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Blood Pressure and Cholesterol-lowering Efficacy of a Fixed-dose Combination With Irbesartan and Atorvastatin in Patients With Hypertension and Hypercholesterolemia: A Randomized, Double-blind, Factorial, Multicenter Phase III Study.
Kim, SH, Jo, SH, Lee, SC, Lee, SY, Yoon, MH, Lee, HL, Lee, NH, Ha, JW, Lee, NH, Kim, DW, et al
Clinical therapeutics. 2016;(10):2171-2184
Abstract
PURPOSE A fixed-dose combination of a stain and an antihypertensive drug may be useful for the treatment of patients with hypertension and hyperlipidemia. It may also improve patient drug compliance to help control risk factors of cardiovascular disease. This study was designed to evaluate the blood pressure-lowering and cholesterol-lowering effect of a fixed-dose combination of irbesartan-atorvastatin compared with monotherapy by either agent over an 8-week treatment period. METHODS Patients with comorbid hypertension and hypercholesterolemia were screened for this randomized, double-blind, Phase III study. Eligible study patients were randomly assigned to test groups receiving a combination of irbesartan 300 mg and atorvastatin 40 mg or 80 mg (IRB300 + ATO40 and IRB300 + ATO80). Comparator groups comprised monotherapy groups with irbesartan 300 mg (IRB300) or atorvastatin 40 mg (ATO40) or atorvastatin 80 mg (ATO80), or placebo. Patients who were eligible at screening were subjected to a 4- to 6-week washout period before commencing 8 weeks of therapy per their assigned group. The primary efficacy end points were percent change in LDL-C and sitting diastolic blood pressure (DBP) levels from baseline to end of therapy. Tolerability profiles of combination therapy were compared with other groups. FINDINGS A total of 733 patients with comorbid hypertension and hypercholesterolemia were screened for this study; 230 eligible patients were randomized to treatment. The mean age of patients was 58.9 (8.5) years, and their mean body mass index was 25.8 (3.2) kg/m2. More than two thirds (70.9%) of the study patients were male. Mean LDL-C and sitting DBP levels at baseline were 149.54 (29.19) mg/dL and 92.32 (6.03) mm Hg, respectively. Percent reductions in LDL-C after 8 weeks were 46.74% (2.06%) in the IRB300 + ATO40 group and 48.98% (2.12%) in the IRB300 + ATO80 group; these values were 47.13% (3.21%) and 48.30% (2.98%) in the ATO40 and ATO80 comparator groups. Similarly, a reduction in sitting DBP after 8 weeks was -8.50 (1.06) mm Hg in the IRB300 + ATO40 group and 10.66 (1.08) mm Hg in the IRB300 + ATO80 group compared with 8.40 (1.65) mm Hg in the IRB300 group. The incidence rate for treatment-emergent adverse events was 22.27% and was similar between the monotherapy and combination groups. IMPLICATIONS A once-daily combination product of irbesartan and atorvastatin provided an effective, safe, and more compliable treatment for patients with coexisting hypertension and hyperlipidemia. ClinicalTrials.gov identifier: NCT01442987.
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A new class of drugs for systolic heart failure: The PARADIGM-HF study.
Sabe, MA, Jacob, MS, Taylor, DO
Cleveland Clinic journal of medicine. 2015;(10):693-701
Abstract
The PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) found a combination drug containing sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin II receptor blocker) superior to enalapril (an angiotensin-converting enzyme inhibitor) in patients with systolic heart failure. Recently approved by the US Food and Drug Administration, sacubitril-valsartan is the first new drug in over a decade to decrease death rates in patients with systolic heart failure.
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Angiotensin II receptor blockade and skeletal muscle metabolism in overweight and obese adults with elevated blood pressure.
Boutagy, NE, Marinik, EL, McMillan, RP, Anderson, AS, Frisard, MI, Davy, BM, Rivero, JM, Davy, KP, Hulver, MW
Therapeutic advances in cardiovascular disease. 2015;(2):45-50
Abstract
OBJECTIVES Whether angiotensin II receptor blockade improves skeletal muscle fatty acid oxidation in overweight and obese humans is unknown. The purpose of the study was to test the hypothesis that the angiotensin II receptor blocker, olmesartan, would increase fatty acid oxidation and the activity of enzymes associated with oxidative metabolism in skeletal muscle of overweight and obese humans. METHODS A total of 12 individuals (6 men and 6 women) aged 18-75 and with a body mass index ⩾25 kg/m2 were assigned to olmesartan or placebo for 8 weeks in a crossover fashion. Fatty acid oxidation was measured before and after each intervention by counting the (14)CO2 produced from [1-(14)C] palmitic acid in skeletal muscle homogenates. RESULTS Fatty acid oxidation was not significantly different between treatment periods at baseline and post intervention. In addition, the enzyme activities of citrate synthase and β-hydroxyacyl-coenzyme A dehydrogenase in skeletal muscle homogenates did not differ between treatment periods at baseline or post intervention. CONCLUSIONS Treatment with olmesartan for 8 weeks does not improve fatty acid oxidation or the activity of enzymes associated with oxidative metabolism in skeletal muscle from overweight and obese individuals. Taken together, our results indicate that improvements in skeletal muscle metabolism are not among the additional benefits of olmesartan that extend beyond blood pressure reduction.
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High doses of irbesartan offer long-term kidney protection in cases of established diabetic nephropathy.
Ros-Ruiz, S, Aranda-Lara, P, Fernández, JC, Martínez-Esteban, MD, Jironda, C, Hidalgo, P, Hernández-Marrero, D
Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia. 2012;(2):187-96
Abstract
BACKGROUND Hypothetically, the greater the blockade of angiotensin AT1 receptors from ultra-high doses of angiotensin receptors blockers (ARB), the greater the expected renoprotection effects. The aim of our study was to evaluate the effects of ultra-high doses of irbesartan on proteinuria and renal function in diabetics with established or overt diabetic nephropathy (ODN). MATERIAL AND METHOD Ours was a prospective, non-randomised 3-year follow-up study, using a multifactorial therapeutic approach based on irbesartan 600mg daily. Demographic variables, anthropometric data, and biochemical parameters were comparatively analysed at the beginning and end of the study. Forty patients (75% with type 2 diabetes) were included, average age 57.1 +/- 10, 29 male (72.5%). RESULTS SBP (157.6 +/- 27mm Hg vs 130.1 +/- 14mm Hg) and DBP (88.8 +/- 10mm Hg vs 76.2 +/- 8mm Hg) decreased significantly at the end of follow-up (P<.001). Serum creatinine increased by only 0.17mg/dl, although this was a statistically significant difference (P<.05). Proteinuria markedly decreased from 2.64 +/- 1.99 to 0.98 +/- 1.18 (P<.0001), i.e. 59.2%. Twenty-five percent of patients had normal albuminuria at the end of the follow-up period. Lipid profiles significantly improved. No patients withdrew from the study due to side effects, and serum potassium did not change significantly over the course of the study. Except for BMI and HbA1c, all other therapeutic targets set out by ADA recommendations improved significantly. CONCLUSIONS The treatment of ODN with ultra-high doses of irbesartan was highly effective and safe in reducing proteinuria and slowing the progressive course to ESRD.
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Office and ambulatory blood pressure control with a fixed-dose combination of candesartan and hydrochlorothiazide in previously uncontrolled hypertensive patients: results of CHILI CU Soon.
Mengden, T, Hübner, R, Bramlage, P
Vascular health and risk management. 2011;:761-9
Abstract
BACKGROUND Fixed-dose combinations of candesartan 32 mg and hydrochlorothiazide (HCTZ) have been shown to be effective in clinical trials. Upon market entry we conducted a noninterventional study to document the safety and effectiveness of this fixed-dose combination in an unselected population in primary care and to compare blood pressure (BP) values obtained during office measurement (OBPM) with ambulatory blood pressure measurement (ABPM). METHODS CHILI CU Soon was a prospective, noninterventional, noncontrolled, open-label, multicenter study with a follow-up of at least 10 weeks. High-risk patients aged ≥18 years with previously uncontrolled hypertension were started on candesartan 32 mg in a fixed-dose combination with either 12.5 mg or 25 mg HCTZ. OBPM and ABPM reduction and adverse events were documented. RESULTS A total of 4131 patients (52.8% male) with a mean age of 63.0 ± 11.0 years were included. BP was 162.1 ± 14.8/94.7 ± 9.2 mmHg during office visits at baseline. After 10 weeks of candesartan 32 mg/12.5 mg or 25 mg HCTZ, mean BP had lowered to 131.7 ± 10.5/80.0 ± 6.6 mmHg (P < 0.0001 for both comparisons). BP reduction was comparable irrespective of prior or concomitant medication. In patients for whom physicians regarded an ABPM to be necessary (because of suspected noncontrol over 24 hours), ABP at baseline was 158.2/93.7 mmHg during the day and 141.8/85.2 mmHg during the night. At the last visit, BP had significantly reduced to 133.6/80.0 mmHg and 121.0/72.3 mmHg, respectively, resulting in 20.8% being normotensive over 24 hours (<130/80 mmHg). The correlation between OBPM and ABPM was good (r = 0.589 for systolic BP and r = 0.389 for diastolic BP during the day). Of those who were normotensive upon OBPM, 35.1% had high ABPM during the day, 49.3% were nondippers, and 3.4% were inverted dippers. Forty-nine adverse events (1.19%) were reported, of which seven (0.17%) were regarded as serious. CONCLUSION Candesartan 32 mg in a fixed-dose combination with either 12.5 mg or 25 mg HCTZ is safe and effective for further BP lowering irrespective of prior antihypertensive drug class not being able to control BP.
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In vitro dissolution/permeation system to predict the oral absorption of poorly water-soluble drugs: effect of food and dose strength on it.
Kataoka, M, Itsubata, S, Masaoka, Y, Sakuma, S, Yamashita, S
Biological & pharmaceutical bulletin. 2011;(3):401-7
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Abstract
The aim of the present work was to confirm the usefulness of the dissolution/permeation system (D/P system) in the estimation of human oral absorption of poorly water-soluble drugs. The D/P system, which can simultaneously evaluate drug absorption processes, dissolution and permeation, can predict the oral absorption of poorly water-soluble drugs in fasted and fed humans, with a correlation between in vivo oral absorption (% of absorbed) and in vitro permeated amount (% of dose/2 h) in the D/P system. The oral absorption (fraction of absorbed dose, %) of poorly water-soluble drugs in the fasted and fed states was predicted using the D/P system. The effect of food on the oral absorption of various drugs estimated by the D/P system significantly correlated with clinical data (correlation coefficient: r(2)=0.924). Moreover, the proportion of oral absorption of cilostazol was predicted to decrease with an increase in its dose strength, which significantly correlated with in vivo human absorption. Consequently, the D/P system was demonstrated to be a useful in vitro system for prediction of the oral absorption of poorly water-soluble drugs.
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Long-term antiproteinuric effect of dual renin-angiotensin system blockade.
Robles, NR, Fernandez Carbonero, E, Romero, B, Sánchez Casado, E, Cubero, JJ
Cardiovascular therapeutics. 2009;(2):101-7
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Abstract
We evaluated the long-term changes on overt proteinuria induced by dual blockade of the renin-angiotensin system (RAS). Dual blockade was produced by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an angiotensin converting enzyme (ACE) inhibitor in proteinuric patients. A total of 28 patients (19 men and 9 women) with proteinuria higher than 1 g/24 h were enrolled in this trial of treatment with the ARB candesartan (from 4 up to 32 mg daily) added to existing treatment with an ACE inhibitor. At 6, 12, 24, and 36 months, we evaluated proteinuria in 24-h urinary collections, office blood pressure (BP), plasmatic creatinine (Cr), serum potassium (K), and 24 h urine collection creatinine clearance (CrC). During monoblockade of the RAS by ACE inhibitor treatment, albuminuria was 2.94 +/- 1.92 mg/24 h; BP was 137/76 mmHg; K+ was 4.8 +/- 0.5 mmol/l, Cr was 1.76 +/- 0.67 mg/dL, and CrC was 62 +/- 31.9 mL/min. After 6 months, dual blockade of the RAS albuminuria was 2.18 +/- 2.29 mg/24 h (P < 0.01 vs. baseline) and BP was 133/75 mmHg (not significant). At 36 months, albuminuria was 2.21 +/- 2.20 mg/24 h (P < 0.05 vs. baseline); BP was 133/73 mmHg (not significant). CrC was not changed along the follow up. A small increment of Cr was detected at 24 months (2.11 +/- 1.06 mg/mL, P < 0.05). The antiproteinuric effect of dual renin-angiotensin system blockade combining candesartan and ACE inhibitors remain after 36 months without losing its initial effect. Blood pressure changes seem not to explain this long-term antiproteinuric effect.
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Effect of the angiotensin receptor blocker irbesartan on metabolic parameters in clinical practice: the DO-IT prospective observational study.
Parhofer, KG, Münzel, F, Krekler, M
Cardiovascular diabetology. 2007;:36
Abstract
AIMS: A number of intervention studies have shown that therapy with angiotensin receptor blockers, such as irbesartan, can improve metabolic parameters and reduce the incidence of diabetes mellitus. It is unknown whether this observation also holds true in routine clinical settings. METHODS We evaluated the effect of irbesartan (150 mg or 300 mg/d) together with or without hydrochlorothiazide (12.5 mg/d) in 3259 German patients. A total of 750 primary care physicians evaluated up to 5 subsequent patients with metabolic syndrome (58.9% diabetic), in whom irbesartan therapy was newly initiated (87%) or continued (13%). RESULTS Six months of irbesartan therapy decreased systolic blood pressure by 14% (157.4 +/- 14.7 vs. 135.0 +/- 10.7 mmHg) and diastolic blood pressure by 13% (92.9 +/- 9.2 vs. 80.8 +/- 6.8 mmHg). This was associated with a decrease in body weight (-2.3%), fasting glucose (-9.5%), HbA1c (-4.6%), LDL-cholesterol (-11%), triglycerides (-16%) and gamma-GT (-12%) and an increase in HDL-cholesterol (+5%). These changes were somewhat more pronounced in male than in female patients and in obese than in lean patients. Changes in glucose concentration and HbA1c were much more prominent in diabetic patients. CONCLUSION Irbesartan therapy improves metabolic parameters in routine clinical settings. Thus, our study confirms previously published results from large intervention trials and extends the findings to routine clinical practice.
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[Valsartan in patients with arterial hypertension and type 2 diabetes mellitus. The lapaval study].
Rodríguez Pérez, JC, Novoa Novoa, J, Caballero, A, Anabitarte, A, Plaza, C, Palop, L, Rodríguez Esparragón, F
Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia. 2005;(5):500-8
Abstract
UNLABELLED Arterial hypertension and diabetes mellitus give rise to a situation of high cardiovascular risk. The potential renoprotection from inhibition of the renin-angiotensin system is a valid option in this type of patient. OBJECTIVE Evaluate the effect of valsartan on blood pressure (BP) and renal function in albuminuric patients with type 2 diabetes and arterial hypertension. PATIENTS AND METHODS This was a prospective, observational study. Seventy-four diabetic patients with a blood pressure of > or = 140/90 mmHg, with micro or macroalbuminuria and a) blood creatinine levels lower 1.5 mg/dl (group 1) or b) blood creatinine levels between 1.5 and 2 mg/dl (group 2), were studied and followed up for a 12-week period. Treatment was started with valsartan 80 mg/d, increasing to 160 mg/d, adding torasemide at a dose of 5 mg/d if the target blood pressure of 130/85 mmHg has not been achieved. The degree of BP reduction was analyzed comparatively using a mercury sphygmomanometer and a semi-automatic monitor, the Omron HEM 705 CP. RESULTS All patients showed a significant reduction of the systolic (SBP) and diastolic (DBP) blood pressures (p< 0.001) over the study period, decreasing from 150.7 +/- 12.8 to 130.8 +/- 9.6 and from 94.7 +/- 7.7 to 76.8 +/- 6.3 mmHg, respectively. A significant reduction was observed only for diastolic blood pressure (101.4 +/- 8.8 to 79.4 +/- 5.6; p < 0.001) in the group 2 of patients. Lowest BP values were always obtained with the semiautomatic device. At the end of the study, 9.5% maintained valsartan 80 mg/d and 36.5% reqcuired the addition of a second or third drug to valsartan 160 mg in order to achieve the therapeutic target BP A significant reduction was observed in the microalbuminuria (75.5 +/- 9.5 to 54.7 +/- 7.3 microg/min; p < 0.001) and macroalbuminuria (n = 20; 0.93 +/- 0.4 to 0.68 +/- 0.4 g/day; p < 0.001). CONCLUSION Valsartan significantly reduced SBP and DBP Valsartan at 160 mg/d had a significantly greater effect in reducing micro and macroalbuminuria. No changes were observed in renal function, HbA1c or serum potassium. The rate of adverse events was very low.
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Impact of diabetic nephropathy and angiotensin II receptor blockade on urinary polypeptide patterns.
Rossing, K, Mischak, H, Parving, HH, Christensen, PK, Walden, M, Hillmann, M, Kaiser, T
Kidney international. 2005;(1):193-205
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BACKGROUND New insights into the pathogenesis and treatment of diabetic renal disease may emerge from recent advances in proteomics using high-throughput mass spectrometry (MS) of urine. METHODS Using a combination of online capillary electrophoresis (CE) and MS we evaluated urinary polypeptide patterns in four groups of type 2 diabetic patients matched for age, gender, and diabetes duration, including 20 normoalbuminuric patients with and 20 without diabetic retinopathy, 20 microalbuminuric patients with diabetic retinopathy, and 18 macroalbuminuric patients with diabetic retinopathy. Furthermore, changes in urinary polypeptide patterns during treatment with the angiotensin II receptor blocker (ARB) candesartan were evaluated in the macroalbuminuric patients in a randomized double-blinded, cross-over trial where each patient received treatment with placebo, candesartan 8, 16, and 32 mg daily each for 2 months. RESULTS Overall, 4551 different polypeptides were found in the samples. Urinary polypeptide patterns were comparable in normo- (with and without diabetic retinopathy) and microalbuminuric patients, whereas distinct differences were found in macroalbuminuric patients. Differences in urinary polypeptide patterns between normo- and macroalbuminuric patients permitted the establishment of a "diabetic renal damage" pattern consisting of 113 polypeptides. Eleven of these polypeptides had been sequenced and identified. Candesartan treatment in macroalbuminuric patients significantly changed 15 of the 113 polypeptides in the diabetic renal damage pattern toward levels in normoalbuminuric patients. Change in the diabetic renal damage pattern was not candesartan dose-dependent but individual changes correlated with changes in urinary albumin excretion at each dose level. CONCLUSION CE-MS serves as a fast and sensitive tool for identification of biomarkers and urinary polypeptide patterns specific for macroalbuminuric type 2 diabetic patients and may be used to explore and monitor renoprotective effects of ARB.