-term cardiac transplant recipients.

Comparison of the effect of valsartan and lisinopril on autonomic nervous system activity in chronic heart failure.

PubMed

De Tommasi, Elisabetta; Iacoviello, Massimo; Romito, Roberta; Ceconi, Claudio; Guida, Pietro; Massari, Francesco; Francolini, Gloria; Bertocchi, Federico; Ferrari, Roberto; Rizzon, Paolo; Pitzalis, Maria Vittoria

2003-11-01

In chronic heart failure (CHF), the derangement of autonomic nervous system activity has a deep impact on the progression of the disease. It has been demonstrated that modulation of the renin-angiotensin aldosterone system (RAAS) increases autonomic control of heart rate and reduces adrenergic activity. We sought to evaluate, in CHF, the different effects of an ACE inhibitor (lisinopril) and of an AT1 receptor antagonist (valsartan) on heart rate variability, baroreflex sensitivity and norepinephrine plasma levels. Ninety patients (61 +/- 10 years, 2.3 +/- 0.5, New York Heart Association class) with CHF and left ventricular ejection fraction <40% were randomly assigned in a double-blind fashion to receive lisinopril (uptitrated to 20 mg/d) or valsartan (uptitrated to 160 mg/d) therapy for 16 weeks. Heart rate variability (evaluated by measuring standard deviation of normal R-R intervals on 24-hour ECG recordings), spontaneous baroreflex sensitivity and aldosterone and norepinephrine plasma levels were assessed before and after drug therapy. There were no significant differences between valsartan and lisinopril in their effects on left ventricular function, arterial pressure, aldosterone plasma levels and autonomic control of heart rate. Both lisinopril and valsartan significantly reduced plasma norepinephrine levels, but the reduction induced by valsartan was significantly greater than that observed for lisinopril (27% vs 6%, P <.05). This study shows a comparable effect of ACE inhibition (lisinopril) and of AT1 receptor antagonism (valsartan) on cardiac vagal control of heart rate, whereas valsartan has shown a more effective modulation of sympathetic activity measured by plasma norepinephrine levels.

Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach.

PubMed

Iborra-Egea, Oriol; Gálvez-Montón, Carolina; Roura, Santiago; Perea-Gil, Isaac; Prat-Vidal, Cristina; Soler-Botija, Carolina; Bayes-Genis, Antoni

2017-01-01

Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post-infarct remodeling.

Quantitative analysis of valsartan by two-dimensional liquid chromatography (2D-HPLC) and its application in a bioequivalence study in Chinese volunteers
.

PubMed

Zhang, Min; Deng, Yang; Cai, Hua-Lin; Fang, Ping-Fei; Yan, Miao; Zhang, Bi-Kui; Wu, Yan-Qin

2017-04-01

To develop a sensitive, two-dimensional liquid chromatography (2D-LC) method for determination of valsartan, applied to investigate bioequivalence of two valsartan tablets in Chinese volunteers under fasting condition. A full automatic 2D-HPLC system was used to quantify valsartan in human plasma. The analytes were extracted by protein precipitation, using telmisartan as internal standard. The analytical method was applied in a randomized, crossover bioequivalence study of valsartan tablets; the study enrolled 18 Chinese volunteers (12 were men and 6 were women). The subjects received a single 160-mg dose of test or reference preparation with 7-days of washout under fasting state. Plasma samples were collected, pharmacokinetic parameters were obtained and the bioequivalence was evaluated. The calibration range was 9.2 - 4213.8 ng×mL-1. Inter- and intraprecision was less than 7.0%, and accuracies ranged from 99.5 to 103.8%. The extraction recovery for valsartan varied between 89.3 and 97.8%, and the stability in all conditions was excellent. The 90% CI of AUC_0→36h and C_max were 96.5 - 109.4% and 94.2 - 108.6%, respectively. The relative bioavailability was 103.9 ± 15.7%. No gender difference was observed in pharmacokinetic parameters. A sensitive 2D-HPLC method was established for the estimation of valsartan in human plasma and successfully applied in a bioequivalence study of valsartan, which suggests that these two formulations can be assumed to be bioequivalent.
.

STROKE OUTCOMES AMONG PARTICIPANTS RANDOMIZED TO CHLORTHALIDONE, AMLODIPINE OR LISINOPRIL IN ALLHAT

PubMed Central

Yamal, José-Miguel; Oparil, Suzanne; Davis, Barry R.; Alderman, Michael H.; Calhoun, David A.; Cushman, William C.; Fendley, Herbert F.; Franklin, Stanley S.; Habib, Gabriel B.; Pressel, Sara L.; Probstfield, Jeffrey L.; Sastrasinh, Sithiporn

2014-01-01

Background The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in 33,357 high-risk hypertensive participants. Methods and Results ALLHAT compared cardiovascular disease outcomes in participants initially treated with angiotensin-converting enzyme inhibitor (lisinopril), calcium channel blocker (amlodipine), or thiazide-type diuretic (chlorthalidone). We report stroke outcomes in 1517 participants in-trial and 1596 additional participants during post-trial passive surveillance, for total follow-up of 8–13 years. Stroke rates were higher with lisinopril (6-year rate/100=6.4) than with chlorthalidone (5.8) or amlodipine (5.5) in-trial but not including post-trial (10-year rates/100=13.2 [chlorthalidone], 13.1[amlodipine], and 13.7 [lisinopril]). In- trial differences were driven by race (race-by-lisinopril/chlorthalidone interaction P=0.005, race-by-amlodipine/lisinopril interaction P=0.012) and gender (gender-by-lisinopril/amlodipine interaction P=0.041), separately. No treatment differences overall, or by race or gender, were detected over the 10-year period. No differences appeared among treatment groups in adjusted risk of all-cause mortality including post-trial for participants with nonfatal in-trial strokes. Conclusions Among Blacks and women, lisinopril was less effective in preventing stroke in-trial than either chlorthalidone or amlodipine, even after adjusting for differences in systolic blood pressure. These differences abated by the end of the post-trial period. PMID:25455006

Efficacy and tolerability of the single-pill combination of aliskiren 300 mg/amlodipine 10 mg in hypertensive patients not controlled by olmesartan 40 mg/amlodipine 10 mg.

PubMed

Axthelm, Christoph; Sieder, Christian; Meister, Franziska; Kaiser, Edelgard

2012-01-01

We aimed to investigate whether the single pill combination (SPC) of aliskiren 300 mg and amlodipine 10 mg (ALIS 300/AMLO 10) improves blood pressure (BP) reduction in hypertensive patients not adequately controlled by the SPC olmesartan 40 mg and amlodipine 10 mg (OLM 40/AMLO 10). Open-label, non-randomized single-arm study. Patients with stage 2 hypertension were titrated to the SPC OLM 40/AMLO 10 (4-week Phase 1). If hypertension was not controlled they were switched to the SPC ALIS 300/AMLO 10 (4-week Phase 2). In the optional 4-week study extension hydrochlorothiazide (HCT) 12.5 mg was added. EudraCT 2009-016693-33. In the 342 patients treated, OLM 40/AMLO 10 reduced systolic BP (SBP)/diastolic BP (DBP) by 24.5/14.5 mmHg by end of Phase 1. Those 187 patients with uncontrolled hypertension at the end of Phase 1 switched to ALIS 300/AMLO 10 experienced a further SBP reduction of 5.1 mmHg (95% confidence interval [CI] 3.7 to 6.5, p < 0.0001) and a DBP reduction of 4.8 mmHg (95% CI 3.8 to 5.8; p < 0.0001) in Phase 2. DBP or SBP responder rates were achieved by 51.3% or 44.4%, respectively, SBP and DBP normalization by 36.4%. In 65 patients whose BP was not controlled in Phase 2, SPC ALIS 300/AMLO 10/HCT 12.5 mg decreased SBP/DBP by further 8.1/6.7 mmHg (p < 0.0001 each). No deaths or serious adverse events were noted. Significant adverse events leading to study discontinuation were reported in 2.6% (Phase 1), 2.7% (Phase 2), and 0% (extension). Limitations included the open-label, single-arm non-randomized design, and the relatively short duration. In this switch study reflecting clinical practice, patients with moderate hypertension not controlled by the SPC OLM 40/AMLO 10 achieved a clinically and statistically significant reduction of blood pressure from the SPC ALIS 300/AMLO 10 and the optional addition of HCT. All drug combinations were well tolerated.

TELMISARATAN PROVIDES BETTER RENAL PROTECTION THAN VALSARTAN IN A RAT MODEL OF METABOLIC SYNDROME

PubMed Central

Khan, Abdul Hye; Imig, John D.

2013-01-01

BACKGROUND Angiotension receptor blockers (ARB), telmisartan and valsartan were compared for renal protection in spontaneously hypertensive rats (SHR) fed high fat diet. We hypothesized that in cardiometabolic syndrome, telmisartan an ARB with PPAR-γ activity will offer better renal protection. METHODS SHR were fed either normal (SHR-NF, 7% fat) or high fat (SHR-HF, 36% fat) diet and treated with an ARB for 10 weeks. RESULTS Blood pressure was similar between SHR-NF (190±3 mmHg) and SHR-HF (192±4 mmHg) at the end of the 10 week period. Telmisartan and valsartan decreased blood pressure to similar extents in SHR-NF and SHR-HF groups. Body weight was significantly higher in SHR-HF (368±5g) compared to SHR-NF (328±7g). Telmisartan but not valsartan significantly reduced the body weight gain in SHR-HF. Telmisartan was also more effective than valsartan in improving glycemic and lipid status in SHR-HF. Monocyte chemoattractant protein-1 (MCP-1), an inflammatory marker, was higher in SHR-HF (24±2 ng/d) compared to SHR-NF (14±5 ng/d). Telmisartan reduced MCP-1 excretion in both SHR-HF and SHR-NF to a greater extent than valsartan. An indicator of renal injury, urinary albumin excretion increased to 85±8 mg/d in SHR-HF compared to 54±9 mg/d in SHR-NF. Telmisartan (23±5 mg/d) was more effective than valsartan (45±3 mg/d) in lowering urinary albumin excretion in SHR-HF. Moreover, telmisartan reduced glomerular damage to a greater extent than valsartan in the SHR-HF. CONCLUSIONS Collectively, our data demonstrate that telmisartan was more effective than valsartan in reducing body weight gain, renal inflammation, and renal injury in a rat model of cardiometabolic syndrome. PMID:21415842

Impact of sacubitril/valsartan on heart failure admissions: insights from real-world patient prescriptions.

PubMed

Martens, Pieter; Lambeets, Seppe; Lau, Chirikwah; Dupont, Matthias; Mullens, Wilfried

2018-06-17

Sacubitril/valsartan reduced heart failure (HF)-admissions and cardiovascular mortality in the PARADIGM-HF-trial. However, real-world patients are often frailer and less able to tolerate high doses of sacubitril/valsartan. We performed a retrospective analysis of consecutive patients prescribed sacubitril/valsartan in a single tertiary HF-clinic between December 2016 and January 2018. HF-admissions were assessed in a paired fashion, comparing the amount of antecedent HF-episodes with incident HF-episodes after the initiation. Baseline risk for adverse events was assessed by the EMPHASIS-HF-risk-score Results: A total of 201-HF-patients were retrospectively identified (age = 68 ± 11 years, ejection fraction = 29 ± 8%). Real world patients were older, had higher serum creatinine and a higher New-York Heart-Association (NYHA)-class (p < .05 for all) than in the PARADIGM-HF trial. Over a mean duration of 221 ± 114 days after initiation of sacubitril/valsartan a total of 23-individual patients experienced at least one HF-episodes. Over the same time period preceding initiation of sacubitril/valsartan, 51 individual patients experienced a HF-episodes (p < .001). Sacubitril/valsartan significantly reduced the rate of incident vs. antecedent HF-admissions, in patients with low or high baseline NYHA-class (II vs. III and IV; p value = 0.019 respectively p = .004) or patients with an EMPHASIS-HF risk score below or above the mean (p = .002 respectively p = .016). Patients older than 75-years exhibited a trend towards HF-reduction. Higher doses of sacubitril/valsartan were associated with more reduction in incident versus antecedent HF-episodes. Despite being frailer and older, real-world patients exhibit a significant and early reduction in incident HF-hospitalisations following initiation of sacubitril/valsartan. Higher doses might be associated with more reduction in HF-admissions, underscoring the importance of dose uptitration.

▼ Sacubitril valsartan for heart failure.

PubMed

2016-06-01

▼ Sacubitril valsartan (Entresto-Novartis) is a new oral drug licensed for the treatment of symptomatic chronic heart failure in adults with reduced ejection fraction.(1) It is described as an angiotensin receptor neprilysin inhibitor and contains the neprilysin inhibitor, sacubitril and the angiotensin II receptor antagonist, valsartan.(1-3) Here, we review the evidence for sacubitril valsartan and consider its place in the management of heart failure. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

New Medications for Heart Failure

PubMed Central

Gordin, Jonathan S.; Fonarow, Gregg C.

2016-01-01

Heart failure is common and results in substantial morbidity and mortality. Current guideline-based therapies for heart failure with reduced ejection fraction, including beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and aldosterone antagonists aim to interrupt deleterious neurohormonal pathways and have shown significant success in reducing morbidity and mortality associated with heart failure. Continued efforts to further improve outcomes in patients with heart failure with reduced ejection fraction have led to the first new-in-class medications approved for heart failure since 2005, ivabradine and sacubitril/valsartan. Ivabradine targets the If channels in the sinoatrial node of the heart, decreasing heart rate. Sacubitril/valsartan combines a neprilysin inhibitor that increases levels of beneficial vasodilatory peptides with an angiotensin receptor antagonist. On a background of previously approved, guideline-directed medical therapies for heart failure, these medications have shown improved clinical outcomes ranging from decreased hospitalizations in a select group of patients to a reduction in all-cause mortality across all pre-specified subgroups. In this review, we will discuss the previously established guideline-directed medical therapies for heart failure with reduced ejection fraction, the translational research that led to the development of these new therapies, and the results from the major clinical trials of ivabradine and sacubitril/valsartan. PMID:27038558

Effect of valsartan on systemic right ventricular function: a double-blind, randomized, placebo-controlled pilot trial.

PubMed

van der Bom, Teun; Winter, Michiel M; Bouma, Berto J; Groenink, Maarten; Vliegen, Hubert W; Pieper, Petronella G; van Dijk, Arie P J; Sieswerda, Gertjan T; Roos-Hesselink, Jolien W; Zwinderman, Aeilko H; Mulder, Barbara J M

2013-01-22

The role of angiotensin II receptor blockers in patients with a systemic right ventricle has not been elucidated. We conducted a multicenter, double-blind, parallel, randomized controlled trial of angiotensin II receptor blocker valsartan 160 mg twice daily compared with placebo in patients with a systemic right ventricle caused by congenitally or surgically corrected transposition of the great arteries. The primary end point was change in right ventricular ejection fraction during 3-year follow-up, determined by cardiovascular magnetic resonance imaging or, in patients with contraindication for magnetic resonance imaging, multirow detector computed tomography. Secondary end points were change in right ventricular volumes and mass, Vo(2)peak, and quality of life. Primary analyses were performed on an intention-to-treat basis. A total of 88 patients (valsartan, n=44; placebo, n=44) were enrolled in the trial. No serious adverse effects occurred in either group. There was no significant effect of 3-year valsartan therapy on systemic right ventricular ejection fraction (treatment effect, 1.3%; 95% confidence interval, -1.3% to 3.9%; P=0.34), maximum exercise capacity, or quality of life. There was a larger increase in right ventricular end-diastolic volume (15 mL; 95% confidence interval, 3-28 mL; P<0.01) and mass (8 g; 95% confidence interval, 2-14 g; P=0.01) in the placebo group than in the valsartan group. There was no significant treatment effect of valsartan on right ventricular ejection fraction, exercise capacity, or quality of life. Valsartan was associated with a similar frequency of significant clinical events as placebo. Small but significant differences between valsartan and placebo were present for change in right ventricular volumes and mass. URL: http://www.controlled-trials.com. Unique identifier: ISRCTN52352170.

Cost-Effectiveness of Sacubitril-Valsartan in Patients With Heart Failure With Reduced Ejection Fraction.

PubMed

Sandhu, Alexander T; Ollendorf, Daniel A; Chapman, Richard H; Pearson, Steven D; Heidenreich, Paul A

2016-11-15

Sacubitril-valsartan therapy reduces cardiovascular mortality compared with enalapril therapy in patients with heart failure with reduced ejection fraction. To evaluate the cost-effectiveness of sacubitril-valsartan versus angiotensin-converting enzyme inhibitor therapy in patients with chronic heart failure. Markov decision model. Clinical trials, observational analyses, reimbursement data from the Centers for Medicare & Medicaid Services, drug pricing databases, and Centers for Disease Control and Prevention life tables. Patients at an average age of 64 years, New York Heart Association (NYHA) class II to IV heart failure, and left ventricular ejection fraction of 0.40 or less. Lifetime. Societal. Treatment with sacubitril-valsartan or lisinopril. Life-years, quality-adjusted life-years (QALYs), costs, heart failure hospitalizations, and incremental cost-effectiveness ratios. The sacubitril-valsartan group experienced 0.08 fewer heart failure hospitalization, 0.69 additional life-year, 0.62 additional QALY, and $29 203 in incremental costs, equating to a cost per QALY gained of $47 053. The cost per QALY gained was $44 531 in patients with NYHA class II heart failure and $58 194 in those with class III or IV heart failure. Sacubitril-valsartan treatment was most sensitive to the duration of improved outcomes, with a cost per QALY gained of $120 623 if the duration was limited to the length of the trial (median, 27 months). No variations in other parameters caused the cost to exceed $100 000 per QALY gained. The benefit of sacubitril-valsartan is based on a single clinical trial. Treatment with sacubitril-valsartan provides reasonable value in reducing cardiovascular mortality and morbidity in patients with NYHA class II to IV heart failure. U.S. Department of Veterans Affairs and Institute for Clinical and Economic Review.

Transport properties of valsartan, sacubitril and its active metabolite (LBQ657) as determinants of disposition.

PubMed

Hanna, Imad; Alexander, Natalya; Crouthamel, Matthew H; Davis, John; Natrillo, Adrienne; Tran, Phi; Vapurcuyan, Arpine; Zhu, Bing

2018-03-01

1. The potential for drug-drug interactions of LCZ696 (a novel, crystalline complex comprising sacubitril and valsartan) was investigated in vitro. 2. Sacubitril was shown to be a highly permeable P-glycoprotein (P-gp) substrate and was hydrolyzed to the active anionic metabolite LBQ657 by human carboxylesterase 1 (CES1b and 1c). The multidrug resistance-associated protein 2 (MRP2) was shown to be capable of LBQ657 and valsartan transport that contributes to the elimination of either compound. 3. LBQ657 and valsartan were transported by OAT1, OAT3, OATP1B1 and OATP1B3, whereas no OAT- or OATP-mediated sacubitril transport was observed. 4. The contribution of OATP1B3 to valsartan transport (73%) was appreciably higher than that by OATP1B1 (27%), Alternatively, OATP1B1 contribution to the hepatic uptake of LBQ657 (∼70%) was higher than that by OATP1B3 (∼30%). 5. None of the compounds inhibited OCT1/OCT2, MATE1/MATE2-K, P-gp, or BCRP. Sacubitril and LBQ657 inhibited OAT3 but not OAT1, and valsartan inhibited the activity of both OAT1 and OAT3. Sacubitril and valsartan inhibited OATP1B1 and OATP1B3, whereas LBQ657 weakly inhibited OATP1B1 but not OATP1B3. 6. Drug interactions due to the inhibition of transporters are unlikely due to the redundancy of the available transport pathways (LBQ657: OATP1B1/OAT1/3 and valsartan: OATP1B3/OAT1/3) and the low therapeutic concentration of the LCZ696 analytes.

Formulation and Pharmacokinetic Evaluation of Polymeric Dispersions Containing Valsartan.

PubMed

Chella, Naveen; Daravath, Bhaskar; Kumar, Dinesh; Tadikonda, Rama Rao

2016-10-01

Valsartan exhibits poor aqueous solubility and dissolution rate limited absorption. The lower solubility in the upper part of gastrointestinal tract (pH-dependant solubility) where its absorption window exists further contributes to the low oral bioavailability of valsartan. The present work was aimed to improve the in vivo pharmacokinetics of valsartan by preparing amorphous polymeric dispersions using Eudragit E 100 as carrier. Eudragit E 100 is a cationic polymer soluble in gastric fluid up to pH 5.0 and exhibits pH-dependent release. Hence, the dispersions prepared using Eudragit E 100 rapidly dissolves at lower pH presenting drug in molecularly dispersed and soluble form at its absorption site. Polymeric solid dispersions were prepared in different drug-to-carrier ratios. The prepared dispersions were evaluated for drug-carrier interactions, solid-state transitions and drug-release properties with the help of Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and in vitro dissolution studies. The optimized formulation containing valsartan was tested in rats for bioavailability and pharmacokinetic parameters and compared with that of valsartan pure drug. The results from FTIR studies indicated no interactions between drug and excipients. DSC studies confirmed reduction in crystallinity of drug. The dissolution studies performed in 0.1 N HCl showed significant improvement (p < 0.05) in the dissolution of valsartan. In vivo pharmacokinetic studies showed 199 % relative bioavailability with significant improvement (p < 0.05) in area under the curve compared to valsartan pure drug. Eudragit E 100 can be used to improve the dissolution of drugs that show low solubility at lower pH and thereby enhancing the bioavailability.

A retrospective study evaluating the tolerability and effectiveness of adjunctive antihypertensive drugs in patients with inadequate response to initial treatment.

PubMed

Ayyagari, Rajeev; Xie, Jipan; Cheng, David; Wu, Eric Q; Huang, Xing-Yue; Chen, Stephanie

2018-06-01

Real-world tolerability and effectiveness of nebivolol as first add-on therapy were compared with hydrochlorothiazide, metoprolol, and amlodipine. Medical records of hypertensive adults initiating nebivolol, hydrochlorothiazide, metoprolol, or amlodipine as first add-on therapy between December 16, 2010 and July 21, 2011 were retrospectively abstracted (N = 1600; 400/treatment). Outcomes included medication-related side-effect rates and blood pressure (BP) reduction and control. Compared with nebivolol, metoprolol and amlodipine had significantly higher side-effect rates (incidence rate ratio [95% CI]: 1.82 [1.14-2.92] and 2.67 [1.69-4.21]), respectively); the hydrochlorothiazide-nebivolol rate ratio was not significant (1.61 [0.95-2.71]). All treatments reduced BP at 2 months. Metoprolol, amlodipine, and hydrochlorothiazide were associated with significantly lower odds of achieving 2-month BP control than nebivolol (odds ratios [95% CI]: 0.34 [0.23-0.51], 0.51 [0.35-0.75] and 0.66 [0.44-0.99], respectively). In a real-world setting, nebivolol as first add-on therapy was associated with fewer side effects than metoprolol or amlodipine and with a higher BP control rate than hydrochlorothiazide, metoprolol, or amlodipine. © 2018 The Authors. The Journal of Clinical Hypertension Published by Wiley Periodicals, Inc.

Sacubitril/Valsartan: From Clinical Trials to Real-world Experience.

PubMed

Joly, Joanna M; Desai, Akshay S

2018-04-23

Compared to enalapril, use of angiotensin-receptor blocker and neprilysin inhibitor sacubitril/valsartan to treat patients with heart failure and reduced ejection fraction (HFrEF) is associated with substantial reductions in both cardiovascular mortality and heart failure progression. The purpose of this review is to discuss the real-world experience of sacubitril/valsartan. In the years following the publication of the landmark PARADIGM-HF trial in 2014 and its subsequent FDA approval, a growing evidence base supports the safety and efficacy of sacubitril/valsartan in a broad spectrum of patients with HFrEF. Updated clinical practice guidelines have embraced the use of sacubitril/valsartan in preference to ACE inhibitors or ARBs in selected patients. In this review, we highlight the clinical trials that led to these key updates to clinical guidelines, offer practical strategies for patient selection and utilization in clinical practice, and identify important areas of uncertainty that require future research.

Simultaneous treatment to attain blood pressure and lipid goals and reduced CV risk burden using amlodipine/atorvastatin single-pill therapy in treated hypertensive participants in a randomized controlled trial

PubMed Central

Grimm, Richard; Malik, Mobin; Yunis, Carla; Sutradhar, Santosh; Kursun, Attila

2010-01-01

TOGETHER investigated whether targeting multiple cardiovascular (CV) risk factors using single-pill amlodipine/atorvastatin (AML/ATO) and therapeutic lifestyle changes (TLC) results in greater blood pressure (BP)/lipid control and additional reduction in estimated cardiovascular disease (CVD) risk compared with blood pressure intervention only using amlodipine (AML) + TLC. TOGETHER was a 6-week, randomized, double-blind, double-dummy trial using hypertensive participants with additional CV risk factors without CVD/diabetes. Participants were randomized to either AML/ATO (5 to 10/20 mg) + TLC or AML (5 to 10 mg) + TLC. The primary end point was the difference in proportion of participants attaining both BP (<140/90 mm Hg) and low-density lipoprotein cholesterol (LDL-C) (<100 mg/dL) goals at week 6. At week 6, 67.8% of participants receiving AML/ATO + TLC attained the combined BP/LDL-C goal versus 9.6% with AML + TLC (RD [A–B]: 58.2; 95% CI [48.1 to 68.4] P < 0.001; OR: 19.0; 95% CI 9.1 to 39.6; P < 0.001). Significant reductions from baseline in LDL-C, total cholesterol and triglycerides and estimated 10-year Framingham risk were also observed. Treatment with AML/ATO was well tolerated. In conclusion, a multifactorial CV management approach is more effective in achieving combined BP/LDL-C targets as well as CV risk reduction compared with BP intervention only in this patient population. PMID:20479948

Simultaneous Estimation of Amlodipine Besilate and Olmesartan Medoxomil in Pharmaceutical Dosage Form

PubMed Central

Wankhede, S. B.; Wadkar, S. B.; Raka, K. C.; Chitlange, S. S.

2009-01-01

Two UV Spectrophotometric and one reverse phase high performance liquid chromatography methods have been developed for the simultaneous estimation of amlodipine besilate and olmesartan medoxomil in tablet dosage form. First UV spectrophotometric method was a determination using the simultaneous equation method at 237.5 nm and 255.5 nm over the concentration range 10-50 μg/ml and 10-50 μg/ml, for amlodipine besilate and olmesartan medoxomil with accuracy 100.09%, and 100.22% respectively. Second UV spectrophotometric method was a determination using the area under curve method at 242.5-232.5 nm and 260.5-250.5 nm over the concentration range of 10-50 μg/ml and 10-50 μg/ml, for amlodipine besilate and olmesartan medoxomil with accuracy 100.10%, and 100.48%, respectively. In reverse phase high performance liquid chromatography analysis carried out using 0.05M potassuim dihydrogen phosphate buffer:acetonitrile (50:50 v/v) as the mobile phase and Kromasil C18 (4.6 mm i.d.×250 mm) column as the stationery phase with detection wavelength of 238 nm. Flow rate was 1.0 ml/min. Retention time for amlodipine besilate and olmesartan medoxomil were 3.69 and 5.36 min, respectively. Linearity was obtained in the concentration range of 4-20 μg/ml and 10-50 μg/ml for amlodipine besilate and olmesartan medoxomil, respectively. Proposed methods can be used for the estimation of amlodipine besilate and olmesartan medoxomil in tablet dosage form provided all the validation parameters are met. PMID:20502580

Simultaneous determination of amlodipine and bisoprolol in rat plasma by a liquid chromatography/tandem mass spectrometry method and its application in pharmacokinetic study.

PubMed

Chang, Huichao; Li, Jinyin; Li, Ji; Guan, Xiaoduo; Sun, Fanlu; Qian, Zhongzhi; Bi, Kaishun; Fan, Guorong

2012-12-01

A sensitive, specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the quantitative determination of amlodipine and bisoprolol, using clenbuterol as the internal standard (IS). The analytes and IS were isolated from 100μL plasma samples by a simple liquid-liquid extraction (LLE). Reverse-phase high performance liquid chromatography (RP-HPLC) separation was accomplished on a Diamonsil C(18) column (50mm×4.6mm, 5μm) with a mobile phase composed of methanol-water-formic acid (75:25:0.01, v/v/v) at a flow rate of 0.3mL/min. The method had a chromatographic total run time of 3min. Multiple reacting monitoring (MRM) transitions of m/z [M+H](+) 409.1→237.9 (amlodipine), m/z [M+H](+) 326.2→116.0 (bisoprolol) and m/z [M+H](+) 277.0→203.0 (clenbuterol, IS) were used to quantify amlodipine, bisoprolol and IS, respectively. The method was sensitive with a lower limit of quantitation (LLOQ) of 0.2ng/mL for both amlodipine and bisoprolol, and the linear range was 0.2-50ng/mL for both amlodipine and bisoprolol (r(2)>0.9961). All the validation data, such as accuracy, precision and inter-day repeatability, were within the required limits. The method was successfully applied to pharmacokinetic studies of amlodipine and bisoprolol in Sprague-Dawley (SD) rats. Copyright © 2012 Elsevier B.V. All rights reserved.

Effects of carvedilol or amlodipine on target organ damage in L-NAME hypertensive rats: their relationship with blood pressure variability.

PubMed

Del Mauro, Julieta S; Prince, Paula D; Donato, Martín; Fernandez Machulsky, Nahuel; Morettón, Marcela A; González, Germán E; Bertera, Facundo M; Carranza, Andrea; Gorzalczany, Susana B; Chiappetta, Diego A; Berg, Gabriela; Morales, Celina; Gelpi, Ricardo J; Taira, Carlos A; Höcht, Christian

2017-04-01

The aim of the study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on blood pressure, blood pressure variability and target organ damage in N-nitro-l-arginine methyl ester (L-NAME) hypertensive rats. Wistar rats were treated with L-NAME administered in the drinking water for 8 weeks together with oral administration of carvedilol 30 mg/kg (n = 6), amlodipine 10 mg/kg (n = 6), or vehicle (n = 6). At the end of the treatment, echocardiographic evaluation, blood pressure, and short-term variability measurements were performed. Left ventricular and thoracic aortas were removed to assess activity of metalloproteinase 2 and 9 and expression levels of transforming growth factor β, tumor necrosis factor α, and interleukin 6. Histological samples were prepared from both tissues. Carvedilol and amlodipine induced a comparable reduction of systolic and mean arterial pressure and its short-term variability in L-NAME rats. The expression of transforming growth factor β, tumor necrosis factor α, and interleukin 6 decreased in both organs after carvedilol or amlodipine treatment and the activity of metalloproteinase was reduced in aortic tissue. Treatment with carvedilol or amlodipine completely prevented left ventricular collagen deposition and morphometric alterations in aorta. Oral chronic treatment with carvedilol or amlodipine significantly attenuates blood pressure variability and reduces target organ damage and biomarkers of tissue fibrosis and inflammation in L-NAME hypertensive rats. Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Amlodipine decreases fibrosis and cardiac hypertrophy in spontaneously hypertensive rats: persistent effects after withdrawal.

PubMed

Sevilla, María A; Voces, Felipe; Carrón, Rosalía; Guerrero, Estela I; Ardanaz, Noelia; San Román, Luis; Arévalo, Miguel A; Montero, María J

2004-07-02

Our objective was to examine the effect of chronic treatment with amlodipine on blood pressure, left ventricular hypertrophy, and fibrosis in spontaneously hypertensive rats and the persistence of such an effect after drug withdrawal. We investigated the effects of treatment with 2, 8 and 20 mg/kg/day of amlodipine given orally for six months and at three months after drug withdrawal. Systolic blood pressure was measured using the tail-cuff method. At the end of the study period, the heart was excised, the left ventricle was isolated, and the left ventricle weight/body weight ratio was calculated as a left ventricular hypertrophy index. Fibrosis, expressed as collagen volume fraction, was evaluated using an automated image-analysis system on sections stained with Sirius red. Age-matched untreated Wistar-Kyoto and SHR were used as normotensive and hypertensive controls, respectively. Systolic blood pressure was reduced in the treated SHR in a dose-dependent way and after amlodipine withdrawal it increased progressively, without reaching the values of the hypertensive controls. Cardiac hypertrophy was reduced by 8 and 20 mg/kg/day amlodipine, but when treatment was withdrawn only the group treated with 8 mg/kg/day maintained significant differences versus the hypertensive controls. All three doses of amlodipine reduced cardiac fibrosis and this regression persisted with the two highest doses after three months without treatment. We concluded that antihypertensive treatment with amlodipine is accompanied by a reduction in left ventricular hypertrophy and regression in collagen deposition. Treatment was more effective in preventing fibrosis than in preventing ventricular hypertrophy after drug withdrawal. Copyright 2004 Elsevier Inc.

A phase III, open-label, multicenter study to evaluate the safety and efficacy of long-term triple combination therapy with azilsartan, amlodipine, and hydrochlorothiazide in patients with essential hypertension.

PubMed

Rakugi, Hiromi; Shimizu, Kohei; Nishiyama, Yuya; Sano, Yuhei; Umeda, Yuusuke

2018-06-01

Patients with essential hypertension who are receiving treatment with an angiotensin II receptor blocker and a calcium channel blocker often develop inadequate blood pressure (BP) control and require the addition of a diuretic. This study aimed to evaluate the long-term safety and efficacy of a triple combination therapy with 20 mg azilsartan (AZL), 5 mg amlodipine (AML) and 12.5 mg hydrochlorothiazide (HCTZ). The phase III, open-label, multicenter study (NCT02277691) comprised a 4-week run-in period and 52-week treatment period. Patients with inadequate BP control despite AZL/AML therapy (n = 341) received 4 weeks' treatment with AZL/AML (combination tablet) + HCTZ (tablet) and 4 weeks' treatment with AZL/AML/HCTZ (combination tablet) in a crossover manner, followed by AZL/AML/HCTZ (combination tablet) from Week 8 of the treatment period up to Week 52. The primary and secondary endpoints were long-term safety and BP (office and home), respectively. Most adverse events (AEs) were mild or moderate in intensity, and no deaths or treatment-related serious AEs were reported. The triple therapy provided consistent BP-lowering effects in both office and home measurements. The triple combination therapy with AZL/AML/HCTZ was well tolerated and effective for 52 weeks in Japanese patients with essential hypertension.

Fabrication and evaluation of valsartan–polymer– surfactant composite nanoparticles by using the supercritical antisolvent process

PubMed Central

Kim, Min-Soo; Baek, In-hwan

2014-01-01

The aim of this study was to fabricate valsartan composite nanoparticles by using the supercritical antisolvent (SAS) process, and to evaluate the correlation between in vitro dissolution and in vivo pharmacokinetic parameters for the poorly water-soluble drug valsartan. Spherical composite nanoparticles with a mean size smaller than 400 nm, which contained valsartan, were successfully fabricated by using the SAS process. X-ray diffraction and thermal analyses indicated that valsartan was present in an amorphous form within the composite nanoparticles. The in vitro dissolution and oral bioavailability of valsartan were dramatically enhanced by the composite nanoparticles. Valsartan–hydroxypropyl methylcellulose–poloxamer 407 nanoparticles exhibited faster drug release (up to 90% within 10 minutes under all dissolution conditions) and higher oral bioavailability than the raw material, with an approximately 7.2-fold higher maximum plasma concentration. In addition, there was a positive linear correlation between the pharmacokinetic parameters and the in vitro dissolution efficiency. Therefore, the preparation of composite nanoparticles with valsartan–hydroxypropyl methylcellulose and poloxamer 407 by using the SAS process could be an effective formulation strategy for the development of a new dosage form of valsartan with high oral bioavailability. PMID:25404856

VALSARTAN REGULATES MYOCARDIAL AUTOPHAGY AND MITOCHONDRIAL TURNOVER IN EXPERIMENTAL HYPERTENSION

PubMed Central

Zhang, Xin; Li, Zi-Lun; Crane, John A.; Jordan, Kyra L.; Pawar, Aditya S.; Textor, Stephen C.; Lerman, Amir; Lerman, Lilach O.

2014-01-01

Renovascular hypertension alters cardiac structure and function. Autophagy is activated during left ventricular hypertrophy and linked to adverse cardiac function. The Angiotensin II receptor blocker Valsartan lowers blood pressure and is cardioprotective, but whether it modulates autophagy in the myocardium is unclear. We hypothesized that Valsartan would alleviate autophagy and improve left ventricular myocardial mitochondrial turnover in swine renovascular hypertension. Domestic pigs were randomized to control, unilateral renovascular hypertension, and renovascular hypertension treated with Valsartan (320 mg/day) or conventional triple therapy (Reserpine+hydralazine+hydrochlorothiazide) for 4 weeks post 6-weeks of renovascular hypertension (n=7 each group). Left ventricular remodeling, function and myocardial oxygenation and microcirculation were assessed by multi-detector computer tomography, blood-oxygen-level-dependent magnetic resonance imaging and microcomputer tomography. Myocardial autophagy, markers for mitochondrial degradation and biogenesis, and mitochondrial respiratory-chain proteins were examined ex vivo. Renovascular hypertension induced left ventricular hypertrophy and myocardial hypoxia, enhanced cellular autophagy and mitochondrial degradation, and suppressed mitochondrial biogenesis. Valsartan and triple therapy similarly decreased blood pressure, but Valsartan solely alleviated left ventricular hypertrophy, ameliorated myocardial autophagy and mitophagy, and increased mitochondrial biogenesis. In contrast, triple therapy only slightly attenuated autophagy and preserved mitochondrial proteins, but elicited no improvement in mitophagy. These data suggest a novel potential role of Valsartan in modulating myocardial autophagy and mitochondrial turnover in renovascular hypertension-induced hypertensive heart disease, which may possibly bolster cardiac repair via a blood pressure-independent manner. PMID:24752430

Functional Vascular Study in Hypertensive Subjects with Type 2 Diabetes Using Losartan or Amlodipine

PubMed Central

Pozzobon, Cesar Romaro; Gismondi, Ronaldo A. O. C.; Bedirian, Ricardo; Ladeira, Marcia Cristina; Neves, Mario Fritsch; Oigman, Wille

2014-01-01

Background Antihypertensive drugs are used to control blood pressure (BP) and reduce macro- and microvascular complications in hypertensive patients with diabetes. Objectives The present study aimed to compare the functional vascular changes in hypertensive patients with type 2 diabetes mellitus after 6 weeks of treatment with amlodipine or losartan. Methods Patients with a previous diagnosis of hypertension and type 2 diabetes mellitus were randomly divided into 2 groups and evaluated after 6 weeks of treatment with amlodipine (5 mg/day) or losartan (100 mg/day). Patient evaluation included BP measurement, ambulatory BP monitoring, and assessment of vascular parameters using applanation tonometry, pulse wave velocity (PWV), and flow-mediated dilation (FMD) of the brachial artery. Results A total of 42 patients were evaluated (21 in each group), with a predominance of women (71%) in both groups. The mean age of the patients in both groups was similar (amlodipine group: 54.9 ± 4.5 years; losartan group: 54.0 ± 6.9 years), with no significant difference in the mean BP [amlodipine group: 145 ± 14 mmHg (systolic) and 84 ± 8 mmHg (diastolic); losartan group: 153 ± 19 mmHg (systolic) and 90 ± 9 mmHg (diastolic)]. The augmentation index (30% ± 9% and 36% ± 8%, p = 0.025) and augmentation pressure (16 ± 6 mmHg and 20 ± 8 mmHg, p = 0.045) were lower in the amlodipine group when compared with the losartan group. PWV and FMD were similar in both groups. Conclusions Hypertensive patients with type 2 diabetes mellitus treated with amlodipine exhibited an improved pattern of pulse wave reflection in comparison with those treated with losartan. However, the use of losartan may be associated with independent vascular reactivity to the pressor effect. PMID:25014057

Functional vascular study in hypertensive subjects with type 2 diabetes using losartan or amlodipine.

PubMed

Pozzobon, Cesar Romaro; Gismondi, Ronaldo A O C; Bedirian, Ricardo; Ladeira, Marcia Cristina; Neves, Mario Fritsch; Oigman, Wille

2014-07-01

Antihypertensive drugs are used to control blood pressure (BP) and reduce macro- and microvascular complications in hypertensive patients with diabetes. The present study aimed to compare the functional vascular changes in hypertensive patients with type 2 diabetes mellitus after 6 weeks of treatment with amlodipine or losartan. Patients with a previous diagnosis of hypertension and type 2 diabetes mellitus were randomly divided into 2 groups and evaluated after 6 weeks of treatment with amlodipine (5 mg/day) or losartan (100 mg/day). Patient evaluation included BP measurement, ambulatory BP monitoring, and assessment of vascular parameters using applanation tonometry, pulse wave velocity (PWV), and flow-mediated dilation (FMD) of the brachial artery. A total of 42 patients were evaluated (21 in each group), with a predominance of women (71%) in both groups. The mean age of the patients in both groups was similar (amlodipine group: 54.9 ± 4.5 years; losartan group: 54.0 ± 6.9 years), with no significant difference in the mean BP [amlodipine group: 145 ± 14 mmHg (systolic) and 84 ± 8 mmHg (diastolic); losartan group: 153 ± 19 mmHg (systolic) and 90 ± 9 mmHg (diastolic)]. The augmentation index (30% ± 9% and 36% ± 8%, p = 0.025) and augmentation pressure (16 ± 6 mmHg and 20 ± 8 mmHg, p = 0.045) were lower in the amlodipine group when compared with the losartan group. PWV and FMD were similar in both groups. Hypertensive patients with type 2 diabetes mellitus treated with amlodipine exhibited an improved pattern of pulse wave reflection in comparison with those treated with losartan. However, the use of losartan may be associated with independent vascular reactivity to the pressor effect.

Design and stability study of an oral solution of amlodipine besylate for pediatric patients.

PubMed

van der Vossen, A C; van der Velde, I; Smeets, O S N M; Postma, D J; Vermes, A; Koch, B C P; Vulto, A G; Hanff, L M

2016-09-20

Amlodipine is an antihypertensive agent recommended for the management of hypertension in children and adolescents. The commercially available tablets of 5 and 10mg do not provide the necessary flexibility in dosing needed for treating children. Our goal was to develop a pediatric oral solution of amlodipine, using a robust manufacturing process suitable for ex-tempora and larger scale production. The parameters API and preservative content, related substances, appearance and pH were studied under four different storage conditions. Samples were analyzed up to 12months. Microbiological quality was studied in an 18-week in-use test based on a two-times daily dosing schedule. The stability of the formulation was influenced by storage conditions and composition. A formulation containing amlodipine besylate, sucrose syrup and methyl paraben remained physically stable for 12months at 4°C with no loss of amlodipine content. Related substances increased during the study but remained below 0.5%. In-use stability was proven up to 18weeks. Storage under refrigerated conditions was necessary to prevent precipitation and to obtain an acceptable shelf-life. In conclusion, we have developed and validated an amlodipine oral solution, suitable for the pediatric population. This liquid formulation is preferred over manipulated commercial dosage forms or non-standardized extemporaneously compounded formulations. Copyright © 2016 Elsevier B.V. All rights reserved.

Protective effects of efonidipine, a T- and L-type calcium channel blocker, on renal function and arterial stiffness in type 2 diabetic patients with hypertension and nephropathy.

PubMed

Sasaki, Hidehisa; Saiki, Atsuhito; Endo, Kei; Ban, Noriko; Yamaguchi, Takashi; Kawana, Hidetoshi; Nagayama, Daizi; Ohhira, Masahiro; Oyama, Tomokazu; Miyashita, Yoh; Shirai, Kohji

2009-10-01

The three types of calcium channel blocker (CCB), L-, T- and N-type, possess heterogeneous actions on endothelial function and renal microvascular function. In the present study, we evaluated the effects of two CCBs, efonidipine and amlodipine, on renal function and arterial stiffness. Forty type 2 diabetic patients with hypertension and nephropathy receiving angiotensin receptor II blockers were enrolled and randomly divided into two groups: the efonidipine group was administered efonidipine hydrochloride ethanolate 40 mg/day and the amlodipine group was admin-istered amlodipine besilate 5 mg/day for 12 months. Arterial stiffness was evaluated by the cardio-ankle vascular index (CAVI). Changes in blood pressure during the study were almost the same in the two groups. Sig-nificant increases in serum creatinine and urinary albumin and a significant decrease in the esti-mated glomerular filtration rate were observed in the amlodipine group, but not in the efonidipine group. On the other hand, significant decreases in plasma aldosterone, urinary 8-hydroxy-2'-deoxy-guanosine and CAVI were observed after 12 months in the efonidipine group, but not in the amlo-dipine group. These results suggest that efonidipine, which is both a T-type and L-type calcium chan-nel blocker, has more favorable effects on renal function, oxidative stress and arterial stiffness than amlodipine, an L-type calcium channel blocker.

Evaluation of palatability of 10 commercial amlodipine orally disintegrating tablets by gustatory sensation testing, OD-mate as a new disintegration apparatus and the artificial taste sensor.

PubMed

Uchida, Takahiro; Yoshida, Miyako; Hazekawa, Mai; Haraguchi, Tamami; Furuno, Hiroyuki; Teraoka, Makoto; Ikezaki, Hidekazu

2013-09-01

The purpose of this study was to evaluate and compare the palatability of 10 formulations (the original manufacturer's formulation and nine generics) of amlodipine orally disintegrating tablets (ODTs) by means of human gustatory sensation testing, disintegration/dissolution testing and the evaluation of bitterness intensity using a taste sensor. Initially, the palatability, dissolution and bitterness intensity of the ODTs were evaluated in gustatory sensation tests. Second, the disintegration times of the ODTs were measured using the OD-mate, a newly developed apparatus for measuring the disintegration of ODTs, and lastly, the bitterness intensities were evaluated using an artificial taste sensor. Using factor analysis, the factors most affecting the palatability of amlodipine ODTs were found to be disintegration and taste. There was high correlation between the disintegration times of the 10 amlodipine ODTs estimated in human gustatory testing and those found using the OD-mate. The bitterness intensities of amlodipine ODTs 10, 20 and 30 s after starting the conventional brief dissolution test and the values determined by the taste sensor were highly correlated with the bitterness intensities determined in gustatory sensation testing. The OD-mate and the taste sensor may be useful for predicting the disintegration and bitterness intensity of amlodipine ODTs in the mouth. © 2013 Royal Pharmaceutical Society.

What proportion of patients with chronic heart failure are eligible for sacubitril-valsartan?

PubMed

Pellicori, Pierpaolo; Urbinati, Alessia; Shah, Parin; MacNamara, Alexandra; Kazmi, Syed; Dierckx, Riet; Zhang, Jufen; Cleland, John G F; Clark, Andrew L

2017-06-01

The PARADIGM-HF trial showed that sacubitril-valsartan, an ARB-neprilysin inhibitor, is more effective than enalapril for some patients with heart failure (HF). It is uncertain what proportion of patients with HF would be eligible for sacubitril-valsartan in clinical practice. Between 2001 and 2014, 6131 patients consecutively referred to a community HF clinic with suspected HF were assessed. The criteria required to enter the randomized phase of PARADIGM-HF, including symptoms, NT-proBNP, and current treatment with or without target doses of ACE inhibitors or ARBs, were applied to identify the proportion of patients eligible for sacubitril-valsartan. Recognizing the diversity of clinical opinion and guideline recommendations concerning this issue, entry criteria were applied singly and in combination. Of 1396 patients with reduced left ventricular ejection fraction (≤40%, HFrEF) and contemporary measurement of NT-proBNP, 379 were on target doses of an ACE inhibitor or ARB at their initial visit and, of these, 172 (45%) fulfilled the key entry criteria for the PARADIGM-HF trial. Lack of symptoms (32%) and NT-proBNP <600 ng/L (49%) were common reasons for failure to fulfil criteria. A further 122 patients became eligible during follow-up (n = 294, 21%). However, if background medication and doses were ignored, then 701 (50%) were eligible initially and a further 137 became eligible during follow-up. Of patients with HFrEF referred to a clinic such as ours, only 21% fulfilled the PARADIGM-HF randomization criteria, on which the ESC Guidelines are based; this proportion rises to 60% if background medication is ignored. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

Simultaneous determination of atorvastatin and valsartan in human plasma by solid-based disperser liquid-liquid microextraction followed by high-performance liquid chromatography-diode array detection.

PubMed

Farajzadeh, Mir Ali; Khorram, Parisa; Pazhohan, Azar

2016-04-01

A simple, sensitive, and efficient method has been developed for simultaneous estimation of valsartan and atorvastatin in human plasma by combination of solid-based dispersive liquid-liquid microextraction and high performance liquid chromatography-diode array detection. In the proposed method, 1,2-dibromoethane (extraction solvent) is added on a sugar cube (as a solid disperser) and it is introduced into plasma sample containing the analytes. After manual shaking and centrifugation, the resultant sedimented phase is subjected to back extraction into a small volume of sodium hydrogen carbonate solution using air-assisted liquid-liquid microextraction. Then the cloudy solution is centrifuged and the obtained aqueous phase is transferred into a microtube and analyzed by the separation system. Under the optimal conditions, extraction recoveries are obtained in the range of 81-90%. Calibration curves plotted in drug-free plasma sample are linear in the ranges of 5-5000μgL(-1) for valsartan and 10-5000μgL(-1) for atorvastatin with the coefficients of determination higher than 0.997. Limits of detection and quantification of the studied analytes in plasma sample are 0.30-2.6 and 1.0-8.2μgL(-1), respectively. Intra-day (n=6) and inter-days (n=4) precisions of the method are satisfactory with relative standard deviations less than 7.4% (at three levels of 10, 500, and 2000μgL(-1), each analyte). These data suggest that the method can be successfully applied to determine trace amounts of valsartan and atorvastatin in human plasma samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Valsartan Attenuates Atherosclerosis via Upregulating the Th2 Immune Response in Prolonged Angiotensin II–Treated ApoE−/− Mice

PubMed Central

Meng, Kai; Zeng, Qiutang; Lu, Qinghua; Lin, Yingzhong; Wu, Bangwei; Yu, Kunwu; Dong, Zhaoqiang; Zhang, Jianwei; Chai, Meng; Liu, Yuyang; Ji, Qingwei; Zhou, Yujie

2015-01-01

Valsartan has a protective effect against hypertension and atherosclerosis in humans and experimental animal models. This study aimed to determine the effect of prolonged treatment with angiotensin II (Ang II) on atherosclerosis and the effect of valsartan on the activity of CD4+ T lymphocyte subsets. The results showed that prolonged treatment (8 wks) with exogenous Ang II resulted in an increased atherosclerotic plaque size and a switch of stable-to-unstable plaque via modulating on CD4+ T lymphocyte activity, including an increase in the T helper cell type 1 (Th1) and Th17 cells and a decrease in Th2 and regulatory T (Treg) cells. In contrast, valsartan treatment efficiently reversed the imbalance in CD4+ T lymphocyte activity, ameliorated atherosclerosis and elicited a stable plaque phenotype in addition to controlling blood pressure. In addition, treatment with anti-interleukin (IL)-5 monoclonal antibodies weakened the antiatherosclerotic effects of valsartan without affecting blood pressure. PMID:25685964

Survival and echocardiographic data in dogs with congestive heart failure caused by mitral valve disease and treated by multiple drugs: a retrospective study of 21 cases.

PubMed

de Madron, Eric; King, Jonathan N; Strehlau, Günther; White, Regina Valle

2011-11-01

This retrospective study reports the survival time [onset of congestive heart failure (CHF) to death from any cause] of 21 dogs with mitral regurgitation (MR) and CHF treated with a combination of furosemide, angiotensin-converting enzyme inhibitor (ACEI, benazepril, or enalapril), pimobendan, spironolactone, and amlodipine. Baseline echocardiographic data: end-systolic and end-diastolic volume indices (ESVI and EDVI), left atrium to aorta ratio (LA/Ao), and regurgitant fraction (RF) are reported. Median survival time (MST) was 430 d. Initial dosage of furosemide (P = 0.0081) and LA/Ao (P = 0.042) were negatively associated with survival. Baseline echocardiographic indices (mean ± standard deviation) were 40.24 ± 16.76 for ESVI, 161.48 ± 44.49 mL/m(2) for EDVI, 2.11 ± 0.75 for LA/Ao, and 64.71 ± 16.85% for RF. Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR and CHF. Severity of MR at onset of CHF is at least moderate.

Survival and echocardiographic data in dogs with congestive heart failure caused by mitral valve disease and treated by multiple drugs: A retrospective study of 21 cases

PubMed Central

de Madron, Eric; King, Jonathan N.; Strehlau, Günther; White, Regina Valle

2011-01-01

This retrospective study reports the survival time [onset of congestive heart failure (CHF) to death from any cause] of 21 dogs with mitral regurgitation (MR) and CHF treated with a combination of furosemide, angiotensin-converting enzyme inhibitor (ACEI, benazepril, or enalapril), pimobendan, spironolactone, and amlodipine. Baseline echocardiographic data: end-systolic and end-diastolic volume indices (ESVI and EDVI), left atrium to aorta ratio (LA/Ao), and regurgitant fraction (RF) are reported. Median survival time (MST) was 430 d. Initial dosage of furosemide (P = 0.0081) and LA/Ao (P = 0.042) were negatively associated with survival. Baseline echocardiographic indices (mean ± standard deviation) were 40.24 ± 16.76 for ESVI, 161.48 ± 44.49 mL/m2 for EDVI, 2.11 ± 0.75 for LA/Ao, and 64.71 ± 16.85% for RF. Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR and CHF. Severity of MR at onset of CHF is at least moderate. PMID:22547843

Stability-indicating UPLC method for determination of Valsartan and their degradation products in active pharmaceutical ingredient and pharmaceutical dosage forms.

PubMed

Krishnaiah, Ch; Reddy, A Raghupathi; Kumar, Ramesh; Mukkanti, K

2010-11-02

A simple, precise, accurate stability-indicating gradient reverse phase ultra-performance liquid chromatographic (RP-UPLC) method was developed for the quantitative determination of purity of Valsartan drug substance and drug products in bulk samples and pharmaceutical dosage forms in the presence of its impurities and degradation products. The method was developed using Waters Aquity BEH C18 (100 mm x 2.1 mm, 1.7 microm) column with mobile phase containing a gradient mixture of solvents A and B. The eluted compounds were monitored at 225 nm, the run time was within 9.5 min, which Valsartan and its seven impurities were well separated. Valsartan was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. Valsartan was found to degrade significantly in acid and oxidative stress conditions and stable in base, hydrolytic and photolytic degradation conditions. The degradation products were well resolved from main peak and its impurities, proving the stability-indicating power of the method. The developed method was validated as per international conference on harmonization (ICH) guidelines with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision and robustness. This method was also suitable for the assay determination of Valsartan in pharmaceutical dosage forms.

Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects.

PubMed

Akahori, Mizuki; Ayalasomayajula, Surya; Langenickel, Thomas; Pal, Parasar; Zhou, Wei; Sunkara, Gangadhar

2017-06-01

LCZ696 (sacubitril/valsartan) is a novel angiotensin receptor neprilysin inhibitor (ARNI) that has been developed for treatment of heart failure patients with reduced ejection fraction and approved in the US, Europe, and many other countries. This randomized, placebo-controlled study was conducted in healthy Japanese male subjects (N = 50) to assess the pharmacokinetics and safety of single ascending oral doses (20-600 mg) of LCZ696. Food effect was also evaluated following administration of 200 mg dose. Plasma and urine samples from 40 subjects receiving LCZ696 were collected to assess pharmacokinetics of LCZ696 analytes (sacubitril, sacubitrilat, and valsartan). Following single oral dose administration of LCZ696, sacubitril and valsartan rapidly appeared in systemic circulation with a dose-linear increase in the exposure to the LCZ696 analytes. Of the administered dose, approximately 0.85 %, 54.0 %, and 8.19 % of sacubitril, sacubitrilat, and valsartan, respectively, were recovered in urine. Food reduced AUC of sacubitril, sacubitrilat, and valsartan by 21, 8, and 40 %, respectively, and C max by 72, 27, and 51 %, respectively. Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.

The effects of sacubitril/valsartan on coronary outcomes in PARADIGM-HF.

PubMed

Mogensen, Ulrik M; Køber, Lars; Kristensen, Søren L; Jhund, Pardeep S; Gong, Jianjian; Lefkowitz, Martin P; Rizkala, Adel R; Rouleau, Jean L; Shi, Victor C; Swedberg, Karl; Zile, Michael R; Solomon, Scott D; Packer, Milton; McMurray, John J V

2017-06-01

Angiotensin converting enzyme inhibitors (ACE-I), are beneficial both in heart failure with reduced ejection fraction (HF-REF) and after myocardial infarction (MI). We examined the effects of the angiotensin-receptor neprilysin inhibitor sacubitril/valsartan, compared with the ACE-I enalapril, on coronary outcomes in PARADIGM-HF. We examined the effect of sacubitril/valsartan compared with enalapril on the following outcomes: i) the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, ii) a pre-defined broader composite including, in addition, MI, stroke, and resuscitated sudden death, and iii) a post hoc coronary composite of CV-death, non-fatal MI, angina hospitalization or coronary revascularization. At baseline, of 8399 patients, 3634 (43.3%) had a prior MI and 4796 (57.1%) had a history of any coronary artery disease. Among all patients, compared with enalapril, sacubitril/valsartan reduced the risk of the primary outcome (HR 0.80 [0.73-0.87], P<.001), the broader composite (HR 0.83 [0.76-0.90], P<.001) and the coronary composite (HR 0.83 [0.75-0.92], P<.001). Although each of the components of the coronary composite occurred less frequently in the sacubitril/valsartan group, compared with the enalapril group, only CV death was reduced significantly. Compared with enalapril, sacubitril/valsartan reduced the risk of both the primary endpoint and a coronary composite outcome in PARADIGM-HF. Additional studies on the effect of sacubitril/valsartan on atherothrombotic outcomes in high-risk patients are merited. Copyright © 2017 Elsevier Inc. All rights reserved.

Valsartan Reduced Atrial Fibrillation Susceptibility by Inhibiting Atrial Parasympathetic Remodeling through MAPKs/Neurturin Pathway.

PubMed

Liu, Lei; Geng, Jianqiang; Zhao, Hongwei; Yun, Fengxiang; Wang, Xiaoyu; Yan, Sen; Ding, Xue; Li, Wenpeng; Wang, Dingyu; Li, Jianqiang; Pan, Zhenwei; Gong, Yongtai; Tan, Xiangyang; Li, Yue

2015-01-01

Angiotensin II receptor blockers (ARBs) have been proved to be effective in preventing atrial structural and electrical remodelinq in atrial fibrillation (AF). Previous studies have shown that parasympathetic remodeling plays an important role in AF. However, the effects of ARBs on atrial parasympathetic remodeling in AF and the underlying mechanisms are still unknown. Canines were divided into sham-operated, pacing and valsartan + pacing groups. Rats and HL-1 cardiomyocytes were divided into control, angiotensin II (Ang II) and Ang II + valsartan groups, respectively. Atrial parasympathetic remodeling was quantified by immunocytochemical staining with anti-choline acetyltransferase (ChAT) antibody. Western blot was used to analysis the protein expression of neurturin. Both inducibility and duration were increased in chronic atrial rapid-pacing canine model, which was significantly inhibited by the treatment with valsartan. The density of ChAT-positive nerves and the protein level of neurturin in the atria of pacing canines were both increased than those in sham-operated canines. Ang II treatment not only induced atrial parasympathetic remodeling in rats, but also up-regulated the protein expression of neurturin. Valsartan significantly prevented atrial parasympathetic remodeling, and suppressed the protein expression of neurturin. Meanwhile, valsartan inhibited Ang II -induced up-regulation of neurturin and MAPKs in cultured cardiac myocytes. Inhibition of MAPKs dramatically attenuated neurturin up-regulation induced by Ang II. Parasympathetic remodeling was present in animals subjected to rapid pacing or Ang II infusion, which was mediated by MAPKs/neurturin pathway. Valsartan is able to prevent atrial parasympathetic remodeling and the occurrence of AF via inhibiting MAPKs/neurturin pathway. © 2015 S. Karger AG, Basel.

Randomized placebo controlled blinded study to assess valsartan efficacy in preventing left ventricle remodeling in patients with dual chamber pacemaker--Rationale and design of the trial.

PubMed

Tomasik, Andrzej; Jacheć, Wojciech; Wojciechowska, Celina; Kawecki, Damian; Białkowska, Beata; Romuk, Ewa; Gabrysiak, Artur; Birkner, Ewa; Kalarus, Zbigniew; Nowalany-Kozielska, Ewa

2015-05-01

Dual chamber pacing is known to have detrimental effect on cardiac performance and heart failure occurring eventually is associated with increased mortality. Experimental studies of pacing in dogs have shown contractile dyssynchrony leading to diffuse alterations in extracellular matrix. In parallel, studies on experimental ischemia/reperfusion injury have shown efficacy of valsartan to inhibit activity of matrix metalloproteinase-9, to increase the activity of tissue inhibitor of matrix metalloproteinase-3 and preserve global contractility and left ventricle ejection fraction. To present rationale and design of randomized blinded trial aimed to assess whether 12 month long administration of valsartan will prevent left ventricle remodeling in patients with preserved left ventricle ejection fraction (LVEF ≥ 40%) and first implantation of dual chamber pacemaker. A total of 100 eligible patients will be randomized into three parallel arms: placebo, valsartan 80 mg/daily and valsartan 160 mg/daily added to previously used drugs. The primary endpoint will be assessment of valsartan efficacy to prevent left ventricle remodeling during 12 month follow-up. We assess patients' functional capacity, blood plasma activity of matrix metalloproteinases and their tissue inhibitors, NT-proBNP, tumor necrosis factor alpha, and Troponin T. Left ventricle function and remodeling is assessed echocardiographically: M-mode, B-mode, tissue Doppler imaging. If valsartan proves effective, it will be an attractive measure to improve long term prognosis in aging population and increasing number of pacemaker recipients. ClinicalTrials.org (NCT01805804). Copyright © 2015 Elsevier Inc. All rights reserved.

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

PubMed

Kusaka, Hiroaki; Sueta, Daisuke; Koibuchi, Nobutaka; Hasegawa, Yu; Nakagawa, Takashi; Lin, BoWen; Ogawa, Hisao; Kim-Mitsuyama, Shokei

2015-12-01

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. (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. (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. 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. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Sacubitril/valsartan: beyond natriuretic peptides.

PubMed

Singh, Jagdeep S S; Burrell, Louise M; Cherif, Myriam; Squire, Iain B; Clark, Andrew L; Lang, Chim C

2017-10-01

Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to their potentially beneficial physiological effects. The angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system (RAAS) by blocking the angiotensin II receptor. It has been shown to improve mortality and hospitalisation outcomes in patients with HF due to left ventricular systolic dysfunction. The key advantage of sacubitril/valsartan has been perceived to be its ability to augment BNP, while its other effects have largely been overlooked. This review highlights the important effects of sacubitril/valsartan, beyond just the augmentation of BNP. First we discuss how NPS physiology differs between healthy individuals and those with HF by looking at mechanisms like the overwhelming effects of RAAS on the NPS, natriuretic peptide receptor desensitisation and absolute natriuretic deficiency. Second, this review explores other hormones that are augmented by sacubitril/valsartan such as bradykinin, substance P and adrenomedullin that may contribute to the efficacy of sacubitril/valsartan in HF. We also discuss concerns that sacubitril/valsartan may interfere with amyloid-β homeostasis with potential implications on Alzheimer's disease and macular degeneration. Finally, we explore the concept of 'autoinhibition' which is a recently described observation that humans have innate NEP inhibitory capability when natriuretic peptide levels rise above a threshold. There is speculation that autoinhibition may provide a surge of natriuretic and other vasoactive peptides to rapidly reverse decompensation. We contend that by pre-emptively inhibiting NEP, sacubitril/valsartan is inducing this surge earlier during decompensation, resulting in the better outcomes observed. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Initial clinical experience with the first drug (sacubitril/valsartan) in a new class - angiotensin receptor neprilysin inhibitors in patients with heart failure with reduced left ventricular ejection fraction in Poland.

PubMed

Kałużna-Oleksy, Marta; Kolasa, Jolanta; Migaj, Jacek; Pawlak, Agnieszka; Lelonek, Małgorzata; Nessler, Jadwiga; Straburzyńska-Migaj, Ewa

2018-01-01

Sacubitril/valsartan is the first drug from a new class of angiotensin receptor neprilysin inhibitors (ARNIs) recommended in the new European Society of Cardiology guidelines instead of angiotensin converting enzyme inhibitors (ACEI), or angiotensin receptor blockers (ARB) that are used if ACEI are not tolerated. Sacubitril/valsartan is recommended for further reduction in the risk of hospitalisation or death in outpatients with heart failure with reduced ejection fraction (HFrEF) if symptoms continue despite optimal treatment with ACEI/ARB, beta-blockers, and mineralocorticoid antagonists. The aim of this study is to present the initial experience with regard to the effectiveness, tolerance, and safety of sacubitril/valsartan in the outpatient cardiology practice in Poland. The study is a retrospective analysis of data obtained through a questionnaire filled in by the physicians who initiated the sacubitril/valsartan treatment in patients with HFrEF between 1 June 2016 and 30 September 2016. Patients were followed-up for three months. The analysis included data on 28 patients aged 61 ± 16 years, of whom 85.7% were males. The drug was used in patients in New York Heart Association (NYHA) class I-III. In 25 (89.2%) patients sacubitril/valsartan was started at the lowest dose (24/26 mg BID). During follow-up the sacubitril/valsartan-treated patients had a reduction in HF symptoms assessed using the NYHA functional class (p = 0.001), a significant drop in N-terminal-pro B-type natriuretic peptide levels (mean, from 2900 to 2270 pg/mL; p = 0.008), and improved exercise tolerance, which occurred shortly after treatment initiation - after a mean of 28 days. It was demonstrated that the use of sacubitril/valsartan in outpatients with HFrEF is safe and is associated with a significant clinical improvement.

An Early View of Real-World Patient Response to Sacubitril/Valsartan: A Retrospective Study of Patients with Heart Failure with Reduced Ejection Fraction.

PubMed

Antol, Dana Drzayich; Casebeer, Adrianne Waldman; DeClue, Richard W; Stemkowski, Stephen; Russo, Patricia A

2018-06-01

Sacubitril/valsartan has been established as an effective treatment for heart failure (HF) with reduced ejection fraction based on clinical trial data; however, little is known about its use or impact in real-world practice. This study included data from medical and pharmacy claims and medical records review for patients (n = 200) who initiated sacubitril/valsartan between August 2015 and March 2016 preceding issuance of American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) focused update on new pharmacological therapy for HF (May 2016), which included recommendations for sacubitril/valsartan. A within-subject analysis compared symptoms and healthcare resource utilization before and after treatment initiation. Patients treated with sacubitril/valsartan had multiple comorbidities, and nearly all had previous treatment for HF. Most patients initiated sacubitril/valsartan at the lowest dose of 24/26 mg twice a day (BID), which remained unchanged during the observation period for half of the patients. During the first 6 weeks of treatment, few patients discontinued sacubitril/valsartan treatment (5.5%), and only 17% achieved the target dose of 97/103 mg BID after 4 months of treatment. The proportion of patients with ≥ 1 all-cause inpatient stay decreased significantly between the pre-initiation period (27.5%) and the post-initiation period (17.0%), P = 0.009. Fatigue was noted in 51.8% of patients pre-initiation and 39.5% post-initiation, P = 0.027. Shortness of breath was documented for 66.7% of patients pre-initiation and 51.8% post-initiation, P = 0.008. The findings of this real-world investigation suggest sacubitril/valsartan is associated with symptom improvements and a reduction in hospitalizations within 4 months of treatment for patients with HF and reduced ejection fraction. Novartis Pharmaceuticals Corporation.

Predictors of stroke in patients with impaired glucose tolerance: results from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial.

PubMed

Preiss, David; Giles, Thomas D; Thomas, Laine E; Sun, Jie-Lena; Haffner, Steven M; Holman, Rury R; Standl, Eberhard; Mazzone, Theodore; Rutten, Guy E; Tognoni, Gianni; Chiang, Fu-Tien; McMurray, John J V; Califf, Robert M

2013-09-01

Risk factors for stroke are well-established in general populations but sparsely studied in individuals with impaired glucose tolerance. We identified predictors of stroke among participants with impaired glucose tolerance in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Cox proportional-hazard regression models were constructed using baseline variables, including the 2 medications studied, valsartan and nateglinide. Among 9306 participants, 237 experienced a stroke over 6.4 years. Predictors of stroke included classical risk factors such as existing cerebrovascular and coronary heart disease, higher pulse pressure, higher low-density lipoprotein cholesterol, older age, and atrial fibrillation. Other factors, including previous venous thromboembolism, higher waist circumference, lower estimated glomerular filtration rate, lower heart rate, and lower body mass index, provided additional important predictive information, yielding a C-index of 0.72. Glycemic measures were not predictive of stroke. Variables associated with stroke were similar in participants with no prior history of cerebrovascular disease at baseline. The most powerful predictors of stroke in patients with impaired glucose tolerance included a combination of established risk factors and novel variables, such as previous venous thromboembolism and elevated waist circumference, allowing moderately effective identification of high-risk individuals.

Effectiveness of perindopril/amlodipine fixed dose combination in everyday clinical practice: results from the EMERALD study.

PubMed

Vlachopoulos, C; Grammatikou, V; Kallistratos, M; Karagiannis, A

2016-09-01

The rates of blood pressure (BP) control worldwide are discouraging. This study had the purpose of assessing the effectiveness of perindopril/amlodipine fixed dose combination on BP-lowering efficacy, and recording adherence, safety and tolerability during a 4 month treatment period. In this multicenter, observational study 2269 hypertensive patients were prospectively enrolled. The data were recorded at 1 and 4 months of treatment. Between the first and third visits mean BP values (systolic/diastolic) decreased from 158.4 ± 13.6/89.9 ± 8.7 mmHg to 130.0 ± 7.9/77.7 ± 6.3 mmHg (P < 0.001). The magnitude of BP reduction depended on baseline blood pressure levels and total cardiovascular (CV) risk (P < 0.001). Patients with grade 1, 2 and 3 showed a BP reduction of 21.9/10.0 mmHg, 34.4/14.2 mmHg and 51.4/21.2 mmHg, accordingly (P < 0.001). Patients with very high, high, moderate and low added CV risk showed a BP reduction of 35.7/14.9 mmHg, 27.5/12.1 mmHg, 28.6/12.2 mmHg and 14.5/5.8 mmHg respectively (P < 0.001). Adherence to treatment was high: 98.3% of the sample was taking the treatment "every day" or "quite often", while only 15 patients (0.7% of the sample) prematurely discontinued treatment. Study interpretation may be limited by the fact that this is an observational study with no comparator and a short follow-up period. A perindopril/amlodipine fixed dose combination significantly decreases BP levels. The degree of BP reduction is related to baseline BP levels and total CV risk.

Phototransformation of Amlodipine: Degradation Kinetics and Identification of Its Photoproducts

PubMed Central

Jakimska, Anna; Śliwka-Kaszyńska, Magdalena; Nagórski, Piotr; Namieśnik, Jacek; Kot-Wasik, Agata

2014-01-01

Nowadays, monitoring focuses on the primary compounds and does not include degradation products formed during various biological and chemical processes. Transformation products may have the same effects to human health and the environment or sometimes they can be more toxic than the parent compound. Unfortunately, knowledge about the formation of degradation products is still limited, however, can be very important for the environmental risk assessment. Firstly, the photodegradation kinetic of amlodipine was investigated in two experimental conditions: during the exposure to solar radiation and during the exposure to the light emitted by the xenon lamp. In all cases degradation of amlodipine followed a pseudo-first-order kinetics. In the next step, identification of transformation products of amlodipine formed during the exposure to xenon lamp irradiation was performed using ultra high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). As a result sixteen photoproducts were identified, their structures were elucidated and ultimately the transformation pathway was proposed. Fifteen compounds (out of 16 photoproducts) were newly identified and reported here for the first time; some of those compounds were formed from the first photoproduct, amlodipine pyridine derivative. Several analytes were formed only in acidic or basic conditions. Furthermore, the occurrence of amlodipine and its identified degradation products was investigated in environmental waters. Only one out of 16 compounds was found in wastewater effluent. The possibility of the sorption of examined analytes to sewage sludge particles was discussed based on QSAR. PMID:25279815

Simultaneous quantitative analysis of olmesartan, amlodipine and hydrochlorothiazide in their combined dosage form utilizing classical and alternating least squares based chemometric methods.

PubMed

Darwish, Hany W; Bakheit, Ahmed H; Abdelhameed, Ali S

2016-03-01

Simultaneous spectrophotometric analysis of a multi-component dosage form of olmesartan, amlodipine and hydrochlorothiazide used for the treatment of hypertension has been carried out using various chemometric methods. Multivariate calibration methods include classical least squares (CLS) executed by net analyte processing (NAP-CLS), orthogonal signal correction (OSC-CLS) and direct orthogonal signal correction (DOSC-CLS) in addition to multivariate curve resolution-alternating least squares (MCR-ALS). Results demonstrated the efficiency of the proposed methods as quantitative tools of analysis as well as their qualitative capability. The three analytes were determined precisely using the aforementioned methods in an external data set and in a dosage form after optimization of experimental conditions. Finally, the efficiency of the models was validated via comparison with the partial least squares (PLS) method in terms of accuracy and precision.

Occurrence and fate of the angiotensin II receptor antagonist transformation product valsartan acid in the water cycle--a comparative study with selected β-blockers and the persistent anthropogenic wastewater indicators carbamazepine and acesulfame.

PubMed

Nödler, Karsten; Hillebrand, Olav; Idzik, Krzysztof; Strathmann, Martin; Schiperski, Ferry; Zirlewagen, Johannes; Licha, Tobias

2013-11-01

The substantial transformation of the angiotensin II receptor antagonist valsartan to the transformation product 2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-carboxylic acid (referred to as valsartan acid) during the activated sludge process was demonstrated in the literature and confirmed in the here presented study. However, there was a severe lack of knowledge regarding the occurrence and fate of this compound in surface water and its behavior during drinking water treatment. In this work a comparative study on the occurrence and persistency of valsartan acid, three frequently used β-blockers (metoprolol, atenolol, and sotalol), atenolol acid (one significant transformation product of atenolol and metoprolol), and the two widely distributed persistent anthropogenic wastewater indicators carbamazepine and acesulfame in raw sewage, treated wastewater, surface water, groundwater, and tap water is presented. Median concentrations of valsartan acid in the analyzed matrices were 101, 1,310, 69, <1.0, and 65 ng L(-1), respectively. Treated effluents from wastewater treatment plants were confirmed as significant source. Regarding concentration levels of pharmaceutical residues in surface waters valsartan acid was found just as relevant as the analyzed β-blockers and the anticonvulsant carbamazepine. Regarding its persistency in surface waters it was comparable to carbamazepine and acesulfame. Furthermore, removal of valsartan acid during bank filtration was poor, which demonstrated the relevance of this compound for drinking water suppliers. Regarding drinking water treatment (Muelheim Process) the compound was resistant to ozonation but effectively eliminated (≥90%) by subsequent activated carbon filtration. However, without applying activated carbon filtration the compound may enter the drinking water distribution system as it was demonstrated for Berlin tap water. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of the angiotensin II receptor blocker valsartan on cardiac hypertrophy and myocardial histone deacetylase expression in rats with aortic constriction

PubMed Central

XU, WEI-PING; YAO, TONG-QING; JIANG, YI-BO; ZHANG, MAO-ZHEN; WANG, YUE-PENG; YU, YING; LI, JING-XIANG; LI, YI-GANG

2015-01-01

The aim of the present study was to observe the myocardial expression of members of the histone deacetylase (HDAC) family (HDAC2, HDAC5 and HDAC9) in rats with or without myocardial hypertrophy (MH) in the presence and absence of the angiotensin II receptor blocker valsartan. Adult male Wistar rats were randomly divided into three groups (n=6/group): Sham-operated control rats, treated with distilled water (1 ml/day) through gavage; rats with MH (established through aortic constriction), treated with distilled water (1 ml/day) through gavage; and MH + valsartan rats, treated with 20 mg/kg/day valsartan through gavage. Treatments commenced one day after surgery and continued for eight weeks. Body weight (BW), heart weight (HW) and plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels were determined, and the myocardial expression of HDAC2, HDAC5 and HDAC9 was analyzed through a reverse transcription semi-quantitative polymerase chain reaction. The BWs of the rats in the three groups were similar at baseline; however, after eight weeks the BW of the rats in the MH + valsartan group was significantly reduced compared with that of the MH rats. Furthermore, the HW/BW ratio and plasma ANP and BNP levels were increased, the myocardial HDAC2 expression was significantly upregulated and the HDAC5 and HDAC9 expression was significantly downregulated in the MH rats compared with those in the control rats; however, these changes were significantly attenuated by valsartan. Modulation of myocardial HDAC5, HDAC9 and HDAC2 expression may therefore be one of the anti-hypertrophic mechanisms of valsartan in this rat MH model. PMID:26136964

Angioedema in heart failure patients treated with sacubitril/valsartan (LCZ696) or enalapril in the PARADIGM-HF study.

PubMed

Shi, Victor; Senni, Michele; Streefkerk, Hendrik; Modgill, Vikas; Zhou, Wenchun; Kaplan, Allen

2018-08-01

PARADIGM-HF demonstrated significant clinical benefits for sacubitril/valsartan (LCZ696, an angiotensin receptor neprilysin inhibitor) versus the angiotensin-converting enzyme inhibitor (ACEI) enalapril in patients with heart failure with reduced ejection fraction. As inhibition of ACE, and co-inhibition of ACE and neprilysin, may increase the risk of angioedema, this was an adverse event of special interest. Following sequential enalapril and sacubitril/valsartan run-ins, patients were randomized to twice-daily sacubitril/valsartan 200 mg or enalapril 10 mg. The study design incorporated two wash-out periods (~36 h each) to minimize any potential risk of angioedema due to overlapping ACE and neprilysin inhibition. Suspected cases of angioedema were reported to, and blindly adjudicated by, an independent angioedema adjudication committee (AAC). Of the 10,513 patients entering the enalapril run-in, 9419 entered the sacubitril/valsartan run-in and 8432 received double-blind treatment. Overall, 148 suspected angioedema events occurring in 144 patients were reported to AAC, with one event reported during screening period. Of the remaining 147 events, 54 were confirmed as angioedema by AAC. A confirmed event was experienced by 15 (0.14%) and 10 (0.11%) patients, during the enalapril and sacubitril/valsartan run-ins, respectively, and by 10 (0.24%) and 19 (0.45%) patients in the corresponding randomized arms during the double-blind phase. The frequency of confirmed angioedema was higher in black patients. Most events were mild. Only five patients required hospitalization and none required mechanical airway support. The number of confirmed angioedema events in PARADIGM-HF was low and there was no-marked excess risk of angioedema with sacubitril/valsartan versus enalapril. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Cost-effectiveness of sacubitril/valsartan in chronic heart-failure patients with reduced ejection fraction.

PubMed

Ademi, Zanfina; Pfeil, Alena M; Hancock, Elizabeth; Trueman, David; Haroun, Rola Haroun; Deschaseaux, Celine; Schwenkglenks, Matthias

2017-11-29

We aimed to assess the cost effectiveness of sacubitril/valsartan compared to angiotensin-converting enzyme inhibitors (ACEIs) for the treatment of individuals with chronic heart failure and reduced-ejection fraction (HFrEF) from the perspective of the Swiss health care system. The cost-effectiveness analysis was implemented as a lifelong regression-based cohort model. We compared sacubitril/valsartan with enalapril in chronic heart failure patients with HFrEF and New York-Heart Association Functional Classification II-IV symptoms. Regression models based on the randomised clinical phase III PARADIGM-HF trials were used to predict events (all-cause mortality, hospitalisations, adverse events and quality of life) for each treatment strategy modelled over the lifetime horizon, with adjustments for patient characteristics. Unit costs were obtained from Swiss public sources for the year 2014, and costs and effects were discounted by 3%. The main outcome of interest was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life years (QALYs) gained. Deterministic sensitivity analysis (DSA) and scenario and probabilistic sensitivity analysis (PSA) were performed. In the base-case analysis, the sacubitril/valsartan strategy showed a decrease in the number of hospitalisations (6.0% per year absolute reduction) and lifetime hospital costs by 8.0% (discounted) when compared with enalapril. Sacubitril/valsartan was predicted to improve overall and quality-adjusted survival by 0.50 years and 0.42 QALYs, respectively. Additional net-total costs were CHF 10 926. This led to an ICER of CHF 25 684. In PSA, the probability of sacubitril/valsartan being cost-effective at thresholds of CHF 50 000 was 99.0%. The treatment of HFrEF patients with sacubitril/valsartan versus enalapril is cost effective, if a willingness-to-pay threshold of CHF 50 000 per QALY gained ratio is assumed.

Sacubitril/Valsartan (LCZ696) in Heart Failure.

PubMed

Khder, Yasser; Shi, Victor; McMurray, John J V; Lefkowitz, Martin P

2017-01-01

It has been known since the 1990s that long-term morbidity and mortality is improved in patients with heart failure with reduced ejection fraction (HFrEF) by treatments that target the renin-angiotensin-aldosterone system (RAAS). It has also long been thought that enhancement of the activity of natriuretic peptides (NPs) could potentially benefit patients with HFrEF, but multiple attempts to realize this benefit had failed over the years - until 2014, when a large, phase III, randomized, controlled clinical trial (PARADIGM-HF) was completed comparing sacubitril/valsartan with enalapril, a well-established treatment for HFrEF. Sacubitril/valsartan (formerly known as LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that simultaneously suppresses RAAS activation through blockade of angiotensin II type 1 receptors and enhances vasoactive peptides including NPs through inhibition of neprilysin, the enzyme responsible for their degradation. In PARADIGM-HF, patients with HFrEF treated with sacubitril/valsartan had 20% less risk for cardiovascular death or hospitalization for heart failure (the primary endpoint), 20% less risk for cardiovascular death, 21% less risk for first hospitalization for heart failure, and 16% less risk for death from any cause, compared with enalapril (all p < 0.001). Concerning tolerability, the sacubitril/valsartan group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough, compared with the enalapril group. The use of sacubitril/valsartan has been endorsed by the latest heart failure treatment guidelines in Europe and the USA. This chapter reviews the discoveries, scientific reasoning, and clinical evidence that led to the development of sacubitril/valsartan, the first novel therapy in a new drug class to improve survival in HFrEF in the last 15 years.

Valsartan attenuates intimal hyperplasia in balloon-injured rat aortic arteries through modulating the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis.

PubMed

Li, Yonghong; Cai, Shanglang; Wang, Qixin; Zhou, Jingwei; Hou, Bo; Yu, Haichu; Ge, Zhiming; Guan, Renyan; Liu, Xu

2016-05-15

The role of the Mas receptor in the activity of valsartan against intimal hyperplasia is unclear. Herein, we investigated the role of the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis on the activity of valsartan against intimal hyperplasiain balloon-injured rat aortic arteries. Wistar rats were randomized equally into the sham control group, injured group, and injured plus valsartan (20 mg/kg/d)-treated group. Valsartan significantly attenuated the vascular smooth muscle cell proliferation and intimal and medial thickening on days 14 and 28 after injury. The angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression were significantly decreased in the injured rats, compared to the uninjured rats; meanwhile, the angiotensin II level as well as the ACE and AT1 receptor mRNA/protein expression were increased (all P < 0.05 or < 0.01). Additionally, the p-ERK protein expression was increased (P < 0.01). Treatment with valsartan significantly increased the angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression but decreased the angiotensin II level, ACE and AT1 receptor mRNA/protein expression, as well as the p-ERK protein expression, compared to the injured group (all P < 0.05 or < 0.01). These results suggest that valsartan attenuates neointimal hyperplasiain balloon-injured rat aortic arteries through activation of the ACE2-angiotensin-(1-7)-Mas axis as well as inhibition of the ACE-angiotensin II-AT1 and p-ERK pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

Valsartan ameliorates KIR2.1 in rats with myocardial infarction via the NF-κB-miR-16 pathway.

PubMed

Li, Xinran; Hu, Hesheng; Wang, Ye; Xue, Mei; Li, Xiaolu; Cheng, Wenjuan; Xuan, Yongli; Yin, Jie; Yang, Na; Yan, Suhua

2016-09-30

MicroRNAs have an important role in regulating arrhythmogenesis. MicroRNA-16 (miR-16) is predicted to target KCNJ2. The regulation of miR-16 is primarily due to NF-κB. Whether valsartan could downregulate miR-16 via the inhibition of NF-κB after MI and whether miR-16 targets KCNJ2 remain unclear. MI rats received valsartan or saline for 7days. The protein levels of NF-κB p65, inhibitor κBα (IκBα), and Kir2.1 were detected by Western blot analysis. The mRNA levels of Kir2.1 and miR-16 were examined by quantitative real-time PCR. Whole cell patch-clamp techniques were applied to record IK1. MiR-16 expression was higher in the infarct border, and was accompanied by a depressed IK1/KIR2.1 level. Additionally, miR-16 overexpression suppressed KCNJ2/KIR2.1 expression. In contrast, miR-16 inhibition or binding-site mutation enhanced KCNJ2/KIR2.1 expression, establishing KCNJ2 as a miR-16 target. In the MI rats, compared to saline treatment, valsartan reduced NF-κB p65 and miR-16 expression and increased IκBα and Kir2.1 expression. In vitro, angiotensin II increased miR-16 expression and valsartan inhibited it. Overexpressing miR-16 in cells treated with valsartan abrogated its beneficial effect on KCNJ2/Kir2.1. NF-κB activation directly upregulates miR-16 expression. miR-16 controls KCNJ2 expression, and valsartan ameliorates Kir2.1 after MI partly depending on the NF-κB-miR-16 pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Valsartan Upregulates Kir2.1 in Rats Suffering from Myocardial Infarction via Casein Kinase 2.

PubMed

Li, Xinran; Hu, Hesheng; Wang, Ye; Xue, Mei; Li, Xiaolu; Cheng, Wenjuan; Xuan, Yongli; Yin, Jie; Yang, Na; Yan, Suhua

2015-06-01

Myocardial infarction (MI) results in an increased susceptibility to ventricular arrhythmias, due in part to decreased inward-rectifier K+ current (IK1), which is mediated primarily by the Kir2.1 protein. The use of renin-angiotensin-aldosterone system antagonists is associated with a reduced incidence of ventricular arrhythmias. Casein kinase 2 (CK2) binds and phosphorylates SP1, a transcription factor of KCNJ2 that encodes Kir2.1. Whether valsartan represses CK2 activation to ameliorate IK1 remodeling following MI remains unclear. Wistar rats suffering from MI received either valsartan or saline for 7 days. The protein levels of CK2 and Kir2.1 were each detected via a Western blot analysis. The mRNA levels of CK2 and Kir2.1 were each examined via quantitative real-time PCR. CK2 expression was higher at the infarct border; and was accompanied by a depressed IK1/Kir2.1 protein level. Additionally, CK2 overexpression suppressed KCNJ2/Kir2.1 expression. By contrast, CK2 inhibition enhanced KCNJ2/Kir2.1 expression, establishing that CK2 regulates KCNJ2 expression. Among the rats suffering from MI, valsartan reduced CK2 expression and increased Kir2.1 expression compared with the rats that received saline treatment. In vitro, hypoxia increased CK2 expression and valsartan inhibited CK2 expression. The over-expression of CK2 in cells treated with valsartan abrogated its beneficial effect on KCNJ2/Kir2.1. AT1 receptor antagonist valsartan reduces CK2 activation, increases Kir2.1 expression and thereby ameliorates IK1 remodeling after MI in the rat model.

Effects of valsartan on ventricular arrhythmia induced by programmed electrical stimulation in rats with myocardial infarction

PubMed Central

Jiao, Kun-Li; Li, Yi-Gang; Zhang, Peng-Pai; Chen, Ren-Hua; Yu, Yi

2012-01-01

Abstract The impact of angiotensin II receptor blockers (ARBs) on electrical remodelling after myocardial infarction (MI) remains unclear. The purpose of the present study was to evaluate the effect of valsartan on incidence of ventricular arrhythmia induced by programmed electrical stimulation (PES) and potential link to changes of myocardial connexins (Cx) 43 expression and distribution in MI rats. Fifty-nine rats were randomly divided into three groups: Sham (n = 20), MI (n = 20) and MI + Val (20 mg/kg/day per gavage, n = 19). After eight weeks, the incidence of PES-induced ventricular tachycardia (VT) and fibrillation (VF) was compared among groups. mRNA and protein expressions of Cx43, angiotensin II type 1 receptor (AT1R) in the LV border zone (BZ) and non-infarct zone (NIZ) were determined by real-time PCR and Western blot, respectively. Connexins 43 protein and collagen distribution were examined by immunohistochemistry in BZ and NIZ sections from MI hearts. Valsartan effectively improved the cardiac function, reduced the prolonged QTc (163.7 ± 3.7 msec. versus 177.8 ± 4.5 msec., P < 0.05) after MI and the incidence of VT or VF evoked by PES (21.1% versus 55%, P < 0.05). Angiotensin II type 1 receptor expression was significantly increased in BZ and NIZ sections after MI, which was down-regulated by valsartan. The mRNA and protein expressions of Cx43 in BZ were significantly reduced after MI and up-regulated by valsartan. Increased collagen deposition and reduced Cx43 expression in BZ after MI could be partly attenuated by Valsartan. Valsartan reduced the incidence of PES-induced ventricular arrhythmia, this effect was possibly through modulating the myocardial AT1R and Cx43 expression. PMID:22128836

Valsartan Attenuates KIR2.1 by Downregulating the Th1 Immune Response in Rats Following Myocardial Infarction.

PubMed

Li, Xinran; Hu, Hesheng; Wang, Ye; Xue, Mei; Li, Xiaolu; Cheng, Wenjuan; Xuan, Yongli; Yin, Jie; Yang, Na; Yan, Suhua

2016-03-01

Myocardial infarction (MI) results in decreased inward-rectifier K⁺ current (IK1), which is mediated primarily by the Kir2.1 protein and is accompanied by upregulated T cells. Interferon γ (IFN-γ), secreted predominantly by Th1 cells, causes a decrease in IK1 in microglia. Whether Th1 cells can induce IK1/Kir2.1 remodeling following MI and whether valsartan can ameliorate this phenomenon remain unclear. Rats experiencing MI received either valsartan or saline for 7 days. Th1-enriched lymphocytes and myocytes were cocultured with or without valsartan treatment. Th1 cells were monitored by flow cytometry. The protein levels of Kir2.1 were detected by Western blot analyses. IK1 was recorded through whole-cell patch clamping. The plasma levels of IFN-γ, interleukin 2, and tumor necrosis factor α were detected by enzyme-linked immunosorbent assay. Th1 cell number and cytokine expression levels were higher following MI, and the Kir2.1 protein level was decreased. In MI rats, valsartan reduced Th1 cell number and cytokine expression levels and increased the Kir2.1 expression and the IK1 current compared with the rats that received saline treatment; these results are consistent with the effect of valsartan in cocultured lymphocytes and myocytes. In vitro, IFN-γ overexpression suppressed the IK1 current, whereas interleukin 2 and tumor necrosis factor α had no significant effect on the current, establishing that Th1 cell regulation of IK1/Kir2.1 expression is mainly dependent on IFN-γ. Valsartan ameliorates IK1/Kir2.1 remodeling by downregulating the Th1 immune response following MI.

Valsartan attenuates cardiac and renal hypertrophy in rats with experimental cardiorenal syndrome possibly through down-regulating galectin-3 signaling.

PubMed

Zhang, M-J; Gu, Y; Wang, H; Zhu, P-F; Liu, X-Y; Wu, J

2016-01-01

Aortocaval fistula (AV) induced chronic volume overload in rats with preexisting mild renal dysfunction (right kidney remove: UNX) could mimic the type 4 cardiorenal syndrome (CRS): chronic renocardiac syndrome. Galectin-3, a β-galactoside binding lectin, is an emerging biomarker in cardiovascular as well as renal diseases. We observed the impact of valsartan on cardiac and renal hypertrophy and galectin-3 changes in this model. Adult male Sprague-Dawley (SD) rats (200-250 g) were divided into S (Sham, n = 7), M (UNX+AV, n = 7) and M+V (UNX+AV+valsartan, n = 7) groups. Eight weeks later, cardiac function was measured by echocardiography. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, renal blood flow and 24 hours albuminuria. Immunohistochemistry and real-time PCR were used to evaluate the expressions of galectin-3 in heart and renal. Cardiac hypertrophy and renal hypertrophy as well as cardiac enlargement were evidenced in this AV shunt induced chronic volume overload rat model with preexisting mild renal dysfunction. Cardiac and renal hypertrophy were significantly attenuated but cardiac enlargement was unaffected by valsartan independent of its blood pressure lowering effect. 24 hours urine albumin was significantly increased, which was significantly reduced by valsartan in this model. Immunohistochemistry and real-time PCR evidenced significantly up-regulated galectin-3 expression in heart and kidney and borderline increased myocardial collagen I expression, which tended to be lower post valsartan treatment. Up-regulated galectin-3 signaling might also be involved in the pathogenesis in this CRS model. The beneficial effects of valsartan in terms of attenuating cardiac and renal hypertrophy and reducing 24 hours albumin in this model might partly be mediated through down-regulating galectin-3 signal pathway.

Effect of LCZ696, a dual angiotensin receptor neprilysin inhibitor, on isoproterenol-induced cardiac hypertrophy, fibrosis, and hemodynamic change in rats.

PubMed

Miyoshi, Toru; Nakamura, Kazufumi; Miura, Daiji; Yoshida, Masashi; Saito, Yukihiro; Akagi, Satoshi; Ohno, Yuko; Kondo, Megumi; Ito, Hiroshi

2018-05-02

Recent clinical studies have shown that treatment with LCZ696, a complex containing the angiotensin receptor blocker valsartan and neprilysin inhibitor sacubitril, improves the prognosis of heart failure patients with a reduced ejection fraction. This study evaluated whether LCZ696 affects left ventricular hypertrophy, fibrosis, and hemodynamics in isoproterenol (ISO)-treated rats compared with valsartan alone. Male Wistar rats received subcutaneous saline (n = 10), subcutaneous ISO (2.4 mg/kg/day; n = 10), subcutaneous ISO + oral LCZ696 (60 mg/kg/day; n = 20) (ISO-LCZ), or subcutaneous ISO + oral valsartan (30 mg/kg/day; n = 20) (ISO-VAL) for 7 days. LCZ696 and valsartan did not significantly reduce the increased heart weight/body weight ratio in rats treated with ISO. Echocardiography showed that the deceleration time shortened by ISO was restored by LCZ696 but not valsartan alone (p = 0.01 vs. the ISO group). Histological analysis showed that cardiac interstitial fibrosis increased by ISO was decreased significantly by LCZ696 but not valsartan alone (control: 0.10 ± 0.14%; ISO: 0.41 ± 0.32%; ISO-LCZ: 0.19 ± 0.23% [p < 0.01 vs. the ISO group]; ISO-VAL: 0.34 ± 0.23% [p = 0.34 vs. the ISO group]). Quantitative PCR showed that mRNA expression of Tgfb1, Col1a1, Ccl2, and Anp increased by ISO was significantly attenuated by LCZ696 but not valsartan alone (p < 0.05 vs. the ISO group). LCZ696 improves cardiac fibrosis, but not hypertrophy, caused by continuous exposure to ISO in rats.

Sacubitril and valsartan fixed combination to reduce heart failure events in post-acute myocardial infarction patients.

PubMed

Zaid Iskandar, M; Lang, C C

2017-10-01

Heart failure is a term used to define a constellation of symptoms and signs that are commonly attributed to the inability of the heart to produce a cardiac output that meets the demands of the body. It remains a deadly disease, affecting between 1-2% of the population, and is more common in the elderly, with around 6-10% of patients over 65 suffering from the condition. Sacubitril/valsartan (LCZ-696) is a combined neprilysin inhibitor and angiotensin AT1 receptor blocker approved in recent years for the treatment of chronic heart failure with reduced ejection fraction. In an area where there have been limited pharmacological advances in the last 10 years, this drug was a game changer and a much welcomed addition to contemporary heart failure therapy. It is currently being studied in patients with heart failure with preserved ejection fraction and for the reduction of heart failure events post-acute myocardial infarction. Results from the ongoing PARADISE-MI study are awaited by the global cardiology community with great interest. Copyright 2017 Clarivate Analytics.

Sacubitril/valsartan and short-term changes in the 6-minute walk test: A pilot study.

PubMed

Beltrán, Paola; Palau, Patricia; Domínguez, Eloy; Faraudo, Mercedes; Núñez, Eduardo; Guri, Olga; Mollar, Anna; Sanchis, Juan; Bayés-Genís, Antoni; Núñez, Julio

2018-02-01

Impaired exercise capacity is the most disabling symptom in patients with heart failure with reduced ejection fraction (HFrEF). Despite sacubitril/valsartan showing reduced long-term morbidity and mortality over enalapril in HFrEF, its effects on short-term functional capacity remain uncertain. We sought to evaluate the effects of sacubitril/valsartan on a 30-day six-minute walk test in eligible patients with HFrEF. From November 1, 2016 to February 1, 2017, a total of 58 stable symptomatic patients with HFrEF were eligible for sacubitril/valsartan and underwent 6-MWT before and 30days after initiation of sacubitril/valsartan therapy. A mixed-effects model for repeated-measures was used to analyze the changes. Mean age was 70±11years. 72.4% males, 46.6% with ischemic heart disease, and 51.7% on NYHA functional class III were included. The mean (SD) values of baseline LVEF and 6MWT were 30±7%, and 300±89m, respectively. The median (IQR) of NT-proBNP at baseline was 2701pg/ml (1087-4200). Compared with baseline, the 6-MWT distance increased significantly at 30days by 13.9% (+∆=41.8m (33.4-50.2); p<0.001). In this pilot study, sacubitril/valsartan was associated with an improvement in exercise tolerance in symptomatic patients with HFrEF. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Benazepril

MedlinePlus

... or pharmacist if you are taking valsartan and sacubitril (Entresto) or if you have stopped taking it ... benazepril, if you are also taking valsartan and sacubitril. Also, tell your doctor if you have diabetes ...

Trandolapril

MedlinePlus

... or pharmacist if you are taking valsartan and sacubitril (Entresto) or if you have stopped taking it ... trandolapril, if you are also taking valsartan and sacubitril. Also, tell your doctor if you have diabetes ...

Quinapril

MedlinePlus

... or pharmacist if you are taking valsartan and sacubitril (Entresto) or if you have stopped taking it ... quinapril, if you are also taking valsartan and sacubitril. Also, tell your doctor if you have diabetes ...

Effectiveness and safety of valsartan in children aged 6 to 16 years with hypertension.

PubMed

Wells, Thomas; Blumer, Jeffrey; Meyers, Kevin E C; Neto, Jose P R; Meneses, Rejane; Litwin, Mieczysław; Vande Walle, Johan; Solar-Yohay, Susan; Shi, Victor; Han, Guangyang

2011-05-01

The effectiveness and safety of valsartan have not been assessed in hypertensive children. Therefore, hypertensive patients aged 6 to 16 years (n=261) were randomized to receive weight-stratified low- (10/20 mg), medium- (40/80 mg), or high-dose (80/160 mg) valsartan for 2 weeks. After 2 weeks, patients were randomized to a 2-week placebo-controlled withdrawal phase. Dose-dependent reductions in sitting systolic blood pressure (SSBP) and sitting diastolic blood pressure (SDBP) were observed after 2 weeks (low dose, -7.9/-4.6 mm Hg; medium dose, -9.6/-5.8 mm Hg; high dose, -11.5/-7.4 mm Hg [P<.0001 for all groups]). During the withdrawal phase, SSBP and SDBP were both lower in the pooled valsartan group than in the pooled placebo group (SSBP, -2.7 mm Hg [P=.0368]; SDBP, -3.0 mm Hg [P=.0047]). Similar efficacy was observed in all subgroups. Valsartan was well tolerated and headache was the most commonly observed adverse event during both the double-blind and 52-week open-label phases. © 2011 Wiley Periodicals, Inc.

Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans

PubMed Central

Liu, Shuyuan; Yue, Longtao; Gu, Wenrui; Li, Xiuyun; Zhang, Liuping; Sun, Shujuan

2016-01-01

Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2). The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane). PMID:26986478

Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.

PubMed

Liu, Shuyuan; Yue, Longtao; Gu, Wenrui; Li, Xiuyun; Zhang, Liuping; Sun, Shujuan

2016-01-01

Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2). The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane).

Insights into implementation of sacubitril/valsartan into clinical practice.

PubMed

Martens, Pieter; Beliën, Hanne; Dupont, Matthias; Mullens, Wilfried

2018-06-01

Sacubitril/valsartan significantly reduced heart failure hospitalization and mortality in PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure). However, real-world data from its use are lacking. We retrospectively assessed all baseline and follow-up data of consecutive heart failure patients with reduced ejection fraction receiving therapy with sacubitril/valsartan for Class I recommendation between December 2016 and July 2017. Baseline characteristics and dose titration of sacubitril/valsartan were compared between patients in clinical practice and in PARADIGM-HF. A total of 120 patients (81% male) were switched from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. A total of 20.1% of patients received dose uptitration. Patients were treated with an equipotential dose of renin-angiotensin system blockers before and after uptitration of sacubitril/valsartan (57 ± 29% vs. 53 ± 29% of target dose indicated by European Society of Cardiology guidelines; P = 0.286). However, they received a lower dose of sacubitril/valsartan in comparison with those in the PARADIGM-HF (219 ± 12 vs. 375 ± 75 mg; P < 0.001). In comparison with the patients receiving sacubitril/valsartan in PARADIGM-HF, patients in clinical practice were older and had a higher serum creatinine, higher New York Heart Association functional classification, and lower left ventricular ejection fraction (all P-value <0.05). Even in comparison with patients who experienced dropout during the run-in phase of PARADIGM-HF, real-world patients exhibited baseline characteristics indicative of more disease severity. Patients were at high absolute baseline risk for adverse outcome as illustrated by the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) risk score of 6 (inter-quartile range 3), in comparison with 5 (inter-quartile range 4) in PARADIGM-HF. After initiation of sacubitril/valsartan, New York Heart Association class significantly improved (P < 0.001), but systolic blood pressure dropped more than was reported in PARADIGM-HF (7.1 ± 8.0 vs. 3.2 ± 0.4 mmHg; P < 0.001). Patients in clinical practice exhibit baseline characteristics associated with more severe disease, which might lead to prescription of lower doses. Nevertheless, patients in clinical practice are at high risk of adverse outcome as illustrated by the EMPHASIS-HF risk score, underscoring the large potential for sacubitril/valsartan therapy to reduce the risk of heart failure hospitalization and all-cause mortality. © 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Insights into implementation of sacubitril/valsartan into clinical practice

PubMed Central

Martens, Pieter; Beliën, Hanne; Dupont, Matthias

2018-01-01

Abstract Background Sacubitril/valsartan significantly reduced heart failure hospitalization and mortality in PARADIGM‐HF (Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With an Angiotensin‐Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure). However, real‐world data from its use are lacking. Methods and results We retrospectively assessed all baseline and follow‐up data of consecutive heart failure patients with reduced ejection fraction receiving therapy with sacubitril/valsartan for Class I recommendation between December 2016 and July 2017. Baseline characteristics and dose titration of sacubitril/valsartan were compared between patients in clinical practice and in PARADIGM‐HF. A total of 120 patients (81% male) were switched from angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. A total of 20.1% of patients received dose uptitration. Patients were treated with an equipotential dose of renin–angiotensin system blockers before and after uptitration of sacubitril/valsartan (57 ± 29% vs. 53 ± 29% of target dose indicated by European Society of Cardiology guidelines; P = 0.286). However, they received a lower dose of sacubitril/valsartan in comparison with those in the PARADIGM‐HF (219 ± 12 vs. 375 ± 75 mg; P < 0.001). In comparison with the patients receiving sacubitril/valsartan in PARADIGM‐HF, patients in clinical practice were older and had a higher serum creatinine, higher New York Heart Association functional classification, and lower left ventricular ejection fraction (all P‐value <0.05). Even in comparison with patients who experienced dropout during the run‐in phase of PARADIGM‐HF, real‐world patients exhibited baseline characteristics indicative of more disease severity. Patients were at high absolute baseline risk for adverse outcome as illustrated by the EMPHASIS‐HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) risk score of 6 (inter‐quartile range 3), in comparison with 5 (inter‐quartile range 4) in PARADIGM‐HF. After initiation of sacubitril/valsartan, New York Heart Association class significantly improved (P < 0.001), but systolic blood pressure dropped more than was reported in PARADIGM‐HF (7.1 ± 8.0 vs. 3.2 ± 0.4 mmHg; P < 0.001). Conclusions Patients in clinical practice exhibit baseline characteristics associated with more severe disease, which might lead to prescription of lower doses. Nevertheless, patients in clinical practice are at high risk of adverse outcome as illustrated by the EMPHASIS‐HF risk score, underscoring the large potential for sacubitril/valsartan therapy to reduce the risk of heart failure hospitalization and all‐cause mortality. PMID:29464879

Ejection fraction improvement and reverse remodeling achieved with Sacubitril/Valsartan in heart failure with reduced ejection fraction patients.

PubMed

Almufleh, Aws; Marbach, Jeffrey; Chih, Sharon; Stadnick, Ellamae; Davies, Ross; Liu, Peter; Mielniczuk, Lisa

2017-01-01

Sacubitril/Valsartan has been shown to improve mortality and reduce hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF). The effect of Sacubitril/Valsartan on ejection fraction (EF) and reverse remodeling parameters have not been previously described. We performed a single-center, retrospective, cohort study of HFrEF patients (n=48) who were treated with Sacubitril/Valsartan for a median duration of 3 months (Interquartile range 2-6 months). Clinical and echocardiographic parameters were reviewed at three time points (pre-baseline which was median of 18 months before starting Sacubitril/Valsartan, baseline before treatment started, and post-Sacubitril/Valsartan). Paired sample t-test and one-way repeated measures ANOVA were used for normally distributed data, while Wilcoxon Signed Rank test for non-normally distributed data. Sacubitril/Valsartan use was associated with an average 5% (±1.2) increase in EF, from a mean baseline of 25.33% to 30.14% (p<0.001) with a median duration of treatment 3 months. There was no significant change in mean LVEF over a median duration of 11 months (IQR 5.5-15.5) between pre-baseline and baseline time points prior to treatment (p=1.0). The mean increase in ejection fraction tended to be marginally greater in the medium/high dose cohort as compared to the low dose cohort, with a mean increase of 5.09% (±1.36) and 4.03% (±3.17), respectively (p=0.184). There was a 3.36 mm reduction in left ventricular end-systolic diameter (p=0.04), a 2.64 mm reduction in left ventricular end-diastolic diameter (p=0.02), and a 14.4 g/m 2 reduction in left ventricular mass index (p<0.01). Sacubitril/Valsartan was found to improve EF and multiple measures of reverse remodeling beyond the effects of concomitant optimal medical therapy. Though these results are encouraging, our small sample, observational study requires confirmation in larger cohorts with longer follow-up periods.

Effect of Angiotensin II Type I Receptor Blockade with Valsartan on Carotid Artery Atherosclerosis: A Double Blind Randomized Clinical Trial Comparing Valsartan and Placebo (EFFERVESCENT).

PubMed

Ramadan, Ronnie; Dhawan, Saurabh S; Binongo, José Nilo G; Alkhoder, Ayman; Jones, Dean P; Oshinski, John N; Quyyumi, Arshed A

2016-04-01

Progression of atherosclerosis is associated with a greater risk for adverse outcomes. Angiotensin II plays a key role in the pathogenesis and progression of atherosclerosis. We aimed to investigate the effects of angiotensin II type-1 receptor blockade with Valsartan on carotid wall atherosclerosis, with the hypothesis that Valsartan will reduce progression of atherosclerosis. Subjects (n = 120) with carotid intima-media thickness >0.65 mm by ultrasound were randomized (2:1) in a double-blind manner to receive either Valsartan or placebo for 2 years. Bilateral T2-weighted black-blood carotid magnetic resonance imaging was performed at baseline, 12 and 24 months. Changes in the carotid bulb vessel wall area and wall thickness were primary endpoints. Secondary endpoints included changes in carotid plaque thickness, plasma levels of aminothiols, C-reactive protein, fibrinogen, and endothelium-dependent and -independent vascular function. Over 2 years, the carotid bulb vessel wall area decreased with Valsartan (-6.7, 95% CI [-11.6, -1.9] mm(2)) but not with placebo (3.4, 95% CI [-2.8, 9.6] mm(2)), P = .01 between groups. Similarly, mean wall thickness decreased with Valsartan (-0.18, 95% CI [-0.30, -0.06] mm), but not with placebo (0.08, 95% CI [-0.07, 0.23] mm), P = .009 between groups. Furthermore, plaque thickness decreased with Valsartan (-0.35, 95% CI [-0.63, -0.08] mm) but was unchanged with placebo (+0.28, 95% CI [-0.11, 0.69] mm), P = .01 between groups. These findings were unaffected by statin therapy or changes in blood pressure. Notably, there were significant improvements in the aminothiol cysteineglutathione disulfide, and trends to improvements in fibrinogen levels and endothelium-independent vascular function. In subjects with carotid wall thickening, angiotensin II type-1 receptor blockade was associated with regression in carotid atherosclerosis. Whether these effects translate into improved outcomes in subjects with subclinical atherosclerosis warrants investigation. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of Angiotensin II Type I Receptor Blockade with Valsartan on Carotid Artery Atherosclerosis: A Double Blind Randomized Clinical Trial Comparing Valsartan and Placebo (EFFERVESCENT)

PubMed Central

Ramadan, Ronnie; Dhawan, Saurabh S.; Binongo, José Nilo G.; Alkhoder, Ayman; Jones, Dean P.; Oshinski, John N.; Quyyumi, Arshed A.

2016-01-01

Background Progression of atherosclerosis is associated with a greater risk for adverse outcomes. Angiotensin II plays a key role in the pathogenesis and progression of atherosclerosis. We aimed to investigate the effects of Angiotensin II type-1 receptor (AT1R) blockade with Valsartan on carotid wall atherosclerosis, with the hypothesis that Valsartan will reduce progression of atherosclerosis. Methods Subjects (n= 120) with carotid intima-media thickness >0.65mm by ultrasound were randomized (2:1) in a double-blind manner to receive either Valsartan or placebo for 2 years. Bilateral T2-weighted black-blood carotid magnetic resonance imaging was performed at baseline, 12 and 24 months. Changes in the carotid bulb vessel wall area (VWA) and wall thickness (WT) were primary endpoints. Secondary endpoints included changes in carotid plaque thickness, plasma levels of aminothiols, C-reactive protein, fibrinogen, and endothelium-dependent and -independent vascular function. Results Over 2 years, the carotid bulb VWA decreased with Valsartan (−6.7, 95% CI: (−11.6,−1.9) mm2) but not with placebo (3.4, 95% CI: (−2.8,9.6) mm2)), p=0.01 between groups. Similarly, mean WT decreased with Valsartan (−0.18, 95% CI: (−0.30,−0.06) mm), but not with placebo (0.08, 95% CI: (−0.07,0.23) mm),), p=0.009 between groups. Furthermore, plaque thickness decreased with Valsartan (−0.35, 95% CI: (−0.63,−0.08) mm) but was unchanged with placebo (+0.28, 95% CI: (−0.11,0.69) mm), p=0.01 between groups. These findings were unaffected by statin therapy or changes in blood pressure. Notably, there were significant improvements in the aminothiol cysteineglutathione disulfide, and trends to improvements in fibrinogen levels and endothelium–independent vascular function. Conclusions In subjects with carotid wall thickening, AT1R blockade was associated with regression in carotid atherosclerosis. Whether these effects translate into improved outcomes in subjects with subclinical atherosclerosis warrants investigation. PMID:26995372

Magnetic Resonance Imaging Measurement of Transmission of Arterial Pulsation to the Brain on Propranolol Versus Amlodipine.

PubMed

Webb, Alastair J S; Rothwell, Peter M

2016-06-01

Cerebral arterial pulsatility is associated with leukoaraiosis and depends on central arterial pulsatility and arterial stiffness. The effect of antihypertensive drugs on transmission of central arterial pulsatility to the cerebral circulation is unknown, partly because of limited methods of assessment. In a technique-development pilot study, 10 healthy volunteers were randomized to crossover treatment with amlodipine and propranolol. At baseline and on each drug, we assessed aortic (Sphygmocor) and middle cerebral artery pulsatility (TCDtranscranial ultrasound). We also performed whole-brain, 3-tesla multiband blood-oxygen level dependent magnetic resonance imaging (multiband factor 6, repetition time=0.43s), concurrent with a novel method of continuous noninvasive blood pressure monitoring. Drug effects on relationships between cardiac cycle variation in blood pressure and blood-oxygen level dependent imaging were determined (fMRI Expert Analysis Tool, fMRIB Software Library [FEAT-FSL]). Aortic pulsatility was similar on amlodipine (27.3 mm Hg) and propranolol (27.9 mm Hg, P diff=0.33), while MCA pulsatility increased nonsignificantly more from baseline on propranolol (+6%; P=0.09) than amlodipine (+1.5%; P=0.58). On magnetic resonance imaging, cardiac frequency blood pressure variations were found to be significantly more strongly associated with blood-oxygen level dependent imaging on propranolol than amlodipine. We piloted a novel method of assessment of arterial pulsatility with concurrent high-frequency blood-oxygen level dependent magnetic resonance imaging and noninvasive blood pressure monitoring. This method was able to identify greater transmission of aortic pulsation on propranolol than amlodipine, which warrants further investigation. © 2016 American Heart Association, Inc.

Comparison of amlodipine versus other calcium channel blockers on blood pressure variability in hypertensive patients in China: a retrospective propensity score-matched analysis.

PubMed

Zhang, Lin; Yang, JinKui; Li, LanTing; Liu, DongDong; Xie, XiaoPing; Dong, Peng; Lin, Yong

2018-06-11

Reducing the fluctuation of blood pressure has recently been recognized as a potential target for improving management of hypertension to prevent cardiovascular events, particularly for strokes. Some randomized controlled trials demonstrated that amlodipine can effectively reduce blood pressure as a well-established, long-acting calcium channel blocker (CCB). However, few data are available for amlodipine on blood pressure variability (BPV) in China in a real-world setting. This study aimed to assess the effect of amlodipine versus other CCB antihypertensive agents on BPV. A retrospective propensity score-matched analysis was conducted, which retrieved the encounter data from 5582 hypertensive inpatients (with a median age of 69, female percentage of 48%, diastolic blood pressure ≥40 and <150 mmHg; systolic blood pressure (SBP) ≥70 mmHg and <260 mmHg), who had taken at least one antihypertensive agent and completed at least three SBP measurements during the visit. International Classification of Diseases was used to identify the hypertensive patients. BPV was calculated with standard deviation (SD) and coefficient of variation (CV) of SBP during a single inpatient visit. The Propensity Score Matching was used to balance the cohort of patients prescribed amlodipine or other CCBs. A series of appropriate statistical tests were applied to the propensity score-matched samples to examine the different effects on BPV. Additionally, the hypertensive patients with comorbidity such as coronary artery disease, diabetes mellitus, myocardial infarction, heart failure and chronic kidney disease were analyzed. For the hypertensive patients (n = 1756, for each cohort), patients prescribed amlodipine showed lower BPV than patients prescribed other CCBs (12.90 vs 13.76 mmHg, p < 0.05 [SD] and 9.47 vs 10.06, p < 0.05 [CV]). For the hypertensive patients with comorbidity (n = 1080, for each cohort), patients prescribed amlodipine had lower BPV than patients prescribed other CCBs as well (13.24 vs 14.23 mmHg, p < 0.05 [SD] and 9.66 vs 10.28, p < 0.05 [CV]). amlodipine was associated with lower BPV than other CCBs for both hypertensive patients and hypertensive patients with comorbidity.

Nano vesicular lipid carriers of angiotensin II receptor blocker: Anti-hypertensive and skin toxicity study in focus.

PubMed

Ahad, Abdul; Aqil, Mohd; Kohli, Kanchan; Sultana, Yasmin; Mujeeb, Mohd

2016-05-01

Nanoethosomal carriers of valsartan have been previously prepared, characterized and optimized. A gel formulation of valsartan vesicular lipid carriers was composed of Carbopol(®) (1% w/w), polyethylene glycol-400 (15% w/w) and triethanolamine (0.5% w/w). The influence of the valsartan nanoethosomal formulation developed on the blood pressure of experimental hypertensive rats, and its potential for skin irritation, are presented in this report. The experimental rats were divided into three groups; the control group received no treatment (Group A). Group B was administered methyl prednisolone acetate (20 mg/kg/week) for two weeks (hypertensive control). Group C received methyl prednisolone acetate, followed by administration of the valsartan ethosomal formulation. The blood pressure of the rats was measured using a non-invasive rat blood pressure instrument based on the tail-cuff technique. The statistical analysis was performed using GraphPad InStat 3 software. The treatment group showed a significant (P < 0.05) and constant fall in blood pressure, for up to 48 h. The valsartan ethosomal formulation was found to be effective, with a 34.11% reduction in blood pressure. The formulation's potential for skin irritation was assessed by the Draize irritation score test, which ruled out the possibility of any skin irritation caused by application of the formulation in rats. Our results suggest that nanoethosomes are efficient carriers for transdermal delivery of valsartan, for the management of hypertension.

Cognition- and Dementia-Related Adverse Effects With Sacubitril-Valsartan: Analysis of the FDA Adverse Event Report System Database.

PubMed

Perlman, Amichai; Hirsh Raccah, Bruria; Matok, Ilan; Muszkat, Mordechai

2018-05-07

Because neprilysin is involved in the degradation of amyloid-beta, there is concern that the angiotensin-neprilysin inhibitor sacubitril-valsartan could increase the risk for dementia. We analyzed adverse event cases submitted to the Food and Drug Administration Adverse Event Report System from July 2015 to March 2017. Cognition- and dementia-related adverse event cases were defined with the use of broad and narrow structured medical queries. During the period evaluated, 9,004 adverse event reports (out of a total of 2,249,479) involved the use of sacubitril-valsartan. Based on the broad definition, sacubitril-valsartan was associated with cognition- and dementia-related adverse events in 459 reports (5.1%), but this was lower than the proportion of these reports among other medications (6.6%, reporting odds ratio [ROR] 0.72, 95% confidence interval [CI] 0.65-0.79). Restricting the comparison to cases with age >60 years and with the use of a comparator group with heart failure resulted in no association between sacubitril-valsartan and dementia-related adverse events, with the use of both the broad and the narrow definitions (ROR 0.87, 95% CI 0.76-1.02, and ROR 1.06, 95% CI 0.4-3.16, respectively). Sacubitril-valsartan is not associated with a disproportionately high rate of short-term dementia-related adverse effect reports. Long-term studies assessing cognitive outcomes are required to better establish the medication's cognition effects. Copyright © 2018 Elsevier Inc. All rights reserved.

Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study).

PubMed

Shaddy, Robert; Canter, Charles; Halnon, Nancy; Kochilas, Lazaros; Rossano, Joseph; Bonnet, Damien; Bush, Christopher; Zhao, Ziqiang; Kantor, Paul; Burch, Michael; Chen, Fabian

2017-11-01

Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown. This global multi-center study will use an adaptive, seamless two-part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to <18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to <18 years; Group 2: 1 to <6 years; Group 3: 1 month to <1 year). Part 2 is a 52-week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst-to-best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient-reported HF symptoms will be used to assess efficacy. The PANORAMA-HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Evaluating the Safety and Tolerability of Sacubitril/Valsartan for HFrEF Managed Within a Pharmacist Clinic.

PubMed

Pogge, Elizabeth K; Davis, Lindsay E

2018-04-01

The objective of this research was to describe the use of pharmacist-managed sacubitril/valsartan therapy in a multi-center, outpatient cardiac group. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNi), is a novel agent for the treatment of heart failure. An ARNi is recommended by national guidelines to be used in place of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy for patients who remain symptomatic. A retrospective chart review was performed to identify patients initiated and fully titrated on sacubitril/valsartan therapy from July 7, 2015 to March 7, 2017. Fifty-two of the 72 symptomatic heart failure with reduced ejection fraction (HFrEF) patients prescribed sacubitril/valsartan during the 21-month period were included in this analysis. The average ejection fraction was 26%. The average age was 69 years. At baseline, 26.9% of patients were not on ACEi/ARB therapy and 13.5% were on target-dose therapy. After completing the uptitration process, the maximally tolerated dose of sacubitril/valsartan was 5.8% low-dose, 7.7% mid-dose, and 86.5% target-dose. Loop and thiazide diuretic use decreased significantly. There was a significant mean reduction in systolic blood pressure of 6 mmHg with no significant changes in serum creatinine, blood urea nitrogen, or potassium levels. With close monitoring and follow-up, ARNi therapy was a safe alternative to ACEi/ARB therapy for chronic symptomatic HFrEF when initiated within a pharmacist clinic.

Effect of formulation variables on design, in vitro evaluation of valsartan SNEDDS and estimation of its antioxidant effect in adrenaline-induced acute myocardial infarction in rats.

PubMed

Amin, Maha M; El Gazayerly, Omaima N; Abd El-Gawad, Nabaweya A; Abd El-Halim, Shady M; El-Awdan, Sally A

2016-12-01

Valsartan is a specific angiotensin II antagonist used for the treatment of hypertension. It suffers from low aqueous solubility and high variability in its absorption after oral administration. The aim of this study was to improve the dissolution and thereby the bioavailability of Valsartan through the development of self nano-emulsifying drug delivery systems. Four ternary phase diagrams were constructed to identify the self-emulsification region of Capmul® MCM, Labrafil® M1944, Capryol™ 90 and Labrafac® PG together with Cremophore® RH 40 and Transcutol™ HP as oil, surfactant and co-surfactant, respectively. The effect of oil type, oil and surfactant concentration on droplet size and in vitro Valsartan dissolution were studied. The protective effect of the optimum formula F5 in adrenaline-induced oxidative stress in rats during myocardial infarction was determined. Formula F5 exhibited globule size of (13.95 nm) with 76.07% ± 1.10 of Valsartan dissolved after five minutes compared to Disartan 80 mg capsules (13.43%). Results revealed a significant reduction (p < 0.05) in serum aspartate transaminase, creatine kinase myocardial band and malondialdehyde levels, while a significant increase (p < 0.05) in serum glutathione in F5. Therefore, self nano-emulsifying drug delivery systems could be considered as a promising approach to improve the dissolution and thereby the bioavailability of Valsartan.

Development and optimization of press coated tablets of release engineered valsartan for pulsatile delivery.

PubMed

Shah, Sunny; Patel, Romik; Soniwala, Moinuddin; Chavda, Jayant

2015-01-01

The present work is aimed to develop and optimize pulsatile delivery during dissolution of an improved formulation of valsartan to coordinate the drug release with circadian rhythm. Preliminary studies suggested that β cyclodextrin could improve the solubility of valsartan and showed AL type solubility curve. A 1:1 stoichiometric ratio of valsartan to β cyclodextrin was revealed from phase solubility studies and Job's plot. The prepared complex showed significantly better dissolution efficiency (p < 0.05) compared to pure drug, which could be due to the formation of inclusion complex as revealed from FTIR and DSC studies. Continuous dissolution-absorption studies revealed that absorption of drug from valsartan β cyclodextrin complex was significantly higher (p < 0.05) compared to pure drug, in second part press-coated tablets of valsartan β cyclodextrin complex were subsequently prepared and application of the Plackett-Burman screening design revealed that HPMC K4M and EC showed significant effect on lag time. A 3(2) full factorial design was used to measure the response of HPMC K4M and EC on lag time and time taken for 90% drug release (T90). The optimized batch prepared according to the levels obtained from the desirability function had a lag time of 6 h and consisted of HPMC K4M:ethylcellulose in a 1:1.5 ratio with 180 mg of coating and revealed a close agreement between observed and predicted value (R(2 )= 0.9694).

Amlodipine: One of the main anti-hypertensive drugs in veterinary therapeutics.

PubMed

Tissier, Renaud; Perrot, Sebastien; Enriquez, Brigitte

2005-05-01

Amlodipine is a dihydropyridine compound and belongs to the pharmacological family of calcium channel blockers. It is one of the main treatments of systemic arterial hypertension in cats and its validity has been confirmed in several reports. Its beneficial effect on the peripheral and coronary vascular bed is due to immediate vasodilation and to a delayed anti-hypertrophic action. The aim of the present review is to highlight the clinically-relevant characteristics of amlodipine, especially regarding its mechanism of action, and to present the main clinical reports supporting its interest in veterinary cardiology.

The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction.

PubMed

Martens, Pieter; Beliën, Hanne; Dupont, Matthias; Vandervoort, Pieter; Mullens, Wilfried

2018-05-17

Major classes of medical therapy for heart failure with reduced ejection fraction (HFrEF) induce reverse remodeling. The revere remodeling response to sacubitril/valsartan remains unstudied. We performed a single-center, prospective assessor-blinded study to determine the reverse remodeling response of sacubitril/valsartan therapy in HFrEF patients with a class I indication (New York heart Association [NYHA]-class II-IV, Left ventricular ejection fraction [LVEF] < 35%, optimal dose with Renin-Angiotensin-System-Blocker [RAS-blocker]). Doses of sacubitril/valsartan were optimized to individual tolerance. Echocardiographic images were assessed offline by 2 investigators blinded to both the clinical data and timing of echocardiograms. One-hundred-twenty-five HFrEF patients (66 ± 10 years) were prospectively included. The amount of RAS-blocker before and after switch to sacubitril/valsartan was similar(P = .290), indicating individual optimal dosing of sacubitril/valsartan. Over a median(IQR) follow-up of 118(77-160) days after initiation of sacubitril/valsartan, LVEF improved (29.6 ± 6% vs 34.8 ± 6%; P < .001) and Left ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) decreased (LVESV; 147 ± 57 mL vs 129 ± 55 mL; P < .001 and LVEDV; 206 ± 71 mL vs197 ± 72 mL; P = .027). Volumetric remodeling was associated with a reduction in the degree of mitral regurgitation (1.59 ± 1.0 vs 1.11 ± 0.8; P < .001; [scale from 0-4]). Metrics of diastolic function improved; including a drop in the E/A-wave ratio (1.75 ± 1.13 vs 1.38 ± 0.88; P = .002) and diastolic filling time (% of cycle length) prolonged (48 ± 9% vs 52 ± 1%; P = .005). The percent of patients with a restrictive mitral filling pattern dropped from 47% to 23% (P = .004). A dose-dependent effect was noted for changes in LVEF (P < .001) and LVESV (P = .031), with higher doses of sacubitril/valsartan leading to more reverse remodeling. Switching therapy in eligible HFrEF patients from a RAS-blocker to sacubitril/valsartan induces beneficial reverse remodeling of both metrics of systolic as diastolic function. © 2018 John Wiley & Sons Ltd.

The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schoenfeld, Heidi A., E-mail: heidi.schoenfeld@nov

Sacubitril/valsartan (LCZ696) is the first angiotensin receptor neprilysin inhibitor approved to reduce cardiovascular mortality and hospitalization in patients with heart failure with reduced ejection fraction. As neprilysin (NEP) is one of several enzymes known to degrade amyloid-β (Aβ), there is a theoretical risk of Aβ accumulation following long-term NEP inhibition. The primary objective of this study was to evaluate the potential effects of sacubitril/valsartan on central nervous system clearance of Aβ isoforms in cynomolgus monkeys using the sensitive Stable Isotope Labeling Kinetics (SILK™)-Aβ methodology. The in vitro selectivity of valsartan, sacubitril, and its active metabolite sacubitrilat was established; sacubitrilat didmore » not inhibit other human Aβ-degrading metalloproteases. In a 2-week study, sacubitril/valsartan (50 mg/kg/day) or vehicle was orally administered to female cynomolgus monkeys in conjunction with SILK™-Aβ. Despite low cerebrospinal fluid (CSF) and brain penetration, CSF exposure to sacubitril was sufficient to inhibit NEP and resulted in an increase in the elimination half-life of Aβ1-42 (65.3%; p = 0.026), Aβ1-40 (35.2%; p = 0.04) and Aβtotal (29.8%; p = 0.04) acutely; this returned to normal as expected with repeated dosing for 15 days. CSF concentrations of newly generated Aβ (AUC{sub (0–24} {sub h)}) indicated elevations in the more aggregable form Aβ1-42 on day 1 (20.4%; p = 0.039) and day 15 (34.7%; p = 0.0003) and in shorter forms Aβ1-40 (23.4%; p = 0.009), Aβ1-38 (64.1%; p = 0.0001) and Aβtotal (50.45%; p = 0.00002) on day 15. However, there were no elevations in any Aβ isoforms in the brains of these monkeys on day 16. In a second study cynomolgus monkeys were administered sacubitril/valsartan (300 mg/kg) or vehicle control for 39 weeks; no microscopic brain changes or Aβ deposition, as assessed by immunohistochemical staining, were present. Further clinical studies are planned to address the relevance of these findings. - Highlights: • Sacubitril/valsartan reduced Aβ clearance on day 1, but not after 15 daily doses. • Sacubitril/valsartan increased CSF Aβ but did not result in increases in brain Aβ. • No Aβ brain pathology in 39 week monkey study with high dose sacubitril/valsartan.« less

Improvement in Retinal Capillary Rarefaction After Valsartan Treatment in Hypertensive Patients.

PubMed

Jumar, Agnes; Harazny, Joanna M; Ott, Christian; Kistner, Iris; Friedrich, Stefanie; Schmieder, Roland E

2016-11-01

Decreased capillary density influences vascular resistance and perfusion. The authors aimed to investigate the influence of the renin-angiotensin receptor blocker valsartan on retinal capillary rarefaction in hypertensive patients. Retinal vascular parameters were measured noninvasively and in vivo by scanning laser Doppler flowmetry before and after 4 weeks of treatment with valsartan in 95 patients with hypertension stage 1 or 2 and compared with 55 healthy individuals. Retinal capillary rarefaction was determined with the parameters intercapillary distance (ICD) and capillary area (CapA). In hypertensive patients, ICD decreased (23.4±5.5 μm vs 21.5±5.6 μm, P<.001) and CapA increased (1564±621 vs 1776±795, P=.001) after valsartan treatment compared with baseline. Compared with healthy normotensive controls (ICD 20.2±4.2 μm, CapA 1821±652), untreated hypertensive patients showed greater ICD (P<.001) and smaller CapA (P=.019), whereas treated hypertensive patients showed no difference in ICD (P=.126) and CapA (P=.728). Therapy with valsartan for 4 weeks diminished capillary rarefaction in hypertensive patients. © 2016 Wiley Periodicals, Inc.

Valsartan decreases TGF-β1 production and protects against chlorhexidine digluconate-induced liver peritoneal fibrosis in rats.

PubMed

Subeq, Yi-Maun; Ke, Chen-Yen; Lin, Nien-Tsung; Lee, Chung-Jen; Chiu, Yi-Han; Hsu, Bang-Gee

2011-02-01

Peritoneal fibrosis (PF) is a recognized complication of long-term peritoneal dialysis (PD) and can lead to ultrafiltration failure. The present study was designed to investigate the protective effects of valsartan on chlorhexidine digluconate-induced PF by decreasing TGF-β1 production in rats. PF was induced in Sprague-Dawley rats by daily administration of 0.5 ml 0.1% chlorhexidine digluconate in normal saline via peritoneal dialysis (PD) tube for 1 week. Rats received daily intravenous injections of low dose valsartan (1 mg/kg) or high dose valsartan (3 mg/kg) for 1 week. After 7 days, conventional 4.25% Dianeal (30 ml) was administered via a PD catheter with a dwell time of 4 h and assessed of peritoneal function. At the end of dialysis, rats were sacrificed and the liver peritoneum was harvested for microscopically and immunohistochemistry. There was no significant difference in mean arterial pressure and heart rate between groups. After 4 h of PD, the D₄/P(4Urea) level was reduced, the D₄/D₀ glucose level, serum and dialysate transforming growth factor-β1 (TGF-β1) level was increased, the liver peritoneum was markedly thicker, and the expression of TGF-β1, alpha-smooth muscle actin (α-SMA), fibronectin, collagen, and vascular endothelial growth factor (VEGF) were elevated in the PF group compared with the vehicle group. High dose of valsartan decreased the serum and dialysate TGF-β1 level, decreased the thickness of the liver peritoneum, and decreased the expression of TGF-β1, α-SMA, fibronectin, collagen, and VEGF-positive cells in liver peritoneum. The low dose of valsartan did not protect against chlorhexidine digluconate-induced PF in rat. Valsartan protected against chlorhexidine digluconate-induced PF in rats by decreasing TGF-β1 production. Copyright © 2010 Elsevier Ltd. All rights reserved.

Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial.

PubMed

Vardeny, Orly; Claggett, Brian; Packer, Milton; Zile, Michael R; Rouleau, Jean; Swedberg, Karl; Teerlink, John R; Desai, Akshay S; Lefkowitz, Martin; Shi, Victor; McMurray, John J V; Solomon, Scott D

2016-10-01

In this analysis, we utilized data from PARADIGM-HF to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to lower doses of enalapril. In a post-hoc analysis from PARADIGM-HF, we characterized patients by whether they received the maximal dose (200 mg sacubitril/valsartan or 10 mg enalapril twice daily) throughout the trial or had any dose reduction to lower doses (100/50/0 mg sacubitril/valsartan or 5/2.5/0 mg enalapril twice daily). The treatment effect for the primary outcome was estimated, stratified by dose level using time-updated Cox regression models. In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. In a time-updated analysis, any dose reduction was associated with a higher subsequent risk of the primary event [hazard ratio (HR) 2.5, 95% confidence interval (CI) 2.2-2.7]. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70-0.93, P < 0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71-0.88, P < 0.001). In PARADIGM-HF, study medication dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of sacubitril/valsartan relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs. © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

The effect of angiotensin-2 receptor blocker valsartan on circulating level of endothelial progenitor cells in diabetic patients with asymptomatic coronary artery disease.

PubMed

Berezin, Alexander E; Kremzer, Alexander A; Martovitskaya, Yulia V; Samura, Tatyana A

2015-01-01

Decreased circulating endothelial progenitor cells (EPCs) are considered as strong and robust biomarkers for the prediction of cardiovascular outcomes in diabetic populations. The perspectives for modulating EPCs levels in T2DM with known coronary artery disease (CAD) with different drugs, affected mechanisms of improving mobilization of EPCs from tissue, are not still understood. To evaluate an effect of angiotensin-2 receptor blocker valsartan on circulating level of EPCs in diabetic patients with asymptomatic CAD. The study population was structured retrospectively after determining the CAD by contrast-enhanced spiral computed tomography angiography in 126 asymptomatic subjects. All subjects were distributed into two cohorts depending on daily doses of valsartan given. Low (80-160 mg daily orally) and high doses (240-320 mg daily orally) of valsartan were used and they were adjusted depending on achieving BP level less than 140/80 mmHg. The change from baseline in CD34(+) subset cells (frequencies and absolute values) was not significantly different between treatment cohorts. We found a significant increase of circulating level of CD14(+)CD309(+) cells in two patient cohorts. But more prominent change of CD14(+)CD309(+) cells was verified in subjects who were given valsartan in high daily doses when compared with persons who were included into cohort with low daily doses of the drug (1.96% versus 2.59%, respectively; P<0.05). Therefore, both frequencies and absolute values in CD14(+)CD309(+)Tie(2+) were increased significantly in patients who were treated with high doses of valsartan only. We found positive influence of angiotensin-2 receptor blocker valsartan in escalation doses on bone marrow-derived EPCs phenotyped as CD14(+)CD309(+) and CD14(+)CD309(+)Tie(2+) in T2DM patients with known asymptomatic CAD. Copyright © 2014 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Valsartan Promoting Atherosclerotic Plaque Stabilization by Upregulating Renalase: A Potential-Related Gene of Atherosclerosis.

PubMed

Zhou, Mingxue; Ma, Chao; Liu, Weihong; Liu, Hongxu; Wang, Ning; Kang, Qunfu; Li, Ping

2015-09-01

Renalase is a protein that can regulate sympathetic nerve activity by metabolizing catecholamines, while redundant catecholamines are thought to contribute to atherosclerosis (As). Catecholamine release can be facilitated by angiotensin (Ang) II by binding to Ang II type 1 (AT1) receptors. Valsartan, a special AT1 antagonist, can dilate blood vessels and reduce blood pressure, but it remained unclear whether valsartan can promote the stability of atherosclerotic plaque by affecting renalase. This study examined the tissue distribution of renalase in ApoE(-/-) mice fed with a high-fat diet and the effect of valsartan on expression of renalase. ApoE(-/-) mice were fed with a high-fat diet for 13 or 26 weeks. As a control, 10 C57BL mice were fed with a standard chow diet. After 13 weeks on the high-fat diet, the ApoE(-/-) mice were randomized (10 mice/group) and treated with valsartan, simvastatin, or distilled water (control group) for an additional 13 weeks accompanied by a high-fat diet. Knockout of ApoE caused a dramatic increase in expression of renalase in mice adipose tissue. With the disturbance of lipid metabolism induced by a high-fat diet, renalase expression decreased in the liver. Renalase can be expressed in smooth muscle cells and M2 macrophages in atherosclerotic plaque, and its expression gradually decreases in the fibrous cap during the transition from stable to vulnerable atherosclerotic plaque. Valsartan, an AT1 receptor antagonist, promotes the stabilization of atherosclerotic plaque by increasing the levels of renalase in serum and the expression of renalase in the fibrous cap of atherosclerotic plaque. It also reduces triglyceride levels in serum and increases the expression of renalase in the liver. Renalase may be a potential-related gene of lipid metabolism and As, and it may be the possible molecular target of valsartan to help stabilize atherosclerotic plaque. © The Author(s) 2015.

Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats.

PubMed

Yao, Jian; Qin, Xiaotong; Zhu, Jianhua; Sheng, Hongzhuan

2016-01-01

It is known that the expression, activity and alternative splicing of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) are dysregulated in the cardiac remodeling process. Recently, we found a further signaling pathway, by which dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) regulates the alternative splicing of CaMKIIδ via the alternative splicing factor (ASF), i.e., Dyrk1A-ASF-CaMKIIδ. In this study, we aimed to investigate whether Dyrk1A-ASF-CaMKIIδ signaling was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats. Rats were subjected to two kidney-one clip (2K1C) surgery and then treated with valsartan (30 mg/kg/day) for 8 weeks. Hypertrophic parameter analysis was then performed. Western blot analysis was used to determine the protein expression of Dyrk1A and ASF and RT-PCR was used to analyze the alternative splicing of CaMKIIδ in the left ventricular (LV) sample. Valsartan attenuated cardiac hypertrophy in 2K1C rats but without impairment of cardiac systolic function. Increased protein expression of Dyrk1A and decreased protein expression of ASF were observed in the LV sample of 2K1C rats. Treatment of 2K1C rats with valsartan reversed the changes in Dyrk1A and ASF expression in the LV sample. Valsartan adjusted the 2K1C-induced imbalance in alternative splicing of CaMKIIδ by upregulating the mRNA expression of CaMKIIδC and downregulating the mRNA expression of CaMKIIδA and CaMKIIδB. Valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats was mediated, at least partly, by Dyrk1A-ASF-CaMKIIδ signaling. © 2015 S. Karger AG, Basel.

Novel mechanism of cardiac protection by valsartan: synergetic roles of TGF-β1 and HIF-1α in Ang II-mediated fibrosis after myocardial infarction

PubMed Central

Sui, Xizhong; Wei, Hongchao; Wang, Dacheng

2015-01-01

Transforming growth factor (TGF)-β1 is a known factor in angiotensin II (Ang II)-mediated cardiac fibrosis after myocardial infarction (MI). Hypoxia inducible factor-1 (Hif-1α) was recently demonstrated to involve in the tissue fibrosis and influenced by Ang II. However, whether Hif-1α contributed to the Ang II-mediated cardiac fibrosis after MI, and whether interaction or synergetic roles between Hif-1α and TGF-β pathways existed in the process was unclear. In vitro, cardiac cells were incubated under hypoxia or Ang II to mimic ischaemia. In vivo, valsartan was intravenously injected into Sprague–Dawley rats with MI daily for 1 week; saline and hydralazine (another anti-hypertensive agent like valsartan) was used as control. The fibrosis-related proteins were detected by Western blotting. Cardiac structure and function were assessed with multimodality methods. We demonstrated in vitro that hypoxia would induce the up-regulation of Ang II, TGF-β/Smad and Hif-1α, which further induced collagen accumulation. By blocking with valsartan, a blocker of Ang II type I (AT1) receptor, we confirmed that the up-regulation of TGF-β/Smad and Hif-1α was through the Ang II-mediated pathway. By administering TGF-β or dimethyloxalylglycine, we determined that both TGF-β/Smad and Hif-1α contributed to Ang II-mediated collagen accumulation and a synergetic effect between them was observed. Consistent with in vitro results, valsartan significantly attenuated the expression of TGF-β/Smad, Hif-1α and fibrosis-related protein in rats after MI. Heart function, infarcted size, wall thickness as well as myocardial vascularization of ischaemic hearts were also significantly improved by valsartan compared with saline and hydralazine. Our study may provide novel insights into the mechanisms of Ang II-induced cardiac fibrosis as well as into the cardiac protection of valsartan. PMID:25823960

Time of administration important? Morning versus evening dosing of valsartan.

PubMed

Zappe, Dion H; Crikelair, Nora; Kandra, Albert; Palatini, Paolo

2015-02-01

Studies suggest that bedtime dosing of an angiotensin-converting enzyme (ACE)-inhibitor or angiotensin receptor blocker shows a more sustained and consistent 24-h antihypertensive profile, including greater night-time blood pressure (BP) reduction. We compared the antihypertensive effects of morning (a.m.) and evening (p.m.) dosing of valsartan on 24-h BP. This 26-week, multicentre, randomized, double-blind study evaluated the efficacy and safety of valsartan 320 mg, dosed a.m. or p.m., versus lisinopril 40 mg (a.m.), a long-acting ACE-inhibitor, in patients with grade 1-2 hypertension and at least one additional cardiovascular risk factor. Patients (n = 1093; BP = 156 ± 11/91 ± 8 mmHg; 62 years, 56% male, 99% white) received (1 : 1 : 1) valsartan 160 mg a.m. or p.m. or lisinopril 20 mg a.m. for 4 weeks, then force-titrated to double the initial dose for 8 weeks. At Week 12, hydrochlorothiazide (HCTZ) 12.5 mg was added for 14 weeks if office BP was more than 140/90 mmHg and/or ambulatory BP more than 130/80 mmHg. Mean 24-h ambulatory SBP change from baseline to Weeks 12 and 26 was comparable between valsartan a.m. (-10.6 and -13.3 mmHg) and p.m. (-9.8 and -12.3 mmHg) and lisinopril (-10.7 and -13.7 mmHg). There was no benefit of valsartan p.m. versus a.m. on night-time BP, early morning BP and morning BP surge. Evening dosing also did not improve BP lowering in patients requiring add-on HCTZ or in nondippers at baseline. All treatments were well tolerated. Once-daily dosing of valsartan 320 mg results in equally effective 24-h BP efficacy, regardless of dosing time. ClinicalTrials.gov Identifier: NCT00241124.

[Valsartan inhibits angiotensin II-Notch signaling of mesangial cells induced by high glucose].

PubMed

Yuan, Qin; Lyu, Chuan; Wu, Can; Lei, Sha; Shao, Ying; Wang, Qiuyue

2016-01-01

To explore the role of angiotensin II (Ang II)-Notch signaling in high glucose-induced secretion of extracellular matrix of rat mesangial cells (RMCs) and to further investigate the protective effect of valsartan (one of Ang II receptor blockers) on kidney. Subcultured RMCs were divided into groups as follows: normal glucose group (5.5 mmol/L glucose); high glucose group (30 mmol/L glucose); high concentration of mannitol as osmotic control group (5.5 mmol/L glucose and 24.5 mmol/L mannitol); normal glucose plus 1 μmol/L N-[N-(3, 5-difluorophenacetyl)-L-alanyl ]-S-phenylglycine t-butyl ester (DAPT) group; normal glucose plus (1, 5, 10) μmol/L valsartan group; high glucose plus 1 μmol/L DAPT group; high glucose plus (1, 5, 10) μmol/L valsartan group. Cells and supernatants were harvested after 12, 24 and 48 hours. Notch1 expression was examined by Western blotting. Secretion of transforming growth factor (TGF-β) and fibronectin (FN) were detected by ELISA. Compared to the normal glucose group, Notch1 expression was elevated in the high glucose group after 12 hours, and peaked at 24 hours. Besides, secretion of TGF-β and FN were much higher in the high glucose group than in the normal glucose group in a time-dependent manner. Compared to the untreated group, Notch1 expression decreased in a dose-dependent manner in the valsartan or DAPT treated group under high glucose after 24 hours. After pre-treatment by either valsartan or DAPT in the high glucose group, secretion of TGF-β and FN obviously decreased as compared to the untreated group. Hyperglycemia could stimulate activation of Notch signaling in cultured RMCs, which may increase secretion of downstream fibrotic factors such as TGF-β and FN. Valsartan may decrease the secretion of downstream FN in a dose-dependent manner via inhibiting AngII-Notch signaling.

Transdermal Amlodipine Besylate in Lipoderm for the treatment of Feline Hypertension: A Report of Two Cases.

PubMed

Mixon, William; Helms, Scott R

2008-01-01

Primary hypertension may be more common in cats than prior research has indicated. Untreated feline hypertension damages organs nourished by a rich vascular supply, and kidney disease, ocular impairment and cardiac irregularites can be caused by this silent and progressive disorder. The effects of hypertension can be minimized with treatment, however, and the long-acting dihydropyridine calcium anatgonist amlodipine has been proven safe and effective in the management of high blood pressure in cats. Because anxiety can increase blood pressure even in normotensive cats, hypertensive feline patients must be protected as much as possible from the stress caused by forced medication. A compounded preparation of amlodipine in a transdermal gel can be easily applied to the feline pinna without subjecting the patient to the trauma of oral treatment. In this report, the potency and effectiveness of amlodipine besylate in Lipoderm transdermal gel for the treatment of feline hypertension are examined, and two case reports describing the outcome of treatment with that preparation in hypertensive cats are presented.

[Effectiveness and safety of losartan and its combination with amlodipine in therapy of arterial hypertension].

PubMed

Boitsov, S A; Bazaeva, E V; Luk'ianov, M M; Drapkina, O M; Panov, A V; Terent'ev, B P; Tiurin, V P; Shchukina, G N

2013-01-01

To estimate effectiveness and safety of losartan and its combination with amlodipine in therapy of arterial hypertension. The study based at 6 clinical centres was conducted in two stages. All 160 patients with grade I-II AH (103 women and 57 men aged 54 ± 12 yr) participated in stage 1 of the study and patients of centre No 1 (n = 100) in stage 2. Losartan was used at a dose of 50-100 mg/24 h for 8 weeks (stage 1) and thereafter from week 9 to 26 (stage 2) in combination with amlodipine (5-10 mg/24 hr) if the desired AP level (< 140/90 mmHg) was not achieved. The following parameters were measured: systolic and diastolic AP (SAP and DAP) (office measurement and 24-hr monitoring), pulse wave propagation rate (PWPR), left ventricle mass index (LVMI), thickness of intima-media complex (IMT), blood biochemistry, tolerability of therapy and its side effects. Losartan alone decreased SAP and DAP from 150 ± 11/91 ± 7 to 132 ± 12/81 ± 8 mm Hg (office measurement) and from 144 ± 10/86 ± 9 to 128 ± 12/76 ± 10 mm Hg (24-hr monitoring); heart rate decreased fom 74 ± 8 to 70 ± 8/min (p < 0.05). SAP and DAP in 66 patients who completed stage 2 was 122 ± 6/73 ± 6 mm Hg or significantly lower than before therapy (147 ± 9/87 ± 9) (p < 0.001). Mean daily decrease of SAP and DAP according to 24-hr monitoring decreased from 144 ± 10 to 128 ± 12 and from 86 ± 9 to 76 ± 10 mm Hg respectively (p < 0.001). The target AP value was reached in 73% of the cases (99 out of 136 patients) after stage 1 and in 95% cases (63 out of 66) after stage 2. The values of LVMI (105 ± 23 and 98 ± 26 g/m2), PWPR from 16 ± 2.1 to 13 ± 3.5 m/s (p < 0.05), IMT (0.76 ± 0.16 and 0.80 ± 42 mm), and microalbuminuria (11.0 ± 1.7 and 8.6 ± 0.7 mg/24 hr) before and after completion of stage 2 were not significantly different in 66 patients (p > 0.05). Biochemical parameters of blood did not appreciably change. The safety profiles of both drugs were on the whole positive. Deaths and adverse reactions were absent barring clinically insignificant side effects in 28 of the 160 patients (17.5%). Losartan and amlodipine are effective and safe agents for AH therapy.

Valsartan ameliorates ageing-induced aorta degeneration via angiotensin II type 1 receptor-mediated ERK activity

PubMed Central

Shan, HaiYan; Zhang, Siyang; Li, Xuelian; yu, Kai; Zhao, Xin; Chen, Xinyue; Jin, Bo; Bai, XiaoJuan

2014-01-01

Angiotensin II (Ang II) plays important roles in ageing-related disorders through its type 1 receptor (AT1R). However, the role and underlying mechanisms of AT1R in ageing-related vascular degeneration are not well understood. In this study, 40 ageing rats were randomly divided into two groups: ageing group which received no treatment (ageing control), and valsartan group which took valsartan (selective AT1R blocker) daily for 6 months. 20 young rats were used as adult control. The aorta structure were analysed by histological staining and electron microscopy. Bcl-2/Bax expression in aorta was analysed by immunohistochemical staining, RT-PCR and Western blotting. The expressions of AT1R, AT2R and mitogen-activated protein kinases (MAPKs) were detected. Significant structural degeneration of aorta in the ageing rats was observed, and the degeneration was remarkably ameliorated by long-term administration of valsartan. With ageing, the expression of AT1R was elevated, the ratio of Bcl-2/Bax was decreased and meanwhile, an important subgroup of MAPKs, extracellular signal-regulated kinase (ERK) activity was elevated. However, these changes in ageing rats could be reversed to some extent by valsartan. In vitro experiments observed consistent results as in vivo study. Furthermore, ERK inhibitor could also acquire partial effects as valsartan without affecting AT1R expression. The results indicated that AT1R involved in the ageing-related degeneration of aorta and AT1R-mediated ERK activity was an important mechanism underlying the process. PMID:24548645

Pharmacokinetic, pharmacodynamic, and antihypertensive effects of the neprilysin inhibitor LCZ-696: sacubitril/valsartan.

PubMed

Chrysant, Steven G

2017-07-01

LCZ-696, sacubitril/valsartan, is a dual-acting molecule consisting of the angiotensin II (Ang II) receptor blocker valsartan and the neprilysin (neutral endopeptidase) inhibitor AHU-377 with significant beneficial effects in patients with hypertension and heart failure (HF). Several recent studies have demonstrated a higher effectiveness of LCZ-696 compared to valsartan in the treatment of hypertension and HF. The rationale for the development and the Food and Drug Administration approval of LCZ-696 was based on the concept of an additive effect of the Ang II receptor blocker valsartan and the neutral endopeptidase (neprilysin) inhibitor AHU-377 for the treatment of hypertension and HF. The synergism from these drugs arises from the vasodilating effects of valsartan through its blockade of Ang II type 1 receptor and the action of natriuretic peptides atrial natriuretic peptide and B-type natriuretic peptide (BNP) by preventing their catabolism with neprilysin resulting in increase of cyclic guanosine monophosphate. This action of neprilysin is associated with increased natriuresis, diuresis, and systemic vasodilation, since these peptides have been shown to have potent diuretic, natriuretic, and vasodilating effects. In addition, it reduces the levels of N terminal pro-BNP. Therefore, administration of LCZ-696 results in significant reduction of wall stress from pressure and volume overload of the left ventricle as demonstrated by the reduction of N terminal pro-BNP, both significant constituents of hypertension and HF, and it is safe, well tolerated and is almost free of cough and angioedema. Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

The Sacubitril/Valsartan, a First-in-Class, Angiotensin Receptor Neprilysin Inhibitor (ARNI): Potential Uses in Hypertension, Heart Failure, and Beyond.

PubMed

Kario, Kazuomi

2018-01-27

Sacubitril/valsartan (LCZ696) is a first-in-class, novel-acting, angiotensin receptor neprilysin inhibitor (ARNI) that provides inhibition of neprilysin and the angiotensin (AT 1 ) receptor. A recent clinical trial PRARDIGM-HF demonstrated that this drug is superior to angiotensin-converting enzyme (ACE) inhibitors for improving the prognosis in the patients with heart failure, and this has resulted in the drug being included in clinical practice guidelines for the management of heart failure with reduced ejection fraction (EF). In addition, sacubitril/valsartan has been developed for the management of hypertension, because it has unique anti-aging properties. However, the clinical evidence of mechanism has not been well validated. A recent mechanistic study PARAMETER demonstrated that sacubitril/valsartan (LCZ696) is superior to angiotensin receptor blocker (ARB) monotherapy for reducing central aortic systolic pressure (primary endpoint) as well as for central aortic pulse pressure (secondary endpoint) and nocturnal BP preferentially. Considering these results, sacubitril/valsartan may be an attractive therapeutic agent to treat the elderly with age-related hypertension phenotypes, such as drug-uncontrolled (resistant) hypertension characterized as systolic (central) hypertension (structural hypertension) and/or nocturnal hypertension (salt-sensitive hypertension). These are the high-risk hypertension phenotypes which are prone to develop heart failure with preserved EF and chronic kidney disease. Sacubitril/valsartan may be effective to suppress the age-related continuum from hypertension to heart failure, and it could be clinically useful not only for secondary prevention, but also as primary prevention of heart failure in uncontrolled elderly hypertensive patients.

Long-term efficacy of a combination of amlodipine and olmesartan medoxomil ± hydrochlorothiazide in patients with hypertension stratified by age, race and diabetes status: a substudy of the COACH trial.

PubMed

Oparil, S; Chrysant, S G; Melino, M; Lee, J; Karki, S; Heyrman, R

2010-12-01

A prespecified subgroup analysis of a 44-week open-label extension study is presented. The efficacy and safety of the combination of amlodipine (AML) + olmesartan medoxomil (OM), with and without the addition of hydrochlorothiazide (HCTZ), were investigated in patients aged ≥65 and <65 years, Blacks and non-Blacks and patients with and without type 2 diabetes. After an 8-week double-blind, placebo-controlled portion of the study, patients initiated therapy on AML 5 + OM 40 mg per day, were uptitrated stepwise to AML 10 + OM 40 mg per day, with the addition of HCTZ 12.5 mg, and 25 mg if blood pressure (BP) goal was not achieved (<140/90 or <130/80 mm Hg for patients with diabetes). Endpoints included the change from baseline in mean seated systolic BP, mean seated diastolic BP and achievement of BP goal. BP decreased from baseline for all treatments in each prespecified subgroup. By the end of the study, BP goal was achieved in 61.0% of patients aged ≥65 years, 68.1% of patients aged <65 years, 63.3% of Blacks, 67.8% of non-Blacks, 26.9% of patients with diabetes and 72.9% of patients without diabetes. The combination of AML + OM ± HCTZ was efficacious, safe and well tolerated by these subgroups.

Gateways to clinical trials. July-August 2008.

PubMed

Tomillero, A; Moral, M A

2008-01-01

(-)-Epigallocatechin gallate, 501516, 89-12; Abatacept, Adalimumab, Adefovir dipivoxil, AG-701, Agatolimod sodium, Alefacept, Aliskiren fumarate, Apixaban, Atazanavir sulfate, Atrasentan, Axitinib; BI-1744-CL, BIBF-1120, BIBW-2992, Bortezomib; Carboxyamidotriazole, Caspofungin acetate, CBP-501, Cediranib, Ceftobiprole, Certolizumab pegol, Cetuximab, Cholesteryl hydrophobized polysaccharide-Her2 protein complex, CHP-NY-ESO-1, Cypher; Dalbavancin, Dalcetrapib, Daptomycin, Darapladib, Deferasirox, Deforolimus, Denosumab, DNA-HIV-C, Dovitinib, DR-5001, Dronedarone hydrochloride, DT388IL3; E75, EC-17/EC-90, Ecogramostim, Efungumab, Entecavir, EP HIV-1090, EP-2101, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Faropenem daloxate, Fluticasone furoate, Fondaparinux sodium, Fospropofol disodium, Fulvestrant; Golimumab, GSK-089, GW-590735; HO/03/03, hTERT572, hTERT572Y; Iloperidone; Immunoglobulin intravenous (human), Ispinesib mesylate, Istradefylline, Ixabepilone; JR-031, JX-594; KLH; Laropiprant, Lecozotan hydrochloride, Lenalidomide, Lestaurtinib, Linezolid; MGCD-0103, MK-0646, MVA-BN Measles; NI-0401, Niacin/laropiprant, NSC-719239, NYVAC-C; Ospemifene; Paliperidone palmitate, PAN-811, PCV7, Pegfilgrastim, Peginterferon alfa-2a, PEGirinotecan, Perifosine, Pertuzumab, PF-00299804, Picoplatin, Pimavanserin tartrate, Pitavastatin calcium, Pomalidomide, Prasterone, Pratosartan, Prucalopride, PSMA27/pDOM, Pyridoxal phosphate; QS-21, Quercetin; Rebimastat, Rimonabant, Rolofylline, Romidepsin, Rosuvastatin calcium, RTS,S/SBAS2; SCH-530348, SN-29244, Soblidotin, Sodium dichloroacetate, Solifenacin succinate, Sorafenib, Spheramine, SU-6668, Succinobucol; Taranabant, Taxus, Telaprevir, Telavancin hydrochloride, Telbivudine, Tenofovir disoproxil fumarate, Tigecycline, Tiotropium bromide, Tocilizumab, Triphendiol; UC-781, Udenafil, UNIL-025; V-5 Immunitor, Valsartan/amlodipine besylate, Varenicline tartrate, Velafermin, Vernakalant hydrochloride, Vinflunine, Vitespen, Vorinostat, VX-001; Xience V, XRP-0038; Yttrium Y90 Epratuzumab; Z-360, Ziconotide, Ziprasidone hydrochloride, Zotarolimus, Zotarolimus-eluting stent. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

Physicochemical properties of valsartan and the effect of ethyl alcohol, propylene glycol and pH on its solubility.

PubMed

Mbah, C J

2005-11-01

The aqueous solubility and partition coefficient of valsartan were determined at room temperature. The effect of ethyl alcohol, propylene glycol and pH on its solubility was also investigated. It was found that both solvents increased the solubility of the drug in water. The solubilizing power of ethyl alcohol was found to be higher than that of propylene glycol. Valsartan solubility was also observed to increase at high pH values and its lipophilicity wasdemonstrated by the high positive value of the logarithm of partition coefficient.

Sacubitril/Valsartan in an Elderly Patient with Heart Failure: A Case Report.

PubMed

Cameli, Matteo; Pastore, Maria Concetta; Pagliaro, Antonio; Di Tommaso, Cristina; Reccia, Rosanna; Curci, Valeria; Mandoli, Giulia Elena; Mondillo, Sergio

2017-01-01

Sacubitril/valsartan has recently been approved for the treatment of heart failure with reduced ejection fraction. Given its recent introduction in the armamentarium for the treatment of heart failure (HF), "field-practice" evidence is required to deepen the clinical management of sacubitril/valsartan therapy. We report a relevant case of an elderly patient who achieved major clinical benefits after only 3 months of sacubitril/valsartan therapy. Importantly, in our assessment, we employed speckle tracking echocardiography (STE), a recent echocardiography technique that is non-Doppler and not angle dependent, which analyzes deformations of heart chambers from standard images and allows a fast, reliable, and reproducible assessment of heart function. After 3 months of therapy, NHYA class decreased from III to I-II and hypertension was controlled. Echocardiography examination also showed a marked improvement, with a reduction of left ventricular diameter, improved diastolic function (E = 0.39 m/s; A 0.69 m/s; E/A 0.55), normalized diastolic function index (E/E' TDI = 6.93), normalized atrial volume (63 mL), and improved atrial strain (15.44%). This case report documents the fast clinical and symptom improvement with sacubitril/valsartan in an elderly patient with HF; comprehensive echocardiographic assessment, including STE, also revealed a marked functional improvement with this compound. © 2017 S. Karger AG, Basel.

Sacubitril/Valsartan: Effect on Walking Test and Physical Capability.

PubMed

Sgorbini, Luca; Rossetti, Antonella; Galati, Alfonso

The 6-min walk test (6MWT) is a simple and inexpensive exercise test to evaluate physical functional capacity that is widely used in heart failure (HF) patients. With the 6MWT, a distance <350 m is associated with increased mortality in patients with HF, and change in walking distance >50 m is considered clinically relevant. To our knowledge, information on improvement in physical functional capacity with sacubitril/valsartan, as assessed by the 6MWT, is still scant. In our daily practice, we apply this test to all patients whenever possible; therefore, we report here the findings observed in a small series of 5 patients with HF with reduced ejection fraction after a 1-month treatment with sacubitril/valsartan at full dose. The mean distance walked on the 6MWT at baseline was 129 m (±64 SD), and this value increased to 436 m (±156) after 1 month of therapy with sacubitril/valsartan 97/103 mg b.i.d. The mean difference from baseline was 305 m (±110). According to these preliminary findings, in clinical practice, a 1-month therapy of sacubitril/valsartan optimized at a 97/103-mg b.i.d. dose appears to be associated with a relevant improvement in the 6MWT. © 2017 S. Karger AG, Basel.

Effects of Angiotensin Inhibitor Valsartan on the Expression of the Angiotensin II 1 Receptor, Matrix Metalloproteinases -2 and -9 in Human Bladder Cancer Cell Lines.

PubMed

Yang, Delin; Huo, Qian; Luan, Ting; Wang, Jiansong; Tang, Zhaoran; Wang, Haifeng

2016-08-01

In order to investigate how valsartan-the angiotensin II 1 receptor (AT1R) antagonist-affects the expressions of AT1R antigen, matrix metalloproteinases (MMPs) -2 and -9 in carcinoma of urinary bladder (CUB) cell lines with different invasive abilities. Three cell lines, EJ-M3, EJ, and BIU-87, with different invasive abilities were cultured and treated with valsartan. Cell proliferation states were determined by the methyl thiazolyl tetrazolium (MTT) method. The expressions at protein level and gene level were determined by Western blot and real-time fluorescence reverse transcription polymerase chain reaction (RT-PCR), respectively. The invasive abilities and migratory abilities of the three cell lines were determined by Transwell in vitro cell invasion assay and wound healing assay, respectively. MTT results show that valsartan can inhibit the proliferation of CUB cells, and the inhibition effect is enhanced with the increase of concentration. AngII promotes the MMP2 and MMP9 expressions (both protein and gene levels) in CUB cells through AT1R, but their expressions can be effectively inhibited by valsartan, the AngII inhibitor. AngII inhibitor may become a novel drug that can inhibit CUB metastasis and prolong the survival of CUB patients.

Cardiac Protection of Valsartan on Juvenile Rats with Heart Failure by Inhibiting Activity of CaMKII via Attenuating Phosphorylation.

PubMed

Wu, Yao; Si, Feifei; Ji, Xiaojuan; Jiang, Kunfeng; Song, Sijie; Yi, Qijian

2017-01-01

Background . This study was undertaken to determine relative contributions of phosphorylation and oxidation to the increased activity of calcium/calmodulin-stimulated protein kinase II (CaMKII) in juveniles with cardiac myocyte dysfunction due to increased pressure overload. Methods . Juvenile rats underwent abdominal aortic constriction to induce heart failure. Four weeks after surgery, rats were then randomly divided into two groups: one group given valsartan (HF + Val) and the other group given placebo (HF + PBO). Simultaneously, the sham-operated rats were randomly given valsartan (Sham + Val) or placebo (Sham + PBO). After 4 weeks of treatment, Western blot analysis was employed to quantify CaMKII and relative calcium handling proteins (RyR2 and PLN) in all groups. Results . The deteriorated cardiac function was reversed by valsartan treatment. In ventricular muscle cells of group HF + PBO, Thr287 phosphorylation of CaMKII and S2808 phosphorylation of RyR2 and PLN were increased and S16 phosphorylation of PLN was decreased compared to the other groups, while Met281 oxidation was not significantly elevated. In addition, these changes in the expression of calcium handling proteins were ameliorated by valsartan administration. Conclusions . The phosphorylation of Thr286 is associated with the early activation of CaMKII rather than the oxidation of Met281.

Efficacy of olmesartan amlodipine in Colombian hypertensive patients (soat study).

PubMed

Buendia, Richard; Zambrano, Monica

2017-04-26

Emerging evidence has shown a significant deficit in the control of hypertension (blood pressure <140/90 mmHg) among Hispanics or Latinos in about 65%. This study aims to determine the efficacy of the combination in fixed doses of olmesartan and amlodipine (20/5, 40/5, and 40/10 mg) in hypertensive patients treated in daily clinical practice by Colombian doctors. This was an observational, retrospective, open-label, multi-center, non-comparative study. The primary outcome was a change in systolic and diastolic blood pressure from the baseline to week 12; the secondary outcome was the proportion of patients achieving a target blood pressure of <140/90 mmHg. Safety and tolerability were also evaluated. For analysis, a student t test was used for paired data, McNemar test, and ANCOVA. A total of 428 patients were enrolled from 16 centers in Colombia. At 12 weeks, patients' systolic blood pressure decreased in response to all three doses: by 27.75 ± 20.73 mmHg in 20/5 mg, 31.13 ± 22.23 mmHg in 40/5 mg, and 46.96 ± 20.15 mmHg in 40/10 mg (all p < 0.001). Furthermore, the diastolic blood pressure decreased by 14.19 ± 12.89 mmHg in 20/5 mg, 16.25 ± 10.87 mmHg in 40/5 mg, and 24.83 ± 10.41 mmHg in 40/10 mg (all p < 0.001). The percentage of patients achieving target blood pressure was 71.31% in 20/5 mg, 70.16% in 40/5 mg, and 63.33% in 40/10 mg. This study demonstrates the efficacy of the combination in fixed doses of olmesartan and amlodipine in the treatment of Colombian hypertensive patients.

Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction

PubMed Central

McMurray, John J V; Trueman, David; Hancock, Elizabeth; Cowie, Martin R; Briggs, Andrew; Taylor, Matthew; Mumby-Croft, Juliet; Woodcock, Fionn; Lacey, Michael; Haroun, Rola; Deschaseaux, Celine

2018-01-01

Objective Chronic heart failure with reduced ejection fraction (HF-REF) represents a major public health issue and is associated with considerable morbidity and mortality. We evaluated the cost-effectiveness of sacubitril/valsartan (formerly LCZ696) compared with an ACE inhibitor (ACEI) (enalapril) in the treatment of HF-REF from the perspective of healthcare providers in the UK, Denmark and Colombia. Methods A cost-utility analysis was performed based on data from a multinational, Phase III randomised controlled trial. A decision-analytic model was developed based on a series of regression models, which extrapolated health-related quality of life, hospitalisation rates and survival over a lifetime horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER). Results In the UK, the cost per quality-adjusted life-year (QALY) gained for sacubitril/valsartan (using cardiovascular mortality) was £17 100 (€20 400) versus enalapril. In Denmark, the ICER for sacubitril/valsartan was Kr 174 000 (€22 600). In Colombia, the ICER was COP$39.5 million (€11 200) per QALY gained. Deterministic sensitivity analysis showed that results were most sensitive to the extrapolation of mortality, duration of treatment effect and time horizon, but were robust to other structural changes, with most scenarios associated with ICERs below the willingness-to-pay threshold for all three country settings. Probabilistic sensitivity analysis suggested the probability that sacubitril/valsartan was cost-effective at conventional willingness-to-pay thresholds was 68%–94% in the UK, 84% in Denmark and 95% in Colombia. Conclusions Our analysis suggests that, in all three countries, sacubitril/valsartan is likely to be cost-effective compared with an ACEI (the current standard of care) in patients with HF-REF. PMID:29269379

Rationale and methods of the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF).

PubMed

Januzzi, James L; Butler, Javed; Fombu, Emmanuel; Maisel, Alan; McCague, Kevin; Piña, Ileana L; Prescott, Margaret F; Riebman, Jerome B; Solomon, Scott

2018-05-01

Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor indicated for the treatment of patients with chronic heart failure (HF) with reduced ejection fraction; however, its mechanism of benefit remains unclear. Biomarkers that are linked to ventricular remodeling, myocardial injury, and fibrosis may provide mechanistic insight and important clinical guidance regarding sacubitril/valsartan use. This 52-week, multicenter, open-label, single-arm study is designed to (1) correlate biomarker changes with cardiac remodeling parameters, cardiovascular outcomes, and patient-reported outcome data and (2) determine short- and long-term changes in concentrations of biomarkers related to potential mechanisms of action and effects of sacubitril/valsartan therapy. Approximately 830 patients with HF with reduced ejection fraction will be initiated and titrated on sacubitril/valsartan according to United States prescribing information. Primary efficacy end points include the changes in N-terminal pro-B-type natriuretic peptide concentrations and cardiac remodeling from baseline to 1 year. Secondary end points include changes in concentrations of N-terminal pro-B-type natriuretic peptide and remodeling to 6 months, and changes in patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire-23 from baseline to 1 year. In addition, several other relevant biomarkers will be measured. Biomarker changes relative to the number of cardiovascular events in 12 months will also be assessed as exploratory end points. Results from the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) will help establish a mechanistic understanding of angiotensin receptor-neprilysin inhibitor therapeutic benefits and provide clinicians with clarity on how to interpret information on biomarkers during treatment (PROVE-HF ClinicalTrials.gov identifier: NCT02887183). Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Effect of low-dose valsartan on proteinuria in normotensive immunoglobulin A nephropathy with minimal proteinuria: a randomized trial.

PubMed

Jo, Young-Il; Na, Ha-Young; Moon, Ju-Young; Han, Sang-Woong; Yang, Dong-Ho; Lee, Sang-Ho; Park, Hyeong-Cheon; Choi, Hoon-Young; Lim, So-Dug; Kie, Jeong-Hae; Lee, Yong-Kyu; Shin, Sug-Kyun

2016-03-01

Immunoglobulin A nephropathy (IgAN) is a generally progressive disease, even in patients with favorable prognostic features. In this study, we aimed to investigate the antiproteinuric effect and tolerability of low-dose valsartan (an angiotensin II receptor blocker) therapy in normotensive IgAN patients with minimal proteinuria of less than 0.5 to 1.0 g/day. Normotensive IgAN patients, who had persistent proteinuria with a spot urine protein-to-creatinine ratio of 0.3 to 1.0 mg/mg creatinine, were recruited from five hospitals and randomly assigned to either 40 mg of valsartan as the low-dose group or 80 mg of valsartan as the regular-dose group. Clinical and laboratory data were collected at baseline, and at 4, 8, 12, and 24 weeks after valsartan therapy. Forty-three patients (low-dose group, n = 23; regular-dose group, n = 20) were enrolled in the study. Proteinuria decreased significantly not only in the regular-dose group but also in the low-dose group. The change in urine protein-to-creatinine ratio at week 24 was -41.3% ± 26.1% (p < 0.001) in the regular-dose group and -21.1% ± 45.1% (p = 0.005) in the low-dose group. In the low-dose group, blood pressure was constant throughout the study period, and there was no symptomatic hypotension. In the regular-dose group, blood pressure decreased at weeks 8 and 12. No significant change in glomerular filtration rate, serum creatinine level, or serum potassium level was observed during the study period. Our results suggest that low-dose valsartan can significantly reduce proteinuria without causing any intolerability in normotensive IgAN patients with minimal proteinuria.

Pharmacokinetic Evaluation of Improved Oral Bioavailability of Valsartan: Proliposomes Versus Self-Nanoemulsifying Drug Delivery System.

PubMed

Nekkanti, Vijaykumar; Wang, Zhijun; Betageri, Guru V

2016-08-01

The objective of this study was to develop proliposomes and self-nanoemulsifying drug delivery system (SNEDDS) for a poorly bioavailable drug, valsartan, and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin-film hydration method using different lipids such as soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoyl phosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. SNEDDS formulations were prepared using varying concentrations of capmul MCM, labrafil M 2125, and Tween 80. Both proliposomes and SNEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water and 0.1 N HCl using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal permeation techniques. Among the formulations, the proliposomes with drug/DMPG/cholesterol in the ratio of 1:1:0.5 and SNEDDS with capmul MCM (16.0% w/w), labrafil M 2125 (64.0% w/w), and Tween 80 (18.0% w/w) showed the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SNEDDS as compared to pure valsartan. Valsartan permeability across PAMPA and everted rat intestinal permeation models was significantly higher with proliposomes and SNEDDS. Following single oral administration of proliposomes and SNEDDS, a relative bioavailability of 202.36 and 196.87%, respectively, was achieved compared to pure valsartan suspension. The study results indicated that both proliposomes and SNEDDS formulations are comparable in improving the oral bioavailability of valsartan.

Modest blood pressure reduction with valsartan in acute ischemic stroke: a prospective, randomized, open-label, blinded-end-point trial.

PubMed

Oh, Mi Sun; Yu, Kyung-Ho; Hong, Keun-Sik; Kang, Dong-Wha; Park, Jong-Moo; Bae, Hee-Joon; Koo, Jaseong; Lee, Juneyoung; Lee, Byung-Chul

2015-07-01

To assess the efficacy and safety of modest blood pressure (BP) reduction with valsartan within 48 h after symptom onset in patients with acute ischemic stroke and high BP. This was a multicenter, prospective, randomized, open-label, blinded-end-point trial. A total of 393 subjects were recruited at 28 centers and then randomly assigned in a 1:1 ratio to receive valsartan (n = 195) or no treatment (n = 198) for seven-days after presentation. The primary outcome was death or dependency, defined as a score of 3-6 on the modified Rankin Scale (mRS) at 90 days after symptom onset. Early neurological deterioration (END) within seven-days and 90-day major vascular events were also assessed. There were 372 patients who completed the 90-day follow-up. The valsartan group had 46 of 187 patients (24·6%) with a 90-day mRS 3-6, compared with 42 of 185 patients (22·6%) in the control group (odds ratio [OR], 1·11; 95% confidence interval [CI], 0·69-1·79; P = 0·667). The rate of major vascular events did not differ between groups (OR, 1·41; 95% CI, 0·44-4·49; P = 0·771). There was a significant increase of END in the valsartan group (OR, 2·43; 95% CI, 1·25-4·73; P = 0·008). Early reduction of BP with valsartan did not reduce death or dependency and major vascular events at 90 days, but increased the risk of END. © 2015 World Stroke Organization.

Valsartan Protects Against Contrast-Induced Acute Kidney Injury in Rats by Inhibiting Endoplasmic Reticulum Stress-Induced Apoptosis.

PubMed

Sun, Yan; Peng, Ping-An; Ma, Yue; Liu, Xiao-Li; Yu, Yi; Jia, Shuo; Xu, Xiao-Han; Wu, Si-Jing; Zhou, Yu-Jie

2017-01-01

Contrast-induced acute kidney injury (CI-AKI) is a serious complication of the administration of iodinated contrast media (CM) for diagnostic and interventional cardiovascular procedures and is associated with substantial morbidity and mortality. While the preventative measures can mitigate the risk of CI-AKI, there remains a need for novel and effective therapeutic approaches. The pathogenesis of CI-AKI is complex and not completely understood. CM-induced renal tubular cell apoptosis caused by the activation of endoplasmic reticulum (ER) stress is involved in CIAKI. We previously demonstrated that valsartan alleviated CM-induced human renal tubular cell apoptosis by inhibiting ER stress in vitro. However, the nephroprotective effect of valsartan on CI-AKI in vivo has not been investigated. Therefore, the aim of this study was to explore the protective effect of valsartan in a rat model of CI-AKI by measuring the amelioration of renal damage and the changes in ER stressrelated biomarkers. Our results showed that the radiocontrast agent meglumine diatrizoate caused significant renal insufficiency, renin-angiotensin system (RAS) activation, and renal tubular apoptosis by triggering ER stress through activation of glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), caspase 12, CCAAT/enhancer-binding protein-homologous protein (CHOP) and c-Jun N-terminal protein kinase (JNK) (P<0.05; n=6 in each group). Pre-treatment with valsartan significantly alleviated renal dysfunction, pathological injury, and apoptosis along with the inhibition of ER stressrelated biomarkers (P<0.05; n=8 in each group). Valsartan could protect against meglumine diatrizoate-induced kidney injury in rats by inhibiting the ER stress-induced apoptosis, making it a promising strategy for preventing CI-AKI. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effect of low-dose valsartan on proteinuria in normotensive immunoglobulin A nephropathy with minimal proteinuria: a randomized trial

PubMed Central

Jo, Young-Il; Na, Ha-Young; Moon, Ju-Young; Han, Sang-Woong; Yang, Dong-Ho; Lee, Sang-Ho; Park, Hyeong-Cheon; Choi, Hoon-Young; Lim, So-Dug; Kie, Jeong-Hae; Lee, Yong-Kyu; Shin, Sug-Kyun

2016-01-01

Background/Aims: Immunoglobulin A nephropathy (IgAN) is a generally progressive disease, even in patients with favorable prognostic features. In this study, we aimed to investigate the antiproteinuric effect and tolerability of low-dose valsartan (an angiotensin II receptor blocker) therapy in normotensive IgAN patients with minimal proteinuria of less than 0.5 to 1.0 g/day. Methods: Normotensive IgAN patients, who had persistent proteinuria with a spot urine protein-to-creatinine ratio of 0.3 to 1.0 mg/mg creatinine, were recruited from five hospitals and randomly assigned to either 40 mg of valsartan as the low-dose group or 80 mg of valsartan as the regular-dose group. Clinical and laboratory data were collected at baseline, and at 4, 8, 12, and 24 weeks after valsartan therapy. Results: Forty-three patients (low-dose group, n = 23; regular-dose group, n = 20) were enrolled in the study. Proteinuria decreased significantly not only in the regular-dose group but also in the low-dose group. The change in urine protein-to-creatinine ratio at week 24 was −41.3% ± 26.1% (p < 0.001) in the regular-dose group and −21.1% ± 45.1% (p = 0.005) in the low-dose group. In the low-dose group, blood pressure was constant throughout the study period, and there was no symptomatic hypotension. In the regular-dose group, blood pressure decreased at weeks 8 and 12. No significant change in glomerular filtration rate, serum creatinine level, or serum potassium level was observed during the study period. Conclusions: Our results suggest that low-dose valsartan can significantly reduce proteinuria without causing any intolerability in normotensive IgAN patients with minimal proteinuria. PMID:26874511

Molecular insight into atypical instability behavior of fixed-dose combination containing amlodipine besylate and losartan potassium.

PubMed

Handa, Tarun; Jhajra, Shalu; Bhagat, Shweta; Bharatam, P V; Chakraborti, Asit K; Singh, Saranjit

2017-03-20

Combination therapy with the use of fixed-dose combinations (FDCs) is evincing increasing interest of prescribers, manufacturers and even regulators, evidently due to the primary benefit of improved patient compliance. However, owing to potential of drug-drug interaction, FDCs require closer scrutiny with respect to their physical and chemical stability. Accordingly, the purpose of the present study was to explore stability behavior of a popular antihypertensive combination of amlodipine besylate (AML) and losartan potassium (LST). Physical mixtures of the two drugs and multiple marketed formulations were stored under accelerated conditions of temperature and humidity (40°C/75% RH) in a stability chamber and samples were withdrawn after 1 and 3 months. The physical changes were observed visibly, while chemical changes were monitored by HPLC employing a method that could separate the two drugs and all other components present. The combination revealed strong physical instability and also chemical degradation of AML in the presence of LST. Interestingly, three isomeric interaction products of AML were formed in the combination, which otherwise were reported in the literature to be generated on exposure of AML free base above its melting point. The same unusual products were even formed when multiple marketed FDCs were stored under accelerated conditions outside their storage packs. However, these were absent when AML alone was stored in the same studied conditions. Therefore, reasons for physical and chemical incompatibility and the mechanism of degradation of AML in the presence of LST were duly explored at the molecular level. The outcomes of the study are expected to help in development of stable FDCs of the two drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparison of ambulatory blood pressure-lowering effects of higher doses of different calcium antagonists in uncontrolled hypertension: the Calcium Antagonist Controlled-Release High-Dose Therapy in Uncontrolled Refractory Hypertensive Patients (CARILLON) Study.

PubMed

Mizuno, Hiroyuki; Hoshide, Satoshi; Tomitani, Naoko; Kario, Kazuomi

2017-10-01

Data are sparse regarding ambulatory blood pressure (BP) reduction of up-titration from a standard dose to a high dose in both nifedipine controlled-release (CR) and amlodipine. This was a prospective, randomized, multicenter, open-label trial. Fifty-one uncontrolled hypertensives medicated by two or more antihypertensive drugs including a renin-angiotensin system inhibitor and a calcium antagonist were randomly assigned to either the nifedipine CR (80 mg)/candesartan (8 mg) group or the amlodipine (10 mg)/candesartan (8 mg) group. The changes in 24-hr BP were comparable between the groups. The nifedipine group demonstrated a significant decrease in their urinary albumin creatinine ratio, whereas the amlodipine group demonstrated a significant decrease in their NTproBNP level. However, there was no significant difference in any biomarkers between the two groups. Nifedipine showed an almost equal effect on ambulatory blood pressure as amlodipine. Their potentially differential effects on renal protection and NTproBNP should be tested in larger samples.

Novel mechanism of cardiac protection by valsartan: synergetic roles of TGF-β1 and HIF-1α in Ang II-mediated fibrosis after myocardial infarction.

PubMed

Sui, Xizhong; Wei, Hongchao; Wang, Dacheng

2015-08-01

Transforming growth factor (TGF)-β1 is a known factor in angiotensin II (Ang II)-mediated cardiac fibrosis after myocardial infarction (MI). Hypoxia inducible factor-1 (Hif-1α) was recently demonstrated to involve in the tissue fibrosis and influenced by Ang II. However, whether Hif-1α contributed to the Ang II-mediated cardiac fibrosis after MI, and whether interaction or synergetic roles between Hif-1α and TGF-β pathways existed in the process was unclear. In vitro, cardiac cells were incubated under hypoxia or Ang II to mimic ischaemia. In vivo, valsartan was intravenously injected into Sprague-Dawley rats with MI daily for 1 week; saline and hydralazine (another anti-hypertensive agent like valsartan) was used as control. The fibrosis-related proteins were detected by Western blotting. Cardiac structure and function were assessed with multimodality methods. We demonstrated in vitro that hypoxia would induce the up-regulation of Ang II, TGF-β/Smad and Hif-1α, which further induced collagen accumulation. By blocking with valsartan, a blocker of Ang II type I (AT1) receptor, we confirmed that the up-regulation of TGF-β/Smad and Hif-1α was through the Ang II-mediated pathway. By administering TGF-β or dimethyloxalylglycine, we determined that both TGF-β/Smad and Hif-1α contributed to Ang II-mediated collagen accumulation and a synergetic effect between them was observed. Consistent with in vitro results, valsartan significantly attenuated the expression of TGF-β/Smad, Hif-1α and fibrosis-related protein in rats after MI. Heart function, infarcted size, wall thickness as well as myocardial vascularization of ischaemic hearts were also significantly improved by valsartan compared with saline and hydralazine. Our study may provide novel insights into the mechanisms of Ang II-induced cardiac fibrosis as well as into the cardiac protection of valsartan. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Time of administration important? Morning versus evening dosing of valsartan

PubMed Central

Zappe, Dion H.; Crikelair, Nora; Kandra, Albert; Palatini, Paolo

2015-01-01

Objective: Studies suggest that bedtime dosing of an angiotensin-converting enzyme (ACE)-inhibitor or angiotensin receptor blocker shows a more sustained and consistent 24-h antihypertensive profile, including greater night-time blood pressure (BP) reduction. We compared the antihypertensive effects of morning (a.m.) and evening (p.m.) dosing of valsartan on 24-h BP. Methods: This 26-week, multicentre, randomized, double-blind study evaluated the efficacy and safety of valsartan 320 mg, dosed a.m. or p.m., versus lisinopril 40 mg (a.m.), a long-acting ACE-inhibitor, in patients with grade 1–2 hypertension and at least one additional cardiovascular risk factor. Patients (n = 1093; BP = 156 ± 11/91 ± 8 mmHg; 62 years, 56% male, 99% white) received (1 : 1 : 1) valsartan 160 mg a.m. or p.m. or lisinopril 20 mg a.m. for 4 weeks, then force-titrated to double the initial dose for 8 weeks. At Week 12, hydrochlorothiazide (HCTZ) 12.5 mg was added for 14 weeks if office BP was more than 140/90 mmHg and/or ambulatory BP more than 130/80 mmHg. Results: Mean 24-h ambulatory SBP change from baseline to Weeks 12 and 26 was comparable between valsartan a.m. (–10.6 and –13.3 mmHg) and p.m. (–9.8 and –12.3 mmHg) and lisinopril (–10.7 and –13.7 mmHg). There was no benefit of valsartan p.m. versus a.m. on night-time BP, early morning BP and morning BP surge. Evening dosing also did not improve BP lowering in patients requiring add-on HCTZ or in nondippers at baseline. All treatments were well tolerated. Conclusion: Once-daily dosing of valsartan 320 mg results in equally effective 24-h BP efficacy, regardless of dosing time. Trial Registration: ClinicalTrials.gov Identifier: NCT00241124. PMID:25259546

Protective effect of amlodipine on rat bone tissue after orchidectomy.

PubMed

Gradosova, Iveta; Zivna, Helena; Palicka, Vladimir; Hubena, Sona; Svejkovska, Klara; Zivny, Pavel

2012-01-01

Our study aimed to investigate the effect of amlodipine on bone metabolism in orchidectomized rats. Eight-week-old rats were divided into three groups. The sham-operated control group (SHAM) and the control group after orchidectomy (ORX) received the standard laboratory diet (SLD). The experimental group after orchidectomy (ORX+AML) received SLD enriched with amlodipine for 12 weeks. Bone marker concentrations in serum of PINP, OPG and IGF-1, and the levels of CTX-I, BAP and BMP-2 in a bone homogenate were measured using enzyme-linked immunosorbent assay. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry. The femurs were used for biomechanical testing. Bone markers (CTX-I, BAP, BMP-2) in ORX were higher versus SHAM. In ORX+AML there was a decrease in PINP, CTX-I, BAP, BMP-2 and OPG versus ORX. IGF-1 was decreased in ORX versus SHAM. In ORX+AML it was increased versus ORX. In ORX, a decrease was demonstrated versus SHAM in BMD of the whole body, in the lumbar vertebrae and in both femurs. In ORX+AML there was an increase in BMD of the whole body versus ORX. Three-point bending test revealed a decrease in maximal load values in ORX versus SHAM. After amlodipine administration there was an increase in the left femur versus ORX. Amlodipine is capable of mitigating the negative effects of orchidectomy and could be a good prevention of osteoporosis. Copyright © 2012 S. Karger AG, Basel.

Development and Validation of a Chromatography Method Using Tandem UV/Charged Aerosol Detector for Simultaneous Determination of Amlodipine Besylate and Olmesartan Medoxomil: Application to Drug-Excipient Compatibility Study

PubMed Central

Brondi, Ariadne M.; Garcia, Jerusa S.

2017-01-01

A study was carried out to investigate compatibility of amlodipine besylate and olmesartan medoxomil with a variety of pharmaceutical excipients. Both drugs are antihypertensive agents that can be administered alone, in monotherapy, or in pharmaceutical association. The studies were performed using binary and ternary mixtures, and samples were stored for 3 and 6 months at 40°C under 75% relative humidity and dry conditions. For this study, a method based on high-performance liquid chromatography (HPLC) was developed and validated for the simultaneous determination of amlodipine besylate and olmesartan medoxomil in samples from pharmaceutical preformulation studies using diode array detector (DAD) and charged aerosol detector (CAD). The runtime per sample was 10 min with retention time of 7.926 min and 4.408 min for amlodipine and olmesartan, respectively. The validation was performed according to ICH guidelines. The calibration curve presents linear dynamic range from 12 to 250 μg mL−1 for amlodipine and from 25 to 500 μg mL−1 for olmesartan with coefficient of determination (R2 ≥ 0.9908) while repeatability and reproducibility (expressed as relative standard deviation) were lower than 1.0%. The excipients such as corn starch, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, talc, polyvinylpyrrolidone, lactose monohydrate, and polyethylene glycol showed potential incompatibilities after accelerated stability testing. PMID:29391967

Comparative study between univariate spectrophotometry and multivariate calibration as analytical tools for quantitation of Benazepril alone and in combination with Amlodipine.

PubMed

Farouk, M; Elaziz, Omar Abd; Tawakkol, Shereen M; Hemdan, A; Shehata, Mostafa A

2014-04-05

Four simple, accurate, reproducible, and selective methods have been developed and subsequently validated for the determination of Benazepril (BENZ) alone and in combination with Amlodipine (AML) in pharmaceutical dosage form. The first method is pH induced difference spectrophotometry, where BENZ can be measured in presence of AML as it showed maximum absorption at 237nm and 241nm in 0.1N HCl and 0.1N NaOH, respectively, while AML has no wavelength shift in both solvents. The second method is the new Extended Ratio Subtraction Method (EXRSM) coupled to Ratio Subtraction Method (RSM) for determination of both drugs in commercial dosage form. The third and fourth methods are multivariate calibration which include Principal Component Regression (PCR) and Partial Least Squares (PLSs). A detailed validation of the methods was performed following the ICH guidelines and the standard curves were found to be linear in the range of 2-30μg/mL for BENZ in difference and extended ratio subtraction spectrophotometric method, and 5-30 for AML in EXRSM method, with well accepted mean correlation coefficient for each analyte. The intra-day and inter-day precision and accuracy results were well within the acceptable limits. Copyright © 2013 Elsevier B.V. All rights reserved.

Comparison between the effects of amlodipine and lisinopril on proteinuria in nondiabetic renal failure: a double-blind, randomized prospective study.

PubMed

Janssen, J J; Gans, R O; van der Meulen, J; Pijpers, R; ter Wee, P M

1998-09-01

Double-blind, randomized controlled studies of longer than 1 week in duration comparing the antiproteinuric potential of long-acting dihydropyridine calcium channel blockers with that of angiotensin converting enzyme (ACE) inhibitors are lacking. Therefore, we performed such a study in patients with nondiabetic renal disease and proteinuria. After a 4-week wash-out period in which patients did not use any medication known to affect proteinuria, 21 patients were randomized in a double-blind fashion to receive either the calcium channel blocker amlodipine (Amlo, 5 to 10 mg) or the ACE-inhibitor lisinopril (Lis, 5 to 10 mg). Throughout the 16-week study period, blood pressure, creatinine clearances, and proteinuria were measured every 2 weeks. In addition, device-measured blood pressure and renal hemodynamic studies were performed at the start and end of the study. Systolic blood pressure fell in the Lis group from 163+/-7 (SEM) to 140+/-8 mm Hg (P < .01) and from 157+/-10 to 147+/-6 mm Hg in the Amlo group; diastolic blood pressure fell from 101+/-3 to 86+/-7 mm Hg in the Lis group and from 98+/-3 to 91+/-2 mm Hg in the Amlo group. Renal hemodynamics were not affected by amlodipine treatment, whereas a fall in glomerular filtration rate (GFR) was seen in lisinopril-treated patients (from 55+/-11 to 50+/-10 mL/min; P < .01). Amlodipine did not significantly affect proteinuria. Lisinopril induced a decline in the protein-creatinine ratio with a maximal effect reached after 12 to 16 weeks of therapy (from 0.39+/-0.17 to 0.26 +/-0.11 g/mmol; P < .009). In conclusion, we could not demonstrate an antiproteinuric effect of the long-acting dihydropyridine calcium channel blocker amlodipine, whereas therapy with the ACE-inhibitor lisinopril resulted in a decrease in proteinuria. Amlodipine did not affect renal hemodynamics, whereas lisinopril induced a fall in GFR.

Long-term prehypertension treatment with losartan effectively prevents brain damage and stroke in stroke-prone spontaneously hypertensive rats.

PubMed

He, De-Hua; Zhang, Liang-Min; Lin, Li-Ming; Ning, Ruo-Bing; Wang, Hua-Jun; Xu, Chang-Sheng; Lin, Jin-Xiu

2014-02-01

Prehypertension has been associated with adverse cerebrovascular events and brain damage. The aims of this study were to investigate ⅰ) whether short‑ and long-term treatments with losartan or amlodipine for prehypertension were able to prevent blood pressure (BP)-linked brain damage, and ⅱ) whether there is a difference in the effectiveness of treatment with losartan and amlodipine in protecting BP-linked brain damage. In the present study, prehypertensive treatment with losartan and amlodipine (6 and 16 weeks treatment with each drug) was performed on 4-week‑old stroke-prone spontaneously hypertensive rats (SHRSP). The results showed that long-term (16 weeks) treatment with losartan is the most effective in lowering systolic blood pressure in the long term (up to 40 weeks follow-up). Additionally, compared with the amlodipine treatment groups, the short‑ and long-term losartan treatments protected SHRSP from stroke and improved their brains structurally and functionally more effectively, with the long-term treatment having more benefits. Mechanistically, the short‑ and long-term treatments with losartan reduced the activity of the local renin-angiotensin-aldosterone system (RAAS) in a time-dependent manner and more effectively than their respective counterpart amlodipine treatment group mainly by decreasing AT1R levels and increasing AT2R levels in the cerebral cortex. By contrast, the amlodipine treatment groups inhibited brain cell apoptosis more effectively as compared with the losartan treatment groups mainly through the suppression of local oxidative stress. Taken together, the results suggest that long-term losartan treatment for prehypertension effectively protects SHRSP from stroke-induced brain damage, and this protection is associated with reduced local RAAS activity than with brain cell apoptosis. Thus, the AT1R receptor blocker losartan is a good candidate drug that may be used in the clinic for long-term treatment on prehypertensive populations in order to prevent BP-linked brain damage.

[Pharmacogenetic approaches to predicting the efficiency and safety of amlodipine in patients with arterial hypertension].

PubMed

Sychev, D A; Shih, N V; Kalle, E G; Ryzhikova, K A; Morozova, T E

2017-10-01

An open, non-comparative, prospective clinical study was conducted to evaluate the antihypertensive efficacy and tolerability of amlodipine, a calcium antagonist, in patients with arterial hypertension (AH) I-II stages, depending on the genotype for the polymorphic marker C3435T of the ABCB1 gene. The study included 100 patients with AH I-II stages, aged from 45 to 58 years. The initial dose of amlodipine was 5 mg, duration of treatment was 12 weeks. General clinical examination methods, office measurement and daily blood pressure monitoring, tolerance evaluation, and genotyping using the ABCB1 polymorphic marker C3435T by the PCR-RFLP method (polymerase chain reaction and restriction fragment length polymorphism) were used. The statistical analysis of results was carried out using the Mann-Whitney U test for quantitative variables, Kruskal-Wallis one-way analysis of variance (ANOVA) for three independent groups of quantitative data. Excellent antihypertensive efficacy with the CC genotype was found in 11.8% patients, with CT - 33.9%, with TT - 43.3%; good - 35.3%, 32.1%, and 33.3% respectively, satisfactory - 52.9%, 34,0% and 23.4% respectively. Six patients with the CT genotype and nine patients with the CC genotype required the increase in the dose to 10 mg. The number of patients with Adverse drug reactions (ADR) were found in 35.3% of patients with the CC genotype, 6.7% with the TT genotype and 11.3% with the CT genotype. The Kruskal-Wallis test revealed significant differences between CC and TT genotypes in the degree of decrease in SBP (p=0.02), antihypertensive efficacy parameter (p=0.02), an increase in dose requirements (p = 0.04) and the incidence of ADR(p=0.05). In AH patients (I-II stage) with the TT genotype of the C3435T gene polymorphism one can expect higher rates of antihypertensive efficacy of amlodipine in combination with a good safety profile and the lowest ADR percentage, while patients with the CC genotype more likely to develop ADR and lower antihypertensive responsiveness.

Should Antihypertensive Treatment Recommendations Differ in Patients With and Without Coronary Heart Disease? (From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT])

PubMed Central

Alderman, Michael H.; Davis, Barry R.; Piller, Linda B.; Ford, Charles E.; Baraniuk, M. Sarah; Pressel, Sara L.; Assadi, Mahshid A.; Einhorn, Paula T.; Haywood, L. Julian; Ilamathi, Ekambaram; Oparil, Suzanne; Retta, Tamrat M.

2015-01-01

Thiazide-type diuretics have been recommended for initial treatment of hypertension in most patients, but should this recommendation differ for patients with and without coronary heart disease (CHD)? The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind hypertension treatment trial in 42,418 participants with high risk of combined cardiovascular disease (CVD) (25% with pre-existing CHD). This post-hoc analysis compares long-term major clinical outcomes in those assigned amlodipine (n=9048) or lisinopril (n=9054) with those assigned chlorthalidone (n=15,255), stratified by CHD status. After 4–8 years, randomized treatment was discontinued. Total follow-up (active treatment + passive surveillance using national databases for deaths and hospitalizations) was 8–13 years. For most CVD outcomes, ESRD, and total mortality, there were no differences across randomized treatment arms regardless of baseline CHD status. In-trial rates of CVD were significantly higher for lisinopril compared with chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared with chlorthalidone in those with and without CHD (overall HRs: 1.10, p<0.001 and 1.38, p<0.001, respectively). During extended follow-up, significant outcomes according to CHD status interactions (p=0.012) were noted in amlodipine versus chlorthalidone comparison for CVD and CHD mortality, HR=0.88, p=0.04 and 0.84, p=0.04, respectively, in those with CHD at baseline and 1.06, p=0.15 and 1.08, p=0.17 in those without. The results of the overall increased stroke mortality in lisinopril compared to chlorthalidone (HR=1.2; p=0.03) and hospitalized heart failure in amlodipine compared to chlorthalidone (HR=1.12; p=0.01) during extended follow-up did not differ by baseline CHD status. In conclusion, these results provide no reason to alter our previous recommendation to include a properly dosed diuretic (such as chlorthalidone 12.5–25 mg/day) in the initial antihypertensive regimen for most hypertensive patients. PMID:26589819

Should Antihypertensive Treatment Recommendations Differ in Patients With and Without Coronary Heart Disease? (from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]).

PubMed

Alderman, Michael H; Davis, Barry R; Piller, Linda B; Ford, Charles E; Baraniuk, M Sarah; Pressel, Sara L; Assadi, Mahshid A; Einhorn, Paula T; Haywood, L Julian; Ilamathi, Ekambaram; Oparil, Suzanne; Retta, Tamrat M

2016-01-01

Thiazide-type diuretics have been recommended for initial treatment of hypertension in most patients, but should this recommendation differ for patients with and without coronary heart disease (CHD)? The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind hypertension treatment trial in 42,418 participants with high risk of combined cardiovascular disease (CVD) (25% with preexisting CHD). This post hoc analysis compares long-term major clinical outcomes in those assigned amlodipine (n = 9048) or lisinopril (n = 9,054) with those assigned chlorthalidone (n = 15,255), stratified by CHD status. After 4 to 8 years, randomized treatment was discontinued. Total follow-up (active treatment + passive surveillance using national databases for deaths and hospitalizations) was 8 to 13 years. For most CVD outcomes, end-stage renal disease, and total mortality, there were no differences across randomized treatment arms regardless of baseline CHD status. In-trial rates of CVD were significantly higher for lisinopril compared with chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared with chlorthalidone in those with and without CHD (overall hazard ratios [HRs] 1.10, p <0.001, and 1.38, p <0.001, respectively). During extended follow-up, significant outcomes according to CHD status interactions (p = 0.012) were noted in amlodipine versus chlorthalidone comparison for CVD and CHD mortality (HR 0.88, p = 0.04, and 0.84, p = 0.04, respectively) in those with CHD at baseline (HR 1.06, p = 0.15, and 1.08, p = 0.17) and in those without. The results of the overall increased stroke mortality in lisinopril compared with chlorthalidone (HR 1.2; p = 0.03) and hospitalized heart failure in amlodipine compared with chlorthalidone (HR 1.12; p = 0.01) during extended follow-up did not differ by baseline CHD status. In conclusion, these results provide no reason to alter our previous recommendation to include a properly dosed diuretic (such as chlorthalidone 12.5 to 25 mg/day) in the initial antihypertensive regimen for most hypertensive patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial.

PubMed

Chandra, Alvin; Lewis, Eldrin F; Claggett, Brian L; Desai, Akshay S; Packer, Milton; Zile, Michael R; Swedberg, Karl; Rouleau, Jean L; Shi, Victor C; Lefkowitz, Martin P; Katova, Tzvetana; McMurray, John J V; Solomon, Scott D

2018-04-04

Health-related quality of life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities. In the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, sacubitril/valsartan improved overall HRQL compared with enalapril, as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ). To examine the effects of sacubitril/valsartan on physical and social activities. The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled clinical trial performed from December 8, 2009, to March 31, 2014, in 8399 patients with New York Heart Association class II to IV disease and a left ventricular ejection fraction of 40% or less at 1043 centers in 38 countries. Data analysis was performed from August 1, 2017, to December 25, 2017. Sacubitril/valsartan, 200 mg twice daily, or enalapril, 10 mg twice daily. Patients completed HRQL assessments using the KCCQ at randomization, 4-month, 8-month, and annual visits. The effect of sacubitril/valsartan on components of the physical and social limitation sections of the KCCQ at 8 months and longitudinally and related biomarkers and clinical outcomes were studied. At baseline, 7618 of 8399 patients (90.7%) (mean [SD] age, 64 [11] years; 5987 [78.6%] male and 1631 [21.4%] female) completed the initial KCCQ assessment. Patients reported the greatest limitations at baseline in jogging and sexual relationships. Patients receiving sacubitril/valsartan had significantly better adjusted change scores in most physical and social activities at 8 months and during 36 months compared with those receiving enalapril. The largest improvement over enalapril was in household chores (adjusted change score difference, 2.35; 95% CI, 1.19-3.50; P < .001) and sexual relationships (adjusted change score difference, 2.72; 95% CI, 0.97-4.46; P = .002); both persisted through 36 months (overall change score difference, 1.69 [95% CI, 0.78-2.60], P < .001; and 2.36 [95% CI, 1.01-3.71], P = .001, respectively). In patients with heart failure with reduced ejection fraction, sacubitril/valsartan significantly improved nearly all KCCQ physical and social activities compared with enalapril, with the largest responses in household chores and sexual relationships. In addition to reduced likelihood of cardiovascular death, all-cause mortality, and heart failure hospitalization, sacubitril/valsartan may improve limitations in common activities in these patients. clinicaltrials.gov Identifier: NCT01035255.

Antihypertensive effect of barnidipine 10 mg or amlodipine 5 to 10 mg once daily in treatment-naive patients with essential hypertension: A 24-week, randomized, open-label, pilot study

PubMed Central

Rossetti, Giuseppe; Pizzocri, Samuele; Brasca, Francesco; Pozzi, Marta; Beltrami, Laura M.; Bolla, Giovanni B.; Famiani, Roberta; Caimi, Barbara; Omboni, Stefano; Magrini, Fabio; Carugo, Stefano

2008-01-01

Background: Dihydropyridine calcium antagonists are largely employed for the treatment of hypertension, coronary heart disease, and heart failure. Objective: The aim of our study was to compare the antihypertensive effect of the dihydropyridine calcium antagonists barnidipine and amlodipine. Methods: This was a 24-week, randomized, open-label, pilot study. Consecutive treatment-naive patients with grade I or II essential hypertension (office sitting systolic blood pressure [BP] of 140–179 mm Hg and diastolic BP of 90–109 mm Hg) were enrolled. The primary end points were the effect of treatment with either barnidipine 10 mg or amlodipine 5 mg once daily on office and ambulatory BP, left ventricular mass index (LVMI), and markers of cardiac damage, serum procollagen type I C-terminal propeptide, and plasma amino-terminal pro-B-type natriuretic peptide concentrations. Patients were assessed at enrollment, and 12 and 24 weeks. During each visit, the prevalence of adverse events (AEs) was also monitored using spontaneous reporting, patient interview, and physical examination, the relationship to study drug being determined by the investigators. Compliance with treatment was assessed at each study visit by counting returned tablets. Results: Thirty eligible patients (20 men, 10 women; mean [SD] age, 47 [12] years) were included in the study; all patients completed the 24 weeks of study treatment. Twelve weeks after randomization, 6 patients in the amlodipine group had their dose doubled to 10 mg due to inadequate BP control. Mean BP reductions at study end were not significantly different between the barnidipine and amlodipine groups (office BP, −10.3/−9.4 vs −16.6/−9.1 mm Hg; ambulatory BP, 9.4/6.4 vs 8.1/5.1 mm Hg). Reductions in LVMI and markers of cardiac damage were not significantly different between the 2 groups. Significantly more patients in the amlodipine group reported drug-related AEs compared with those in the barnidipine group (9 [60%] vs 2 [13%]; P < 0.05). Conclusion: In this small sample of treatment-naive hypertensive patients, the antihypertensive effect of barnidipine 10 mg once daily was not significantly different from that of amlodipine 5 to 10 mg once daily. PMID:24692798

Sacubitril/valsartan in heart failure: latest evidence and place in therapy

PubMed Central

Kaplinsky, Edgardo

2016-01-01

Despite significant therapeutic advances, patients with chronic heart failure (HF) remain at high risk for HF progression and death. Sacubitril/valsartan (previously known as LCZ696) is a first-in-class medicine that contains a neprilysin (NEP) inhibitor (sacubitril) and an angiotensin II (Ang-II) receptor blocker (valsartan). NEP is an endopeptidase that metabolizes different vasoactive peptides including natriuretic peptides, bradykinin and Ang-II. In consequence, its inhibition increases mainly the levels of both, natriuretic peptides (promoting diuresis, natriuresis and vasodilatation) and Ang-II whose effects are blocked by the angiotensin receptor blocker, valsartan (reducing vasoconstriction and aldosterone release). Results from the 8442 patient PARADIGM-HF study showed in patients with New York Heart Association (NYHA) class II–IV and reduced ejection fraction treated with LCZ696 (versus enalapril), the following benefits: reduction of the risk of death from cardiovascular causes by 20%; reduction of HF hospitalizations by 21%; reduction of the risk of all-cause mortality by 16%. Overall there was a 20% risk reduction on the primary endpoint, composite measure of cardiovascular (CV) death or time to first HF hospitalization. PARADIGM-HF was stopped early after a median follow up of 27 months. Post hoc analyses of PARADIGM-HF as well as the place in therapy of sacubitril/valsartan, including future directions, are included in the present review. PMID:27803793

The association of ACE gene polymorphism with diabetic kidney disease and renoprotective efficacy of valsartan.

PubMed

Wang, Yuying; Peng, Wen; Zhang, Xiaoxue; Qiao, Huibo; Wang, Li; Xu, Zhigang; Wu, Chenguang

2016-07-01

To investigate the associations between the insertion/deletion (I/D) polymorphisms in the angiotensin converting enzyme (ACE) gene and susceptibility to diabetic kidney disease (DKD); and the efficacy of valsartan in reducing the urine protein in Type 2 diabetes mellitus (T2DM) patients. We enrolled 128 T2DM patients in this study, including 54 cases with DKD (DKD+) and 74 controls (DKD-). The ACE polymorphism was assayed by polymerase chain reaction (PCR), and the genotype distribution and allele frequency were analyzed. The DKD+ group was subdivided into the DD, ID and II subgroups, based on their genotypes. In addition, patients with DKD received valsartan treatment for 12 weeks. We determined changes in the urinary albumin to creatinine ratio (ACR) and serum creatinine (SCr). The frequencies of the genotypes DD and ID were higher in the DKD+ than in the DKD- group. The frequency of allele D was higher, and of allele I was lower, in the DKD+ than in DKD- group (p < 0.05). Following valsartan treatment, albuminuria was significantly decreased in subgroups DD and ID (p < 0.05). In T2DM patients, the ACE I/D polymorphism was associated with onset of DKD. Furthermore, the ACE I/D polymorphism influenced the renoprotective response to valsartan: Patients with the DD genotype benefitted the most from this treatment. © The Author(s) 2016.

Cardiac Protection of Valsartan on Juvenile Rats with Heart Failure by Inhibiting Activity of CaMKII via Attenuating Phosphorylation

PubMed Central

Wu, Yao; Si, Feifei; Ji, Xiaojuan; Jiang, Kunfeng; Song, Sijie

2017-01-01

Background. This study was undertaken to determine relative contributions of phosphorylation and oxidation to the increased activity of calcium/calmodulin-stimulated protein kinase II (CaMKII) in juveniles with cardiac myocyte dysfunction due to increased pressure overload. Methods. Juvenile rats underwent abdominal aortic constriction to induce heart failure. Four weeks after surgery, rats were then randomly divided into two groups: one group given valsartan (HF + Val) and the other group given placebo (HF + PBO). Simultaneously, the sham-operated rats were randomly given valsartan (Sham + Val) or placebo (Sham + PBO). After 4 weeks of treatment, Western blot analysis was employed to quantify CaMKII and relative calcium handling proteins (RyR2 and PLN) in all groups. Results. The deteriorated cardiac function was reversed by valsartan treatment. In ventricular muscle cells of group HF + PBO, Thr287 phosphorylation of CaMKII and S2808 phosphorylation of RyR2 and PLN were increased and S16 phosphorylation of PLN was decreased compared to the other groups, while Met281 oxidation was not significantly elevated. In addition, these changes in the expression of calcium handling proteins were ameliorated by valsartan administration. Conclusions. The phosphorylation of Thr286 is associated with the early activation of CaMKII rather than the oxidation of Met281. PMID:28536695

Systemic arterial hypertension secondary to chronic kidney disease in two captive-born large felids.

PubMed

Leclerc, A; Trehiou-Sechi, E; Greunz, E M; Damoiseaux, C; Bouvard, J; Chetboul, V

2017-06-01

Systemic arterial hypertension (SHT) has been widely described in the domestic cat (Felis catus). In these feline patients, SHT is considered as the most common vascular disorder of middle-aged to older animals, and secondary SHT related to chronic kidney disease (CKD) represents the most common form of the disease. We describe here the first two cases of spontaneous SHT in large felids, i.e. one 18-year old, 34.4 kg, male North-Chinese leopard (Panthera pardus japonensis, case #1) and one 20-year old, 28.7 kg, female snow leopard (Panthera uncia, case #2), both captive-bred and previously diagnosed with CKD. Both animals underwent complete echocardiographic examination under general anesthesia due to abnormal cardiac auscultation (heart murmur and/or gallop sound), and recurrent lethargy in case #1. The combination of left ventricular remodeling with moderate aortic regurgitation of high velocity was highly suggestive of SHT, which was confirmed by indirect blood pressure measurement (systolic arterial blood pressure of 183 mmHg for case #1 and 180 mmHg for case #2). Amlodipine was prescribed (0.35-0.70 mg/kg/day orally) for 31 and 6 months respectively after the initial diagnosis. In case #1, concurrent amlodipine and benazepril treatment was associated with decreased heart murmur grade and reduced aortic insufficiency severity. These reports illustrate that, similarly to domestic cats, SHT should be suspected in old large felids with CKD and that amlodipine is a well-tolerated antihypertensive drug in these species. Copyright © 2017 Elsevier B.V. All rights reserved.

In vitro and clinical evaluation of OATP-mediated drug interaction potential of sacubitril/valsartan (LCZ696).

PubMed

Ayalasomayajula, S; Han, Y; Langenickel, T; Malcolm, K; Zhou, W; Hanna, I; Alexander, N; Natrillo, A; Goswami, B; Hinder, M; Sunkara, G

2016-08-01

Sacubitril/valsartan (LCZ696) has been recently approved for the treatment of heart failure (HF) patients with reduced ejection fraction. Several HF patients receive statins as co-medication. Because clearance of statins is meditated via OATP1B1/1B3, the inhibition potential of these transporters by LCZ696 analytes was evaluated in vitro. Furthermore, an open-label, fixed-sequence clinical study was conducted to determine the effect of LCZ696 on the exposure of simvastatin and its active metabolite simvastatin acid. In this clinical study, 26 healthy subjects received simvastatin 40 mg alone or in combination with LCZ696 or after 1 or 2 h of LCZ696 dosing. Although no significant inhibition by LBQ657 (an active metabolite of sacubitril) and valsartan was observed, sacubitril inhibited OATP1B1 and OATP1B3 in vitro, with IC50 of 1·91 and 3·81 μm, respectively. Upon co-administration of simvastatin with LCZ696, the Cmax of simvastatin and simvastatin acid decreased by 7% and 13%, respectively. When administered 1 h after LCZ696 dosing, the corresponding Cmax of simvastatin and simvastatin acid decreased by 16% and 4%, respectively. When administered 2 h after LCZ696 dosing, the Cmax of simvastatin decreased by 33% and that of simvastatin acid increased by 16%. However, no notable changes were observed in the AUCs of simvastatin or simvastatin acid upon co-administration or time-separated administration with LCZ696. No notable impact of simvastatin co-administration was observed on the pharmacokinetics of LCZ696 analytes. LCZ696 and simvastatin were generally well tolerated when administered alone or in combination. Overall, the results of this study suggest that although sacubitril inhibited OATP1B1 and OATP1B3 in vitro, it does not translate into any clinically relevant in vivo effect. © 2016 John Wiley & Sons Ltd.

Long-term efficacy of a combination of amlodipine and olmesartan medoxomil±hydrochlorothiazide in patients with hypertension stratified by age, race and diabetes status: a substudy of the COACH trial

PubMed Central

Oparil, S; Chrysant, S G; Melino, M; Lee, J; Karki, S; Heyrman, R

2010-01-01

A prespecified subgroup analysis of a 44-week open-label extension study is presented. The efficacy and safety of the combination of amlodipine (AML)+ olmesartan medoxomil (OM), with and without the addition of hydrochlorothiazide (HCTZ), were investigated in patients aged ⩾65 and <65 years, Blacks and non-Blacks and patients with and without type 2 diabetes. After an 8-week double-blind, placebo-controlled portion of the study, patients initiated therapy on AML 5+OM 40 mg per day, were uptitrated stepwise to AML 10+OM 40 mg per day, with the addition of HCTZ 12.5 mg, and 25 mg if blood pressure (BP) goal was not achieved (<140/90 or <130/80 mm Hg for patients with diabetes). Endpoints included the change from baseline in mean seated systolic BP, mean seated diastolic BP and achievement of BP goal. BP decreased from baseline for all treatments in each prespecified subgroup. By the end of the study, BP goal was achieved in 61.0% of patients aged ⩾65 years, 68.1% of patients aged <65 years, 63.3% of Blacks, 67.8% of non-Blacks, 26.9% of patients with diabetes and 72.9% of patients without diabetes. The combination of AML+OM±HCTZ was efficacious, safe and well tolerated by these subgroups. PMID:20200547

Amelioration of hypertensive heart failure by amlodipine may occur via antioxidative effects.

PubMed

Hasegawa, Hiroshi; Takano, Hiroyuki; Kohro, Takahide; Ueda, Kazutaka; Niitsuma, Yuriko; Aburatani, Hiroyuki; Komuro, Issei

2006-09-01

Although recent clinical studies have suggested that long-acting calcium channel blockers (CCBs) have beneficial effects on heart failure, the precise mechanism is unknown. In this study, Dahl salt-sensitive rats fed a high salt diet were treated with the long-acting CCB amlodipine, the low-molecular-weight membrane permeable superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol), or saline from 11 weeks after birth. The cardiac geometry and function, and gene expression profiles were determined at 17 weeks. Dahl salt-sensitive rats fed a high salt diet followed by saline as a non-treatment control (HS group) showed a marked increase in blood pressure and developed concentric hypertrophy at 11 weeks, followed by left ventricular (LV) dilation and congestive heart failure by 17 weeks. The treatment with amlodipine (AMLO group) or Tempol (TEMP group) significantly inhibited the development of LV hypertrophy and cardiac dysfunction. Analysis using an Affymetrix GeneChip U34 revealed that the expression levels of 195 genes were changed by the treatment with amlodipine. Among these 195 genes, 110 genes were increased in HS rats and decreased in AMLO rats. And of these 110 genes, 54 genes were also decreased in TEMP rats. In contrast, 85 genes were decreased in HS rats and increased in AMLO rats. Of these 85 genes, 38 genes were also increased in TEMP rats. Approximately 48% of the genes were changed in similar fashion in AMLO and TEMP rats, suggesting that amlodipine shows beneficial effects on heart failure mainly via antioxidative mechanisms.

Losartan vs. amlodipine treatment in elderly oncologic hypertensive patients: a randomized clinical trial.

PubMed

Motta, Massimo; Russo, Cristina; Vacante, Marco; Liardo, Rocco Luca Emanuele; Reitano, Francesca; Cammalleri, Lisa; Costanzo, Mario; Benfatto, Giuseppe; Frazzetto, Paola; Mondati, Enrico; Malaguarnera, Michele; Pennisi, Giovanni

2011-01-01

Elderly neoplastic patients frequently may show hypertension and hyperuricemia, before and after chemotherapeutic treatments. The purpose of this study was to evaluate the efficacy of losartan which is an antihypertensive drug with uricosuric properties vs. amlodipine in hypertensive neoplastic elderly patients. This was an open-labeled, randomized, comparative trial. The study was performed as a 30-day study. Seventy patients with cancer were randomly assigned to receive losartan or amlodipine. Blood pressure (BP), blood urea nitrogen (BUN) levels, creatinine, serum and urinary uric acid, creatinine and uric acid clearance were determined before and after chemotherapy. One day after chemotherapy in losartan group vs. amlodipine group we observed a significant difference in urinary uric acid (p<0.001) of 18 mg/24 h vs. 40 mg/24 h. Thirty days after chemotherapy we observed a significant difference in azotemia of 0.0 mg/dl vs. 3.8 mg/dl (p<0.001), serum uric acid of 0.05 mg/dl vs. 0.49 mg/dl (p<0.001), urinary uric acid (p<0.001) of 23 mg/24 h vs. 0.0 mg/24 h, GFR of 2 ml/min/1.73 m(2) vs. -8 ml/min/1.73 m(2) (p<0.05) and systolic BP (SBP) of 3.6 mmHg vs. 0.8 mmHg (p<0.05). The findings of the present study support the effective role of losartan compared to amlodipine in treating hypertension and hyperuricemia in elderly patients under chemotherapeutic treatment. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Development and validation of different methods manipulating zero order and first order spectra for determination of the partially overlapped mixture benazepril and amlodipine: A comparative study

NASA Astrophysics Data System (ADS)

Hemdan, A.

2016-07-01

Three simple, selective, and accurate spectrophotometric methods have been developed and then validated for the analysis of Benazepril (BENZ) and Amlodipine (AML) in bulk powder and pharmaceutical dosage form. The first method is the absorption factor (AF) for zero order and amplitude factor (P-F) for first order spectrum, where both BENZ and AML can be measured from their resolved zero order spectra at 238 nm or from their first order spectra at 253 nm. The second method is the constant multiplication coupled with constant subtraction (CM-CS) for zero order and successive derivative subtraction-constant multiplication (SDS-CM) for first order spectrum, where both BENZ and AML can be measured from their resolved zero order spectra at 240 nm and 238 nm, respectively, or from their first order spectra at 214 nm and 253 nm for Benazepril and Amlodipine respectively. The third method is the novel constant multiplication coupled with derivative zero crossing (CM-DZC) which is a stability indicating assay method for determination of Benazepril and Amlodipine in presence of the main degradation product of Benazepril which is Benazeprilate (BENZT). The three methods were validated as per the ICH guidelines and the standard curves were found to be linear in the range of 5-60 μg/mL for Benazepril and 5-30 for Amlodipine, with well accepted mean correlation coefficient for each analyte. The intra-day and inter-day precision and accuracy results were well within the acceptable limits.

Development and validation of different methods manipulating zero order and first order spectra for determination of the partially overlapped mixture benazepril and amlodipine: A comparative study.

PubMed

Hemdan, A

2016-07-05

Three simple, selective, and accurate spectrophotometric methods have been developed and then validated for the analysis of Benazepril (BENZ) and Amlodipine (AML) in bulk powder and pharmaceutical dosage form. The first method is the absorption factor (AF) for zero order and amplitude factor (P-F) for first order spectrum, where both BENZ and AML can be measured from their resolved zero order spectra at 238nm or from their first order spectra at 253nm. The second method is the constant multiplication coupled with constant subtraction (CM-CS) for zero order and successive derivative subtraction-constant multiplication (SDS-CM) for first order spectrum, where both BENZ and AML can be measured from their resolved zero order spectra at 240nm and 238nm, respectively, or from their first order spectra at 214nm and 253nm for Benazepril and Amlodipine respectively. The third method is the novel constant multiplication coupled with derivative zero crossing (CM-DZC) which is a stability indicating assay method for determination of Benazepril and Amlodipine in presence of the main degradation product of Benazepril which is Benazeprilate (BENZT). The three methods were validated as per the ICH guidelines and the standard curves were found to be linear in the range of 5-60μg/mL for Benazepril and 5-30 for Amlodipine, with well accepted mean correlation coefficient for each analyte. The intra-day and inter-day precision and accuracy results were well within the acceptable limits. Copyright © 2016 Elsevier B.V. All rights reserved.

A study of the action of amlodipine on adrenergically regulated sodium handling by the kidney in normotensive and hypertensive rats.

PubMed Central

Johns, E. J.

1988-01-01

1. An investigation was undertaken to examine the effect of calcium channel blockade, induced by amlodipine, on the ability of the renal sympathetic nerves to cause an antidiuresis and anti-natriuresis in normotensive Sprague Dawley and spontaneously hypertensive rats anaesthetized with pentobarbitone. 2. Low frequency renal nerve stimulation in normotensive rats, which did not change renal blood flow, caused a 15% reduction in glomerular filtration rate and was associated with falls in urine flow of 37%, absolute sodium excretion of 47%, and fractional sodium excretion of 38%. The magnitude of these renal excretory changes was unaffected by prior administration of amlodipine at either 200 micrograms kg-1 plus 50 micrograms kg-1 h-1 or 400 micrograms kg-1 plus 100 micrograms kg-1 h-1. Amlodipine given in the higher dose, decreased basal levels of blood pressure and increased basal urine flow and sodium excretion. 3. In spontaneously hypertensive rats, renal nerve stimulation minimally affected renal haemodynamics but decreased urine flow, absolute and fractional sodium excretion by 29%, 31% and 24%, respectively. 4. Similar renal nerve stimulation in spontaneously hypertensive rats given amlodipine at 200 micrograms kg-1 plus 50 micrograms kg-1 h-1 or 400 micrograms kg-1 plus 100 micrograms kg-1 h-1 caused minimal changes in renal haemodynamics and in the excretion of water and sodium. The higher dose of drug resulted in decreased blood pressure and increased basal rates of urine flow and sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2967097

The bone morphogenic protein inhibitor, noggin, reduces glycemia and vascular inflammation in db/db mice

PubMed Central

Koga, Mitsuhisa; Engberding, Niels; Dikalova, Anna E.; Chang, Kyung Hwa; Seidel-Rogol, Bonnie; Long, James S.; Lassègue, Bernard; Jo, Hanjoong

2013-01-01

Vascular diseases frequently accompany diabetes mellitus. Based on the current understanding of atherosclerosis as an inflammatory disorder of the vascular wall, it has been speculated that diabetes may accelerate atherosclerosis by inducing a proinflammatory milieu in the vasculature. ANG II and bone morphogenic proteins (BMPs) have been implicated in vascular inflammation. We evaluated the effect of angiotensin receptor blockade by valsartan and BMP inhibition by noggin on markers of vascular inflammation in a mouse model of diabetes. Noggin had no effect on blood pressure but decreased serum glucose levels, whereas valsartan significantly decreased blood pressure, but not serum glucose. Both inhibitors reduced reactive oxygen species production in the aorta. Additionally, noggin and valsartan diminish gene transcription and protein expression of various inflammatory molecules in the vascular wall. These observations indicate that although both inhibitors block superoxide production and have similar effects on inflammatory gene expression, glycemia and blood pressure may represent a secondary target differentially affected by noggin and valsartan. Our data clearly identify the BMP pathway as a potentially potent therapeutic target in diabetic inflammatory vascular disease. PMID:23812391

Simultaneous Analysis of Losartan Potassium, Amlodipine Besylate, and Hydrochlorothiazide in Bulk and in Tablets by High-Performance Thin Layer Chromatography with UV-Absorption Densitometry

PubMed Central

Santhana Lakshmi, Karunanidhi; Lakshmi, Sivasubramanian

2012-01-01

A Simple high-performance thin layer chromatography (HPTLC) method for separation and quantitative analysis of losartan potassium, amlodipine, and hydrochlorothiazide in bulk and in pharmaceutical formulations has been established and validated. After extraction with methanol, sample and standard solutions were applied to silica gel plates and developed with chloroform : methanol : acetone : formic acid 7.5 : 1.3 : 0.5 : 0.03 (v/v/v/v) as mobile phase. Zones were scanned densitometrically at 254 nm. The R f values of amlodipine besylate, hydrochlorothiazide, and losartan potassium were 0.35, 0.57, and 0.74, respectively. Calibration plots were linear in the ranges 500–3000 ng per spot for losartan potassium, amlodipine and hydrochlorothiazide, the correlation coefficients, r, were 0.998, 0.998, and 0.999, respectively. The suitability of this method for quantitative determination of these compounds was by validation in accordance with the requirements of pharmaceutical regulatory standards. The method can be used for routine analysis of these drugs in bulk and in formulation. PMID:22567550

Influence of betel quid on effect of calcium channel blockers on isoprenaline induced myocardial necrosis in mice.

PubMed

Kumar, Vinod; Asdaq, Syed Mohammed Basheeruddin; Asad, Mohammed

2009-09-01

It is known that chewing Betel quid with tobacco (BQT) or without tobacco (BQ) is a major etiological factor for cardiovascular complications and calcium channel blockers (CCBs) are the major class of drugs prescribed widely for myocardial disturbances. The possible pharmacodynamic interaction between CCBs (verapamil, amlodipine and diltiazem) and BQ/BQT was studied on isoproterenol (ISO)-induced myocardial necrosis in mice. Influence of (CCBs) therapy on pretreated animals at times of myocardial stress were determined by estimating diagnostic marker enzymes such as lactate dehydrogenase (LDH) and creatine phosphokinase isoenzyme (CK-MB) in serum and heart tissue homogenate (HTH). Administration of CCBs to mice pretreated with BQ produced a significant decrease and increase in biomarker enzyme levels in serum and HTH respectively. Further, incorporation of diltiazem and amlodipine in BQT pretreated mice significantly elevated enzyme levels in HTH, whereas, amlodipine administration during BQT treatment showed significant fall in enzyme levels in serum. The results indicated that BQT is cardiotoxic and its effect cannot be reversed using CCBs while BQ is cardioprotective, whose activity was further augmented by amlodipine. Histopathological studies confirmed the biochemical findings.

Ultrasound evaluation of valsartan therapy for renal cortical perfusion.

PubMed

Kishimoto, Noriko; Mori, Yasukiyo; Nishiue, Takashi; Nose, Atsuko; Kijima, Yasuaki; Tokoro, Toshiko; Yamahara, Hideki; Okigaki, Mitsuhiko; Kosaki, Atsushi; Iwasaka, Toshiji

2004-05-01

An increase in renal blood flow with a concomitant decrease in filtration fraction at the onset of angiotensin II receptor blocker treatment has been shown to predict a long-term renoprotective effect. However, no studies are available regarding angiotensin receptor blocker-induced changes in renal cortical perfusion observed in the clinical setting. We have recently developed a convenient method of evaluating human renal cortical blood flow with contrast-enhanced harmonic ultrasonography. The goal of this study was to use this method to examine the effect of valsartan, an angiotensin II receptor blocker, on renal cortical perfusion. We performed intermittent second harmonic imaging with venous infusion of a microbubble contrast agent in 7 healthy volunteers. Contrast-enhanced harmonic ultrasonography performed after oral administration of valsartan (80mg) showed a significant increase in microbubble velocity, which correlated well with the increase in total renal blood flow determined by p-aminohippurate clearance (r=0.950, p < 0.001). Although fractional vascular volume was not significantly increased, alterations in renal cortical blood flow calculated by the product of microbubble velocity and fractional volume were also correlated with the change in total renal blood flow (r=0.756, p < 0.05). These results indicate that valsartan increases the renal cortical blood flow in normal kidneys, mainly by increasing blood flow velocity. Contrast-enhanced harmonic ultrasonography is a promising technique for evaluating the precise effect on renal cortical perfusion and optimal dose of valsartan in diseased kidneys.

The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan

PubMed Central

Jhund, Pardeep S; McMurray, John J V

2016-01-01

Inhibition of neurohumoural pathways such as the renin angiotensin aldosterone and sympathetic nervous systems is central to the understanding and treatment of heart failure (HF). Conversely, until recently, potentially beneficial augmentation of neurohumoural systems such as the natriuretic peptides has had limited therapeutic success. Administration of synthetic natriuretic peptides has not improved outcomes in acute HF but modulation of the natriuretic system through inhibition of the enzyme that degrades natriuretic (and other vasoactive) peptides, neprilysin, has proven to be successful. After initial failures with neprilysin inhibition alone or dual neprilysin-angiotensin converting enzyme (ACE) inhibition, the Prospective comparison of angiotensin receptor neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) trial demonstrated that morbidity and mortality can be improved with the angiotensin receptor blocker neprilysin inhibitor sacubitril/valsartan (formerly LCZ696). In comparison to the ACE inhibitor enalapril, sacubitril/valsartan reduced the occurrence of the primary end point (cardiovascular death or hospitalisation for HF) by 20% with a 16% reduction in all-cause mortality. These findings suggest that sacubitril/valsartan should replace an ACE inhibitor or angiotensin receptor blocker as the foundation of treatment of symptomatic patients (NYHA II–IV) with HF and a reduced ejection fraction. This review will explore the background to neprilysin inhibition in HF, the results of the PARADIGM-HF trial and offer guidance on how to use sacubitril/valsartan in clinical practice. PMID:27207980

Cardioprotective effect of valsartan in mice with short-term high-salt diet by regulating cardiac aquaporin 1 and angiogenic factor expression.

PubMed

Jiang, Yong; Wang, Hui-Yan; Zheng, Sheng; Mu, Shang-Qiang; Ma, Meng-Ni; Xie, Xin; Zhang, Yang-Yang; Zhang, Chun-Xue; Cai, Jian-Hui

2015-01-01

Hypertension is the most common risk factor for various cardiovascular and cerebrovascular diseases that affects approximately 61 million, or 25% of the population in United States. The dietary salt intake is one of the most important but modifiable factors for hypertension. In the current study, we aim to elucidate the role of aquaporin 1 in high-salt-induced hypertension and cardiac injuries and whether angiotensin II receptor blocker valsartan could ameliorate the effect of high salt on blood pressure. Mice were fed with normal diet, high-salt diet in the presence or absence of valsartan for 4 weeks. The body weight gain, feeding behavior, blood pressure, and cardiac pathology changes were monitored after 4 weeks. The expression of aquaporin 1, vascular endothelial growth factor, transforming growth factor β1, and basic fibroblast growth factor were analyzed using quantitative real-time polymerase chain reaction, Western blot, and immunohistochemical staining. Valsartan partially reversed the effects of high-salt diet on hypertension, cardiac injuries such as fibrosis and inflammatory cell infiltration, and inhibition of aquaporin 1 and angiogenic factors; valsartan alone did not exert such effects. The current data demonstrated that the reduction of cardiac aquaporin 1 and angiogenic factor expression level might be associated with high-salt-induced hypertension and cardiac injuries in mice, which could be ameliorated by angiotensin II receptor blocker treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Development of self-nanoemulsifying drug delivery system for oral bioavailability enhancement of valsartan in beagle dogs.

PubMed

Li, Zhenbao; Zhang, Wenjuan; Gao, Yan; Xiang, Rongwu; Liu, Yan; Hu, Mingming; Zhou, Mei; Liu, Xiaohong; Wang, Yongjun; He, Zhonggui; Sun, Yinghua; Sun, Jin

2017-02-01

Valsartan, an angiotensin II receptor antagonist, is widely used to treat high blood pressure in the clinical setting. However, its poor water solubility results in the low oral bioavailability. The aim of this study was to improve dissolution rate and oral bioavailability by developing a self-nanoemulsifying drug delivery system. Saturation solubility of valsartan in various oils, surfactants, and cosurfactants was investigated, and the optimized formulation was determined by central composite design-response surface methodology. The shape of resultant VAL-SNEDDS was spherical with an average diameter of about 27 nm. And the drug loading efficiency is approximately 14 wt%. Differential scanning calorimetry and XRD studies disclosed the molecular or amorphous state of valsartan in VAL-SNEDDS. The dissolution study indicated that the self-nanoemulsifying drug delivery systems (SNEDDS) exhibited significantly enhanced dissolution compared with market capsules (Diovan®) in various media. Furthermore, the stability of formulation revealed that valsartan SNEDDS was stable under low temperature and accelerated test condition. Furthermore, the pharmacokinetics demonstrated that C max and AUC (0-∞) of SNEDDS capsules were about three- and twofold higher than Diovan® in beagle dogs, respectively. Meanwhile, the safety evaluation implied that VAL-SNEDDS was innocuous to beagle dogs during 15 days of continuous administration. Our results suggested that VAL-SNEDDS was a potential and safe delivery system with enhanced dissolution rate and oral bioavailability, as well as offered a strategy for the engineering of poorly water-soluble drugs in the clinical setting.

Neprilysin inhibition: a brief review of past pharmacological strategies for heart failure treatment and future directions

PubMed Central

Howell, Erik H.; Cameron, Scott J.

2016-01-01

Heart failure (HF) is a manifestation of aberrant vascular responses and remains a public health concern with a worldwide prevalence of around 23 million and a 5-year mortality numerically equivalent to many cancers. Over the last two decades, mortality from HF reached a plateau with current pharmaceutical agents and mechanical cardiac support. In the last several years, various “novel” pharmaceutical agents have been tested in clinical trials and ultimately met with disappointment, showing only incremental benefit in the treatment of HF. Designing a HF drug with enhanced efficacy over existing agents seemed like a Sisyphean task. Yet again, pharmaceutical chemists have demonstrated their prowess in lateral thinking by developing a vasoactive agent which is a co-crystallized compound of valsartan and sacubitril in a one-to-one molar ratio; the former molecule belongs to a family of agents that are the current standard of care for HF and the latter molecule is a novel agent which inhibits neprilysin — a neutral endopeptidase found in human plasma which alters neurohumoral responses. In July of 2015, a drug which is a combination of valsartan and sacubitril was formally licensed by the United States Food and Drug Administration for the treatment of HF. This review describes the evolution of HF medications focusing on rational drug design with the first HF medication, the beta adrenergic receptor antagonist. We then discuss the biochemical and physiological properties of sacubitril/valsartan which likely lead to its dramatic ability to ameliorate HF mortality. PMID:27665860

Melt dispersion granules: formulation and evaluation to improve oral delivery of poorly soluble drugs - a case study with valsartan.

PubMed

Chella, Naveen; Tadikonda, Ramarao

2015-06-01

Solid dispersion (SD) technique is a promising strategy to improve the solubility and dissolution of BCS class II drugs. However, only few products are marketed till today based on SD technology due to poor flow properties and stability. The present work was intended to solve these problems by using combination approach, melt dispersion and surface adsorption technologies. The main aim of the present work is to improve the absorption in the stomach (at lower pH) where the absorption window exists for the drug by improving the dissolution, resulting in the enhancement of oral bioavailability of poorly soluble, weakly acidic drug with pH dependant solubility, i.e. valsartan. Melt dispersion granules were prepared in different ratios using different carriers (Gelucire 50/13, PEG 8000 and Pluronic F-68) and lactose as an adsorbent. Similarly, physical mixtures were also prepared at corresponding ratios. The prepared dispersion granules and physical mixtures were characterized by FTIR, DSC and in vitro dissolution studies. DSC studies revealed reduction in the crystallinity with a possibility of presence of amorphous character of drug in the dispersion granules. From dissolution studies, valsartan Gelucire dispersion (GSD4; 1:4 ratio) showed complete drug release in 30 min against the plain drug which showed only 11.31% of drug release in 30 min. Pharmacokinetic studies of optimized formulation in male Wistar rats showed 2.65-fold higher bioavailability and 1.47-fold higher Cmax compared to pure drug. The melt dispersion technology has the potential to improve dissolution and the bioavailability of BCS class II drugs.

Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction.

PubMed

McMurray, John J V; Trueman, David; Hancock, Elizabeth; Cowie, Martin R; Briggs, Andrew; Taylor, Matthew; Mumby-Croft, Juliet; Woodcock, Fionn; Lacey, Michael; Haroun, Rola; Deschaseaux, Celine

2018-06-01

Chronic heart failure with reduced ejection fraction (HF-REF) represents a major public health issue and is associated with considerable morbidity and mortality. We evaluated the cost-effectiveness of sacubitril/valsartan (formerly LCZ696) compared with an ACE inhibitor (ACEI) (enalapril) in the treatment of HF-REF from the perspective of healthcare providers in the UK, Denmark and Colombia. A cost-utility analysis was performed based on data from a multinational, Phase III randomised controlled trial. A decision-analytic model was developed based on a series of regression models, which extrapolated health-related quality of life, hospitalisation rates and survival over a lifetime horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER). In the UK, the cost per quality-adjusted life-year (QALY) gained for sacubitril/valsartan (using cardiovascular mortality) was £17 100 (€20 400) versus enalapril. In Denmark, the ICER for sacubitril/valsartan was Kr 174 000 (€22 600). In Colombia, the ICER was COP$39.5 million (€11 200) per QALY gained. Deterministic sensitivity analysis showed that results were most sensitive to the extrapolation of mortality, duration of treatment effect and time horizon, but were robust to other structural changes, with most scenarios associated with ICERs below the willingness-to-pay threshold for all three country settings. Probabilistic sensitivity analysis suggested the probability that sacubitril/valsartan was cost-effective at conventional willingness-to-pay thresholds was 68%-94% in the UK, 84% in Denmark and 95% in Colombia. Our analysis suggests that, in all three countries, sacubitril/valsartan is likely to be cost-effective compared with an ACEI (the current standard of care) in patients with HF-REF. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Rationale and design of TRANSITION: a randomized trial of pre‐discharge vs. post‐discharge initiation of sacubitril/valsartan

PubMed Central

Wachter, Rolf; Senni, Michele; Belohlavek, Jan; Noè, Adele; Carr, David; Butylin, Dmytro

2017-01-01

Abstract Aims The prognosis after hospitalization for acute decompensated heart failure (ADHF) remains poor, especially <30 days post‐discharge. Evidence‐based medications with prognostic impact administered at discharge improve survival and hospital readmission, but robust studies comparing pre‐discharge with post‐discharge initiation are rare. The PARADIGM‐HF trial established sacubitril/valsartan as a new evidence‐based therapy in patients with heart failure (HF) and reduced left ventricular ejection fraction (<40%) (rEF). In common with other landmark studies, it enrolled patients who were ambulatory at the time of inclusion. In addition, there is also still limited knowledge of initiation and up‐titration of sacubitril/valsartan in ACEi/ARB‐ naïve patients and in de novo HF with rEF patients. Methods and results TRANSITION is a multicentre, open‐label study in which ~1000 adults hospitalized for ADHF with rEF are randomized to start sacubitril/valsartan in a pre‐discharge arm (initiated ≥24 h after haemodynamic stabilization) or a post‐discharge arm (initiated within Days 1–14 after discharge). The protocol allows investigators to select the appropriate starting dose and dose adjustments according to clinical circumstances. Over a 10 week treatment period, the primary and secondary objectives assess the feasibility and safety of starting sacubitril/valsartan in‐hospital, early after haemodynamic stabilization. Exploratory objectives also include assessment of HF signs and symptoms, readmissions, N‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity troponin T levels, and health resource utilization parameters. Conclusions TRANSITION will provide new evidence about initiating sacubitril/valsartan following hospitalization for ADHF, occurring either as de novo ADHF or as deterioration of chronic HF, and in patients with or without prior ACEI/ARB therapy. The results of TRANSITION will thus be highly relevant to the management of patients hospitalized for ADHF with rEF. PMID:29239515

Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives

PubMed Central

Yandrapalli, Srikanth; Andries, Gabriela; Biswas, Medha; Khera, Sahil

2017-01-01

With an estimated prevalence of 5.8 million in the USA and over 23 million people worldwide, heart failure (HF) is growing in epidemic proportions. Despite the use of guideline-directed medical therapies such as angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists for chronic systolic HF for almost two decades, HF remains a leading cause of morbidity, mortality, and health care expenditures. The Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial provided compelling evidence for the cardiovascular and mortality benefit of sacubitril/valsartan when compared to enalapril in patients with heart failure and reduced ejection fraction (HFrEF). Sacubitril/valsartan performed better than enalapril across various HFrEF patient characteristics and showed substantial benefit in patients with other common comorbidities. Following the trial, the US Food and Drug Administration approved this drug for the treatment of HF. Various international HF consensus guidelines endorse sacubitril/valsartan as a class I recommendation for the management of symptomatic HFrEF. Although this high-quality clinical study is the largest and the most globally represented trial in HFrEF patients, concerns have been raised regarding the generalizability of the trial results in real-world HF population. The gaps in US Food and Drug Administration labeling and guideline recommendations might lead to this medication being used in a larger population than it was studied in. In this review, we will discuss the current role of sacubitril/valsartan in the management of HF, concerns related to PARADIGM-HF and answers, shortcomings of this novel drug, effects on patient characteristics, real-world eligibility, and the role of ongoing and further investigations to clarify the profile of sacubitril/valsartan in the management of HF. PMID:29042791

Rationale and design of TRANSITION: a randomized trial of pre-discharge vs. post-discharge initiation of sacubitril/valsartan.

PubMed

Pascual-Figal, Domingo; Wachter, Rolf; Senni, Michele; Belohlavek, Jan; Noè, Adele; Carr, David; Butylin, Dmytro

2018-04-01

The prognosis after hospitalization for acute decompensated heart failure (ADHF) remains poor, especially <30 days post-discharge. Evidence-based medications with prognostic impact administered at discharge improve survival and hospital readmission, but robust studies comparing pre-discharge with post-discharge initiation are rare. The PARADIGM-HF trial established sacubitril/valsartan as a new evidence-based therapy in patients with heart failure (HF) and reduced left ventricular ejection fraction (<40%) (rEF). In common with other landmark studies, it enrolled patients who were ambulatory at the time of inclusion. In addition, there is also still limited knowledge of initiation and up-titration of sacubitril/valsartan in ACEi/ARB- naïve patients and in de novo HF with rEF patients. TRANSITION is a multicentre, open-label study in which ~1000 adults hospitalized for ADHF with rEF are randomized to start sacubitril/valsartan in a pre-discharge arm (initiated ≥24 h after haemodynamic stabilization) or a post-discharge arm (initiated within Days 1-14 after discharge). The protocol allows investigators to select the appropriate starting dose and dose adjustments according to clinical circumstances. Over a 10 week treatment period, the primary and secondary objectives assess the feasibility and safety of starting sacubitril/valsartan in-hospital, early after haemodynamic stabilization. Exploratory objectives also include assessment of HF signs and symptoms, readmissions, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T levels, and health resource utilization parameters. TRANSITION will provide new evidence about initiating sacubitril/valsartan following hospitalization for ADHF, occurring either as de novo ADHF or as deterioration of chronic HF, and in patients with or without prior ACEI/ARB therapy. The results of TRANSITION will thus be highly relevant to the management of patients hospitalized for ADHF with rEF. © 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives.

PubMed

Yandrapalli, Srikanth; Andries, Gabriela; Biswas, Medha; Khera, Sahil

2017-01-01

With an estimated prevalence of 5.8 million in the USA and over 23 million people worldwide, heart failure (HF) is growing in epidemic proportions. Despite the use of guideline-directed medical therapies such as angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists for chronic systolic HF for almost two decades, HF remains a leading cause of morbidity, mortality, and health care expenditures. The Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial provided compelling evidence for the cardiovascular and mortality benefit of sacubitril/valsartan when compared to enalapril in patients with heart failure and reduced ejection fraction (HFrEF). Sacubitril/valsartan performed better than enalapril across various HFrEF patient characteristics and showed substantial benefit in patients with other common comorbidities. Following the trial, the US Food and Drug Administration approved this drug for the treatment of HF. Various international HF consensus guidelines endorse sacubitril/valsartan as a class I recommendation for the management of symptomatic HFrEF. Although this high-quality clinical study is the largest and the most globally represented trial in HFrEF patients, concerns have been raised regarding the generalizability of the trial results in real-world HF population. The gaps in US Food and Drug Administration labeling and guideline recommendations might lead to this medication being used in a larger population than it was studied in. In this review, we will discuss the current role of sacubitril/valsartan in the management of HF, concerns related to PARADIGM-HF and answers, shortcomings of this novel drug, effects on patient characteristics, real-world eligibility, and the role of ongoing and further investigations to clarify the profile of sacubitril/valsartan in the management of HF.

Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects.

PubMed

Han, Yi; Ayalasomayajula, Surya; Pan, Wei; Yang, Fan; Yuan, Yaozong; Langenickel, Thomas; Hinder, Markus; Kalluri, Sampath; Pal, Parasar; Sunkara, Gangadhar

2017-02-01

Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max ) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2 ) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC 0-last ), and maximum plasma concentration (C max ) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

Valsartan ameliorates podocyte loss in diabetic mice through the Notch pathway.

PubMed

Gao, Feng; Yao, Min; Cao, Yanping; Liu, Shuxia; Liu, Qingjuan; Duan, Huijun

2016-05-01

The Notch pathway is known to be linked to diabetic nephropathy (DN); however, its underlying mechanism was poorly understood. In the present study, we examined the effect of Valsartan, an angiotensin II type 1 receptor antagonist, on the Notch pathway and podocyte loss in DN. Diabetes was induced in mice by an intraperitoneal injection of streptozotocin and and this was followed by treatment with Valsartan. Levels of blood glucose, kidney weight and body weight, as well as proteinuria were measured. Samples of the kidneys were also histologically examined. The relative levels of Jagged1, Notch1, Notch intracellular domain 1 (NICD1), Hes family BHLH transcription factor 1 (Hes1) and Hes-related family BHLH transcription factor with YRPW motif 1 expression (Hey1) in the glomeruli were determined by immunohistochemical analysis, western blot analysis and RT-qPCR. The B-Cell CLL/Lymphoma 2 (Bcl-2) and p53 pathways were examined by western blot analysis. Apoptosis and detachment of podocytes from the glomerular basement membrane were examined using a TUNEL assay, flow cytometric analysis and ELISA. The number of podocytes was quantified by measuring Wilms tumor-1 (WT-1) staining. We noted that the expression of Jagged1, Notch1, NICD1, Hes1 and Hey1 was increased in a time-dependent manner in the glomeruli of mice with streptozotocin (STZ)-induced diabetes. Moreover, in diabetic mice, Valsartan significantly reduced kidney weight and proteinuria, and mitigated the pathogenic processes in the kidneys. Valsartan also inhibited the activation of Notch, Bcl-2 and p53 pathways and ameliorated podocyte loss in the glomeruli of mice with STZ-induced diabetes. Taken together, these findings indicated that Valsartan exerted a beneficial effect on reducing podocyte loss, which is associated with inhibition of Notch pathway activation in the glomeruli of diabetic mice.

Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial.

PubMed

Solomon, Scott D; Claggett, Brian; Desai, Akshay S; Packer, Milton; Zile, Michael; Swedberg, Karl; Rouleau, Jean L; Shi, Victor C; Starling, Randall C; Kozan, Ömer; Dukat, Andrej; Lefkowitz, Martin P; McMurray, John J V

2016-03-01

The angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and reduced ejection fraction (EF) in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. We evaluated the influence of EF on clinical outcomes and on the effectiveness of sacubitril/valsartan compared with enalapril. Eight thousand three hundred ninety-nine patients with New York Heart Association class II to IV HF with reduced EF [left ventricular EF (LVEF) ≤40%] were randomized to sacubitril/valsartan 97/103 mg twice daily versus enalapril 10 mg twice daily and followed for a median of 27 months. The primary study end point was cardiovascular death or HF hospitalization. LVEF was assessed at the sites and recorded on case report forms. We related LVEF to study outcomes and assessed the effectiveness of sacubitril/valsartan across the LVEF spectrum. The mean LVEF in PARADIGM-HF, reported by sites, was 29.5 (interquartile range, 25-34). The risk of all outcomes increased with decreasing LVEF. Each 5-point reduction in LVEF was associated with a 9% increased risk of cardiovascular death or HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.05-1.13; P<0.001), a 9% increased risk for CV death (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14), a 9% increased risk in HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14) and a 7% increased risk in all-cause mortality (hazard ratio, 1.07; 95% confidence interval, 1.03-1.12) in adjusted analyses. Sacubitril/valsartan was effective across the LVEF spectrum, with no evidence of heterogeneity, when modeled either in tertiles (P interaction=0.87) or continuously (P interaction=0.95). In patients with HF and reduced EF enrolled in PARADIGM-HF, LVEF was a significant and independent predictor of all outcomes. Sacubitril/valsartan was effective at reducing cardiovascular death and HF hospitalization throughout the LVEF spectrum. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255. © 2016 American Heart Association, Inc.

Comparison of Plasma Levels of Renin, Vasopressin and Atrial Natriuretic Peptide in Hypertensive Amlodipine Induced Pedal Oedema, Non-Oedema and Cilnidipine Treated Patients

PubMed Central

Shetty, Kiran; Rao, Pragna; Ballal, Mamatha; Kiran, Amruth; Reddy, Sravan; Pai, Umesh; Samanth, Jyothi

2017-01-01

Introduction Amlodipine is a third generation dihydropyridine group of calcium channel blocker and having an excellent antihypertensive profile. Pedal Oedema (PE) is the major drawback of amlodipine therapy and the incidence of Amlodipine Induced Pedal Oedema (AIPE) has been found significantly high. Several neurohumoral factors influence the incidence of oedema. Aim We aimed to compare the plasma levels of renin, vasopressin and atrial natriuretic peptide in hypertensive AIPE, non-oedema and cilnidipine treated patients. Materials and Methods The present prospective, interventional study was conducted on 104 mild to moderate hypertensive patients (52 patients in each group), after due consideration of eligibility criteria. Plasma Renin (PR), Vasopressin (VAS), and the Atrial Natriuretic Peptide (ANP) was estimated by ELISA test and compared between the AIPE, Amlodipine Treated Non-Oedema (ATNE) in Phase I, and AIPE and Cilnidipine Treated (CT) Groups in Phase II. Results The clinical and demographic parameters were matched. PR was significantly high in AIPE group than the ATNE, and it was significantly reduced after one month follow up with the substitution of cilnidipine. The median (IQR) value of PR was 4.87 (3.58, 6.63), 3.50 (1.44, 5.47) and 2.66 (1.02, 5.66) ng/ml in AIPE, ATNE, CT group respectively. VAS was significantly high in AIPE group than ATNE, and it significantly reduced after one month follow up with CT group. The median (IQR) value of vasopressin was 6.78 (2.55, 9.16), 2.58 (1.61, 5.73) and 2.50 (1.23, 5.00) ng/ml in AIPE, ATNE and CT groups respectively. There was no significant difference seen in plasma ANP levels between the groups. The p-value was <0.05 which is statistically significant. Conclusion The AIPE may not be volume overload or fluid retention; it may be due to persistent raise in adrenergic activity followed chronic amlodipine therapy. Cilnidipine relatively suppresses the sympathetic activity, and completely resolves the AIPE by significantly reducing PR and VAS levels. ANP did not show a difference between groups. Cilnidipine is the suitable alternative antihypertensive drug for AIPE patients. PMID:28764190

Losartan improves resistance artery lesions and prevents CTGF and TGF-beta production in mild hypertensive patients.

PubMed

Gómez-Garre, D; Martín-Ventura, J L; Granados, R; Sancho, T; Torres, R; Ruano, M; García-Puig, J; Egido, J

2006-04-01

Although structural and functional changes of resistance arteries have been proposed to participate in arterial hypertension (HTA) outcome, not all therapies may correct these alterations, even if they normalize the blood pressure (BP). The aim of this study was to investigate the mechanisms of the protection afforded by the angiotensin receptor antagonist losartan in resistance arteries from patients with essential HTA. In all, 22 untreated hypertensive patients were randomized to receive losartan or amlodipine for 1 year and the morphological characteristics of resistance vessels from subcutaneous biopsies were evaluated. Protein expression of connective tissue growth factor (CTGF), transforming growth factor beta (TGF-beta), and collagens III and IV was detected by immunohistochemistry. In comparison with normotensive subjects, resistance arteries from hypertensive patients showed a significant media:lumen (M/L) ratio increment and a higher protein expression of CTGF, TGF-beta, and collagens. After 1 year of treatment, both losartan and amlodipine similarly controlled BP. However, M/L only decreased in patients under losartan treatment, whereas in the amlodipine-treated group this ratio continued to increase significantly. The administration of losartan prevented significant increments in CTGF, TGF-beta, and collagens in resistance arteries. By contrast, amlodipine-treated patients showed a higher vascular CTGF, TGF-beta, and collagen IV staining than before treatment. Our results show that the administration of losartan, but not amlodipine, to hypertensive patients improves structural abnormalities and prevents the production of CTGF and TGF-beta in small arteries, despite similar BP lowering. These data may explain the molecular mechanisms of the better vascular protection afforded by drugs interfering with the renin-angiotensin system.

Direct renin inhibition modulates insulin resistance in caveolin-1-deficient mice

PubMed Central

Chuengsamarn, Somlak; Garza, Amanda E.; Krug, Alexander W.; Romero, Jose R.; Adler, Gail K.; Williams, Gordon H.; Pojoga, Luminita H.

2012-01-01

Objective To test the hypothesis that aliskiren improves the metabolic phenotype in a genetic mouse model of the metabolic syndrome (the caveolin-1 knock out (KO) mouse). Materials/Methods Eleven-week-old cav-1 KO and genetically matched wild-type (WT) mice were randomized to three treatment groups: placebo (n = 8/group), amlodipine (6 mg/kg/day, n = 18/ group), and aliskiren (50 mg/kg/day, n = 18/ group). After three weeks of treatment, all treatment groups were assessed for several measures of insulin resistance (fasting insulin and glucose, HOMA-IR, and the response to an intraperitoneal glucose tolerance test (ipGTT)) as well as for triglyceride levels and the blood pressure response to treatment. Results Treatment with aliskiren did not affect the ipGTT response but significantly lowered the HOMA-IR and insulin levels in cav-1 KO mice. However, treatment with amlodipine significantly degraded the ipGTT response, as well as the HOMA-IR and insulin levels in the cav-1 KO mice. Aliskiren also significantly lowered triglyceride levels in the cav-1 KO but not in the WT mice. Moreover, aliskiren treatment had a significantly greater effect on blood pressure readings in the cav-1 KO vs. WT mice, and marginally more effective than amlodipine. Conclusions Our results support the hypothesis that aliskiren reduces insulin resistance as indicated by improved HOMA-IR in cav-1 KO mice whereas amlodipine treatment resulted in changes consistent with increased insulin resistance. In addition, aliskiren was substantially more effective in lowering blood pressure in the cav-1 KO mouse model than in WT mice and marginally more effective than amlodipine. PMID:22954672

Antihypertensive and cardioprotective effects of pumpkin seed oil.

PubMed

El-Mosallamy, Aliaa E M K; Sleem, Amany A; Abdel-Salam, Omar M E; Shaffie, Nermeen; Kenawy, Sanaa A

2012-02-01

Pumpkin seed oil is a natural product commonly used in folk medicine for treatment of prostatic hypertrophy. In the present study, the effects of treatment with pumpkin seed oil on hypertension induced by the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME) (50 mg /kg/day) in rats were studied and compared with those of the calcium channel blocker amlodipine. Pumpkin seed oil (40 or 100 mg/kg), amlodipine (0.9 mg/kg), or vehicle (control) was given once daily orally for 6 weeks. Arterial blood pressure (BP), heart rate, electrocardiogram (ECG) changes, levels of serum nitric oxide (NO) (the concentrations of nitrite/nitrate), plasma malondialdehyde (MDA), blood glutathione, and erythrocytic superoxide dismutase activity were measured. Histopathological examination of heart and aorta was conducted as well. L-NAME administration resulted in a significant increase in BP starting from the second week. Pumpkin seed oil or amlodipine treatment significantly reduced the elevation in BP by L-NAME and normalized the L-NAME-induced ECG changes-namely, prolongation of the RR interval, increased P wave duration, and ST elevation. Both treatments significantly decreased the elevated levels of MDA and reversed the decreased levels of NO metabolites to near normal values compared with the L-NAME-treated group. Amlodipine also significantly increased blood glutathione content compared with normal (but not L-NAME-treated) rats. Pumpkin seed oil as well as amlodipine treatment protected against pathological alterations in heart and aorta induced by L-NAME. In conclusion, this study has shown that pumpkin seed oil exhibits an antihypertensive and cardioprotective effects through a mechanism that may involve generation of NO.

Early treatment with losartan effectively ameliorates hypertension and improves vascular remodeling and function in a prehypertensive rat model.

PubMed

He, De-Hua; Lin, Jin-Xiu; Zhang, Liang-Min; Xu, Chang-Sheng; Xie, Qiang

2017-03-15

Pharmacological treatment of prehypertension may ameliorate hypertension and improve vascular structure and function. This study investigated 1) whether early treatment with either losartan or amlodipine at the onset of prehypertension can prevent hypertension and 2) whether losartan and amlodipine equally improve vascular remodeling and function in a rat model of hypertension. Stroke-prone spontaneously hypertensive (SHRSP) rats were administered losartan, amlodipine or saline for 6 or 16weeks at the onset of prehypertension. Wistar-Kyoto rats were used as a control. All groups were observed for 40weeks. Systolic blood pressure was measured using the tail-cuff method. Vascular structure and function were determined by microscopy and vascular ring contractility assays, respectively. Angiotensin II (Ang II) and aldosterone (Aldo) were measured by radioimmunoassays. Angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) expression was measured by western blot. Losartan effectively reduced progression from prehypertension to hypertension as well as vascular remodeling and improved vascular contractility in SHRSP rats. Long-term losartan (16weeks) had greater benefits than short-term (6weeks) treatment. Losartan increased Ang II and decreased Aldo levels in the serum and vessel walls of resistance vessels in a time-dependent manner. Losartan significantly decreased AT1R and increased AT2R vascular expression. Amlodipine had no effect on vascular AT1R and AT2R expression. Losartan administered at the onset of prehypertension is more effective than amlodipine in ameliorating hypertension and improving vascular remodeling and function, which is likely mediated by the renin-angiotensin-aldosterone system. Copyright © 2017 Elsevier Inc. All rights reserved.

The therapeutic advantage of combination antihypertensive drug therapy using amlodipine and irbesartan in hypertensive patients: Analysis of the post-marketing survey data from PARTNER (Practical combination therapy of Amlodin and angiotensin II Receptor blocker; safety and efficacy in patients with hypertension) study.

PubMed

Ishimitsu, Toshihiko; Fukuda, Hirofumi; Uchida, Masako; Ishibashi, Kazushi; Sato, Fusako; Nukui, Kazuhiko; Nagao, Munehiko

2015-01-01

Two-thirds of hypertensive patients need a combination antihypertensive therapy to achieve the target blood pressure (BP). The PARTNER (Practical combination therapy of Amlodin and angiotensin II Receptor blocker; Safety and efficacy in paTieNts with hypERtension) study is a prospective specific clinical use survey examining the efficacy and safety of 12-week treatment with amlodipine (AML) and Angiotensin II Receptor Blocker (ARB) in 5900 hypertensive patients. The current analysis was performed as to the BP control, adverse reactions, and the effects on laboratory data in patients treated with the combination of AML and irbesartan (IRB), namely the patients added AML to already taking IRB (AML add-on group, n = 1202) and the patients added IRB to AML (IRB add-on group, n = 1050). Both study groups showed distinct decreases in office BP at 4 week (p < 0.001) and the antihypertensive effects were sustained to 12 week (p < 0.001). The percentage of patients achieving BP < 140/90 mmHg was ∼70% in either group. Proteinuria and estimated glomerular filtration rate (eGFR) were significantly improved in hypertensive patients with baseline eGFR <60 ml/min/1.73 m(2). Serum uric acid was reduced either by adding AML or IRB, and the reductions were prominent in patients with serum uric acid >7 mg/dl. The incidence of adverse reactions was as few as 1.11% and there were no severe adverse reactions which hampered the continuation of combination therapy. In conclusion, combination antihypertensive therapy with AML and IRB effectively lowers BP without particular safety problems, reduces serum uric acid especially in patients with hyperuricemia and exhibits renoprotective effects in patients with chronic kidney disease.

Microemulsion Transdermal Formulation for Simultaneous Delivery of Valsartan and Nifedipine: Formulation by Design.

PubMed

Sood, Jatin; Sapra, Bharti; Tiwary, Ashok K

2017-08-01

The objective of the study was to optimize the proportion of different components for formulating oil in water microemulsion formulation meant for simultaneous transdermal delivery of two poorly soluble antihypertensive drugs. Surface response methodology of Box-Behnken design was utilized to evaluate the effect of two oils (Captex 500 - x1 and Capmul MCM - x2) and surfactant (Acrysol EL135 - x3) on response y1 (particle size), y2 (solubility of valsartan), and y3 (solubility of nifedipine). The important factors which significantly affected the responses were identified and validated using ANOVA. The model was diagnosed using normal plot of residuals and Box-Cox plot. The design revealed an inverse correlation between particle size and concentration of Capmul MCM and Acrysol EL 135. However, an increase in concentration of Captex 500 led to an increase in particle size of microemulsion. Solubility of valsartan decreased while that of nifedipine increased with increase in concentration of Captex 500. Capmul MCM played a significant role in increasing the solubility of valsartan. The effect of Acrysol EL 135 on solubility of both drugs, although significant, was only marginal as compared to that of Captex 500 and Capmul MCM. The optimized microemulsion was able to provide an enhancement ratio of 27.21 and 63.57-fold for valsartan and nifedipine, respectively, with respect to drug dispersion in aqueous surfactant system when evaluated for permeation studies. The current studies candidly suggest the scope of microemulsion systems for solubilizing as well as promoting the transport of both drugs across rat skin at an enhanced permeation rate.

Effect of Valsartan on Cerebellar Adrenomedullin System Dysregulation During Hypertension.

PubMed

Figueira, Leticia; Israel, Anita

2017-02-01

Adrenomedullin (AM) and its receptors components, calcitonin-receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP1, RAMP2, and RAMP3) are expressed in cerebellum. Cerebellar AM, AM binding sites and receptor components are altered during hypertension, suggesting a role for cerebellar AM in blood pressure regulation. Thus, we assessed the effect of valsartan, on AM and its receptor components expression in the cerebellar vermis of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Additionally, we evaluated AM action on superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity, and thiobarbituric acid reactive substances (TBARS) production in cerebellar vermis. Animals were treated with valsartan or vehicle for 11 days. Rats were sacrificed by decapitation; cerebellar vermis was dissected; and AM, CRLR, RAMP1, RAMP2, and RAMP3 expression was quantified by Western blot analysis. CAT, SOD, and GPx activity was determined spectrophotometrically and blood pressure by non-invasive plethysmography. We demonstrate that AM and RAMP2 expression was lower in cerebellum of SHR rats, while CRLR, RAMP1, and RAMP3 expression was higher than those of WKY rats. AM reduced cerebellar CAT, SOD, GPx activities, and TBARS production in WKY rats, but not in SHR rats. Valsartan reduced blood pressure and reversed the altered expression of AM and its receptors components, as well the loss of AM capacity to reduce antioxidant enzyme activity and TBARS production in SHR rats. These findings demonstrate that valsartan is able to reverse the dysregulation of cerebellar adrenomedullinergic system; and they suggest that altered AM system in the cerebellum could represent the primary abnormality leading to hypertension.

Preparation and evaluation of valsartan by a novel semi-solid self-microemulsifying delivery system using Gelucire 44/14.

PubMed

Zhao, Kun; Yuan, Yue; Wang, Hui; Li, Panpan; Bao, Zhihong; Li, Yue

2016-10-01

The aim of the present study was to develop a novel semi-solid self-microemulsifying drug delivery system (SMEDDS) using Gelucire(®) 44/14 as oil with strong solid character to improve the oral bioavailability of poorly soluble drug valsartan. The solubility of valsartan in various excipients was determined, the pseudo-ternary phase diagram was constructed in order to screen the optimal excipients, and DSC analysis was performed to evaluate the melting point of SMEDDS. The optimal drug-loaded SMEDDS formulation was consisted of 30% Gelucire(®) 44/14 (oil), 40% Solutol(®) HS 15 (surfactant), and 30% Transcutol(®) P (cosurfactant) (w/w) with 80 mg valsartan/g excipients. The average droplet sizes of the optimized blank and drug-loaded SMEDDS formulations were 26.20 ± 1.43 and 33.34 ± 2.15 nm, and the melting points of them were 35.6 and 36.8 °C, respectively. The in vitro dissolution rate of optimal semi-solid SMEDDS was increased compared with commercial capsules, resulting in the 2.72-fold and 2.97-fold enhancement of Cmax and AUC0-t after oral administration in rats, respectively. These results indicated that the novel semi-solid SMEDDS formulation could potentially improve the oral bioavailability of valsartan, and the semi-solid SMEDDS was a desirable system than the traditional liquid SMEDDS because it was convenient for preparation, storage and transportation due to semi-solid state at room temperature and melted state at body temperature.

Potential beneficial effects of sacubitril-valsartan in renal disease: a new field for a new drug.

PubMed

Gervasini, Guillermo; Robles, Nicolas Roberto

2017-05-01

Patients with renal dysfunction are at a higher risk of cardiovascular disease (CVD), which often shares manifestations with heart failure (HF). Last year, the FDA approved the use of sacubitril-valsartan in patients with HF. This dual-acting agent enhances the functions of natriuretic peptides and inhibits the renin-angiotensin system. Areas covered: This review summarizes the existing preclinical and clinical studies carried out with sacubitril-valsartan (and other drugs with similar pharmacological mechanisms) in HF and hypertensive patients. We put the focus on the renal data provided by these studies. Data were obtained from English peer-reviewed articles on PubMed and clinical trials registered in ClinicalTrials.gov. Expert opinion: Overall, sacubitril-valsartan might be a promising therapeutic approach in patients with renal dysfunction. Renal conditions with marked CV risk, such as arterionephrosclerosis, could constitute a particular setting where to evaluate the impact of the drug. Nevertheless, large, randomized trials are needed to confirm the beneficial effects and safety profile of the drug in renal patients, as well as to elucidate some concerns observed in HF trials, such as the slight increase in proteinuria.

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

PubMed

Senni, Michele; Trimarco, Bruno; Emdin, Michele; De Biase, Luciano

2017-01-01

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.

Disposition and metabolism of [(14)C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects.

PubMed

Flarakos, Jimmy; Du, Yancy; Bedman, Timothy; Al-Share, Qusai; Jordaan, Pierre; Chandra, Priya; Albrecht, Diego; Wang, Lai; Gu, Helen; Einolf, Heidi J; Huskey, Su-Er; Mangold, James B

2016-11-01

1. Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor. 2. Following oral administration, [(14)C]LCZ696 delivers systemic exposure to valsartan and AHU377 (sacubitril), which is rapidly metabolized to LBQ657 (M1), the biologically active neprilysin inhibitor. Peak sacubitril plasma concentrations were reached within 0.5-1 h. The mean terminal half-lives of sacubitril, LBQ657 and valsartan were ∼1.3, ∼12 and ∼21 h, respectively. 3. Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7-67.8% and feces for 36.9 to 48.3 % of the total radioactivity. The majority of the drug was excreted as the active metabolite LBQ657 in urine and feces, total accounting for ∼85.5% of the total dose. 4. Based upon in vitro studies, the potential for LCZ696 to inhibit or induce cytochrome P450 (CYP) enzymes and cause CYP-mediated drug interactions clinically was found to be low.

Treatment for hepatitis C virus-induced portal hypertension in leukemic children.

PubMed

El-Ashry, Rasha; Malek, Hala Abdel; Ghayaty, Essam A Desoky; El-Gendy, Ahmed A; Darwish, Ahmad; Al-Tonbary, Youssef

2013-01-01

Children with acute leukemia are at high risk of hepatitis C infection, either by immunosuppression secondary to chemotherapy or by multiple transfusions of blood products during the course of the disease. Hepatitis C virus (HCV) infection constitutes a major problem during management of acute leukemia due to resultant portal hypertension or bleeding esophageal varices. Chronic HCV infection is a major cause of liver cirrhosis and hepatocellular carcinoma in leukemic survivors. The effect of amlodipine treatment on children with acute lymphoblastic leukemia (ALL) having portal hypertension secondary to HCV infection during maintenance chemotherapy has been studied. Sixty male children (mean age 11.83 ± 1.1 years) with ALL in remission and have HCV infection were included. Diagnosis of HCV infection was confirmed by real-time PCR. Thirty patients received 5 mg amlodipine orally per day for 4 weeks and compared to another 30 patients received placebo therapy and 30 age- and sex-matched children as a control group. Amlodipine significantly reduced the elevated portal blood pressure to normal level in doses which did not interfere with mechanism of action of chemotherapy (p ≤ 0.001). Treatment with amlodipine can be used to control portal hypertension in leukemic children having HCV-induced portal hypertension. HCV in leukemics could be virtually eliminated by proper testing of the blood transfusion pool.

Nephrotoxicity of high- and low-osmolar contrast media. The protective role of amlodipine in a rat model.

PubMed

Duan, S B; Liu, F Y; Luo, J A; Wu, H W; Liu, R H; Peng, Y M; Yang, X L

2000-09-01

To evaluate the nephrotoxicity of high- and low-osmolar contrast media (HOCM, LOCM) on kidneys in Sprague-Dawley rats. The protective role of amlodipine was studied. Forty rats of both sexes were randomly divided into 5 groups (n=8/group) and glycerine for inducing renal failure was given to all rats except controls. In diatrizoate-injected rats, blood urea nitrogen (BUN) and serum creatinine (SCr) were increased; levels of phospholipase A2 (PLA2), lipid peroxide (LPO) and calcium were also increased in renal tissues. There was no significant difference between LOCM (iohexol) animals and glycerol controls either in the renal levels of PLA2, LPO and calcium or in the levels of BUN and SCr. The histologic changes were milder in the LOCM animals than in the HOCM animals. In the group pretreated with amlodipine, no increase in the levels of BUN or SCr was discovered and the renal content of PLA2, LPO and calcium were significantly lower than in the HOCM group; the renal injuries induced by diatrizoate were alleviated. The HOCM, diatrizoate, was more toxic to rat kidneys than the LOCM iohexol; PLA2, LPO and calcium load played a role in producing renal function impairment induced by diatrizoate meglumine; amlodipine protected the renal tissue from nephrotoxicity induced by diatrizoate.

[Effects of qishenyiqi gutta pills on calcium/calmodulin dependent protein kinase II in rats with renal hypertension].

PubMed

Zhang, Xiao-ying; Wei, Wan-lin; Shu, Chang-cheng; Zhang, Ling; Tian, Guo-xiang

2013-02-05

To explore the effects of qishenyiqi gutta pills on myocardial hypertrophy of left ventricle and calcium/calmodulin dependent protein kinase II (CAMK II) in rats with renal hypertension and elucidate its intervention mechanism for myocardial hypertrophy. A total of 50 Wistar rats were randomly divided into 5 groups of sham-operation, control, high-dose qishenyiqi gutta pills, low-dose qishenyiqi gutta pills and valsartan (n = 10 each). The rat model of myocardial hypertrophy with renal hypertension was established by the 2-kidney 1-clip (2K1C) method. The experimental animals were divided into control, high-dose, low-dose and valsartan groups. At Week 5 postoperation, valsartan group received an oral dose of valsartan (30 mg×kg(-1)×d(-1)), high-dose and low-dose groups took qishenyiqi gutta pills (250 and 125 mg×kg(-1)×d(-1)) while sham-operation and control groups had the same dose of normal saline solution. Tail arterial pressure was detected weekly and continued for 8 weeks. At the end of Week 12, the animals were sacrificed to harvest myocardial tissue of left ventricle for detecting left ventricular mass index (LVMI). The collagen volume fraction (CVF) of myocardium was examined by Van Gieson staining, the activities of superoxide dismutase (SOD) and reactive oxygen species (ROS) were detected by enzyme-linked immunosorbent assay (ELISA) and the expression of CAMK II was detected by immunohistochemistry and Western blot. (1) Blood pressures were significantly higher in high-dose, low-dose and control groups than those in sham-operation and valsartan groups ((167.66 ± 11.48), (166.72 ± 13.51), (174.34 ± 14.52) vs (119.57 ± 6.30), (131.80 ± 12.49) mm Hg, P < 0.01). The changes of blood pressure had no significant difference between high-dose and low-dose groups. (2) LVMI and CVF increased significantly in high-dose, low-dose and valsartan groups versus sham-operation group (LVMI: (1.98 ± 0.16), (2.09 ± 0.14), (1.97 ± 0.17) vs (1.74 ± 0.17) g/kg; CVF: 0.94% ± 0.22%, 2.53% ± 0.61%, 0.81% ± 0.20% vs 0.45% ± 0.13%) (P < 0.01, P < 0.05), but decreased significantly versus control group (LVMI: (1.98 ± 0.16), (2.09 ± 0.14), (1.97 ± 0.17) vs (2.28 ± 0.28) g/kg; CVF: 0.94% ± 0.22%, 2.53% ± 0.61%, 0.81% ± 0.20% vs 4.73% ± 1.04%) (P < 0.01, P < 0.05). (3) The expression of CAMK II was significantly higher in high-dose, low-dose, valsartan and control groups than that in sham-operation group (65.9%, 95.3%, 84.8%, 160.1% vs 67.7%). And it was significantly lower in high-dose, low-dose and valsartan groups than that in control group (65.9%, 95.3%, 84.8% vs 160.1%). There was no statistical difference among high-dose, low-dose and valsartan groups. Qishenyiqi gutta pills may retard myocardial hypertrophy of left ventricle in rats with renal hypertension. And the mechanism is probably be correlated with its antioxidant activity and inhibited expression of myocardial CAMK II.

Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial.

PubMed

Velazquez, Eric J; Morrow, David A; DeVore, Adam D; Ambrosy, Andrew P; Duffy, Carol I; McCague, Kevin; Hernandez, Adrian F; Rocha, Ricardo A; Braunwald, Eugene

2018-04-01

The objective is to assess the safety, tolerability, and efficacy of sacubitril/valsartan compared with enalapril in patients with heart failure (HF) with a reduced ejection fraction (EF) stabilized during hospitalization for acute decompensated HF. Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor, improves survival among ambulatory HF patients with a reduced EF. However, there is very limited experience with the in-hospital initiation of sacubitril/valsartan in patients who have been stabilized following hospitalization for acute decompensated HF. PIONEER-HF is a 12-week, prospective, multicenter, double-blind, randomized controlled trial enrolling a planned 882 patients at more than 100 participating sites in the United States. Medically stable patients >18 years of age with an EF <40% and an amino terminal-pro b-type natriuretic peptide >1600 pg/mL or b-type natriuretic peptide >400 pg/mL are eligible for participation no earlier than 24 hours and up to 10 days from initial presentation while still hospitalized. Patients are randomly assigned 1:1 to in-hospital initiation of sacubitril/valsartan titrated to 97/103 mg by mouth twice daily versus enalapril titrated to 10 mg by mouth twice daily for 8 weeks. All patients receive open-label treatment with sacubitril/valsartan for the remaining 4 weeks of the study. The primary efficacy end point is the time-averaged proportional change in amino terminal-pro b-type natriuretic peptide from baseline through weeks 4 and 8. Secondary and exploratory end points include serum and urinary biomarkers as well as clinical outcomes. Safety end points include the incidence of angioedema, hypotension, renal insufficiency, and hyperkalemia. The PIONEER-HF trial will inform clinical practice by providing evidence on the safety, tolerability, and efficacy of in-hospital initiation of sacubitril/valsartan among patients who have been stabilized following an admission for acute decompensated HF with a reduced EF. Copyright © 2018 Elsevier Inc. All rights reserved.

The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey.

PubMed

Schoenfeld, Heidi A; West, Tim; Verghese, Philip B; Holubasch, Mary; Shenoy, Neeta; Kagan, David; Buono, Chiara; Zhou, Wei; DeCristofaro, Marc; Douville, Julie; Goodrich, Geoffrey G; Mansfield, Keith; Saravanan, Chandra; Cumin, Frederic; Webb, Randy L; Bateman, Randall J

2017-05-15

Sacubitril/valsartan (LCZ696) is the first angiotensin receptor neprilysin inhibitor approved to reduce cardiovascular mortality and hospitalization in patients with heart failure with reduced ejection fraction. As neprilysin (NEP) is one of several enzymes known to degrade amyloid-β (Aβ), there is a theoretical risk of Aβ accumulation following long-term NEP inhibition. The primary objective of this study was to evaluate the potential effects of sacubitril/valsartan on central nervous system clearance of Aβ isoforms in cynomolgus monkeys using the sensitive Stable Isotope Labeling Kinetics (SILK™)-Aβ methodology. The in vitro selectivity of valsartan, sacubitril, and its active metabolite sacubitrilat was established; sacubitrilat did not inhibit other human Aβ-degrading metalloproteases. In a 2-week study, sacubitril/valsartan (50mg/kg/day) or vehicle was orally administered to female cynomolgus monkeys in conjunction with SILK™-Aβ. Despite low cerebrospinal fluid (CSF) and brain penetration, CSF exposure to sacubitril was sufficient to inhibit NEP and resulted in an increase in the elimination half-life of Aβ1-42 (65.3%; p=0.026), Aβ1-40 (35.2%; p=0.04) and Aβtotal (29.8%; p=0.04) acutely; this returned to normal as expected with repeated dosing for 15days. CSF concentrations of newly generated Aβ (AUC (0-24h) ) indicated elevations in the more aggregable form Aβ1-42 on day 1 (20.4%; p=0.039) and day 15 (34.7%; p=0.0003) and in shorter forms Aβ1-40 (23.4%; p=0.009), Aβ1-38 (64.1%; p=0.0001) and Aβtotal (50.45%; p=0.00002) on day 15. However, there were no elevations in any Aβ isoforms in the brains of these monkeys on day 16. In a second study cynomolgus monkeys were administered sacubitril/valsartan (300mg/kg) or vehicle control for 39weeks; no microscopic brain changes or Aβ deposition, as assessed by immunohistochemical staining, were present. Further clinical studies are planned to address the relevance of these findings. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data.

PubMed

2017-12-01

Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor-neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin-angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III—rationale, trial design and baseline data

PubMed Central

Judge, PK; Haynes, R; Herrington, WG; Storey, BC; Staplin, N; Bethel, A; Bowman, L; Brunskill, N; Cockwell, P; Dayanandan, R; Hill, M; Kalra, PA; McMurray, JJ; Taal, M; Wheeler, DC; Landray, MJ; Baigent, C; Baigent, C; Haynes, R; Landray, MJ; Dayanandan, R; Baxter, A; Staplin, N; Bethel, A; Bowman, L; Brunskill, N; Cockwell, P; Herrington, WG; Hill, M; Judge, PK; Kalra, PA; Knott, C; McMurray, JJ; Murphy, K; Taal, M; Wheeler, DC; Wheatley, K; Emberson, J; Tomson, C; Roderick, P

2017-01-01

Abstract Background Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. Methods UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor–neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin–angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. Results Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. Conclusions UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD. PMID:27646835

Oral vitamin-A-coupled valsartan nanomedicine: High hepatic stellate cell receptors accessibility and prolonged enterohepatic residence.

PubMed

El-Mezayen, Nesrine S; El-Hadidy, Wessam F; El-Refaie, Wessam M; Shalaby, Thanaa I; Khattab, Mahmoud M; El-Khatib, Aiman S

2018-05-22

So far, liver fibrosis still has no clinically-approved treatment. The loss of stored vitamin-A (V A ) in hepatic stellate cells (HSCs), the main regulators to hepatic fibrosis, can be applied as a mechanism for their targeting. Valsartan is a good candidate for this approach; it is a marketed oral-therapy with inverse- and partial-agonistic activity to the over-expressed angiotensin-II type1 receptor (AT1R) and depleted nuclear peroxisome proliferator-activated receptor-gamma (PPAR-γ), respectively, in activated HSCs. However, efficacy on AT1R and PPAR-γ necessitates high drug permeability which is lacking in valsartan. In the current study, liposomes were used as nanocarriers for valsartan to improve its permeability and hence efficacy. They were coupled to V A and characterized for HSCs-targeting. Tracing of orally-administered fluorescently-labeled V A -coupled liposomes in normal rats and their fluorescence intensity quantification in different organs convincingly demonstrated their intestinal entrapment. On the other hands, their administration to rats with induced fibrosis revealed preferential hepatic, and less intestinal, accumulation which lasted up to six days. This indicated their uptake by intestinal stellate cells that acted as a depot for their release over time. Confocal microscopical examination of immunofluorescently-stained HSCs in liver sections, with considerable formula accumulation, confirmed HSCs-targeting and nuclear uptake. Consequently, V A -coupled valsartan-loaded liposomes (VLC)-therapy resulted in profound re-expression of hepatic Mas-receptor and PPAR-γ, potent reduction of fibrogenic mediators' level and nearly normal liver function tests. Therefore, VLC epitomizes a promising antifibrotic therapy with exceptional extended action and additional PPAR-γ agonistic activity. Copyright © 2018 Elsevier B.V. All rights reserved.

Development of an Experimental Model to Study the Relationship Between Day-to-Day Variability in Blood Pressure and Aortic Stiffness

PubMed Central

Bouissou-Schurtz, Camille; Lindesay, Georges; Regnault, Véronique; Renet, Sophie; Safar, Michel E.; Molinie, Vincent; Dabire, Hubert; Bezie, Yvonnick

2015-01-01

We aimed to develop an animal model of long-term blood pressure variability (BPV) and to investigate its consequences on aortic damage. We hypothesized that day-to-day BPV produced by discontinuous treatment of spontaneously hypertensive rats (SHR) by valsartan may increase arterial stiffness. For that purpose, rats were discontinuously treated, 2 days a week, or continuously treated by valsartan (30 mg/kg/d in chow) or placebo. Telemetered BP was recorded during 2 min every 15 min, 3 days a week during 8 weeks to cover the full BP variations in response to the treatment schedule. Pulse wave velocity (PWV) and aortic structure evaluated by immunohistochemistry were investigated in a second set of rats treated under the same conditions. Continuous treatment with valsartan reduced systolic BP (SBP) and reversed the aortic structural alterations observed in placebo treated SHR (decrease of medial cross-sectional area). Discontinuous treatment with valsartan decreased SBP to a similar extent but increased the day-to-day BPV, short term BPV, diastolic blood pressure (DBP), and PWV as compared with continuous treatment. Despite no modifications in the elastin/collagen ratio and aortic thickness, an increase in PWV was observed following discontinuous treatment and was associated with a specific accumulation of fibronectin and its αv-integrin receptor compared with both groups of rats. Taken together the present results indicate that a discontinuous treatment with valsartan is able to induce a significant increase in day-to-day BPV coupled to an aortic phenotype close to that observed in hypertension. This experimental model should pave the way for future experimental and clinical studies aimed at assessing how long-term BPV increases aortic stiffness. PMID:26696902

The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan.

PubMed

Jhund, Pardeep S; McMurray, John J V

2016-09-01

Inhibition of neurohumoural pathways such as the renin angiotensin aldosterone and sympathetic nervous systems is central to the understanding and treatment of heart failure (HF). Conversely, until recently, potentially beneficial augmentation of neurohumoural systems such as the natriuretic peptides has had limited therapeutic success. Administration of synthetic natriuretic peptides has not improved outcomes in acute HF but modulation of the natriuretic system through inhibition of the enzyme that degrades natriuretic (and other vasoactive) peptides, neprilysin, has proven to be successful. After initial failures with neprilysin inhibition alone or dual neprilysin-angiotensin converting enzyme (ACE) inhibition, the Prospective comparison of angiotensin receptor neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) trial demonstrated that morbidity and mortality can be improved with the angiotensin receptor blocker neprilysin inhibitor sacubitril/valsartan (formerly LCZ696). In comparison to the ACE inhibitor enalapril, sacubitril/valsartan reduced the occurrence of the primary end point (cardiovascular death or hospitalisation for HF) by 20% with a 16% reduction in all-cause mortality. These findings suggest that sacubitril/valsartan should replace an ACE inhibitor or angiotensin receptor blocker as the foundation of treatment of symptomatic patients (NYHA II-IV) with HF and a reduced ejection fraction. This review will explore the background to neprilysin inhibition in HF, the results of the PARADIGM-HF trial and offer guidance on how to use sacubitril/valsartan in clinical practice. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Effect of food on the oral bioavailability of the angiotensin receptor - neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects
.

PubMed

Ayalasomayajula, Surya; Langenickel, Thomas H; Chandra, Priya; Wolfson, Edward D; Albrecht, Diego; Zhou, Wei; Pal, Parasar; Rajman, Iris; Sunkara, Gangadhar

2016-12-01

Sacubitril/valsartan (LCZ696) provides a novel therapeutic approach of neurohormonal modulation in heart failure via simultaneous inhibition of neprilysin and blockade of the angiotensin II type-1 receptor. This study was conducted to evaluate the effect of food on the oral bioavailability of LCZ696 analytes. This was an open-label, randomized, 3-period crossover study in healthy subjects. Eligible subjects (N = 36) were randomized to 6 treatment sequences, each comprising 3 treatment periods during which subjects received a single oral dose of 400 mg LCZ696 under fasting condition and following a low- and high-fat meal. Following administration of LCZ696 after low- and high-fat meals, the mean C_max of sacubitril and sacubitrilat (the active neprilysin inhibitor) decreased by 42 - 54% and 19 - 28%, respectively, while the t_max values increased. However, systemic exposure (AUC_inf and AUC_last) of sacubitril was slightly decreased (by 16% with low-fat meal) and that of sacubitrilat was unchanged in the presence of food. For valsartan, the C_max decreased by ~ 40% when LCZ696 was administered after low- and high-fat meals. The systemic exposure of valsartan decreased by ~ 33% with a low-fat meal; however, it was unchanged with a high-fat meal. LCZ696 was generally safe and well tolerated in healthy subjects when administered under fasting or fed condition. Overall, administration of LCZ696 with meals decreased the rate and extent of absorption of sacubitril with little impact on the systemic exposure to sacubitrilat, its active metabolite. The systemic exposure to valsartan was decreased in the presence of food.
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The application of anethole, menthone, and eugenol in transdermal penetration of valsartan: Enhancement and mechanistic investigation.

PubMed

Ahad, Abdul; Aqil, Mohd; Ali, Asgar

2016-01-01

The main barrier for transdermal delivery is the obstacle property of the stratum corneum. Many types of chemical penetration enhancers have been used to breach the skin barrier; among the penetration enhancers, terpenes are found as the most highly advanced, safe, and proven category. In the present investigation, the terpenes anethole, menthone, and eugenol were used to enhance the permeation of valsartan through rat skin in vitro and their enhancement mechanism was investigated. Skin permeation studies of valsartan across rat skin in the absence and the presence of terpenes at 1% w/v, 3% w/v, and 5% w/v in vehicle were carried out using the transdermal diffusion cell sampling system across rat skin and samples were withdrawn from the receptor compartment at 1, 2, 3, 4, 6, 8, 10, 12, and 24 h and analysed for drug content by the HPLC method. The mechanism of skin permeation enhancement of valsartan by terpenes treatment was evaluated by Fourier transform infrared spectroscopy (FTIR) analysis and differential scanning calorimetry (DSC). All the investigated terpenes provided a significant (p < 0.01) enhancement in the valsartan flux at a concentration of 1%, and less so at 3% and 5%. The effectiveness of terpenes at 1% concentration was in the following order: anethole > menthone > eugenol with 4.4-, 4.0-, and 3.0-fold enhancement ratio over control, respectively. DSC study showed that the treatment of stratum corneum with anethole shifted endotherm down to lower melting point while FTIR studies revealed that anethole produced maximum decrease in peak height and area than other two terpenes. The investigated terpenes can be successfully used as potential enhancers for the enhancement of skin permeation of lipophilic drug.

Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension.

PubMed

White, William B; Weber, Michael A; Sica, Domenic; Bakris, George L; Perez, Alfonso; Cao, Charlie; Kupfer, Stuart

2011-03-01

Azilsartan medoxomil is an angiotensin receptor blocker (ARB) being developed for hypertension treatment. To compare this ARB with others in the class, we studied the effects of 2 doses of azilsartan medoxomil, with valsartan 320 mg and olmesartan medoxomil (olmesartan) 40 mg, in a randomized, double-blind, placebo-controlled trial using ambulatory blood pressure (BP) monitoring and clinic BP measurements. The primary efficacy end point was the change from baseline in 24-hour mean systolic BP. Hierarchical analysis testing for superiority over placebo was followed by noninferiority analysis and then superiority testing of azilsartan medoxomil (80 mg and then 40 mg) versus the comparator ARBs. For 1291 randomized patients, mean age was 56 years, 54% were men, and baseline 24-hour mean systolic BP was 145 mm Hg. Azilsartan medoxomil at 80 mg had superior efficacy to both valsartan at 320 mg and olmesartan at 40 mg: placebo-adjusted 24-hour systolic BP was lowered (-14.3 mm Hg) more than 320 mg of valsartan (-10.0 mm Hg; P<0.001) and 40 mg of olmesartan (-11.7 mm Hg; P=0.009). Azilsartan medoxomil at 40 mg was noninferior to 40 mg of olmesartan (difference: -1.4 mm Hg [95% CI: -3.3 to 0.5]). For clinic systolic BP, both doses of azilsartan medoxomil were superior to the comparator ARBs. Safety and tolerability were similar among the placebo and 4 active treatments. These data demonstrate that azilsartan medoxomil at its maximal dose has superior efficacy to both olmesartan and valsartan at their maximal, approved doses without increasing adverse events. Azilsartan medoxomil could provide higher rates of hypertension control within the ARB class.

The ameliorated longevity and pharmacokinetics of valsartan released from a gel system of ultradeformable vesicles.

PubMed

Ahad, Abdul; Aqil, Mohd; Kohli, Kanchan; Sultana, Yasmin; Mujeeb, Mohd

2016-09-01

The present study traces the development and characterization of the gel formulation of valsartan-loaded ultradeformable vesicles for management of hypertension. The prepared gel formulation of ultradeformable vesicles was evaluated for in vitro skin permeation, release kinetics, skin irritation, pharmacokinetics, and stability. The in vitro skin permeation study showed that the gel formulation of ultradeformable vesicles presented a flux value of 368.74 μg/cm(2)/h, in comparison to that of the traditional liposomal gel formulation, with an enhancement ratio of 26.91, through rat skin. The data for release kinetics showed that the release profile followed zero-order kinetics, and that the drug release mechanism was non-Fickian. The results of the skin irritation study demonstrated that the prepared formulation was safe, less irritant, and well-tolerated for transdermal delivery. The results of the pharmacokinetic study demonstrated that the AUC value of valsartan after transdermal administration was apparently increased. The formulation stored under a refrigerated condition showed greater stability, and results were found to be within the specification under storage conditions. It is evident from this study that the gel formulation of ultradeformable vesicles of valsartan is a promising delivery system for lipophilic drugs, and has reasonably good stability characteristics.

Does GastroPlus Support Similarity and Dissimilarity Factors of in vitro-in vivo Prediction in Biowaiver Studies? A Lower Strength Amlodipine As a Model Drug.

PubMed

Naser Zaid, Abdel; Shraim, Naser; Radwan, Asmaa; Jaradat, Nidal; Hirzallah, Samah; Issa, Ibrahim; Khraim, Aya

2018-05-23

Many generic pharmaceutical products are currently available on the market place worldwide. Recently, there is a growing concern on the quality and efficacy of generic products. However, health care professionals such as physicians and pharmacists are in difficult situations to choose among alternatives. The aim of this study is to assess the effectiveness of the in silico technique (Gastro Plus ® ) in the biowaiver study and whether similarity and dissimilarity factors ( f 2 and f 1 respectively) are effective in this regard. The concentration of amlodipine in the sample was calculated by comparing the absorbance of the sample with that of a previously prepared amlodipine standard solution using validated HPLC method. The dissolution profile for each product (brand and generics) was constructed. The similarity ( f2) and dissimilarity ( f 1 ) factors were calculated for the generic product according to equation 1 and 2. GastroPlus™ software (version 9.0, Simulations Plus Inc., Lancaster, CA, USA) was used to predict the absorption profiles of amlodipine from the generic product Amlovasc ® and the reference Norvasc ® . These results may provide a rationale for the interchangeability between the RLD and generic version based on in vitro release profiles in silico technique especially in a lower strength dose drug. © Georg Thieme Verlag KG Stuttgart · New York.

Dose Uniformity of Scored and Unscored Tablets: Application of the FDA Tablet Scoring Guidance for Industry.

PubMed

Ciavarella, Anthony B; Khan, Mansoor A; Gupta, Abhay; Faustino, Patrick J

This U.S. Food and Drug Administration (FDA) laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs. Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product, and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance. All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5 to 2.1 standard deviation (SD) of the percent label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5-25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3 to 9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation. Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting can have an effect on the amount of drug present in a split tablet and available for absorption. Tablet splitting has become a very common practice in the United States and throughout the world. Tablets are often split to modify dose strength, make swallowing easier, and reduce cost to the consumer. To better address product quality for this widely used practice, the U.S. Food and Drug Administration (FDA) published a Guidance for Industry that addresses tablet splitting. The guidance provides testing criteria for scored tablets, which is a part of the FDA review process for drugs. The model drugs selected for this study were amlodipine and gabapentin, which have different sizes, shapes, and tablet scores. Whole and split amlodipine tablets were tested for drug content because of a concern that the low-dose strength may cause greater variability. Whole and split gabapentin tablets were tested for weight variation because of their higher dosage strength of 600 mg. All whole tablets met the acceptance criteria for the Uniformity of Dosage Units based on the guidance recommendations. When unscored amlodipine tablets were split by a splitter, all formulations did not meet the acceptance criteria. When fully scored gabapentin tablets were split by hand and by splitter, they met the acceptance criteria. The findings of this FDA study indicated physical characteristics such as size, shape, and tablet score can affect the uniformity of split tablets. © PDA, Inc. 2016.

Amlodipine at high dose increases preproendothelin-1 expression in the ventricles and aorta of normotensive rats.

PubMed

Krenek, Peter; Morel, Nicole; Kyselovic, Jan; Wibo, Maurice

2004-04-01

High doses of dihydropyridine calcium channel blockers can activate the sympathetic nervous system and the renin-angiotensin system. Both noradrenaline and angiotensin II stimulate preproendothelin-1 gene expression, yet the effects of high doses of dihydropyridines on preproendothelin-1 expression in vivo remain unknown. To investigate the effects of high doses of dihydropyridines on preproendothelin-1 expression in the ventricles and aorta of normotensive rats. Sprague-Dawley rats were treated with amlodipine 5 or 20 mg/kg per day (Amlo 5 or Amlo 20) in drinking water for 5 days or 5 weeks. Systolic blood pressure and heart rate were measured by tail-cuff plethysmography. Gene expression was examined by reverse transcriptase polymerase chain reaction. Amlo 5 increased heart rate during the first week only and had no effect on blood pressure and ventricular weight and gene expression. Amlo 20 reduced blood pressure transiently and increased heart rate consistently. It did not change relative left ventricular weight (corrected for body weight) after 5 days, but increased it after 5 weeks; it increased relative right ventricular weight at both time points. Aorta weight (mg/mm) was decreased after 5 weeks of treatment with both dosages of amlodipine. Preproendothelin-1 mRNA levels were increased by Amlo 20 in the ventricles and aorta and, concomitantly, renin mRNA was increased in the kidney. Less consistently, interleukin-6 mRNA also increased in ventricles, whereas cardiotrophin-1 mRNA remained unchanged. The sensitivity of isolated aorta to the contractile effect of noradrenaline was decreased by Amlo 5, but not by Amlo 20. In Sprague-Dawley rats, high-dose amlodipine, while promoting neurohormonal activation, induced overexpression of preproendothelin-1 mRNA in the ventricles and aorta. Endothelin-1 overexpression could contribute to the lack of inhibitory effect of high-dose amlodipine on ventricular mass in normotensive rats.

Transient prehypertensive treatment in spontaneously hypertensive rats: a comparison of losartan and amlodipine regarding long-term blood pressure, cardiac and renal protection.

PubMed

Peng, Feng; Lin, Jinxiu; Lin, Liming; Tang, Hong

2012-12-01

The aim of this study was to compare the effectiveness of transient prehypertensive treatment with losartan compared with amlodipine in spontaneously hypertensive rats (SHRs) on long-term blood pressure (BP), cardiac and renal protection. SHRs were prehypertensively treated with losartan, amlodipine or saline. Rats were followed up until 46 weeks of age. The left ventricular (LV) geometry and function were assessed by echocardiography. Angiotensin II (Ang II) and aldosterone (Aldo) were measured by radioimmunoassay. Ang II type 1 (AT1R) and type 2 (AT2R) receptor protein expression was determined by western blotting. The systolic blood pressure (SBP) in losartan-treated SHRs (SHR-Los) was persistently reduced until 46 weeks of age, but returned to untreated SHR levels in amlodipine-treated SHRs (SHR-Aml) from 30 weeks onwards. Compared to untreated SHRs, the albuminuria excretion in SHR-Los at week 46 was markedly decreased, the plasma, myocardium and renal tissue Ang II and Aldo levels in SHR-Los at week 46 were markedly decreased; AT1R and TGF-β1 protein expression was downregulated and AT2R protein was upregulated. Compared to untreated SHRs, the left ventricular mass index (LVMI) and collagen volume fraction (CVF) in SHR-Los were markedly decreased until week 46, and the left ventricular ejection fraction (LVEF) and cardiac brain natriuretic peptide mRNA expression were improved, whereas similar LVMI and elevated CVF were observed in SHR-Aml, and the LVEF decreased significantly below that of untreated SHRs at week 46, with cardiac BNP mRNA expression increasing slightly. Prehypertensive treatment with losartan was more effective than amlodipine on delaying long-term BP increase and ameliorating cardiac, renal structure and function, which may be related to the permanent attenuation of the circulating and local renin-angiotensin systems.

Dose uniformity of scored and unscored tablets: Application of the FDA Tablet Scoring Guidance for Industry.

PubMed

Ciavarella, Anthony; Khan, Mansoor; Gupta, Abhay; Faustino, Patrick

2016-06-20

This FDA laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs. Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance. All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5-2.1 standard deviation (SD) of the % label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5-25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3-9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation. Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting "can affect how much drug is present in the split tablet and available for absorption" as stated in the guidance (1). Copyright © 2016, Parenteral Drug Association.

Comparison of Fixed-dose Combinations of Amlodipine/Losartan Potassium/Chlorthalidone and Amlodipine/Losartan Potassium in Patients With Stage 2 Hypertension Inadequately Controlled With Amlodipine/Losartan Potassium: A Randomized, Double-blind, Multicenter, Phase III Study.

PubMed

Hong, Soon Jun; Jeong, Han Saem; Han, Seung Hwan; Chang, Ki Yuk; Hong, Bum Kee; Lee, Bong Ki; Chae, Shung Chull; Kim, Woo Shik; Park, Chang Gyu; Heo, Jung Ho; Lee, Seung Uk; Kim, Young Dae; Kim, Kee Sik; Choi, Jung Hyun; Kang, Hyun Jae; Kim, Jae Joong; Kang, Seok Min; Choi, Young Jin; Shin, Joon Han; Chun, Kook Jin; Shin, Dong Gu; Park, Seong Hoon; Kwan, Jun; Choi, Yu Jeong; Jeong, Myung Ho; Chae, Jei Keon; Kim, Dong Woon; Cho, Jung Rae; Han, Kyoo Rok; Won, Kyung Heon; Park, Sang Ho; Lee, Sang Kon; Kim, Sang Hoon; Jung, Jina; Kim, Cheol Ho

2017-10-01

The goal of this study was to compare the efficacy and safety of fixed-dose combinations of amlodipine/losartan potassium/chlorthalidone (A/L/C) and A/L in Korean patients with stage 2 hypertension inadequately controlled by A/L. This study was an 8-week, randomized double-blind, multicenter, phase III clinical trial. Three hundred forty volunteer patients with stage 2 hypertension were randomized to receive A/L/C or A/L. The primary end point was a change in sitting systolic blood pressure (SitSBP) after 8 weeks of treatment. As secondary end points, the change in SitSBP after 2 weeks of treatment and the change in sitting diastolic blood pressure (SitDBP) were compared between treatment groups. All patients were assessed for adverse events, clinical laboratory data, and vital signs. Of 330 patients from 33 medical centers, 328 patients who had available efficacy data were analyzed. After 8 weeks of double-blind treatment, the mean (SD) changes in SitSBP at 8 weeks were -16.4 (0.9) mm Hg and -6.9 (1.0) mm Hg in the A/L/C and A/L groups, respectively. A/L/C had a statistically superior blood pressure-lowering effect compared with that of A/L (mean [SD] difference, 9.5 [1.3] mm Hg; P < 0.001). The mean (SD) change in SitDBP at 8 weeks was significantly greater with A/L/C (-8.0 [0.6] mm Hg) than with A/L (-3.6 [0.6] mm Hg) (P < .001). In terms of the mean (SD) change in SitDBP at 2 weeks compared with baseline, A/L/C (-5.9 [0.5] mm Hg) was statistically different from A/L (-2.9 [0.5] mm Hg) (P < .001). Mean (SD) SitSBP change from baseline to week 2 was -13.2 (0.9) and -5.5 (0.9) in the A/L/C and A/L groups, respectively, with a statistically significant blood pressure-lowering effect (P < 0.001). The number of participants who achieved target blood pressure at week 8 was significantly higher in the A/L/C group (93 patients [55.7%]) than in the A/L group (48 [29.8%]) (P < 0.001). Adverse drug reactions were observed in 23 patients (7.0%), and the incidence of dizziness was significantly higher in the A/L/C group than in the A/L group (4.8% vs 0.6%, P = 0.037) There were no serious adverse events associated with the study drugs. The results of this study suggest that A/L/C had a significantly increased blood pressure-lowering efficacy compared with that of A/L and had a good safety profile. ClinicalTrials.gov identifier: NCT02916602. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Concentrations of prioritized pharmaceuticals in effluents from 50 large wastewater treatment plants in the US and implications for risk estimation.

PubMed

Kostich, Mitchell S; Batt, Angela L; Lazorchak, James M

2014-01-01

We measured concentrations of 56 active pharmaceutical ingredients (APIs) in effluent samples from 50 large wastewater treatment plants across the US. Hydrochlorothiazide was found in every sample. Metoprolol, atenolol, and carbamazepine were found in over 90% of the samples. Valsartan had the highest concentration (5300 ng/L), and also had the highest average concentration (1600 ng/L) across all 50 samples. Estimates of potential risks to healthy human adults were greatest for six anti-hypertensive APIs (lisinopril, hydrochlorothiazide, valsartan, atenolol, enalaprilat, and metoprolol), but nevertheless suggest risks of exposure to individual APIs as well as their mixtures are generally very low. Estimates of potential risks to aquatic life were also low for most APIs, but suggest more detailed study of potential ecological impacts from four analytes (sertraline, propranolol, desmethylsertraline, and valsartan). Published by Elsevier Ltd.

Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study.

PubMed

Senni, Michele; McMurray, John J V; Wachter, Rolf; McIntyre, Hugh F; Anand, Inder S; Duino, Vincenzo; Sarkar, Arnab; Shi, Victor; Charney, Alan

2018-03-01

The TITRATION trial investigated two strategies to initiate and up-titrate sacubitril/valsartan (LCZ696) to the same target dose, over a condensed (3-week) or conservative (6-week) period, in patients with heart failure with reduced ejection fraction (HFrEF) and systolic blood pressure (SBP) of ≥100 mmHg. This post hoc analysis examined the relationship between baseline SBP at screening and achievement of the target dose of sacubitril/valsartan of 97 mg/103 mg (also termed 'LCZ696 200 mg') twice per day during the study. Patients (n = 498) were categorized in four groups based on SBP at screening: 100-110 mmHg (n = 70); 111-120 mmHg (n = 93); 121-139 mmHg (n = 168) and ≥140 mmHg (n = 167). Overall, 72.7%, 76.1%, 85.6% and 82.9%, respectively, of patients in these SBP categories achieved and maintained the target dose of sacubitril/valsartan without down-titration/dose interruption over 12 weeks ('treatment success'). Compared with patients with SBP of 100-110 mmHg, rates of treatment success among patients in the higher SBP groups [111-120 mmHg (P = 0.96); 121-139 mmHg (P = 0.06) and ≥140 mmHg (P = 0.25)] did not differ significantly. A higher percentage of patients with lower SBP (100-110 mmHg) achieved treatment success with gradual up-titration (6 weeks) (∼80%) than with rapid up-titration (∼69%). Similar findings were observed with regard to 'tolerability success' (maintenance of the target dose for at least the final 2 weeks prior to study completion). Hypotension occurred more frequently in patients with lower SBP. The majority of patients (>80%) with SBP of ≥100 mmHg achieved and maintained the target dose of sacubitril/valsartan if the treatment was titrated gradually. These findings suggest that low SBP should not prevent clinicians from considering the initiation of sacubitril/valsartan. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

Rationale, study design, and implementation of the ACS1 study: effect of azilsartan on circadian and sleep blood pressure as compared with amlodipine.

PubMed

Kario, Kazuomi; Hoshide, Satoshi

2014-06-01

The ACS1 (Azilsartan Circadian and Sleep Pressure - the first study) is a multicenter, randomized, open-label, two parallel-group study carried out to investigate the efficacy of an 8-week oral treatment with azilsartan 20 mg in comparison with amlodipine 5 mg. The patients with stage I or II primary hypertension will be randomly assigned to either an azilsartan group (n=350) or an amlodipine group (n=350). The primary endpoint is a change in nocturnal systolic blood pressure (BP) as measured by ambulatory BP monitoring at the end of follow-up relative to the baseline level during the run-in period. In addition, we will carry out the same analysis after dividing four different nocturnal BP dipping statuses (extreme-dippers, dippers, nondipper, and risers). The findings of this study will help in establishing an appropriate antihypertensive treatment for hypertensive patients with a disrupted circadian BP rhythm.

Rationale, study design, and implementation of the ACS1 study: effect of azilsartan on circadian and sleep blood pressure as compared with amlodipine

PubMed Central

Hoshide, Satoshi

2014-01-01

Objective The ACS1 (Azilsartan Circadian and Sleep Pressure – the first study) is a multicenter, randomized, open-label, two parallel-group study carried out to investigate the efficacy of an 8-week oral treatment with azilsartan 20 mg in comparison with amlodipine 5 mg. Materials and methods The patients with stage I or II primary hypertension will be randomly assigned to either an azilsartan group (n=350) or an amlodipine group (n=350). The primary endpoint is a change in nocturnal systolic blood pressure (BP) as measured by ambulatory BP monitoring at the end of follow-up relative to the baseline level during the run-in period. In addition, we will carry out the same analysis after dividing four different nocturnal BP dipping statuses (extreme-dippers, dippers, nondipper, and risers). Conclusion The findings of this study will help in establishing an appropriate antihypertensive treatment for hypertensive patients with a disrupted circadian BP rhythm. PMID:24637789

Valsartan protects HK-2 cells from contrast media-induced apoptosis by inhibiting endoplasmic reticulum stress.

PubMed

Peng, Ping-An; Wang, Le; Ma, Qian; Xin, Yi; Zhang, Ou; Han, Hong-Ya; Liu, Xiao-Li; Ji, Qing-Wei; Zhou, Yu-Jie; Zhao, Ying-Xin

2015-12-01

Contrast-induced acute kidney injury (CI-AKI) is associated with increasing in-hospital and long-term adverse clinical outcomes in high-risk patients undergoing percutaneous coronary intervention (PCI). Contrast media (CM)-induced renal tubular cell apoptosis is reported to participate in this process by activating endoplasmic reticulum (ER) stress. An angiotensin II type 1 receptor (AT1R) antagonist can alleviate ER stress-induced renal apoptosis in streptozotocin (STZ)-induced diabetic mice and can reduce CM-induced renal apoptosis by reducing oxidative stress and reversing the enhancement of bax mRNA and the reduction of bcl-2 mRNA, but the effect of the AT1R blocker on ER stress in the pathogenesis of CI-AKI is still unknown. In this study, we explored the effect of valsartan on meglumine diatrizoate-induced human renal tubular cell apoptosis by measuring changes in ER stress-related biomarkers. The results showed that meglumine diatrizoate caused significant cell apoptosis by up-regulating the expression of ER stress markers, including glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein-homologous protein (CHOP) and caspase 12, in a time- and dose-dependent manner, which could be alleviated by preincubation with valsartan. In conclusion, valsartan had a potential nephroprotective effect on meglumine diatrizoate-induced renal cell apoptosis by inhibiting ER stress. © 2015 International Federation for Cell Biology.

Uniform nano-sized valsartan for dissolution and bioavailability enhancement: influence of particle size and crystalline state.

PubMed

Ma, Qiuping; Sun, Hongrui; Che, Erxi; Zheng, Xin; Jiang, Tongying; Sun, Changshan; Wang, Siling

2013-01-30

The central purpose of this study was to evaluate the impact of drug particle size and crystalline state on valsartan (VAL) formulations in order to improve its dissolution and bioavailability. VAL microsuspension (mean size 22 μm) and nanosuspension (30-80nm) were prepared by high speed dispersing and anti-solvent precipitation method and converted into powders through spray drying. Differential scanning calorimetry studies indicated amorphization of VAL in the spray-dried valsartan nanosuspension (SD-VAL-Nano) but recrystallization occurred after 6 months storage at room temperature. The spray-dried valsartan microsuspension (SD-VAL-Micro) conserved the crystalline form. The VAL dissolution rate and extent were markedly enhanced with both SD-VAL-Micro and SD-VAL-Nano as compared to crude VAL crystals over the pH range of 1.2-6.8. Pharmacokinetic studies in rats demonstrated a 2.5-fold increase in oral bioavailability in the case of SD-VAL-Nano compared with the commercial product while the SD-VAL-Micro provided a much less desirable pharmacokinetic profile. In conclusion, reducing particle size to the nano-scale appears to be a worthwhile and promising approach to obtain VAL products with optimum bioavailability. In addition, the impact of crystalline state on the bioavailability of nano-sized VAL might be not as big as that of particle size. Copyright © 2012 Elsevier B.V. All rights reserved.

Effect of renal function on the pharmacokinetics of LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor.

PubMed

Ayalasomayajula, Surya P; Langenickel, Thomas H; Jordaan, Pierre; Zhou, Wei; Chandra, Priyamvada; Albrecht, Diego; Pal, Parasar; Rajman, Iris; Sunkara, Gangadhar

2016-09-01

LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor, is indicated for chronic heart failure (HF) and reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death and hospitalization for HF. Following oral administration, LCZ696 provides systemic exposure to valsartan and sacubitril (a prodrug), and its metabolite sacubitrilat (the active neprilysin inhibitor, formerly named as LBQ657), which is eliminated primarily via renal route. Since renal dysfunction is a common comorbidity in patients with HF, two open-label studies assessing the effect of mild, moderate, and severe renal impairment were conducted. Patients with mild (N = 8; creatinine clearance [CrCl] 50 to ≤80 mL/min), moderate (N = 8; CrCl 30 to <50 mL/min), and severe (N = 6; CrCl <30 mL/min) renal impairment and matching healthy subjects (CrCl >80 mL/min) for each severity group were enrolled to assess the pharmacokinetics of LCZ696 analytes following administration of LCZ696 400 mg once daily (QD) on days 1 and 5. The steady-state Cmax and AUC0-24h of sacubitril and valsartan were unchanged in patients with renal impairment compared with healthy subjects. However, the steady-state Cmax of sacubitrilat was increased by ∼60 % in patients irrespective of degree of renal impairment; half-life increased from 12 h (in healthy subjects) to 21.1, 23.7, and 38.5 h, respectively; and AUC0-24h was increased 2.10-, 2.24-, and 2.70-fold, respectively, in patients with mild, moderate, and severe renal impairment. Renal dysfunction increases exposure to sacubitrilat while not impacting sacubitril and valsartan exposure. LCZ696 was generally well tolerated in patients with renal impairment.

Efficacy of Sacubitril/Valsartan Relative to a Prior Decompensation: The PARADIGM-HF Trial.

PubMed

Solomon, Scott D; Claggett, Brian; Packer, Milton; Desai, Akshay; Zile, Michael R; Swedberg, Karl; Rouleau, Jean; Shi, Victor; Lefkowitz, Martin; McMurray, John J V

2016-10-01

This study assessed whether the benefit of sacubtril/valsartan therapy varied with clinical stability. Despite the benefit of sacubitril/valsartan therapy shown in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, it has been suggested that switching from an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker should be delayed until occurrence of clinical decompensation. Outcomes were compared among patients who had prior hospitalization within 3 months of screening (n = 1,611 [19%]), between 3 and 6 months (n = 1,009 [12%]), between 6 and 12 months (n = 886 [11%]), >12 months (n = 1,746 [21%]), or who had never been hospitalized (n = 3,125 [37%]). Twenty percent of patients without prior HF hospitalization experienced a primary endpoint of cardiovascular death or heart failure (HF) hospitalization during the course of the trial. Despite the increased risk associated with more recent hospitalization, the efficacy of sacubitril/valsartan therapy did not differ from that of enalapril according to the occurrence of or time from hospitalization for HF before screening, with respect to the primary endpoint or with respect to cardiovascular or all-cause mortality. Patients with recent HF decompensation requiring hospitalization were more likely to experience cardiovascular death or HF hospitalization than those who had never been hospitalized. Patients who were clinically stable, as shown by a remote HF hospitalization (>3 months prior to screening) or by lack of any prior HF hospitalization, were as likely to benefit from sacubitril/valsartan therapy as more recently hospitalized patients. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Anti-albuminuric effect of losartan versus amlodipine in hypertensive Japanese patients with type 2 diabetes mellitus: A prospective, open-label, randomized, comparative study

PubMed Central

Ohno, Yasuhiro; Nishimura, Akiyoshi; Iwai, Hiroshi; Hirota, Noriyuki; Yamauchi, Takaaki; Fujimoto, Mika; Miyatake, Toshiyuki; Arai, Hiroshi; Aoki, Norihiko

2007-01-01

Abstract Background The antiproteinuric effect of the angiotensin II receptor-antagonist losartan has been observed in patients with type 2 diabetes mellitus (T2DM). Proteinuria is considered to be a predictor of the progression of kidney disease. Objective The aims of the present study were to compare and examine the ability of losartan and amlodipine to ameliorate albuminuria in hypertensive Japanese patients (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) with T2DM and whether the change in albuminuria was associated with a change in glomerular filtration rate (GFR). Methods This prospective, open-label, randomized, comparative study was conducted over 3 months at the Kinki University School of Medicine, Osaka-Sayama, Japan. Hypertensive patients with T2DM were enrolled and randomly assigned to 1 of 2 study groups receiving either losartan (25–100 mg/d) or the calcium channel-blocker amlodipine (2.5–5 mg/d). Urinary albumin excretion (UAE), creatinine clearance, and GFR were recorded at study initiation (baseline) and study end (month 3). The GFR was measured from the fractional renal accumulation of 99mTc-diethylenetriaminepentaacetic acid. Adverse events (AEs) were monitored by a clinical research nurse during the examination. Results Fifty patients were asked to enroll and 38 returned the informed written consent. Thirty-five Japanese patients were included in the final study analysis. Seventeen patients were assigned to the losartan group (male sex, 10 [58.8%]; mean [SD] age, 58.1 [8.2] years) and 18 were assigned to the amlodipine group (male sex, 10 [55.6%]; mean [SD] age, 57.4 [8.9] years); no significant between-group difference in demographics was observed. A significant decrease from baseline to month 3 of mean (SD) UAE was observed in the losartan group (352.5 [556.6] mg/d vs 275.7 [466.1] mg/d; P = 0.048). No significant difference in mean (SD) UAE was observed in the amlodipine group for the same time period (298.2 [416.6] mg/d vs 322.7 [415.4] mg/d). There was a statistically significant difference found in the mean (SD) percent change of UAE from baseline to month 3 in the losartan group compared with the amlodipine group (−23.52 [28.42] vs +27.90 [63.51]; P = 0.004). Neither group was associated with a significant change in GFR during the course of the study. No patient discontinued the study due to AEs that were considered, by the investigator, to be possibly or probably associated with study treatment. Conclusions Treatment with losartan, but not amlodipine, was associated with a reduction in albuminuria in these hypertensive Japanese patients with T2DM within a period as short as 3 months. Neither drug was associated with a significant change in GFR. Therefore, the reduction of UAE was independent of a change in the GFR. PMID:24678123

Assessment of Drug-Drug Interaction Potential Between Atorvastatin and LCZ696, A Novel Angiotensin Receptor Neprilysin Inhibitor, in Healthy Chinese Male Subjects.

PubMed

Ayalasomayajula, Surya; Pan, Wei; Han, Yi; Yang, Fan; Langenickel, Thomas; Pal, Parasar; Zhou, Wei; Yuan, Yaozong; Rajman, Iris; Sunkara, Gangadhar

2017-04-01

LCZ696 (sacubitril/valsartan), a novel angiotensin receptor neprilysin inhibitor has been recently approved for the treatment of patients with heart failure (HF) and reduced ejection fraction. As several HF patients are likely to use statins as co-medications, the potential for a pharmacokinetic drug-drug interaction between atorvastatin and LCZ696 was evaluated. This was an open-label, three-period, single-sequence study in 28 healthy Chinese male subjects wherein LCZ696 200 mg was administered twice daily for 5 days in period 1. Following a washout period, atorvastatin 80 mg was administered once daily for 4 days (period 2) and subsequently co-administered with LCZ696 200 mg for 5 days (period 3). Serial plasma samples were collected to determine pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan) and atorvastatin and its metabolites. Atorvastatin co-administration had no effect on the pharmacokinetics of LBQ657, while the AUC τ,ss and C max,ss of sacubitril increased by 30 and 19 %, respectively, and the corresponding values for valsartan decreased by 19 and 9 %, respectively. Co-administration with LCZ696 increased C max,ss of atorvastatin, o-hydroxyatorvastatin, and p-hydroxyatorvastatin by 74, 68, and 108 %, respectively, and the AUC τ,ss of corresponding analytes increased by 34, 22, and 26 %, respectively. While atorvastatin had no significant impact on the pharmacokinetics of LCZ696 analytes upon co-administration, the C max of atorvastatin and its metabolites increased twofold, with a marginal increase in AUC (<1.3-fold). Multiple-dose administration of LCZ696 200 mg twice daily and atorvastatin 80 mg once daily either alone or in combination was generally safe and well tolerated in healthy subjects.

Different effect of losartan and amlodipine on penile structures in male spontaneously hypertensive rats.

PubMed

Toblli, Jorge Eduardo; Stella, Inés; Mazza, Osvaldo Néstor; Ferder, León; Inserra, Felipe

2004-01-01

Erectile dysfunction is highly prevalent in hypertensive patients. Since both angiotensin II receptor type-1 blockers (ARBs) and calcium antagonists are current and effective antihypertensive drugs, the aim of this study was to determine possible differences between ARBs and calcium antagonists concerning the protection of penile structures from the deleterious effects of arterial hypertension. During 6 months, 3 groups of male spontaneously hypertensive rats (SHR) and 1 of Wistar-Kyoto (WKY) rats, as a control group, were studied: SHR without treatment; SHR with losartan (L) 30 mg/kg/day; SHR with amlodipine (A) 3 mg/kg/day, and WKY without treatment. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries, cavernous tissue fibrosis and collagen type III (COL III) were evaluated. After 6 months, SHR+L and SHR+A showed a similar reduction in blood pressure compared with untreated SHR. However, only SHR+L and control WKY presented significantly lower values of: CSM (p < 0.01), VSM (p < 0.01), and COL III (p < 0.01) when compared with either untreated SHR or SHR+A. There was also a positive correlation between left ventricular mass and proteinuria with VSM from cavernous arteries, CSM and COL III in untreated SHR and SHR+A. These relations were not present in SHR+L and WKY. Although losartan and amlodipine achieved similar blood pressure control, losartan but not amlodipine showed a significant protective role against structural changes in the vessels and cavernous spaces of the erectile tissue caused by arterial hypertension. Copyright 2004 S. Karger AG, Basel

Development of a Radiolabeled Amlodipine Analog for L-type Calcium Channel Imaging.

PubMed

Firouzyar, Tahereh; Jalilian, Amir Reza; Aboudzadeh, Mohammad Reza; Sadeghpour, Hossein; Pooladi, Mehrban; Shafiee-Ardestani, Mahdi; Khalaj, Ali

2017-01-01

The non-invasive imaging and quantification of L-type calcium channels (also known as dihydropyridine channels) in living tissues is of great interest in diagnosis of congestive heart failure, myocardial hypertrophy, irritable bowel syndrome etc. Technetium-99m labeled amlodipine conjugate ([99mTc]-DTPA-AMLO) was prepared starting freshly eluted (<1 h) 99mTechnetium pertechnetate (86.5 MBq) and conjugated DTPAAMLO at pH 5 in 30 min at room temperature in high radiochemical purity (>99%, RTLC; specific activity: 55-60 GBq/mmol). The calcium channel blockade activity (CCBA) and apoptosis/necrosis assay of DTPA-amlodipine conjugate evaluations were performed for the conjugate. Log P, stability, bio-distribution and imaging studies were performed for the tracer followed by biodistribution studies as well as imaging. The conjugate demonstrated low toxicity on MCF-7 cells and CCBA (at µm level) compared to the amlodipine. The tracer was stable up to 4 h in final production and presence of human serum and log P (-0.49) was consistent with a water soluble complex. The tracer was excreted through kidneys and liver as expected for dihydropyridines; excluding excretory organs, calcium channel rich smooth muscle cells; including colon, intestine and lungs which demonstrated significant uptake. SPECT images supported the bio-distribution data up to 4 h. significant uptake of [99mTc]-DTPA-AMLO was obtained in calcium channel rich organs. The complex can be a candidate for further SPECT imaging for L-type calcium channels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Long-term effects of L- and N-type calcium channel blocker on uric acid levels and left atrial volume in hypertensive patients.

PubMed

Masaki, Mitsuru; Mano, Toshiaki; Eguchi, Akiyo; Fujiwara, Shohei; Sugahara, Masataka; Hirotani, Shinichi; Tsujino, Takeshi; Komamura, Kazuo; Koshiba, Masahiro; Masuyama, Tohru

2016-11-01

Left ventricular (LV) diastolic dysfunction is associated with hypertension and hyperuricemia. However, it is not clear whether the L- and N-type calcium channel blocker will improve LV diastolic dysfunction through the reduction of uric acid. The aim of this study was to investigate the effects of anti-hypertensive therapy, the L- and N-type calcium channel blocker, cilnidipine or the L-type calcium channel blocker, amlodipine, on left atrial reverse remodeling and uric acid in hypertensive patients. We studied 62 patients with untreated hypertension, randomly assigned to cilnidipine or amlodipine for 48 weeks. LV diastolic function was assessed with the left atrial volume index (LAVI), mitral early diastolic wave (E), tissue Doppler early diastolic velocity (E') and the ratio (E/E'). Serum uric acid levels were measured before and after treatment. After treatment, systolic and diastolic blood pressures equally dropped in both groups. LAVI, E/E', heart rate and uric acid levels decreased at 48 weeks in the cilnidipine group but not in the amlodipine group. The % change from baseline to 48 weeks in LAVI, E wave, E/E' and uric acid levels were significantly lower in the cilnidipine group than in the amlodipine group. Larger %-drop in uric acid levels were associated with larger %-reduction of LAVI (p < 0.01). L- and N-type calcium channel blocker but not L-type calcium channel blocker may improve LV diastolic function in hypertensive patients, at least partially through the decrease in uric acid levels.

Inhibition of angiotensin-converting enzyme increases oestradiol production in ewes submitted to oestrous synchronization protocol.

PubMed

Costa, A s; Junior, A S; Viana, G E N; Muratori, M C S; Reis, A M; Costa, A P R

2014-10-01

This study aimed at evaluating the effects of angiotensin-converting enzyme inhibitor (enalapril) and angiotensin II antagonist (valsartan) on the oestradiol and progesterone production in ewes submitted to oestrous synchronization protocol. The animals were weighed and randomly divided into three groups (n = 7). A pre-experiment conducted to verify the effectiveness and toxicity of enalapril (0.5 mg/kg LW) and valsartan (2.2 mg/kg LW) showed that, in the doses used, these drugs were effective in reducing blood pressure without producing toxic effects. In the experiment, all animals were subjected to oestrous synchronization protocol during 12 days. On D10, D11 and D12, animals received saline, enalapril or valsartan (same doses of the pre-experiment), according to the group randomly divided. The hormonal analysis showed an increase in oestradiol on the last day of the protocol (D12) in animals that received enalapril (p < 0.05), but not in other groups, without changing the concentration of progesterone in any of the treatments. It is concluded that valsartan and enalapril are safe and effective subcutaneously for use in sheep and that the angiotensin-converting enzyme (ACE) inhibition with enalapril leads to an increase in oestradiol production near ovulation without changing the concentration of progesterone. This shows that ACE inhibition may be a useful tool in reproductive biotechnologies involving induction and synchronization of oestrus and ovulation in sheep. © 2014 Blackwell Verlag GmbH.

A Comparison between Use of Spray and Freeze Drying Techniques for Preparation of Solid Self-Microemulsifying Formulation of Valsartan and In Vitro and In Vivo Evaluation

PubMed Central

Singh, Sanjay Kumar; Vuddanda, Parameswara Rao; Singh, Sanjay; Srivastava, Anand Kumar

2013-01-01

The objective of the present study was to develop self micro emulsifying formulation (SMEF) of valsartan to improve its oral bioavailability. The formulations were screened on the basis of solubility, stability, emulsification efficiency, particle size and zeta potential. The optimized liquid SMEF contains valsartan (20% w/w), Capmul MCM C8 (16% w/w), Tween 80 (42.66% w/w) and PEG 400 (21.33% w/w) as drug, oil, surfactant and co-surfactant, respectively. Further, Liquid SMEF was adsorbed on Aerosol 200 by spray and freeze drying methods in the ratio of 2 : 1 and transformed into free flowing powder. Both the optimized liquid and solid SMEF had the particle size <200 nm with rapid reconstitution properties. Both drying methods are equally capable for producing stable solid SMEF and immediate release of drug in in vitro and in vivo conditions. However, the solid SMEF produced by spray drying method showed high flowability and compressibility. The solid state characterization employing the FTIR, DSC and XRD studies indicated insignificant interaction of drug with lipid and adsorbed excipient. The relative bioavailability of solid SMEF was approximately 1.5 to 3.0 folds higher than marketed formulation and pure drug. Thus, the developed solid SMEF illustrates an alternative delivery of valsartan as compared to existing formulations with improved bioavailability. PMID:23971048

Development of a stability-indicating CE assay for the determination of amlodipine enantiomers in commercial tablets.

PubMed

Fakhari, Ali Reza; Nojavan, Saeed; Haghgoo, Soheila; Mohammadi, Ali

2008-11-01

A simple, accurate, precise and sensitive method using CD for separation and stability indicating assay of enantiomers of amlodipine in the commercial tablets has been established. Several types of CD were evaluated and best results were obtained using a fused-silica capillary with phosphate running buffer (100 mM, pH 3.0) containing 5 mM hydroxypropyl-alpha-CD. The method has shown adequate separation for amlodipine enantiomers from its degradation products. The drug was subjected to oxidation, hydrolysis, photolysis and heat to apply stress conditions. The range of quantitation for both enantiomers was 5-150 microg/mL. Intra- and inter-day RSD (n=6) was <4%. The limit of quantification that produced the requisite precision and accuracy was found to be 5 microg/mL for both enantiomers. The LOD for both enantiomers was found to be 0.5 microg/mL. Degradation products produced as a result of stress studies did not interfere with the detection of enantiomers and the assay can thus be considered stability indicating.

Preparation and preclinical evaluation of 68Ga-DOTA-amlodipine for L-type calcium channel imaging.

PubMed

Firuzyar, Tahereh; Jalilian, Amir Reza; Aboudzadeh, Mohammad Reza; Sadeghpour, Hossein; Shafiee-Ardestani, Mahdi; Khalaj, Ali

2016-01-01

In order to develop a possible tracer for L-type calcium channel imaging, we here report the development of a Ga-68 amlodipine derivative for possible PET imaging. Amlodipine DOTA conjugate was synthesized, characterized and went through calcium channel blockade, toxicity, apoptosis/necrosis tests. [ 68 Ga] DOTA AMLO was prepared at optimized conditions followed by stability tests, partition coefficient determination and biodistribution studies using tissue counting and co incidence imaging up to 2 h. [ 68 Ga] DOTA AMLO was prepared at pH 4-5 in 7-10 min at 95°C in high radiochemical purity (>99%, radio thin layer chromatography; specific activity: 1.9-2.1 GBq/mmol) and was stable up to 4 h with a log P of -0.94. Calcium channel rich tissues including myocardium, and tissues with smooth muscle cells such as colon, intestine, and lungs demonstrated significant uptake. Co incidence images supported the biodistribution data up to 2 h. The complex can be a candidate for further positron emission tomography imaging for L type calcium channels.

Influence of pHo on calcium channel block by amlodipine, a charged dihydropyridine compound. Implications for location of the dihydropyridine receptor

PubMed Central

1989-01-01

We have investigated the modulation of L-type calcium channel currents in isolated ventricular cells by the dihydropyridine derivative amlodipine, a weak base with a pKa of 8.6. Under conditions that favor neutral drug molecules, amlodipine block resembles other, previously described, neutral dihydropyridine derivatives: block is more pronounced at depolarized voltages, repetitive pulsing is not needed to promote block, and recovery is complete at hyperpolarized voltages. When the drug is ionized, depolarized voltages still enhance block, however, the time course is slow and speeded by repetitive pulses that open channels. Recovery from block by ionized drug molecules is very slow and incomplete, but can be rapidly modified by changes in external hydrogen ion concentration. We conclude from these observations that the degree of ionization of the drug molecule can affect access to the dihydropyridine receptor and that external protons can interact with the drug-receptor complex even if channels are blocked and closed. These observations place limitations on the location of this receptor in the ventricular cell membrane. PMID:2549176

Amlodipine and the Successful Management of Post-Electroconvulsive Therapy Agitation.

PubMed

Shahriari, Ali; Khooshideh, Maryam; Sheikh, Mahdi

2016-01-01

Electroconvulsive therapy (ECT) is a highly effective nonpharmacologic treatment for the management of depression and some other psychiatric disorders. Post-ECT agitation occurs in up to 12% of ECT treatments and is characterized by motor restlessness, irritability, disorientation, and panic-like behaviors. The severity of post-ECT agitation ranges from mild and self-limited to serious and severe forms requiring prompt medical intervention to protect the patient and the medical staff. In severe agitation medical management may be necessary which consists of using sedative agents, either benzodiazepines or propofol. The side-effects of these sedative agents, especially in the elderly population, necessitate finding ways that could help the prevention of the occurrence of agitation after ECT treatments. We report a 68-year-old female with major depression who was referred for ECT. She experienced severe post-ECT agitation requiring medical intervention after all ECT treatments. Administering of oral amlodipine (5 mg) one hour before ECT treatment successfully prevented the occurrence of post-ECT agitation in this patient. We briefly discuss the possible underlying mechanisms and pathophysiology of amlodipine in the prevention of post-ECT agitation.

The effect of valsartan versus non-RAAS treatment on autoregulation of cerebral blood flow.

PubMed

Périard, Daniel; Rey, Marie-Antoinette; Casagrande, Damien; Vesin, Jean-Marc; Carrera, Emmanuel; Hayoz, Daniel

2012-01-01

Cerebral autoregulation (CA) is a protective mechanism which maintains the steadiness of the cerebral blood flow (CBF) through a broad range of systemic blood pressure (BP). Acute hypertension has been shown to reduce the cerebrovascular adaptation to BP variations. However, it is still unknown whether CA is impaired in chronic hypertension. This study evaluated whether a strict control of BP affects the CA in patients with chronic hypertension, and compared a valsartan-based regimen to a regimen not inhibiting the renin-angiotensin-aldosterone system (non-RAAS). Eighty untreated patients with isolated systolic hypertension were randomized to valsartan 320 mg or to a non-RAAS regimen during 6 months. The medication was upgraded to obtain BP <140/90 mm Hg. Continuous recordings of arterial BP and CBF velocity (transcranial Doppler) were performed during periods of 5 minutes, at rest, and at different levels of alveolar CO(2) pressure provided by respiratory maneuvers. The dominant frequency of CBF oscillations was determined for each patient. Dynamic CA was measured as the mean phase shift between BP and CBF by cross-spectral analysis in the medium frequency and in the dominant CBF frequency. Mean ambulatory 24-hour BP fell from 144/87 to 127/79 mm Hg in the valsartan group and from 144/87 to 134/81 mm Hg in the non-RAAS group (p = 0.13). Both groups had a similar reduction in the central BP and in the carotido-femoral pulse wave velocity. The average phase shift between BP fluctuations and CBF response at rest was normal at randomization (1.82 ± 0.08 s), which is considered a preserved autoregulation and increased to 1.91 ± 0.12 s at the end of study (p = 0.45). The comparison of both treatments showed no significant difference (-0.01 ± 0.17 s vs. 0.16 ± 0.16 s, p = 0.45) for valsartan versus non-RAAS groups. The plasmatic level of glycosylated hemoglobin decreased in the valsartan arm compared to the non-RAAS arm (-0.23 ± 0.06 vs. -0.08 ± 0.07%, p = 0.07). In elderly hypertensive men with isolated chronic systolic hypertension, CA seems efficient at baseline and is not significantly affected by 6 months of BP-lowering treatment. This suggests that the preventive effects of BP medication against stroke are not mediated through a restoration of the CA. Copyright © 2012 S. Karger AG, Basel.

Efficacy of methylene blue in an experimental model of calcium channel blocker-induced shock.

PubMed

Jang, David H; Donovan, Sean; Nelson, Lewis S; Bania, Theodore C; Hoffman, Robert S; Chu, Jason

2015-04-01

Calcium channel blocker poisonings account for a substantial number of reported deaths from cardiovascular drugs. Although supportive care is the mainstay of treatment, experimental therapies such as high-dose insulin-euglycemia and lipid emulsion have been studied in animal models and used in humans. In the most severe cases, even aggressive care is inadequate and deaths occur. In both experimental models and clinical cases of vasodilatory shock, methylene blue improves hemodynamic measures. It acts as a nitric oxide scavenger and inhibits guanylate cyclase that is responsible for the production of cyclic guanosine monophosphate (cGMP). Excessive cGMP production is associated with refractory vasodilatory shock in sepsis and anaphylaxis. The aim of this study is to determine the efficacy of methylene blue in an animal model of amlodipine-induced shock. Sprague-Dawley rats were anesthetized, ventilated, and instrumented for continuous blood pressure and pulse rate monitoring. The dose of amlodipine that produced death within 60 minutes was 17 mg/kg per hour (LD50). Rats were divided into 2 groups: amlodipine followed by methylene blue or amlodipine followed by normal saline solution, with 15 rats in each group. Rats received methylene blue at 2 mg/kg during 5 minutes or an equivalent amount of normal saline solution in 3 intervals from the start of the protocol: minutes 5, 30, and 60. The animals were observed for a total of 2 hours after the start of the protocol. Mortality risk and survival time were analyzed with Fisher's exact test and Kaplan-Meier survival analysis with the log rank test. Overall, 1 of 15 rats (7%) in the saline solution-treated group survived to 120 minutes compared with 5 of 15 (33%) in the methylene blue-treated group (difference -26%; 95% confidence interval [CI] -54% to 0.3%). The median survival time for the normal saline solution group was 42 minutes (95% CI 28.1 to 55.9 minutes); for the methylene blue group, 109 minutes (95% CI 93.9 to 124.1 minutes). Pulse rate and mean arterial pressure (MAP) differences between groups were analyzed until 60 minutes. Pulse rate was significantly higher in the methylene blue-treated group beginning 25 minutes after the start of the amlodipine infusion (95% CI 30 to 113 minutes) that was analyzed until 60 minutes. MAP was significantly higher in the methylene blue-treated group starting 25 minutes after the amlodipine infusion (95% CI 2 to 30 minutes) that was analyzed until 60 minutes. Methylene blue did not result in a significant difference in mortality risk. There was an increased pulse rate, MAP, and median survival time in the methylene blue group. Copyright © 2014 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

Efficacy of Methylene Blue in an Experimental Model of Calcium Channel Blocker Induced Shock

PubMed Central

Jang, David H.; Donovan, Sean; Nelson, Lewis S.; Bania, Theodore C.; Hoffman, Robert S.; Chu, Jason

2014-01-01

BACKGROUND Calcium channel blocker poisonings account for a substantial number of reported deaths from cardiovascular drugs. While supportive care is the mainstay of treatment, experimental therapies such as high dose insulin-euglycemia and lipid emulsion have been studied in animal models and used in humans. In the most severe cases even aggressive care is inadequate and deaths occur. In both experimental models and clinical cases of vasodilatory shock, methylene blue improves hemodynamic measures. Methylene blue acts as both a nitric oxide scavenger and inhibits guanylate cyclase that is responsible for the production of cGMP. Excessive cGMP production is associated with refractory vasodilatory shock in sepsis and anaphylaxis. The aim of this study was to determine the efficacy of methylene blue in an animal model of amlodipine-induced shock. METHODS Sprague-Dawley rats were anesthetized, ventilated and instrumented for continuous blood pressure and heart rate monitoring. The dose of amlodipine that produced death within 60 minutes was 17 mg/kg/hour (LD50). Rats were divided into 2 groups: amlodipine followed by methylene blue or amlodipine followed by normal saline (NS) with 15 rats in each group. Rats received methylene blue at 2 mg/kg over 5 mins or an equivalent amount of NS in three intervals from the start of the protocol: Minute 5, 30, and 60. The animals were observed for a total of 2 hours after the start of the protocol. Mortality risk and survival time were analyzed using Fisher’s exact test and Kaplan Meier survival analysis with the log rank test. RESULTS Overall, 1/15 (7%) rats in the saline-treated group survived to 120 minutes compared with 5/15 (33%) rats in the methylene blue-treated group (difference −26%, 95% CI –54%, 0.3%). The median survival time for the NS group was 42 min (95% CI, 28.1,55.9) and the methylene blue group was 109 min (95% CI, 93.9,124.1). Heart rate and MAP differences between groups were analyzed until 60 minutes. Heart rate was significantly higher in the methylene blue-treated group starting 25 min after the start of the amlodipine infusion (95% CI, 30–113) that was analyzed until 60 minutes. MAP was significantly higher in the methylene blue-treated group starting 25 min after the amlodipine infusion (95% CI, 2–30) that was analyzed up until 60 minutes. CONCLUSIONS Methylene blue did not result in a significant difference in mortality risk. There was an increase heart rate, MAP and median survival time in the methylene blue group. PMID:25441767

Impaired endothelial function and arterial stiffness in patients with type 2 diabetes - The effect of a very low-dose combination of fluvastatin and valsartan.

PubMed

Boncelj Svetek, Maja; Eržen, Barbara; Kanc, Karin; Šabovič, Mišo

2017-03-01

Patients with type 2 diabetes are at increased cardiovascular risk. The aim was to explore whether the impaired arterial wall characteristics typical of these patients could be improved by the unique beneficial effects of a very low-dose combination of fluvastatin and valsartan (low-flu/val). Forty middle-aged males (50.4±6.1years) with type 2 diabetes were recruited to a double-blind, randomized study. Patients (N=20) received low-flu/val (10/20mg) or placebo (N=20) over 30days in addition to their regular therapy. Brachial artery flow mediated dilation (FMD), common carotid artery pulse wave velocity (PWV) and β-stiffness were assessed before and after treatment, and 3 and 6months after treatment discontinuation. The treatment was then repeated. Arterial wall characteristics significantly improved. After 30days of intervention, FMD increased from 2.4±0.3 to 4.2±0.3 (p<0.001), PWV decreased from 6.4±0.1 to 5.8±0.2 (p<0.001) and β stiffness decreased from 7.8±0.4 to 6.7±0.4 (p<0.001). Lipids and arterial pressure did not change. After treatment discontinuation, the beneficial effects decreased over the following months. The repetition of treatment completely regained the initial benefits. No changes were observed in the placebo group. Low-flu/val added on-top of optimal therapy substantially improves arterial wall characteristics in patients with type 2 diabetes. Copyright © 2016 Elsevier Inc. All rights reserved.

The effects of the combined use of a PDE5 inhibitor and medications for hypertension, lower urinary tract symptoms and dyslipidemia on corporal tissue tone.

PubMed

Lee, J H; Chae, M R; Park, J K; Jeon, J H; Lee, S W

2012-01-01

ED is closely associated with its comorbidities (hypertension, dyslipidemia and lower urinary tract symptoms (LUTS)). Therefore, several drugs have been prescribed simultaneously with PDE5 inhibitors. If a specific medication for ED comorbidities has enhancing effects on PDE5 inhibitors, it offers alternative combination therapy in nonresponders to monotherapy with PDE5 inhibitors and allows clinicians to treat ED and its comorbidities simultaneously. To establish theoretical basis of choosing an appropriate medication for ED and concomitant disease, we examined the effects combining a PDE5 inhibitor with representative drugs for hypertension, dyslipidemia and LUTS on relaxing the corpus cavernosum of rabbits using the organ-bath technique. The effect of mirodenafil on relaxing phenylephrine-induced cavernosal contractions was significantly enhanced by the presence of 10(-4) M losartan, 10(-6) M nifedipine, 10(-6) M amlodipine, 10(-7) M doxazosin and 10(-9) M tamsulosin (P<0.05). The maximum relaxation effects were 47.2±3.8%, 57.6±2.6%, 64.0±3.7%, 76.1±5.7% and 71.7±5.4%, respectively. Enalapril and simvastatin had no enhancing effects. The relaxation induced by sodium nitroprusside alone (39.0±4.0%) was significantly enhanced in the presence of the 10(-4) M losartan (66.0±6.0%, P<0.05). Tetraethylammonium (1 mM) significantly inhibited the enhancement effects of tamsulosin and doxazosin on mirodenafil-induced relaxation (doxazosin: 76.1±5.7% vs 45.3±2.3%; tamsulosin: 71.7±5.4% vs 48.1±3.5%). On the basis of these findings, losartan seemed to induce synergistic effects through an interaction with nitric oxide. In addition, K(+) channel activation could be one of the mechanisms for the synergistic effect of combining mirodenafil with doxazosin or tamsulosin. We believe that the combination of a PDE5 inhibitor with losartan, nifedipine, amlodipine, doxazosin or tamsulosin could be a pharmacologic strategy for simultaneously treating ED and its comorbidities and increasing response rates to PDE5 inhibitors.

Effects of Sacubitril/Valsartan in the PARADIGM-HF Trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) According to Background Therapy.

PubMed

Okumura, Naoki; Jhund, Pardeep S; Gong, Jianjian; Lefkowitz, Martin P; Rizkala, Adel R; Rouleau, Jean L; Shi, Victor C; Swedberg, Karl; Zile, Michael R; Solomon, Scott D; Packer, Milton; McMurray, John J V

2016-09-01

In the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan was more effective than the angiotensin-converting enzyme inhibitorenalapril in patients with heart failure and reduced ejection fraction. We examined whether this benefit was consistent irrespective of background therapy. We examined the effect of study treatment in the following subgroups: diuretics (yes/no), digitalis glycoside (yes/no), mineralocorticoid receptor antagonist (yes/no),and defibrillating device (implanted defibrillating device, yes/no). We also examined the effect of study drug according to β-blocker dose (≥50% and <50% of target dose) and according to whether patients had undergone previous coronary revascularization. We analyzed the primary composite end point of cardiovascular death or heart failure hospitalization, as well as cardiovascular death. Most randomized patients (n=8399)were treated with a diuretic (80%) and β-blocker (93%); 47% of those taking a β-blocker were treated with ≥50% of the recommended dose. In addition, 4671 (56%) were treated with a mineralocorticoid receptor antagonist, 2539 (30%) with digoxin, and 1243 (15%) had a defibrillating device; 2640 (31%) had undergone coronary revascularization. Overall, the sacubitril/valsartan versus enalapril hazard ratio for the primary composite end point was 0.80 (95% confidence interval,0.73-0.87;P<0.001) and for cardiovascular death was0.80 (0.71-0.89;P<0.001). The effect of sacubitril/valsartan was consistent across all subgroups examined. The hazard ratio for primary end point ranged from 0.74 to 0.85 and for cardiovascular death rangedfrom 0.75 to 0.89, with no treatment-by-subgroup interaction. The benefit of sacubitril/valsartan, over an angiotensin-converting enzyme inhibitor, was consistent regardless of background therapy and irrespective of previouscoronary revascularization or β-blocker dose. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255. © 2016 American Heart Association, Inc.

Long-term blockade of L/N-type Ca2+ channels by cilnidipine ameliorates repolarization abnormality of the canine hypertrophied heart

PubMed Central

Takahara, A; Nakamura, Y; Wagatsuma, H; Aritomi, S; Nakayama, A; Satoh, Y; Akie, Y; Sugiyama, A

2009-01-01

Background and purpose: The heart of the canine model of chronic atrioventricular block is known to have a ventricular electrical remodelling, which mimics the pathophysiology of long QT syndrome. Using this model, we explored a new pharmacological therapeutic strategy for the prevention of cardiac sudden death. Experimental approach: The L-type Ca2+ channel blocker amlodipine (2.5 mg·day−1), L/N-type Ca2+ channel blocker cilnidipine (5 mg·day−1), or the angiotensin II receptor blocker candesartan (12 mg·day−1) was administered orally to the dogs with chronic atrioventricular block for 4 weeks. Electropharmacological assessments with the monophasic action potential (MAP) recordings and blood sample analyses were performed before and 4 weeks after the start of drug administration. Key results: Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval, MAP duration and beat-to-beat variability of the ventricular repolarization period were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of adrenaline, angiotensin II and aldosterone decreased in the cilnidipine group. In contrast, plasma concentrations of angiotensin II and aldosterone were elevated in the amlodipine group, whereas in the candesartan group an increase in plasma levels of angiotensin II and a decrease in noradrenaline and adrenaline concentrations were observed. Conclusions and implications: Long-term blockade of L/N-type Ca2+ channels ameliorated the ventricular electrical remodelling in the hypertrophied heart which causes the prolongation of the QT interval. This could provide a novel therapeutic strategy for the treatment of cardiovascular diseases. PMID:19785655

Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR.

PubMed

Rahman, Mahboob; Ford, Charles E; Cutler, Jeffrey A; Davis, Barry R; Piller, Linda B; Whelton, Paul K; Wright, Jackson T; Barzilay, Joshua I; Brown, Clinton D; Colon, Pedro J; Fine, Lawrence J; Grimm, Richard H; Gupta, Alok K; Baimbridge, Charles; Haywood, L Julian; Henriquez, Mario A; Ilamaythi, Ekambaram; Oparil, Suzanne; Preston, Richard

2012-06-01

CKD is common among older patients. This article assesses long-term renal and cardiovascular outcomes in older high-risk hypertensive patients, stratified by baseline estimated GFR (eGFR), and long-term outcome efficacy of 5-year first-step treatment with amlodipine or lisinopril, each compared with chlorthalidone. This was a long-term post-trial follow-up of hypertensive participants (n=31,350), aged ≥55 years, randomized to receive chlorthalidone, amlodipine, or lisinopril for 4-8 years at 593 centers. Participants were stratified by baseline eGFR (ml/min per 1.73 m(2)) as follows: normal/increased (≥90; n=8027), mild reduction (60-89; n=17,778), and moderate/severe reduction (<60; n=5545). Outcomes were cardiovascular mortality (primary outcome), total mortality, coronary heart disease, cardiovascular disease, stroke, heart failure, and ESRD. After an average 8.8-year follow-up, total mortality was significantly higher in participants with moderate/severe eGFR reduction compared with those with normal and mildly reduced eGFR (P<0.001). In participants with an eGFR <60, there was no significant difference in cardiovascular mortality between chlorthalidone and amlodipine (P=0.64), or chlorthalidone and lisinopril (P=0.56). Likewise, no significant differences were observed for total mortality, coronary heart disease, cardiovascular disease, stroke, or ESRD. CKD is associated with significantly higher long-term risk of cardiovascular events and mortality in older hypertensive patients. By eGFR stratum, 5-year treatment with amlodipine or lisinopril was not superior to chlorthalidone in preventing cardiovascular events, mortality, or ESRD during 9-year follow-up. Because data on proteinuria were not available, these findings may not be extrapolated to proteinuric CKD.

Platelet morphology and plasma indices of platelet activation in essential hypertension: effects of amlodipine-based antihypertensive therapy.

PubMed

Nadar, Sunil; Blann, Andrew D; Lip, Gregory Y H

2004-01-01

Platelet abnormalities have been described in hypertension, especially in the presence of target organ damage. Our aim was to study the differences in morphology and indices of platelet activation in treatment-naive patients with essential hypertension as compared to normotensive controls and secondly, to study the effects of amlodipine-based antihypertensive therapy on these indices. We recruited 42 previously untreated, newly diagnosed hypertensive patients (25 men; mean age 53 years) for the cross-sectional study, where data were compared with those from 30 normotensive controls (20 men; mean age 57 years). Of the 42 untreated hypertensive patients who were recruited, 27 patients successfully completed, the six-month treatment phase with amlodipine-based antihypertensive therapy. Platelet morphology (volume and mass) was quantified, and plasma markers of platelet activation (betaTG and sPsel) measured in citrated plasma. The mass of P-selectin in each platelet (pPsel) was determined by lysing a fixed number of platelets and then determining the levels of P-selectin in the lysate. Hypertensive patients had significantly higher platelet volume (P = 0.01) and mass (P = 0.003), plasma betaTG and sPsel, and pPsel levels (all P < 0.001) compared to the controls. After a mean treatment time of 6 months, there was a decrease in platelet volume (P < 0.001) and mass (P = 0.02), with lower pPsel, sPsel and BTG levels (all P < 0.001) compared to the untreated state. Treatment of uncomplicated essential hypertension using amlodipine-based anti-hypertensive therapy results in a reversal of the platelet morphology abnormalities and indices of platelet activation. This may contribute to a reduction in thrombosis-related complications seen in those whose blood pressure lowering is effective.

Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

PubMed

Gan, Lu; Jiang, Xuemin; Mendonza, Anisha; Swan, Therese; Reynolds, Christine; Nguyen, Joanne; Pal, Parasar; Neelakantham, Srikanth; Dahlke, Marion; Langenickel, Thomas; Rajman, Iris; Akahori, Mizuki; Zhou, Wei; Rebello, Sam; Sunkara, Gangadhar

2016-01-01

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions. © 2015, The American College of Clinical Pharmacology.

Use of compounded dispersing media for extemporaneous pediatric syrups with candesartan cilexetil and valsartan.

PubMed

Musko, Monika; Sznitowska, Malgorzata

2014-12-01

Available tablets or capsules for adults are often used to prepare extemporaneously formulated medicines appropriate for children. The most acceptable drug forms in pediatric population are oral liquids and pharmacists use commercial dispersing media to compound syrups from an active substance or from tablets available on the market. In many countries ready-to-use dispersing media are not available or refunded, but pharmacists can use other compounded media, providing their compatibility and stability are proven. The aim of this study was to formulate and evaluate the stability of syrups with candesartan cilexetil (1 mg mL-1) and valsartan (4 mg mL-1) extemporaneously prepared using commercial tablets (Diovan® and Atacand®). The following three different suspending media, which could be easily made in a pharmacy, were investigated: V1 - with xanthan gum (0.5 %), V2 - the USP/NF vehicle for oral solution and V3 - the medium based on a simple sucrose syrup. The stability of preparations was studied during 35 days of storage in a dark place at controlled temperature of 25 and 4 °C. During the study, microscopic observation was carried out and pH, viscosity, and concentration of candesartan cilexetil and valsartan were analyzed. Syrups with valsartan prepared with V2 and V3 media were stable for 3 or 4 weeks when stored at 25 °C, while syrups with candesartan were stable for as long as 35 days. For syrups prepared using V1 medium, the 14-day expiry date was not achieved because of microbial deterioration.

Angiotensin-converting enzyme inhibition and angiotensin AT1 receptor blockade downregulate angiotensin-converting enzyme expression and attenuate renal injury in streptozotocin-induced diabetic rats.

PubMed

Motawi, Tarek K; El-Maraghy, Shohda A; Senousy, Mahmoud A

2013-07-01

Angiotensin-converting enzyme (ACE) is upregulated in the diabetic kidney and contributes to renal injury. This study investigates the possible beneficial effects of the ACE inhibitor (ACEI), enalapril and the AT1 receptor blocker (ARB), valsartan, on renal ACE expression, renal structure, and function in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were allocated into four groups: control, STZ-diabetic rats, and STZ-diabetic rats treated with either enalapril (10 mg/kg/day) or valsartan (50 mg/kg/day) for 8 weeks. Enalapril and valsartan reduced renal ACE mRNA and protein expression, Na(+) /K(+) -ATPase activity, oxidative stress, and serum transforming growth factor-β1 levels compared to the diabetic group. Both treatments normalized renal nitrate/nitrite levels and ameliorated the observed histopathological changes. In conclusion, ACE downregulation by ACEI and ARB indicates that angiotensin II upregulates ACE through AT1 receptor. Prevention of diabetes-induced changes in ACE expression and Na(+) /K(+) -ATPase activity could be a new explanation of the renoprotective effects of ACEIs and ARBs. © 2013 Wiley Periodicals, Inc.

The impact of different proportions of a treated effluent on the biotransformation of selected micro-contaminants in river water microcosms.

PubMed

Nödler, Karsten; Tsakiri, Maria; Licha, Tobias

2014-10-10

Attenuation of micro-contaminants is a very complex field in environmental science and evidence suggests that biodegradation rates of micro-contaminants in the aqueous environment depend on the water matrix. The focus of the study presented here is the systematic comparison of biotransformation rates of caffeine, carbamazepine, metoprolol, paracetamol and valsartan in river water microcosms spiked with different proportions of treated effluent (0%, 0.1%, 1%, and 10%). Biotransformation was identified as the dominating attenuation process by the evolution of biotransformation products such as atenolol acid and valsartan acid. Significantly decreasing biotransformation rates of metoprolol were observed at treated effluent proportions ≥ 0.1% whereas significantly increasing biotransformation rates of caffeine and valsartan were observed in the presence of 10% treated effluent. Potential reasons for the observations are discussed and the addition of adapted microorganisms via the treated effluent was suggested as the most probable reason. The impact of additional phosphorus on the biodegradation rates was tested and the experiments revealed that phosphorus-limitation was not responsible.

Preconcentration of valsartan by dispersive liquid-liquid microextraction based on solidification of floating organic drop and its determination in urine sample: Central composite design.

PubMed

Pebdani, Arezou Amiri; Shabani, Ali Mohammad Haji; Dadfarnia, Shayesteh; Talebianpoor, Mohammad Sharif; Khodadoust, Saeid

2016-05-01

In this work, a fast, easy, and efficient dispersive liquid-liquid microextraction method based on solidification of floating organic drop followed by high-performance liquid chromatography with UV detection was developed for the separation/preconcentration and determination of the drug valsartan. Experimental design was applied for the optimization of the effective variables (such as volume of extracting and dispersing solvents, ionic strength, and pH) on the extraction efficiency of valsartan from urine samples. The optimized values were 250.0 μL ethanol, 65.0 μL 1-dodecanol, 4.0% w/v NaCl, pH 3.8, 1.0 min extraction time, and 4.0 min centrifugation at 4000 rpm min(-1) . The linear response (r(2) = 0.997) was obtained in the range of 0.013-10.0 μg mL(-1) with a limit of detection of 4.0 ng mL(-1) and relative standard deviations of less than 5.0 % (n = 6). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The role of angiotensin receptor-neprilysin inhibitors in cardiovascular disease-existing evidence, knowledge gaps, and future directions.

PubMed

Ambrosy, Andrew P; Mentz, Robert J; Fiuzat, Mona; Cleland, John G F; Greene, Stephen J; O'Connor, Christopher M; Teerlink, John R; Zannad, Faiez; Solomon, Scott D

2018-02-21

Although traditional renin-angiotensin system antagonists including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have revolutionized the treatment of cardiovascular disease (CVD), the pivotal PARADIGM-HF trial demonstrated that sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was superior to an angiotensin-converting enzyme inhibitor in reducing cardiovascular morbidity and mortality in patients with heart failure and reduced ejection fraction. However, despite international regulatory approval and strong recommendations in the guidelines, uptake of sacubitril/valsartan has been disappointing. Sacubitril/valsartan is now the focus of a large programme of clinical trials testing the hypothesis that ARNIs may supplant conventional renin-angiotensin system inhibitors across the spectrum of CVD, including hypertension, secondary prevention after myocardial infarction, and heart failure with preserved ejection fraction. This review summarizes the existing evidence, knowledge gaps, and future directions of ARNIs in CVD based on discussions between clinical trialists, industry representatives, and regulatory authorities at the 2016 Global CardioVascular Clinical Trialists Forum in Washington, D.C. © 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.

Diabetes Drug Prescription Pattern and Awareness Among Health Care Providers in Sub-Himalayan Region of India: A Population Based Study.

PubMed

Mokta, Jatinder; Mokta, Kiran; Ranjan, Asha; Joshi, Ivan; Garg, Mahak

2017-05-01

To determine the pattern of diabetic drug prescription and awareness about diabetes among primary health providers in the rural areas of Himachal Pradesh situated in the western Himalayas at an elevation range from 350 meters (1,148ft) to 6900 meters (22,966ft) above sea level. Study was conducted in 20 rural areas of Himachal Pradesh, located 50 to 400 Km from state capital, at 2200 to 10,000 feet altitude. Non-pregnant diabetic adults were surveyed through 31 diabetic camps. Detailed history, weight, height, waist circumference, body mass index recorded. Fasting or random blood glucose, glycated hemoglobin, lipid profile measured and blood pressure recorded. 894 diabetic patients were included in the study (59.83% male) with the mean age of 52.94±6.78 years. Two in three patients were on oral hypoglycemic agents (OHAs), and one in three on alternative approaches for diabetes control. Among OHAs, sulphonylureas (SU) were the most commonly prescribed oral agents in 76.09% of patients followed by metformin in 23.87%. Glibenclamide was the most commonly prescribed SU in 44.60%. Amlodipine and atenolol was the commonest anti-hypertensive drug prescribed in 77.85% either in combination or as individual drug. Only 10.59% were on lipid lowering therapy. For primary care providers glycemic target was the mainstay of diabetes treatment with little emphasis on blood pressure control and no emphasis on lipid reduction. Sulphonylureas were the commonest anti-diabetic drug prescribed by the primary care providers followed by metformin. Insulin was prescribed to 2.23% only. Combination of amlodipine and atenolol was the commonest anti-hypertensive drugs prescribed and only 10% of patients were prescribed statin.

Antihypertensive drug use in resistant and nonresistant hypertension and in controlled and uncontrolled resistant hypertension.

PubMed

de la Sierra, Alejandro; Armario, Pedro; Oliveras, Anna; Banegas, José R; Gorostidi, Manuel; Vinyoles, Ernest; de la Cruz, Juan J; Segura, Julián; Ruilope, Luis M

2018-07-01

Treatment-resistant hypertension (TRH) is associated with particular clinical features, nonadherence, and suboptimal treatment. We assessed possible associations of antihypertensive drug classes, specific agents inside each class, and types of combinations, with the presence of non-TRH vs. TRH, and with controlled vs. uncontrolled TRH. Comparisons were done in 14 264 patients treated with three drugs (non-TRH: 2988; TRH: 11 276) and in 6974 treated with at least four drugs (controlled TRH: 1383; uncontrolled TRH: 5591). Associations were adjusted for age, sex, and previous cardiovascular event. In both groups of patients treated with three or with at least four drugs, aldosterone antagonists among drug classes [adjusted odds ratio (OR): 1.82 and 1.41, respectively], and ramipril (OR: 1.28 and 1.30), olmesartan (OR: 1.31 and 1.37), and amlodipine (OR: 1.11 and 1.41) inside each class were significantly associated with blood pressure control (non-TRH or controlled TRH). In patients treated with three drugs, non-TRH was also associated with the use of chlorthalidone (OR: 1.50) and bisoprolol (OR: 1.19), whereas in patients treated with at least four drugs, controlled TRH was significantly associated with the triple combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic (OR: 1.17). The use of aldosterone antagonists is associated with blood pressure control in patients treated with three or more drugs. Similar results are observed with specific agents inside each class, being ramipril, olmesartan, chlorthalidone, amlodipine, and bisoprolol those exhibiting significant results. An increased use of these drugs might probably reduce the burden of TRH.

[Results of the Russian EKSPERT program: post-marketing supervision over efficacy and influence of the preparation Ekvator on quality of life at out-patients with arterial hypertension].

PubMed

Glezer, M G; Vygodin, V A; Avakian, A A; Prokof'eva, E B

2014-01-01

Results of an open multicenter prospective postmarketing observational program EKSPERT (post-marketing surveillance of the effectiveness and impact of the EKVATOR treatment on quality of life in patients with arterial hypertension in ambulatory practice). Observation of 10 000 patients conducted in 300 medical center in various regions of the Russian Federation in 1005 doctors. Selected for the final analysis 4954 registration cards. It is shown that in patients with initially insufficient effective antihypertensive treatment has a large number of risk factors: men older than 55 years--56.5%, women older than 65 years--27.8%, unfavorable family history of arterial hypertension (AH)--87.9%, diabetes mellitus (DM)--13.4%, smoking--of patients 18.6%, obesity--35%, angina--35.59%, heart failure--41.3% with a history of myocardial infarction--10.9%, stroke--4.5%, renal disease--11.8%, hypercholesterolemia > 5.0 mmol/l--76.7%. Initially drug antihypertensive treatment was performed in 76.6% of patients, while 43.9% were treated regularly. Prior studies angiotensin converting enzyme inhibitors (ACE) afforded 60.56%, sartans--11% of patients, beta-blockers--41.9%, duretics--41.46%, calcium antagonists used in 21.42% of the patients. After the cancellation of previously used other ACE inhibitors, calcium antagonists and sartans patients were switched to therapy with the EKVATOR (amlodipine and lisinopril). Intensity reduction in systolic and diastolic blood pressure (SBP and DBP) did not depend on sex of the patients, the presence of angina, diabetes. Greater reduction in blood pressure in hypertensive duration more than 5 years, in the presence of congestive heart failure due to more frequent initiation of therapy with full-dose combination (amlodipine 10 mg and lisinopril 20 mg). After 1 months of starting therapy changes uorvney target blood pressure (< 140 and 90 mmHg) reached 51.5% of patients. Target SBP reached 59.7% of patients, the target level of DBP--69.4%. It is important that the majority of patients crossed over lowti graduation SBP and DBP and significantly improved their quality of life assessment. Incidence of adverse events was low--1.5% of them are the most common were swelling in the legs, headache, dizziness, and dry cough. Replacing the previous therapy different ACE inhibitors, sartans and calcium antagonists to the fixed combination amlodipine and lisinopril) (drug EKVATOR), leads to a rapid, pronounced, and safe reduction of BP and improve health in the majority of patients with previously uncorrected BP.

Electro membrane extraction combined with capillary electrophoresis for the determination of amlodipine enantiomers in biological samples.

PubMed

Nojavan, Saeed; Fakhari, Ali Reza

2010-10-01

Electro membrane extraction as a new microextraction method was applied for the extraction of amlodipine (AM) enantiomers from biological samples. During the extraction time of 15  min, AM enantiomers migrated from a 3  mL sample solution, through a supported liquid membrane into a 20  μL acceptor solution presented inside the lumen of the hollow fiber. The driving force of the extraction was 200  V potential, with the negative electrode in the acceptor solution and the positive electrode in the sample solution. 2-Nitro phenyl octylether was used as the supported liquid membrane. Using 10  mM HCl as background electrolyte in the sample and acceptor solution, enrichment up to 124 times was achieved. Then, the extract was analyzed using CD modified CE method for separation of AM enantiomers. Best results were achieved using a phosphate running buffer (100  mM, pH 2.0) containing 5  mM hydroxypropyl-α-CD. The range of quantitation for both enantiomers was 10-500  ng/mL. Intra- and interday RSD (n=6) were less than 14%. The limits of quantitation and detection for both enantiomers were 10 and 3  ng/mL respectively. Finally, this procedure was applied to determine the concentration of AM enantiomers in plasma and urine samples.

Preparation and preclinical evaluation of 68Ga-DOTA-amlodipine for L-type calcium channel imaging

PubMed Central

Firuzyar, Tahereh; Jalilian, Amir Reza; Aboudzadeh, Mohammad Reza; Sadeghpour, Hossein; Shafiee-Ardestani, Mahdi; Khalaj, Ali

2016-01-01

Aim: In order to develop a possible tracer for L-type calcium channel imaging, we here report the development of a Ga-68 amlodipine derivative for possible PET imaging. Materials and Methods: Amlodipine DOTA conjugate was synthesized, characterized and went through calcium channel blockade, toxicity, apoptosis/necrosis tests. [68Ga] DOTA AMLO was prepared at optimized conditions followed by stability tests, partition coefficient determination and biodistribution studies using tissue counting and co incidence imaging up to 2 h. Results: [68Ga] DOTA AMLO was prepared at pH 4–5 in 7–10 min at 95°C in high radiochemical purity (>99%, radio thin layer chromatography; specific activity: 1.9–2.1 GBq/mmol) and was stable up to 4 h with a log P of −0.94. Calcium channel rich tissues including myocardium, and tissues with smooth muscle cells such as colon, intestine, and lungs demonstrated significant uptake. Co incidence images supported the biodistribution data up to 2 h. Conclusions: The complex can be a candidate for further positron emission tomography imaging for L type calcium channels. PMID:27833311

Amlodipine induced plasma cell granuloma of the gingiva: A novel case report.

PubMed

Vishnudas, Bhandari; Sameer, Zope; Shriram, Bansode; Rekha, Kardile

2014-07-01

Drug-induced gingival overgrowth (DIGO) can be a serious concern for both patients and clinicians. DIGO is a well-documented side-effect of some pharmacologic agents, including, but not limited to, calcium channel blockers, phenytoin, and cyclosporine. Plasma cell granulomas (pseudotumors) are exceedingly rare, non-neoplastic, reactive tumor-like proliferation, primarily composed of plasma cells that manifest primarily in the lungs, but may occur in various anatomic locations. Intraoral plasma cell granulomas involving the lip, oral mucosa, tongue, and gingiva have been reported in the past. This is the first case report of amlodipine induced plasma cell granuloma of the gingiva in the medical literature presenting a 54 year-old female patient with hypertension, who received amlodipine (10 mg/day, single dose orally) for 2 years, sought medical attention because of developing maxillary anterior massive gingival overgrowth causing functional and esthetic problem, which was treated by excisional biopsy. Histologically, these lesions were composed of mature plasma cells, showing polyclonality for both lambda and kappa light chains and fibrovascular connective tissue stroma confirming a diagnosis of plasma cell granuloma. This case also highlights the need to biopsy for unusual lesions to rule out potential neoplasms.

Combination Direct Renin Inhibition with Angiotensin Type 1 Receptor Blockade improves Aldosterone but does not improve Kidney Injury in the Transgenic Ren2 rat

PubMed Central

Whaley-Connell, Adam; Habibi, Javad; Nistala, Ravi; Hayden, Melvin R; Pulakat, Lakshmi; Sinak, Catherine; Locher, Bonnie; Ferrario, Carlos M; Sowers, James R

2012-01-01

Enhanced renin-angiotensin-aldosterone system (RAAS) activation contributes to proteinuria and chronic kidney disease by increasing glomerular and tubulointerstitial oxidative stress, promotion of fibrosis. Renin activation is the rate limiting step in angiotensin (Ang II) and aldosterone generation, and recent work suggests direct renin inhibition improves proteinuria comparable to that seen with Ang type 1 receptor (AT1R) blockade. This is important as, even with contemporary use of AT1R blockade, the burden of kidney disease remains high. Thereby, we sought to determine if combination direct renin inhibition with AT1R blockade in vivo, via greater attenuation of kidney oxidative stress, would attenuate glomerular and proximal tubule injury to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat with increased tissue RAS activity and higher serum levels of aldosterone, which manifests hypertension and proteinuria. Ren2 rats were treated with renin inhibition (aliskiren), AT1R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21 days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic pressure (SBP), circulating aldosterone, proteinuria and greater urine levels of the proximal tubule protein excretory marker beta-N-acetylglucosaminidase (β-NAG). These functional and biochemical alterations were accompanied by increases in kidney tissue NADPH oxidase subunit Rac1 and 3-nitrotyrosine (3-NT) content as well as fibronectin and collagen type III. These findings occurred in conjunction with reductions in the podocyte-specific protein podocin as well as the proximal tubule-specific megalin. Further, in transgenic animals there was increased tubulointerstitial fibrosis on light microscopy as well as ultrastructural findings of glomerular podocyte foot-process effacement and reduced tubular apical endosomal/lysosomal activity. Combination therapy led to greater reductions in SBP and serum aldosterone, but did not result in greater improvement in markers of glomerular and tubular injury (ie. β-NAG) compared to either intervention alone. Further, combination therapy did not improve markers of oxidative stress and podocyte and proximal tubule integrity in this transgenic model of RAAS-mediated kidney damage despite greater reductions in serum aldosterone and BP levels. PMID:22465166

Kicking the tyres of a heart failure trial: physician response to the approval of sacubitril/valsartan in the USA.

PubMed

Packer, Milton

2016-10-01

Angiotensin receptor-neprilysin inhibition has been shown to be superior to target doses of an ACE inhibitor in reducing the risk of cardiovascular death and clinical disease progression in patients with chronic heart failure and a reduced EF. Nevertheless, although sacubitril/valsartan has been available in the USA for a year, uptake of the drug by practitioners has been slow, in part because of misconceptions about the pivotal trial that demonstrated its efficacy in heart failure (PARADIGM-HF). This review addresses questions that have been raised in the USA about the design of the trial as well as the patients who were studied, the replicability and applicability of the results, and the safety of neprilysin inhibition. The totality of evidence indicates that the PARADIGM-HF trial used an appropriate comparator; enrolled patients typical of those seen in the community with mild to moderate symptoms; yielded highly persuasive and replicable results; and demonstrated benefits that are applicable to patients taking subtarget doses of ACE inhibitors and ARBs. Regulatory review in the USA concluded that the established advantages of sacubitril/valsartan on cardiovascular death and disease progression outweighed hypothetical uncertainties about the long-term effects of neprilysin inhibition in patients who might not have survived without the drug. Accordingly, both the new US and European Society of Cardiology heart failure guidelines recommend sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in patients with chronic heart failure who are currently receiving an ACE inhibitor or ARB. © 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.

Is the PARADIGM-HF cohort representative of the real-world heart failure patient population?

PubMed

Rodrigues, Gustavo; Tralhão, António; Aguiar, Carlos; Freitas, Pedro; Ventosa, António; Mendes, Miguel

2018-06-01

A new drug with prognostic impact on heart failure, sacubitril/valsartan, has been introduced in current guidelines. However, randomized trial results can be compromised by lack of representativeness. We aimed to assess the representativeness of the PARADIGM-HF trial in a real-world population of patients with heart failure. We reviewed the records of 196 outpatients followed in a heart failure clinic between January 2013 and December 2014. After exclusion of 44 patients with preserved ejection fraction, the inclusion and exclusion criteria of the trial were applied. Of the 152 patients with systolic heart failure, 106 lacked one or more inclusion criteria and 45 had at least one exclusion criterion. Considering only patients with ejection fraction ≤35% (HFrEF) (n=88), 43 patients lacked at least one inclusion criterion and 25 patients had at least one exclusion criterion. Combining the inclusion and exclusion criteria, 24.3% of patients with systolic HF (ejection fraction ≤50%) and 42% of patients with HFrEF would be eligible for the PARADIGM-HF trial. One in four patients with systolic HF followed in a heart failure outpatient clinic would fulfill the reference study criteria for treatment with the new drug, sacubitril/valsartan. Copyright © 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Spotlight on valsartan-sacubitril fixed-dose combination for heart failure: the evidence to date.

PubMed

Vilela-Martin, José Fernando

2016-01-01

Heart failure is a global problem with elevated prevalence, and it is associated with substantial cardiovascular morbidity and mortality. Treating heart-failure patients has been a very challenging task. This review highlights the main pharmacological developments in the field of heart failure with reduced ejection fraction, giving emphasis to a drug that has a dual-acting inhibition of the neprilysin and renin-angiotensin-aldosterone system. Neprilysin is an enzyme that participates in the breakdown of biologically active natriuretic peptides and several other vasoactive compounds. The inhibition of neprilysin has been a therapeutic target for several drugs tested in cardiovascular disease, mainly for heart failure and/or hypertension. However, side effects and a lack of efficacy led to discontinuation of their development. LCZ696 is a first-in-class neprilysin- and angiotensin-receptor inhibitor that has been developed for use in heart failure. This drug is composed of two molecular moieties in a single crystalline complex: a neprilysin-inhibitor prodrug (sacubitril) and the angiotensin-receptor blocker (valsartan). The PARADIGM-HF trial demonstrated that this drug was superior to an angiotensin-converting enzyme inhibitor (enalapril) in reducing mortality in patients with heart failure with reduced ejection fraction. The ability to block the angiotensin receptor and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.

Effects of Amlodipine on Bone Metabolism in Orchidectomised Spontaneously Hypertensive Rats.

PubMed

Zivna, Helena; Gradošová, Iveta; Zivny, Pavel; Cermakova, Eva; Palicka, Vladimir

2018-06-13

Spontaneously hypertensive rats (SHR) represent a model of essential hypertension. We studied the effect of amlodipine (AML) on bone markers, bone mineral density (BMD), and biomechanical properties of osteopenic bone induced by orchidectomy in male SHR. Rats were allocated to 3 groups and were sacrificed after 12 weeks: sham-operated control; orchidectomised control; and orchidectomised receiving a diet supplemented with AML. Indicators of bone turnover were assessed in bone homogenate, BMD was measured by dual energy X-ray absorptiometry, and the femurs were subjected to biomechanical testing. Long-term AML administration does not have a negative impact on bone metabolism and density in male SHR. © 2018 S. Karger AG, Basel.

Will sacubitril-valsartan diminish the clinical utility of B-type natriuretic peptide testing in acute cardiac care?

PubMed

Mair, Johannes; Lindahl, Bertil; Giannitsis, Evangelos; Huber, Kurt; Thygesen, Kristian; Plebani, Mario; Möckel, Martin; Müller, Christian; Jaffe, Allan S

2017-06-01

Since the approval of sacubitril-valsartan for the treatment of chronic heart failure with reduced ejection fraction, a commonly raised suspicion is that a wider clinical use of this new drug may diminish the clinical utility of B-type natriuretic peptide testing as sacubitril may interfere with B-type natriuretic peptide clearance. In this education paper we critically assess this hypothesis based on the pathophysiology of the natriuretic peptide system and the limited published data on the effects of neprilysin inhibition on natriuretic peptide plasma concentrations in humans. As the main clinical application of B-type natriuretic peptide testing in acute cardiac care is and will be the rapid rule-out of suspected acute heart failure there is no significant impairment to be expected for B-type natriuretic peptide testing in the acute setting. However, monitoring of chronic heart failure patients on sacubitril-valsartan treatment with B-type natriuretic peptide testing may be impaired. In contrast to N-terminal-proBNP, the current concept that the lower the B-type natriuretic peptide result in chronic heart failure patients, the better the prognosis during treatment monitoring, may no longer be true.

Effect of QiShenYiQi pill on myocardial collagen metabolism in experimental autoimmune myocarditis rats.

PubMed

Lv, Shi-Chao; Wu, Meifang; Li, Meng; Wang, Qiang; Wang, Xiao-Jing; Zhang, Ao; Xu, Ling; Zhang, Jun-Ping

2017-04-01

To observe the effect of QiShenYiQi pill (QSYQ) on myocardial collagen metabolism in experimental autoimmune myocarditis rats, and to explore its mechanism of action. Lewis rats underwent the injection of myocardial myosin mixed with freund's complete adjuvant were randomized into three groups: model, valsartan and QSYQ groups. And we treated rats which were injected phosphate buffered saline (PBS) mixed with freund's complete adjuvant as control group. Rats were intervened and euthanized at 4 and 8 weeks. We use alkaline hydrolysis to detect the content of myocardial hydroxyproline (HYP), and ELISA to detect the level of serum procollagen type I carboxyterminal peptide (PICP), procollagen type III amino-terminal peptide (PIIINP), and collagen C telopeptide type I (CTX-I). Myocardial MMP-1 and TIMP-1 protein expression was detected by immunohistochemistry, and myocardial MMP-1 and TIMP-1 mRNA expression was detected by real-time qPCR. QSYQ reduced the content of myocardial HYP, and this reduction was greater over time. QSYQ also reduced the serum concentration of PICP, PIIINP, CTX-I and the PICP/PIIINP ratio, which further reduced over time, whereas its effect on lowering PICP was significantly greater than that of valsartan at 4 and 8 weeks, and lowering CTX-I was significantly greater than that of valsartan at 8 weeks. In addition, after 4 weeks, QSYQ enhanced the protein and mRNA expression of MMP-1 and TIMP-1, and its effect on highering TIMP-1 was significantly greater than that of valsartan, whereas there was no significant difference in the expression of myocardial MMP-1 or TIMP-1 at 8 weeks. QSYQ reduced the ratio of MMP-1/TIMP-1, which further reduced over time, and the effect of QYSQ was significantly greater than that of valsartan after 4 weeks. This study provides evidence that QSYQ can reduce the rate of myocardial collagen synthesis and degradation. It also effectively improved the degree of myocardial fibrosis in experimental autoimmune myocarditis rats and it had a tendency to have a greater effect with longer treatment duration, which is related to the mechanism of regulation of MMP-1 and TIMP-1 expression in the myocardial rat. Copyright © 2017. Published by Elsevier Masson SAS.

Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF.

PubMed

Böhm, Michael; Young, Robin; Jhund, Pardeep S; Solomon, Scott D; Gong, Jianjian; Lefkowitz, Martin P; Rizkala, Adel R; Rouleau, Jean L; Shi, Victor C; Swedberg, Karl; Zile, Michael R; Packer, Milton; McMurray, John J V

2017-04-14

Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP. We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP. All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74-1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65-1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP. In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

PubMed

Senni, Michele; McMurray, John J V; Wachter, Rolf; McIntyre, Hugh F; Reyes, Antonio; Majercak, Ivan; Andreka, Peter; Shehova-Yankova, Nina; Anand, Inder; Yilmaz, Mehmet B; Gogia, Harinder; Martinez-Selles, Manuel; Fischer, Steffen; Zilahi, Zsolt; Cosmi, Franco; Gelev, Valeri; Galve, Enrique; Gómez-Doblas, Juanjo J; Nociar, Jan; Radomska, Maria; Sokolova, Beata; Volterrani, Maurizio; Sarkar, Arnab; Reimund, Bernard; Chen, Fabian; Charney, Alan

2016-09-01

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. © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

The relationship between visfatin and HOMA-IR in hypertensive patients, and the effect of antihypertensive drugs on visfatin and HOMA-IR in hypertensive patients with insulin resistance.

PubMed

Lan, Jianjun; Chen, Xiaoni; Chen, Xiaoping; Wang, Si; Zhang, Xin; Wu, Kai; He, Sen; Peng, Yong; Jiang, Lingyun; Li, Longxin; Wan, Liyan

2011-10-01

To investigate the correlation between serum visfatin and insulin resistance (IR) in non-diabetic essential hypertensive (EH) patients with and without IR, and to evaluate the effect of antihypertensive treatment on serum visfatin and IR in these patients. A total of 81 non-diabetic EH patients, including 54 with IR and 27 without IR, were enrolled. After two weeks wash-out, patients with IR were randomly assigned to telmisartan (group T) or amlodipine (group A) for 6 months. Blood samples were taken before and after treatment for measurement of routine biochemical parameters, visfatin and insulin resistance (measured by HOMA-IR). Visfatin was independently correlated with HOMA-IR (r=0.845, P=0.000). After 6 months of treatment, both drugs lowered HOMA-IR, more significantly so in group T than group A (P=0.010). Serum visfatin levels increased in group T but decreased in group A. Serum visfatin levels were higher in non-diabetic EH patients with IR compared with those without IR. Visfatin is independently correlated with HOMA-IR. Telmisartan lowers HOMA-IR to a greater extent than amlodipine. Interestingly, serum visfatin increased with telmisartan yet decreased with amlodipine treatment. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Design of Chronomodulated Drug Delivery System of Valsartan: In Vitro Characterization.

PubMed

Sokar, M; Hanafy, A; Elkamel, A; El-Gamal, S

2015-01-01

The aim of the present study was to design and evaluate a chronomodulated time-clock pulsatile tablets of valsartan to release it after a certain lag time, independent of the gastrointestinal pH, in its absorption window to cope with the circadian rhythm of human body for blood pressure elevation. Core tablets were prepared by direct compression of a homogenous mixture of valsartan, Avicel PH101, croscarmellose sodium, magnesium stearate and Aerosil. The core tablets were then sprayed coated with a sealing layer formed of ethyl cellulose that was subsequently coated with a release-controlling layer. Three different aqueous dispersions namely; carnauba wax or beeswax or a mixture in a ratio of 2.5:1, respectively, were used to form five time-clock tablet formulations having the release controlling layer with different thickness {B5, B10, B20, BW5 and CW5}. Quality control testing were carried out to the core tablets. Differential scanning calorimetry was also performed to detect the possible drug excipient interaction in the core tablet formulation. The release was carried out, for the prepared time-clock tablet formulations, in 0.1 N hydrochloric acid for the first 2 h, followed by phosphate buffer (pH 6.8) for 4.5 h. The effect of pH on valsartan release was studied through a release study in 0.1 N hydrochloric acid for 6.5 h. Two phase dissolution study was performed to the selected time-clock tablet formulation to predict the drug permeation through the gastrointestinal tract. Stability study of the selected formula was performed at 25°/60% RH and at 40°/75% RH for 3 months. Results showed that a release-controlling layer composed of a mixture of carnauba wax and beeswax in a ratio of 2.5:1 showed a reasonable release lag time. The release lag time of the tablets increased with the increase of the coat thickness, thus B20>B10>B5 with corresponding lag time values of 4.5, 3 and 2.5 h, respectively. Selected B5 tablet formula exhibited a reasonable lag time after which the highest, complete % drug release at pH 6.8 was obtained. In addition, a good partitioning of valsartan, between the aqueous and organic phases in a ratio of 1:7, was observed. The selected formula was stable for at least 3 months under standard long-term and accelerated storage conditions. In conclusion, in vitro studies revealed that the novel time-clock system could be used successfully to deliver valsartan in a pulsatile pH-independent manner. It provided a desirable lag time followed by a rapid and complete drug release accompanied by an expected effective permeation through the biological membranes upon release in the duodenum; the window of absorption, as indicated by the two phase release study.

Design of Chronomodulated Drug Delivery System of Valsartan: In Vitro Characterization

PubMed Central

Sokar, M.; Hanafy, A.; Elkamel, A.; El-Gamal, S.

2015-01-01

The aim of the present study was to design and evaluate a chronomodulated time-clock pulsatile tablets of valsartan to release it after a certain lag time, independent of the gastrointestinal pH, in its absorption window to cope with the circadian rhythm of human body for blood pressure elevation. Core tablets were prepared by direct compression of a homogenous mixture of valsartan, Avicel PH101, croscarmellose sodium, magnesium stearate and Aerosil. The core tablets were then sprayed coated with a sealing layer formed of ethyl cellulose that was subsequently coated with a release-controlling layer. Three different aqueous dispersions namely; carnauba wax or beeswax or a mixture in a ratio of 2.5:1, respectively, were used to form five time-clock tablet formulations having the release controlling layer with different thickness {B5, B10, B20, BW5 and CW5}. Quality control testing were carried out to the core tablets. Differential scanning calorimetry was also performed to detect the possible drug excipient interaction in the core tablet formulation. The release was carried out, for the prepared time-clock tablet formulations, in 0.1 N hydrochloric acid for the first 2 h, followed by phosphate buffer (pH 6.8) for 4.5 h. The effect of pH on valsartan release was studied through a release study in 0.1 N hydrochloric acid for 6.5 h. Two phase dissolution study was performed to the selected time-clock tablet formulation to predict the drug permeation through the gastrointestinal tract. Stability study of the selected formula was performed at 25°/60% RH and at 40°/75% RH for 3 months. Results showed that a release-controlling layer composed of a mixture of carnauba wax and beeswax in a ratio of 2.5:1 showed a reasonable release lag time. The release lag time of the tablets increased with the increase of the coat thickness, thus B20>B10>B5 with corresponding lag time values of 4.5, 3 and 2.5 h, respectively. Selected B5 tablet formula exhibited a reasonable lag time after which the highest, complete % drug release at pH 6.8 was obtained. In addition, a good partitioning of valsartan, between the aqueous and organic phases in a ratio of 1:7, was observed. The selected formula was stable for at least 3 months under standard long-term and accelerated storage conditions. In conclusion, in vitro studies revealed that the novel time-clock system could be used successfully to deliver valsartan in a pulsatile pH-independent manner. It provided a desirable lag time followed by a rapid and complete drug release accompanied by an expected effective permeation through the biological membranes upon release in the duodenum; the window of absorption, as indicated by the two phase release study. PMID:26664064

CYP3A4 and CYP3A5 polymorphisms and blood pressure response to amlodipine among African-American men and women with early hypertensive renal disease.

PubMed

Bhatnagar, Vibha; Garcia, Erin P; O'Connor, Daniel T; Brophy, Victoria H; Alcaraz, John; Richard, Erin; Bakris, George L; Middleton, John P; Norris, Keith C; Wright, Jackson; Hiremath, Leena; Contreras, Gabriel; Appel, Lawrence J; Lipkowitz, Michael S

2010-01-01

To explore the association between CYP3A4 and CYP3A5 gene polymorphisms and blood pressure response to amlodipine among participants from the African-American Study of Kidney Disease and Hypertension Trial randomized to amlodipine (n = 164). Cox proportional hazards models were used to determine the risk of reaching a target mean arterial pressure (MAP) of < or =107 mm Hg by CYP3A4 (A-392G and T16090C) and CYP3A5 (A6986G) gene polymorphisms, stratified by MAP randomization group (low or usual) and controlling for other predictors for blood pressure response. Women randomized to a usual MAP goal with an A allele at CYP3A4 A-392G were more likely to reach a target MAP of 107 mm Hg. The adjusted hazard ratio (AA/AG compared to GG) with 95% confidence interval was 3.41 (1.20-9.64; p = 0.020). Among participants randomized to a lower MAP goal, those with the C allele at CYP3A4 T16090C were more likely to reach target MAP: The adjusted hazard ratio was 2.04 (1.17-3.56; p = 0.010). After adjustment for multiple testing using a threshold significance level of p = 0.016, only the CYP3A4 T16090C SNP remained significant. CYP3A5 A6986G was not associated with blood pressure response. Our findings suggest that blood pressure response to amlodipine among high-risk African-Americans appears to be determined by CYP3A4 genotypes, and sex specificity may be an important consideration. Clinical applications of CYP3A4 genotype testing for individualized treatment regimens warrant further study. Copyright (c) 2009 S. Karger AG, Basel.

CYP3A4 and CYP3A5 Polymorphisms and Blood Pressure Response to Amlodipine among African-American Men and Women with Early Hypertensive Renal Disease

PubMed Central

Bhatnagar, Vibha; Garcia, Erin P.; O’Connor, Daniel T.; Brophy, Victoria H.; Alcaraz, John; Richard, Erin; Bakris, George L.; Middleton, John P.; Norris, Keith C.; Wright, Jackson; Hiremath, Leena; Contreras, Gabriel; Appel, Lawrence J.; Lipkowitz, Michael S.

2010-01-01

Purpose To explore the association between CYP3A4 and CYP3A5 gene polymorphisms and blood pressure response to amlodipine among participants from the African-American Study of Kidney Disease and Hypertension Trial randomized to amlodipine (n = 164). Methods Cox proportional hazards models were used to determine the risk of reaching a target mean arterial pressure (MAP) of ≤107 mm Hg by CYP3A4 (A–392G and T16090C) and CYP3A5 (A6986G) gene polymorphisms, stratified by MAP randomization group (low or usual) and controlling for other predictors for blood pressure response. Results Women randomized to a usual MAP goal with an A allele at CYP3A4 A–392G were more likely to reach a target MAP of 107 mm Hg. The adjusted hazard ratio (AA/AG compared to GG) with 95% confidence interval was 3.41 (1.20–9.64; p = 0.020). Among participants randomized to a lower MAP goal, those with the C allele at CYP3A4 T16090C were more likely to reach target MAP: The adjusted hazard ratio was 2.04 (1.17–3.56; p = 0.010). After adjustment for multiple testing using a threshold significance level of p = 0.016, only the CYP3A4 T16090C SNP remained significant. CYP3A5 A6986G was not associated with blood pressure response. Conclusions Our findings suggest that blood pressure response to amlodipine among high-risk African-Americans appears to be determined by CYP3A4 genotypes, and sex specificity may be an important consideration. Clinical applications of CYP3A4 genotype testing for individualized treatment regimens warrant further study. PMID:19907160

Long-Term Renal and Cardiovascular Outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Participants by Baseline Estimated GFR

PubMed Central

Rahman, Mahboob; Cutler, Jeffrey A.; Davis, Barry R.; Piller, Linda B.; Whelton, Paul K.; Wright, Jackson T.; Barzilay, Joshua I.; Brown, Clinton D.; Colon, Pedro J.; Fine, Lawrence J.; Grimm, Richard H.; Gupta, Alok K.; Baimbridge, Charles; Haywood, L. Julian; Henriquez, Mario A.; Ilamaythi, Ekambaram; Oparil, Suzanne; Preston, Richard

2012-01-01

Summary Background and objectives CKD is common among older patients. This article assesses long-term renal and cardiovascular outcomes in older high-risk hypertensive patients, stratified by baseline estimated GFR (eGFR), and long-term outcome efficacy of 5-year first-step treatment with amlodipine or lisinopril, each compared with chlorthalidone. Design, setting, participants, & measurements This was a long-term post-trial follow-up of hypertensive participants (n=31,350), aged ≥55 years, randomized to receive chlorthalidone, amlodipine, or lisinopril for 4–8 years at 593 centers. Participants were stratified by baseline eGFR (ml/min per 1.73 m2) as follows: normal/increased (≥90; n=8027), mild reduction (60–89; n=17,778), and moderate/severe reduction (<60; n=5545). Outcomes were cardiovascular mortality (primary outcome), total mortality, coronary heart disease, cardiovascular disease, stroke, heart failure, and ESRD. Results After an average 8.8-year follow-up, total mortality was significantly higher in participants with moderate/severe eGFR reduction compared with those with normal and mildly reduced eGFR (P<0.001). In participants with an eGFR <60, there was no significant difference in cardiovascular mortality between chlorthalidone and amlodipine (P=0.64), or chlorthalidone and lisinopril (P=0.56). Likewise, no significant differences were observed for total mortality, coronary heart disease, cardiovascular disease, stroke, or ESRD. Conclusions CKD is associated with significantly higher long-term risk of cardiovascular events and mortality in older hypertensive patients. By eGFR stratum, 5-year treatment with amlodipine or lisinopril was not superior to chlorthalidone in preventing cardiovascular events, mortality, or ESRD during 9-year follow-up. Because data on proteinuria were not available, these findings may not be extrapolated to proteinuric CKD. PMID:22490878

Effects of aerobic dance training on blood pressure in individuals with uncontrolled hypertension on two antihypertensive drugs: a randomized clinical trial.

PubMed

Maruf, Fatai Adesina; Akinpelu, Aderonke Omobonike; Salako, Babatunde Lawal; Akinyemi, Joshua Odunayo

2016-04-01

There is a dearth of reports on possible additive blood pressure (BP)-reducing effect of aerobic exercise on antihypertensive drug in humans. This study investigated the additive BP-reducing effect of aerobic exercise on BP in individuals with uncontrolled hypertension. In this 12-week double-blind study, 120 new-diagnosed individuals with mild-to-moderate hypertension were randomized to receive coamilozide + 5/10 mg of amlodipine + aerobic dance or coamilozide + 5/10 mg of amlodipine alone. Forty-five and 43 participants in exercise and control groups, respectively, completed the 12-week intervention. Addition of aerobic exercise to antihypertensive drug therapy significantly reduced systolic BP (7.1 mm Hg [95% confidence interval: 5.0, 9.3]; P < .001) and diastolic BP (1.7 mm Hg [95% confidence interval: 0.4, 3.0]; P = .009) at 12 weeks. BP control rate differed significantly between exercise (53.9%) and control (35.3%) groups, P < .001. Postintervention, proportion of participants in exercise group who had their number of antihypertensive drug reduced to one (20.3%) differed from that in control group (11.1%); (χ(2) = 11.0; P = .001). Combination of aerobic dance and antihypertensive drugs reduces number of antihypertensive drugs needed to achieve BP control and enhances BP control in individuals with hypertension on two antihypertensive drugs. Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Amlodipine

MedlinePlus

... and other problems. In addition to taking medication, making lifestyle changes will also help to control your ... This branded product is no longer on the market. Generic alternatives may be available.

Combination With Low-dose Dextromethorphan Improves the Effect of Amlodipine Monotherapy in Clinical Hypertension

PubMed Central

Yin, Wei-Hsian; Chen, Pei; Yeh, Hung-I; Wang, Kuo-Yang; Hung, Yi-Jen; Tseng, Wei-Kung; Wen, Ming-Shien; Wu, Tao-Cheng; Wu, Chau-Chung; Cheng, Shu-Meng; Chen, Jaw-Wen

2016-01-01

Abstract The combination of low rather than high dose of dextromethorphan (DXM) with amlodipine (AM) could improve blood pressure (BP) reduction in hypertensive animals. The study aimed to evaluate the feasibility of different doses of DXM combined with standard AM treatment in clinical hypertension. This was a prospective, 14-week, dose-escalation, multicenter study. After 2-week run-in period with AM 5 mg/day, hypertensive patients who got the BP goal of 140/90 mmHg kept receiving AM monotherapy for another 12 weeks. The nonresponders, while kept on AM 5 mg/day, received additional DXM treatment for 3 sequential dose-titrated periods with initially 2.5 mg/day, followed by 7.5 mg/day, and finally 30 mg/day. Each period was for 4 weeks. The patients at BP goal after each treatment period were defined as the responders and kept on the same combination till the end of the study. The responder rate of each treatment period was recorded. The changes of BP and serum antioxidant/endothelial markers between week 14 and week 2 were evaluated. Of the 103 patients initially enrolled, 89 entered the treatment period. In the 78 patients completing the study, 31 (40%) at BP goal after 2-week AM run-in kept on AM monotherapy (DXM0). The addition of 2.5 (DXM2.5) and 7.5 mg/day (DXM7.5) of DXM enabled BP goal achievement in 22 (47%) nonresponders to AM monotherapy including 16 (29%) with DXM2.5 and 6 (18%) with DXM7.5. Only 4 patients (16%) reached BP goal with the combination of DXM 30 mg/day (DXM30). Overall, 73% of the 78 patients reached BP goal at the end of the 14-week study. Mean systolic BP was reduced by 7.9% ± 7.0% with DXM2.5 (P < 0.001) and by 5.4% ± 2.4% with DXM7.5 (P = 0.003) respectively at week 14 from that at week 2, which was unchanged in either DXM0 or DXM30 group. Besides, the effects of combination treatment were particularly significant in the patients with impaired endothelial function suggested by reduced serum NOx level at baseline. Accordingly, the combination with low dose of DXM was feasible to improve BP control in patients who failed to achieve the BP goal by standard AM monotherapy. The benefit effects might be significant especially in patients with impaired endothelial function. PMID:27015224

[Comparative effects of nebivolol and valsartan on atrial electromechanical coupling in newly diagnosed stage 1 hypertensive patients].

PubMed

Altun, Burak; Acar, Gürkan; Akçay, Ahmet; Sökmen, Abdullah; Kaya, Hakan; Köroğlu, Sedat

2011-10-01

Hypertension is an important cardiovascular risk factor for the development of atrial fibrillation (AF). Increased atrial electromechanical coupling time interval measured by tissue Doppler is accepted as an important factor for prediction of AF development in hypertensive patients. The aim of this study was to compare the effects of valsartan, an angiotensin receptor blocker, and nebivolol, a beta-blocker, on atrial electromechanical coupling in newly diagnosed stage 1 hypertensive patients. The study included 60 newly diagnosed stage 1 hypertensive patients with no other systemic disease. The patients were randomized to receive nebivolol 5 mg (30 patients; 21 women, 9 men; mean age 48.4 ± 11.4 years) and valsartan 160 mg (30 patients; 21 women, 9 men; mean age 49.8 ± 11.3 years). All the patients underwent tissue Doppler echocardiographic examination before and three months after treatment to compare the effects of the two drugs on atrial electromechanical coupling. Baseline blood pressures, electrocardiographic and echocardiographic findings, and atrial electromechanical coupling were similar in both groups (p>0.05). Both drugs significantly reduced blood pressure after treatment, with similar efficacy (p>0.05). Atrial electromechanical coupling time intervals showed significant decreases in both groups. Prolonged interatrial electromechanical time intervals in hypertensives are improved with antihypertensive treatment.

Amlodipine and Benazepril

MedlinePlus

... and other problems. In addition to taking medication, making lifestyle changes will also help to control your ... This branded product is no longer on the market. Generic alternatives may be available.

Evaluation of polar organic micropollutants as indicators for wastewater-related coastal water quality impairment.

PubMed

Nödler, Karsten; Tsakiri, Maria; Aloupi, Maria; Gatidou, Georgia; Stasinakis, Athanasios S; Licha, Tobias

2016-04-01

Results from coastal water pollution monitoring (Lesvos Island, Greece) are presented. In total, 53 samples were analyzed for 58 polar organic micropollutants such as selected herbicides, biocides, corrosion inhibitors, stimulants, artificial sweeteners, and pharmaceuticals. Main focus is the application of a proposed wastewater indicator quartet (acesulfame, caffeine, valsartan, and valsartan acid) to detect point sources and contamination hot-spots with untreated and treated wastewater. The derived conclusions are compared with the state of knowledge regarding local land use and infrastructure. The artificial sweetener acesulfame and the stimulant caffeine were used as indicators for treated and untreated wastewater, respectively. In case of a contamination with untreated wastewater the concentration ratio of the antihypertensive valsartan and its transformation product valsartan acid was used to further refine the estimation of the residence time of the contamination. The median/maximum concentrations of acesulfame and caffeine were 5.3/178 ng L(-1) and 6.1/522 ng L(-1), respectively. Their detection frequency was 100%. Highest concentrations were detected within the urban area of the capital of the island (Mytilene). The indicator quartet in the gulfs of Gera and Kalloni (two semi-enclosed embayments on the island) demonstrated different concentration patterns. A comparatively higher proportion of untreated wastewater was detected in the gulf of Gera, which is in agreement with data on the wastewater infrastructure. The indicator quality of the micropollutants to detect wastewater was compared with electrical conductivity (EC) data. Due to their anthropogenic nature and low detection limits, the micropollutants are superior to EC regarding both sensitivity and selectivity. The concentrations of atrazine, diuron, and isoproturon did not exceed the annual average of their environmental quality standards (EQS) defined by the European Commission. At two sampling locations irgarol 1051 exceeded its annual average EQS value but not the maximum allowable concentration of 16 ng L(-1). Copyright © 2016 Elsevier Ltd. All rights reserved.