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Objective: To assess the protective role of benazepril, an angiotensin-converting enzyme inhibitor, in renal damage caused by prenatal inflammation., Methods: Saline or lipopolysaccharide were administered intraperitoneally to pregnant Sprague- Dawley rats on gestation days 8, 10, and 12. After birth, offspring received either tap water or benazepril in water between 7 and 68 weeks. Blood pressure, blood urea nitrogen, creatinine, and 24-h urine volume were measured as indices of renal function. Hematoxylin, eosin, periodic acid-Schiff, and Sirius Red staining were used to evaluate renal damage., Results: Postnatal benazepril treatment ameliorated hypertension and restored normal 24-h urine volume and blood urea nitrogen and serum creatinine levels. Benazepril treatment also reduced glycoprotein accumulation and fibrosis in the glomerulus and in tubular epithelial cells and inhibited nuclear factor-kappa B activation., Conclusion: Together with our previous findings that postnatal inhibition of nuclear factor-kappa B activation blocks intra-renal renin-angiotensin system activation, our current data demonstrate that intra-renal activation of the renin-angiotensin system interacts with nuclear factor-kappa B activation to cause renal damage in adulthood following prenatal inflammation.

We examined whether tolvaptan combined with an angiotensin II receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACE-I) is more effective than tolvaptan alone in the treatment of patients with heart failure (HF). Sixty-five hospitalized patients with acute decompensated HF were included in this study. They were divided into 2 groups; an ARB/ACE-I group (n = 44, who received ARB or ACE-I before the use of tolvaptan) and a non-ARB/ACE-I group (n = 21). There were no significant differences in patient characteristics including medications at baseline between the non-ARB/ACE-I and ARB/ACE-I groups with the exception of the percentages of hypertension and ischemic heart disease. Urinary volume (UV) at baseline in the ARB/ACE-I group was slightly higher than that in the non-ARB/ACE-I group. The increase in UV after the use of tolvaptan in the non-ARB/ACE-I group was significantly higher than that in the ARB/ACE-I group. The cardiothoracic ratio and the reduction in body weight were similar between the groups after tolvaptan use. Finally, in a logistic regression analysis, a response to the use of tolvaptan was independently associated with the non-use of ARB/ACE-I, but not with age, gender, body mass index, loop diuretic, or human arterial natriuretic peptide. In conclusion, tolvaptan alone might induce an increase in UV in decompensated HF patients without ARB/ ACE-I, although the treatment of HF with ARB/ACE-I is the first choice strategy.

Combined use of angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs may induce acute kidney injury, especially when combined with diuretics. The objective of this investigation was to evaluate the effect of benazepril, robenacoxib and their combination in healthy dogs. In each of two studies (studies 1 and 2), 32 beagle dogs were randomized into one of four groups in a parallel-group design. Groups received once-daily oral treatment for 7 days with placebo, benazepril, robenacoxib or benazepril plus robenacoxib. In study 2, all dogs received additionally 2 mg/kg furosemide orally twice daily. The primary endpoint was the glomerular filtration rate (GFR) estimated from the plasma clearance of iohexol. Secondary endpoints included standard clinical monitoring and, in study 2, plasma renin activity, urine volume, specific gravity and aldosterone concentration and water intake. Administration of furosemide induced diuresis, reduced GFR and activated the renin-aldosterone-angiotensin system. Benazepril and robenacoxib, administered alone or in combination, were tolerated well, did not decrease GFR with or without co-administration of furosemide and significantly reduced urinary aldosterone concentrations. No increased risk of acute kidney injury was identified with the combination of benazepril and robenacoxib in healthy dogs. Different effects might occur in dogs with heart or renal disease., (© 2016 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.)

Objective: To determine whether high doses of enalapril and benazepril would be more effective than standard doses of these drugs in suppressing the furosemide-activated renin-angiotensin-aldosterone system (RAAS)., Animals: 6 healthy Beagles., Procedures: 2 experiments were conducted; each lasted 10 days, separated by a 2-week washout period. In experiment 1, all dogs received furosemide (2 mg/kg, PO, q 12 h) and enalapril (1 mg/kg, PO, q 12 h) for 8 days (days 0 through 7). In experiment 2, dogs received furosemide (2 mg/kg, PO, q 12 h) and benazepril (1 mg/kg, PO, q 12 h) for 8 days. Effects on the RAAS were determined by assessing serum angiotensin-converting enzyme (ACE) activity on days -1, 3, and 7; serum aldosterone concentration on days -2, -1, 1, 3, and 7; and the urinary aldosterone-creatinine ratio (UAldo:C) in urine collected in the morning and evening of days -2, -1, 1, 3, and 7., Results: High doses of enalapril and benazepril caused significant reductions in serum ACE activity on all days but were not more effective than standard doses used in other studies. Mean UAldo:C remained significantly higher on days 2 through 7, compared with baseline values. Serum aldosterone concentration also increased after drug administration, which mirrored changes in the UAldo:C., Conclusions and Clinical Relevance: In this study, administration of high doses of enalapril and benazepril significantly inhibited ACE activity, yet did not prevent increases in mean urine and serum aldosterone concentrations resulting from furosemide activation of RAAS. This suggested that aldosterone breakthrough from ACE inhibition was a dose-independent effect of ACE inhibitors.

Purpose: The objective of this research was to provide a comprehensive description of the effect of benazepril on the dynamics of the renin-angiotensin aldosterone system (RAAS) in dogs., Methods: Blood specimens for renin activity (RA), angiotensin II (AII), and aldosterone (ALD) quantitation in plasma were drawn from 12 healthy adult beagle dogs randomly allocated to 2 treatment groups: (i) benazepril 5 mg PO, q24 h (n: 6) and (ii) placebo (n: 6), in a cross-over design. A mechanism-based pharmacokinetic/pharmacodynamic model, which includes the periodic nature of RA, AII, and ALD during placebo treatment and the subsequent changes in dynamics following repeated dosing with benazepril, was developed., Results: The disposition kinetics of benazepril active metabolite, benazeprilat, was characterized using a saturable binding model to the angiotensin converting enzyme. The modulatory effect of benazeprilat on the RAAS was described using a combination of immediate response models. Our data show that benazepril noticeably influences the dynamics of the renin cascade, resulting in a substantial decrease in AII and ALD, while increasing RA throughout the observation span., Conclusions: The model provides a quantitative framework for better understanding the effect of ACE inhibition on the dynamics of the systemic RAAS in dogs.

Background: Renal fibrosis is common in progressive kidney disease. Transforming growth factors β (TGF-β) are important mediators of all types of fibrosis, including renal fibrosis. Chinese rhubarb has been shown to have antifibrotic properties in part because of inhibition of TGF-β and has slowed the progression of kidney disease in rodent models., Hypothesis: That administration of a Chinese rhubarb supplement will slow the progression of chronic kidney disease (CKD) in cats and the concurrent administration of Chinese rhubarb and benazepril will be more effective than either alone., Animals: Twenty-nine client-owned cats with naturally occurring IRIS Stage 2 or early Stage 3 CKD and without comorbidity such as cancer, urinary tract obstruction, urinary tract infection, poorly controlled hyperthyroidism, or systemic hypertension were enrolled in the study., Methods: A randomized, positive-controlled, prospective study was performed. Cats received Chinese rhubarb, benazepril, or both in addition to standard treatment for CKD. Repeated measures ANOVA was used to assess changes in serum creatinine concentration, body weight, hematocrit, urine protein: urine creatinine ratio (UPC), and systemic arterial blood pressure over time between and within treatment groups over an average of 22 months., Results: No significant differences were detected in serum creatinine concentration, body weight, hematocrit, UPC, and systemic arterial pressure over time between or within treatment groups., Conclusions and Clinical Importance: This study failed to detect a significant difference in the progression of CKD in cats treated with Chinese rhubarb, benazepril, or both. Further study in specific subsets of cats with CKD is warranted., (Copyright © 2014 by the American College of Veterinary Internal Medicine.)

Objective: To compare the bioequivalence and 'switchability' of two formulations of benazepril (tablet and liquid) after oral administration., Design: Randomised cross-over design, followed by parallel comparison., Methods: Twelve mixed-breed dogs were administered either a tablet (Group A) or liquid formulation (Group B) of benazepril orally at 0.45 mg/kg daily for 4 days. With no washout period, the dogs then received the alternative treatment at the same dose for a further 4 days. Blood samples taken prior to treatment and serially after treatment were analysed for plasma concentrations of benazepril and benazeprilat and the activity and concentration of angiotensin-converting enzyme (ACE). The calculated percentage inhibition of ACE was defined as the primary outcome variable., Results: No statistically significant differences were found between groups A and B for any variable evaluated. The mean (± SD) percentage of ACE inhibition was 85.5 ± 7.04% for the liquid formulation and 85.9 ± 6.66% for the tablet formulation. The mean of the ratios was 1.00 (80% confidence interval 0.96-1.04). No evaluated effect term (sequence, formulation or period) had any statistical effect on any outcome variable., Conclusion: This study supports a conclusion that, based on pharmacodynamic response, the liquid formulation of benazepril is bioequivalent to the reference tablet formulation. Further, the lack of a sequence effect supports the switchability of these two formulations., (© 2013 Australian Veterinary Association.)

Background: Combination therapy is an effective method to reduce the blood pressure (BP) for patients with hypertension. This study was performed to evaluate the efficacy and safety of benazepril/lercanidipine compared with benazepril alone in patients with mild-to-moderate hypertension., Methods: One hundred and eighty-one patients with mild-to-moderate primary hypertension were assigned in this randomized, single-blind, parallel-group study and were randomly divided into group A (benazepril 10 mg/lercanidipine 10 mg) and group B (benazepril 10 mg) for 8 weeks. At 4 weeks, the dosage of Benazepril was titrated up to 20 mg if the diastolic blood pressure (DBP) remained ≥ 90 mmHg. BP control and side effects were evaluated at the end of 1, 4 and 8 weeks., Results: The baseline characteristics of the two groups were similar. The BP in both groups decreased from the baseline (P < 0.05). At the end of 4 and 8 weeks, Benazepril/Lercanidipine produced greater BP reduction than Benazepril alone (P < 0.05). The comparison of the rate of BP control for the benazepril/lercanidipine and benazepril groups at the end of 1, 4, and 8 weeks were 41.2% vs. 37.6% (P > 0.05), 67.1% vs. 44.7% (P < 0.05), and 71.8% vs. 45.9% (P < 0.05). There was no significant difference of side effects between the two groups., Conclusion: The benazepril/lercanidipine combination is more effective in reducing BP than benazepril alone, while it does not increase the incidence of side effects.

Hyperglycaemia up-regulates intracellular AngII (angiotensin II) production in cardiac myocytes, effects of which are blocked more effectively by renin inhibition than ARBs (angiotensin receptor blockers) or ACEis (angiotensin-converting enzyme inhibitors). In the present study, we determined whether renin inhibition is more effective at preventing diabetic cardiomyopathy than an ARB or ACEi. Diabetes was induced in adult mice for 10 weeks by STZ (streptozotocin). Diabetic mice were treated with insulin, aliskiren (a renin inhibitor), benazeprilat (an ACEi) or valsartan (an ARB) via subcutaneous mini-pumps. Significant impairment in diastolic and systolic cardiac functions was observed in diabetic mice, which was completely prevented by all three RAS (renin-angiotensin system) inhibitors. Hyperglycaemia significantly increased cardiac oxidative stress and circulating inflammatory cytokines, which were blocked by aliskiren and benazeprilat, whereas valsartan was partially effective. Diabetes increased cardiac PRR (prorenin receptor) expression and nuclear translocation of PLZF (promyelocytic zinc finger protein), which was completely prevented by aliskiren and valsartan, and partially by benazeprilat. Renin inhibition provided similar protection of cardiac function to ARBs and ACEis. Activation of PLZF by PRR represented a novel mechanism in diabetic cardiomyopathy. Differential effects of the three agents on oxidative stress, cytokines and PRR expression suggested subtle differences in their mechanisms of action.

Background: Few studies have examined the effect of the angiotensin II type I receptor (AT1R) A1166C polymorphism on the antihypertensive effect of the angiotensin-converting-enzyme inhibitor benazepril in patients with hypertension, and no such studies have performed analysis using the Family-Based Association Test (FBAT), The aim of our study was to examine the association between AT1R A1166C gene polymorphism and the antihypertensive effect of benazepril using the FBAT., Methods and Results: A total of 864 patients (aged, 26-62 years) with essential hypertension were identified in an epidemiological survey and enrolled in this study. Blood pressure (BP) was measured before and after 16 days of treatment with benazepril (10 mg/day). The association between the A1166C gene polymorphism and the antihypertensive effect of benazepril was assessed by FBAT. The frequencies of alleles A and C were 95.1% and 4.9%, respectively. FBAT analysis revealed that the C allele was significantly associated with high baseline diastolic BP (Z = 2.041, p = 0.041), decreased systolic BP after treatment (Z = 2.549, p = 0.011), and decreased diastolic BP after treatment (Z = 2.320, p = 0.020)., Conclusion: Our results, determined using the FBAT, are the first evidence that the AT1R A1166C polymorphism may increase the antihypertensive effect of benazepril in patients with hypertension.

Background: Hypertension is a prevalent condition that is closely associated with chronic complications in patients with diabetes. Fixed-dose combination therapy is currently recommended for the treatment of hypertension due to the advantage of reducing the pill burden. However, the effects of combination therapy may be diverse because of the different components., Objectives: We examined blood pressure reduction and metabolic alterations after amlodipine/benazepril and valsartan/hydrochlorothiazide treatment in patients with type 2 diabetes mellitus and hypertension and microalbuminuria., Methods: This randomized, double-blind, parallel comparison, noninferiority clinical trial included patients with type 2 diabetes mellitus and hypertension and microalbuminuria detected within the past year. After a 2-week, placebo run-in period, patients were assigned to treatment with amlodipine/benazepril or valsartan/hydrochlorothiazide for 16 weeks. The primary end point was mean change in diastolic blood pressure. The prespecified boundary for noninferiority was 3.5 mm Hg of the mean change in diastolic blood pressure between treatments (amlodipine/benazepril minus valsartan/hydrochlorothiazide). If the upper limit of the 95% CI fell within 3.5 mm Hg, amlodipine/benazepril would be considered noninferior to valsartan/hydrochlorothiazide., Results: Of the 226 patients assessed for eligibility, 169 satisfied the inclusion/exclusion criteria and were assigned to a treatment group; 83 patients (54.2% male, mean age of 60.5 [10.0] years) in the amlodipine/benazepril group and 84 patients (64.3% male, mean age of 59.0 [10.6] years) in the valsartan/hydrochlorothiazide group received at least 1 dose of study medication and were included in the intention-to-treat population. In the per-protocol population, amlodipine/benazepril (n = 74) was noninferior to valsartan/hydrochlorothiazide (n = 78) with regard to the mean change in diastolic blood pressure (difference, -0.9 mm Hg; 95% CI, -3.5 to 1.6). The mean change in systolic blood pressure was not significantly different (2.4 mm Hg; 95% CI, -1.2 to 6.0) between study groups (P = 0.195) in the per-protocol population. However, data from the intention-to-treat population suggest that patients in the amlodipine/benazepril group may have better metabolic outcomes than those in the valsartan/hydrochlorothiazide group; specifically, a preservation of the estimated glomerular filtration rate (5.7 mL/min/1.73 m(2) [95% CI, 1.9 to 9.6]; P = 0.004) and improvements in glycosylated hemoglobin (-0.5% [95% CI, -0.7 to -0.2]; P < 0.001), fasting triglycerides (-0.4 mmol/L [95% CI, -0.7 to -0.2]; P = 0.002), HDL-C (0.07 mmol/L [95% CI, 0.01 to 0.12]; P = 0.022), and uric acid (-57.5 μmol/L [95% CI, -74.8 to -40.3]; P < 0.001). There were no significant differences in adverse effects between groups, with the exception of more respiratory disorders in the amlodipine/benazepril group than in the valsartan/hydrochlorothiazide group (17 vs 5; P = 0 .006)., Conclusions: The study results suggest that amlodipine/benazepril is noninferior to valsartan/hydrochlorothiazide with regard to blood pressure reduction and that this combination exerts beneficial effects on renal function, glucose control, HDL-C, and triglyceride levels compared with valsartan/hydrochlorothiazide. However, respiratory adverse events (particularly coughing) were more frequently reported in the amlodipine/benazepril group. ClinicalTrials.gov identifier: NCT01375322., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Objective: To compare the pharmacokinetic (PK) profiles and evaluate the PK interaction of hydrochlorothiazide (HCTZ) used alone and in combination with benazepril (BENA) or valsartan (VAL) in healthy Chinese volunteers., Materials and Methods: Data from two Phase I clinical trials (Study A and Study B) were combined and analyzed. Study A was an open, randomized, three-period crossover study. Eligible healthy male Chinese volunteers were randomly assigned to receive a single dose of the HCTZ (25 mg), BENA (20 mg) or HCTZ/BENA (25/20 mg). Study B was an open randomized, two-period crossover study of VAL/HCTZ (160/12.5 mg) in two formulations. A 7-day washout period was designed between alternate formulations in both studies. Multiple blood samples were collected up to 48 h post-dose, and plasma concentrations of HCTZ were analyzed using high performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS) system. Adverse events (AEs) were monitored and documented throughout the study period., Results: 12 subjects completed Study A and 18 subjects completed Study B. Mean maximum plasma concentration (C(max)) was 168, 121 and 418 ng/ml and mean exposure (AUC(0-48 h)) was 1,160, 955 and 2,801 ng × h/ml following a single dose of HCTZ (25 mg) alone, BENA/HCTZ (20/25 mg) and VAL/HCTZ (160/12.5 mg), respectively. There was significant decrease in C(max) (90% confidence interval: 64.4 - 78.0%) and AUC(0-48 h) (90% confidence interval: 75.9 - 89.5%) of HCTZ with BENA co-administration, whereas concomitant VAL with HCTZ led to significant increase (approximate 1.5-fold) in C(max) and AUC(0-48 h) of plasma HCTZ even without dose normalizing. The apparent terminal half-life (t(1/2)) and the time to C(max) (tmax) were unchanged between the two studies. Overall, HCTZ alone as well as in combination with BENA and VAL was well tolerated within the scope of the current studies in Chinese health volunteers., Conclusions: BENA decreased the bioavailability of HCTZ in Chinese healthy volunteers while VAL greatly increased the concentration of HCTZ in plasma during coadministration. The combination of HCTZ with BENA or VAL was safe and well tolerated.

The renin-angiotensin system is an important mediator of tumor progression and metastasis. A recent meta-analysis of randomized controlled trials reported an increased risk of cancer with angiotensin receptor blockers. It is unknown whether angiotensin-converting enzyme (ACE) inhibitors may have a similar effect. Our primary objective was to determine the effect of ACE inhibitors on cancer occurrence and cancer death. Our secondary objective was to determine the effect of ACE inhibitors on occurrence of gastrointestinal (GI) cancers given previous concerns of increased risk. Systematic searches of SCOPUS (covering MEDLINE, EMBASE, and other databases) and the Food and Drug Administration official web site were conducted for all randomized controlled trials of ACE inhibitors. Trials with ≥1 year of follow-up and enrolling a minimum of 100 patients were included. Fourteen trials reported cancer data in 61,774 patients. This included 10 trials of 59,004 patients providing information on cancer occurrence, 7 trials of 37,515 patients for cancer death, and 5 trials including 23,291 patients for GI cancer. ACE inhibitor therapy did not have an effect on occurrence of cancer (I(2) 0%, risk ratio [RR] 1.01, 95% confidence interval [CI] 0.95 to 1.07, p = 0.78), cancer death (I(2) 0%, RR 1.00, 95% CI 0.88 to 1.13, p = 0.95), or GI cancer (RR 1.09, 95% CI 0.88 to 1.35, p = 0.43). In conclusion, ACE inhibitors did not significantly increase or decrease occurrence of cancer or cancer death. There was also no significant difference in risk of GI cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to determine which combination therapy in patients with hypertension and diabetes most effectively decreases cardiovascular events., Background: The ACCOMPLISH (Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension) trial compared the outcomes effects of a renin-angiotensin system blocker, benazepril, combined with amlodipine (B+A) or hydrochlorothiazide (B+H). A separate analysis in diabetic patients was pre-specified., Methods: A total of 6,946 patients with diabetes were randomized to treatment with B+A or B+H. A subgroup of 2,842 diabetic patients at very high risk (previous cardiovascular or stroke events) was also analyzed, as were 4,559 patients without diabetes. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for angina, resuscitated arrest, and coronary revascularization., Results: In the full diabetes group, the mean achieved blood pressures in the B+A and B+H groups were 131.5/72.6 and 132.7/73.7 mm Hg; during 30 months, there were 307 (8.8%) and 383 (11.0%) primary events (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.68 to 0.92, p = 0.003). For the diabetic patients at very high risk, there were 195 (13.6%) and 244 (17.3%) primary events (HR: 0.77, 95% CI: 0.64 to 0.93, p = 0.007). In the nondiabetic patients, there were 245 (10.8%) and 296 (12.9%) primary events (HR: 0.82, 95% CI: 0.69 to 0.97, p = 0.020). In the diabetic patients, there were clear coronary benefits with B+A, including both acute clinical events (p = 0.013) and revascularizations (p = 0.024). There were no unexpected adverse events., Conclusions: In patients with diabetes and hypertension, combining a renin-angiotensin system blocker with amlodipine, compared with hydrochlorothiazide, was superior in reducing cardiovascular events and could influence future management of hypertension in patients with diabetes. (Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension [ACCOMPLISH]; NCT00170950)., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: This study sought to compare the antihypertensive efficacy and tolerability of a fixed-dose combination with amlodipine/benazepril with that of amlodipine monotherapy in Chinese hypertensive subjects., Results: This multicenter, double-blind, 8-week study randomized 111 patients to fixed-dose amlodipine besylate/benazepril HCl (2.5/5 mg/day titrated to 5/10 mg/day as needed at week 4 to reach goal blood pressure (BP) <140/90 mmHg) or amlodipine besylate monotherapy (5 mg/day titrated to 10 mg/day as needed). At week 8, patients randomized to combination therapy compared with monotherapy had a comparable BP control rate (56.0% vs. 46.2%; p = 0.32). Fixed-dose combination resulted in similar reductions in sitting systolic (SBP) and diastolic BP (DBP) compared with monotherapy (SBP: -19.3 +/- 12.5 vs. -20.9 +/- 13.3 mmHg; DBP: -9.2 +/- 10.4 vs. -11.3 +/-9.3 mmHg; both p=NS). Safety profiles did not differ between groups, but cough was more common in the combination group (11.0% vs. 0%; p = 0.013)., Conclusions: In this group of patients, comparable antihypertensive effects were seen with the fixed-dose combination therapy, compared with amlodipine monotherapy. Both treatments appeared well tolerated in the studied population, but cough was more common in the fixed-dose combination group.

Background: Angiotensin II (AII) is the well-known determinant of kidney damage increasing intraglomerular pressure, matrix expansion and fibroblast proliferation. Renin-angiotensin system (RAS) inhibition, limiting the hemodynamic effects of AII, reduces proteinuria and is renoprotective in the long term., Methods: We studied 15 chronic proteinuric patients by Doppler ultrasonography to clarify the intrarenal hemodynamic changes during RAS blockade by Benazepril (10-20 mg/day) alone and combined with Valsartan (80-160 mg/day). We also investigated the correlation between hemodynamic indices, RAS components and antiproteinuric effect., Results: After 1 month of Benazepril proteinuria, resistive index (RI) and pulsatility index (PI) significantly decreased and proteinuria reduction was directly correlated to decrease in RI (r = 0.55, p = 0.03). Contrarily, after 1 month of combined therapy, RI and PI restored to baseline and progressively increased in the following 3 months, while proteinuria decreased. Increase in RI was directly correlated to concomitant increase in plasma renin activity (r = 0.65, p = 0.01) suggesting a direct role of renin in restoring intrarenal resistances., Conclusion: The hemodynamic changes caused by RAS inhibitors partially contribute to the antiproteinuric effect. Other RAS components, such as renin, may contribute to renal vasoconstriction and could be a further determinant of kidney damage besides a promising target for renoprotection., ((c) 2008 S. Karger AG, Basel.)

1. Heart rate (HR) turbulence describes short-term sinus rhythmic fluctuation after a single premature ventricular beat. Turbulence onset (TO) and turbulence slope (TS) are two essential parameters in HR turbulence. Turbulence onset and TS have been used to evaluate cardiac autonomic nerve function. 2. In the present study, we measured the HR turbulence in dilated cardiomyopathy (DCM) and determined the possible role of benazepril, an angiotensin-converting enzyme inhibitor (ACEI), on these parameters. There were three groups: control, DCM and DCM treated with benazepril. The control group consisted of normal subjects with PVB, but no structural heart disease. Ambulatory electrocardiogram, blood pressure and echocardiography were analysed. 3. There was an increase in TO and a decrease in TS in DCM patients. Benazepril treatment (10 mg/day, p.o.) reduced those changes. There were no significant differences in blood pressure and left ventricular ejection fraction (LVEF) between DCM patients and DCM patients treated with benazepril. 4. Linear regression analysis showed that TO was negatively correlated with LVEF, whereas TS was positively correlated with LVEF, in the DCM group. After benazepril treatment, the correlations between TO and TS and LVEF disappeared. 5. It is concluded that the TO and TS of HR turbulence are altered in patients with DCM. These alterations indicate a dysfunction of the autonomic control of cardiac electrophysiology in DCM patients. Although TO and TS are correlated with LVEF in DCM patients, the effect of benazepril in improving HR turbulence parameters is not a result of its action on heart function, which suggests a new beneficial effect of ACEI in the treatment of DCM patients.

The Renoprotection of Optimal Antiproteinuric Doses (ROAD) study was performed to determine whether titration of benazepril or losartan to optimal antiproteinuric doses would safely improve the renal outcome in chronic renal insufficiency. A total of 360 patients who did not have diabetes and had proteinuria and chronic renal insufficiency were randomly assigned to four groups. Patients received open-label treatment with a conventional dosage of benazepril (10 mg/d), individual uptitration of benazepril (median 20 mg/d; range 10 to 40), a conventional dosage of losartan (50 mg/d), or individual uptitration of losartan (median 100 mg/d; range 50 to 200). Uptitration was performed to optimal antiproteinuric and tolerated dosages, and then these dosages were maintained. Median follow-up was 3.7 yr. The primary end point was time to the composite of a doubling of the serum creatinine, ESRD, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease. Compared with the conventional dosages, optimal antiproteinuric dosages of benazepril and losartan that were achieved through uptitration were associated with a 51 and 53% reduction in the risk for the primary end point (P = 0.028 and 0.022, respectively). Optimal antiproteinuric dosages of benazepril and losartan, at comparable BP control, achieved a greater reduction in both proteinuria and the rate of decline in renal function compared with their conventional dosages. There was no significant difference for the overall incidence of major adverse events between groups that were given conventional and optimal dosages in both arms. It is concluded that uptitration of benazepril or losartan against proteinuria conferred further benefit on renal outcome in patients who did not have diabetes and had proteinuria and renal insufficiency.

This European Community Biomedicine and Health Research-supported, multicenter, randomized, placebo-controlled, double-blind trial investigated the effect of an angiotensin-converting enzyme inhibitor (ACE-I) in children and young people with IgA nephropathy (IgAN), moderate proteinuria (>1 and <3.5 g/d per 1.73 m(2)) and creatinine clearance (CrCl) >50 ml/min per 1.73 m(2). Sixty-six patients who were 20.5 yr of age (range 9 to 35 yr), were randomly assigned to Benazepril 0.2 mg/kg per d (ACE-I) or placebo and were followed for a median of 38 mo. The primary outcome was the progression of kidney disease, defined as >30% decrease of CrCl; secondary outcomes were (1) a composite end point of >30% decrease of CrCl or worsening of proteinuria until > or =3.5 g/d per 1.73 m(2) and (2) proteinuria partial remission (<0.5 g/d per 1.73 m(2)) or total remission (<160 mg/d per 1.73 m(2)) for >6 mo. Analysis was by intention to treat. A single patient (3.1%) in the ACE-I group and five (14.7%) in the placebo group showed a worsening of CrCl >30%. The composite end point of >30% decrease of CrCl or worsening of proteinuria until nephrotic range was reached by one (3.1%) of 32 patients in the ACE-I group, and nine (26.5%) of 34 in the placebo group; the difference was significant (log-rank P = 0.035). A stable, partial remission of proteinuria was observed in 13 (40.6%) of 32 patients in the ACE-I group versus three (8.8%) of 34 in the placebo group (log-rank P = 0.033), with total remission in 12.5% of ACE-I-treated patients and in none in the placebo group (log-rank P = 0.029). The multivariate Cox analysis showed that treatment with ACE-I was the independent predictor of prognosis; no influence on the composite end point was found for gender, age, baseline CrCl, systolic or diastolic BP, mean arterial pressure, or proteinuria.

A sensitive and accurate high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detector was developed and validated for simultaneous determination of benazepril (BZL) and its active metabolite, benazeprilat (BZT), in human plasma. The plasma sample, after spiked with riluzole as an internal standard (IS), was subjected to a solid-phase extraction (SPE) prior to a HPLC analysis. Chromatographic separations were achieved on a Hypersil BDS C(18) (300 mm x 4.6mm, 5 microm). The mobile phase consisted of phosphate buffer (pH 2.6; 10mM) and acetonitrile mixture in a gradient mode. Detection was carried out at a wavelength of 237 nm. The retention times of BZL, BZT and IS were at about 6.2, 15.4 and 16.2 min, respectively. The calibration curve was linear in the range of 20-2000 ng/mL for both BZL and BZT (r(2)>0.997). At three quality control concentrations of 100, 500, and 1500 ng/mL, the intra-day and inter-day relative standard deviation ranged from 2.8 to 8.6% for BZL and from 2.2 to 8.5% for BZT, while the mean absolute percentage error ranged from -7.5 to 6.7% for BZL and from -6.0 to 3.2% for BZT. The limit of detection (LOD) was 10 ng/mL and the limit of quantification (LOQ) was 20 ng/mL for both BZL and BZT in human plasma. The method was successfully applied to bioequivalence evaluation of benazepril hydrochloride formulations in healthy Chinese.

Background: This study compared the efficacy and safety of amlodipine/benazepril (10/40 mg/day and 10/20 mg/day) with amlodipine 10 mg/day in patients whose blood pressure (BP) was not adequately controlled with amlodipine monotherapy., Methods: After a lead-in period with amlodipine monotherapy, 812 non-responder patients (mean sitting diastolic BP > or =95 mmHg) were randomized to one of three treatment groups. Ambulatory BP monitoring was conducted in 276 patients., Results: Treatment with amlodipine/benazepril 10/40 mg/day and 10/20 mg/day resulted in a decrease of mean sitting systolic and mean sitting diastolic BP by 13.3/12.7 mmHg and 12.1/11.6 mmHg, respectively, compared with monotherapy (6.6/8.5 mmHg) (p < 0.0001). Both combinations resulted in more responders than monotherapy (74% and 65% vs. 54%; p < 0.0001 and p < 0.0085, respectively). Amlodipine/benazepril 10/40 mg/day and 10/20 mg/day decreased ambulatory systolic and diastolic BP by 9.9/6.7 mmHg and 7.4/5.2 mmHg compared with monotherapy (p < 0.0001). The incidence of pedal edema was lower in the amlodipine/benazepril combinations compared with monotherapy (4.5%, 5.5% vs. 9.2%, respectively, p=NS). No significant metabolic side-effects were noted among the combination groups., Conclusion: Amlodipine/benazepril combinations were well tolerated and resulted in significant BP reductions and better BP responder rates than amlodipine monotherapy.

It has been suggested that the effects of angiotensin II type 1 receptor (AT1R) blockers are in part because of angiotensin II type 2 receptor (AT2R) signaling. Interactions between the AT2R and kinins modulate cardiovascular function. Because AT2R expression increases after vascular injury, we hypothesized that the effects on vascular remodeling of the AT1R blocker valsartan and the ACE inhibitor benazepril require AT2R signaling through the bradykinin 1 and 2 receptors (B1R and B2R). To test this hypothesis, Brown Norway rats were assigned to 8 treatments (n=16): valsartan, valsartan+PD123319 (AT2R inhibitor), valsartan+des-arg9-[Leu8]-bradykinin (B1R inhibitor), valsartan+HOE140 (B2R inhibitor), benazepril, benazepril+HOE140, amlodipine, and vehicle. After 1 week of treatment, carotid balloon injury was performed. Two weeks later, carotids were harvested for morphometry and analysis of receptor expression by immunohistochemistry and Western blotting. Valsartan and benazepril significantly reduced the intima:media ratio compared with vehicle. Blockade of AT2R, B1R, or B2R in the presence of valsartan prevented the reduction seen with valsartan alone. B2R blockade inhibited the effect of benazepril. Injury increased AT1R, AT2R, B1R, and B2R expression. Treatment with valsartan but not benazepril significantly increased intima AT2R expression 2-fold compared with vehicle, which was not reversed by inhibition of AT2R, B1R, and B2R. Functionally, valsartan increased intimal cGMP levels compared with vehicle, and this increase was inhibited by blocking the AT2R, B1R, and B2R. Results suggest that AT2R expression and increased cGMP represent a molecular mechanism that differentiates AT1R blockers, such as valsartan, from angiotensin-converting enzyme inhibitors like benazepril.

Objective: Our objective was to investigate the association between the -344C/T or A6547G polymorphism of the aldosterone synthase gene and the blood pressure response to angiotensin-converting enzyme inhibitors in a hypertensive cohort., Methods: After a 2-week single-blind placebo run-in period, either benazepril or imidapril was administered for 6 weeks to 509 patients with mild to moderate essential hypertension. Polymerase chain reaction combined with restriction enzyme digestion was used to detect the 2 polymorphisms. The achieved changes in systolic and diastolic blood pressure were analyzed for their association with genotypes at the aldosterone synthase gene loci., Results: Regarding the -344C/T polymorphism, we observed the CC genotype in 53 patients (10.4%), the CT genotype in 204 (40.1%), and the TT genotype in 252 (49.5%). After 6 weeks of treatment, the reductions in diastolic blood pressure were significantly greater in patients carrying the TT or CT genotype compared with those carrying the CC genotype (9.1+/-7.0 mm Hg or 8.9+/-7.0 mm Hg versus 5.1+/-7.3 mm Hg, respectively; P=.001, ANOVA). Regarding the A6547G polymorphism, we observed the AA genotype in 19 patients (3.7%), the AG genotype in 184 (36.2%), and the GG genotype in 306 (60.1%). There were no significant differences in the blood pressure reductions after treatment among the 3 genotype groups, and there was no interaction between it and the -344C/T polymorphism. Stepwise multiple regression analysis showed that the significant predictors of diastolic blood pressure reduction at 6 weeks were baseline diastolic blood pressure (P<.001), -344C/T genotype (P=.007), and sex (P=.033)., Conclusions: The -344C/T variant, but not the A6547G variant, of the aldosterone synthase gene may be a determinant of the blood pressure response to angiotensin-converting enzyme inhibitors in hypertensive patients.

Tablets manufactured from fine powder (average particle size, D[4,3] = 50.1 microm) benazepril hydrochloride exhibited unacceptable processing and quality properties whereas microcrystalline material (D[4,3] = 4.5-7.7 microm) furnished a product with good processing and quality characteristics.

Background: Angiotensin-converting-enzyme inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency (serum creatinine level, 3.0 mg per deciliter or less). We assessed the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency., Methods: We enrolled 422 patients in a randomized, double-blind study. After an eight-week run-in period, 104 patients with serum creatinine levels of 1.5 to 3.0 mg per deciliter (group 1) received 20 mg of benazepril per day, whereas 224 patients with serum creatinine levels of 3.1 to 5.0 mg per deciliter (group 2) were randomly assigned to receive 20 mg of benazepril per day (112 patients) or placebo (112 patients) and then followed for a mean of 3.4 years. All patients received conventional antihypertensive therapy. The primary outcome was the composite of a doubling of the serum creatinine level, end-stage renal disease, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease., Results: Of 102 patients in group 1, 22 (22 percent) reached the primary end point, as compared with 44 of 108 patients given benazepril in group 2 (41 percent) and 65 of 107 patients given placebo in group 2 (60 percent). As compared with placebo, benazepril was associated with a 43 percent reduction in the risk of the primary end point in group 2 (P=0.005). This benefit did not appear to be attributable to blood-pressure control. Benazepril therapy was associated with a 52 percent reduction in the level of proteinuria and a reduction of 23 percent in the rate of decline in renal function. The overall incidence of major adverse events in the benazepril and placebo subgroups of group 2 was similar., Conclusions: Benazepril conferred substantial renal benefits in patients without diabetes who had advanced renal insufficiency. (ClinicalTrials.gov number, NCT00270426.), (Copyright 2006 Massachusetts Medical Society.)

The objective of this study was to investigate renal function in clinically normal dogs receiving tepoxalin, a nonsteroidal inflammatory drug, either in association with or without an angiotensin-converting enzyme inhibitor (ACEI). Ten adult female Beagle dogs were used in the three phases of the study. The dogs were administered the drugs once daily for 7 days (experiment 1: placebo/tepoxalin/tepoxalin and benazepril; experiment 2: enalapril/tepoxalin and enalapril) or for 28 days (experiment 3: tepoxalin and benazepril together). Renal function was assessed by measurement of glomerular filtration rate (GFR) by renal scintigraphy [(renal uptake of 99mTc-diethylenetriaminepentacetic acid (DTPA)] and plasma clearance of 99mTc-DTPA. Compared with the placebo group, renal uptake and plasma clearance of 99mTc-DTPA were not significantly modified after a 7-day period of treatment with tepoxalin or enalapril alone, tepoxalin and benazepril or tepoxalin and enalapril together. No significant change was obtained in GFR after a 28-day period of dosing with tepoxalin and benazepril together. Therefore, it was concluded that tepoxalin did not alter renal function in healthy Beagle dogs receiving ACEI.

Objective: To observe the effects of routine doses of benazepril combined with valsartan on congestive heart failure., Methods: Totally 203 patients with congestive heart failure were randomized into Group A (receiving benazepril 20 mg/day), Group B (benazepril,10 mg/day plus valsartan, 80 mg/day), and group C (valsartan 160 mg/day) for different treatment protocols on the basis of routine therapy for heart failure with digitalis, diuretics and beta blockers. The cardiac functions and echocardiographical findings were evaluated before and after the treatments., Results: All the patients showed improvement of NYHA class, left ventricular end-diastolic dimension (LVEDd), left ventricular end-systolic dimension (LVESd) and left ventricular ejection fraction (LVEF) (P<0.01), and the effect was better in group B than in group A (P>0.05), and both groups A and B had better results than group C (P<0.05). No serious adverse effects were found., Conclusion: The combination of benazepril and valsartan at routine doses can be effective for treating congestive heart failure.

Objective: To compare the additional antihypertensive effects of an angiotensin-converting enzyme inhibitor (ACEI), a dihydropyridine calcium antagonist and a diuretic in patients whose hypertension is not controlled by full-dose angiotensin receptor blocker (ARB) monotherapy., Design and Methods: Individuals with an ambulatory blood pressure (ABP) that was not controlled by valsartan 160 mg once daily were allocated randomly to two groups: those in group A (n = 35) were assigned randomly to treatment with benazepril 20 mg once daily or chlorthalidone 12.5 mg once daily, whereas patients in group B (n = 29) were assigned randomly to benazepril 20 mg once daily or amlodipine 5 mg once daily. All individuals continued to receive background valsartan 160 mg once daily. After 5 weeks, patients crossed over to the alternative valsartan-based combination treatment of each group for a second 5-week period. Twenty-four-hour ABP monitoring was performed before the random allocation to groups and at the end of each randomized combination pharmacotherapy period., Results: Sixty-four individuals completed the study: 32 men and 32 women (mean +/- SD age 48.2 +/- 7.9 years, average 24-h ABP on valsartan monotherapy 143.4 +/- 12.6/87.7 +/- 7.8 mmHg). Significant additional antihypertensive effects on the average 24-h ABP were obtained with benazepril (8.6 +/- 8.8/6.3 +/- 6.7 mmHg), amlodipine (15.2 +/- 12.9/9.9 +/- 6.8 mmHg) and chlorthalidone (13.5 +/- 11.6/9.5 +/- 7.7 mmHg) (P < 0.001 for all additional antihypertensive effects). The additional effects of amlodipine and chlorthalidone added to valsartan were approximately 6/3.5 mmHg (P < 0.05) greater than that of benazepril., Conclusions: In patients in whom hypertension was not controlled by full-dose ARB monotherapy, a diuretic, a calcium antagonist or an ACE inhibitor provided significant additional antihypertensive effect. The antihypertensive effects of the ARB-diuretic and the ARB-calcium antagonist combinations were superior to that of the ARB-ACE inhibitor combination.

Assessment of vascular compliance may be a useful measurement of the clinical effects of antihypertensive treatment. Both angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers are known to improve vascular elasticity. A study was performed to test the hypothesis that combined therapy with an ACE inhibitor and a calcium channel blocker would have additive benefits on vascular compliance at similar levels of blood pressure (BP), as compared with monotherapy with an ACE inhibitor. This 12-week, double-blind study was a substudy of a larger clinical hypertension study conducted in patients with hypertension and type 2 diabetes. Subjects (N = 20) were randomized to either a fixed-dose combination of amlodipine besylate/benazepril HCl or to enalapril monotherapy. BP, heart rate, large- and small-vessel compliance, systemic vascular resistance, and urinary microalbumin excretion were assessed at baseline and after treatment. Both treatments were similarly effective in lowering BP, reducing systemic vascular resistance, and decreasing urinary microalbumin excretion. Improvement in large-vessel compliance was significantly greater among subjects who received ACE-inhibitor/calcium channel blocker combination therapy (52%) as compared with those who received ACE-inhibitor monotherapy (32%; p < 0.05). No significant change in small-vessel compliance was observed with either treatment. Greater improvement in large-vessel compliance with combination therapy was independent of BP lowering.

The molecular mechanisms underlying essential hypertension are not fully elucidated. Although Benazepril is being widely used in antihypertensive medication, the agent is efficacious in only a portion of hypertensive patients. To evaluate the interaction of alpha-adducin gene Gly460Trp and angiotensin I-converting enzyme (ACE) gene I/D polymorphisms in regard to baseline blood pressure (BP) levels and the reductions of blood pressures after Benazepril treatment, we conducted an investigation of 954 Chinese hypertensive patients in Anhui province, China. We found that compared with the baseline systolic BP (SBP) of subjects with one ACE I allele and one alpha-adducin Trp allele, the baseline SBP of those with ACE DD and alpha-adducin Gly/Gly genotypes was significantly higher [Crude: beta(SE) = 7.83(3.09), p = .01; Adjusted: beta(SE) = 5.83(2.83), p = .04]. However, no associations were found between the interaction of ACE I/D and alpha-adducin Gly460Trp polymorphisms and the baseline diastolic BP or the BP response to Benazepril treatment. Our results suggested that the interaction effect of alpha-adducin Gly460Trp and ACE I/D polymorphisms might play a significant role in regulating baseline BP but not BP response to Benazepril.

Objective: Treatment with agents that inhibit the renin-angiotensin system is commonly regarded as a gold standard renoprotective strategy in patients with chronic kidney diseases. For maximum antiproteinuric effect, the dose titration of these agents is recommended. This therapeutic strategy is not used for proteinuric patients who are not able to receive high doses of angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonists., Material and Methods: In patients with primary glomerulonephritis (n=24), a randomized, triple-treatment, triple-period, cross-over study was performed to compare the effects of combined therapy with benazepril 5 mg and losartan 25 mg and monotherapy with either agent alone at a two-fold higher dose on the extent of tubular injury as assessed by alpha1-microglobulin (alpha1-m) excretion and the plasma level of transforming growth factor-beta1 (TGF-beta1)., Results: Combination therapy significantly reduced alpha1-m excretion compared to either agent used alone: 178.29+/-27.36 to 99.63+/-13.03 mg/g creatinine for losartan + benazepril vs 178.29+/-27.36 to 161.59+/-23.22 mg/g creatinine for benazepril alone (p<0.05; ANOVA) and 178.29+/-27.36 to 99.63+/-13.03 mg/g creatinine for losartan + benazepril vs 178.29+/-27.36 to 173.45+/-27.69 mg/g creatinine for losartan alone (p<0.05; ANOVA). There was a significant correlation between change in alpha1-m excretion and reduction in proteinuria (r=0.704; p=0.023). There were no differences in TGF-beta1 level between the studied treatments. Systemic blood pressure reduction did not differ among the therapies., Conclusions: Combination therapy with angiotensin-converting enzyme inhibitor and angiotensin II subtype 1 receptor antagonists at very small doses may be superior to monotherapy with these agents at higher doses as far as tubular injury is concerned. We speculate that such a therapeutic strategy may be a useful approach for patients who are known not to be capable of receiving optimal renoprotective doses of these regimens.

M100240 is a thioester of MDL 100,173, a dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor. Clinical studies have shown that M100240 is capable of decreasing ACE activity and angiotensin II concentrations while increasing plasma renin activity and potentiating the effects of atrial natriuretic peptide. This may result in a unique treatment benefit in disease states characterized by intravascular volume or sodium overload or increased venous pressure. The pharmacokinetics of MDL 100,173 were evaluated in 30 healthy subjects in an open-label, randomized, 2-period crossover design. Subjects received a single oral dose of 50 mg of M100240 administered with a high-fat meal and separately under fasted conditions. Serial plasma concentrations of M100240 and MDL 100,173 were analyzed, and pharmacokinetic parameters were calculated with noncompartmental methods. The intrasubject percent coefficient of variation for MDL 100,173 C(max) and AUC(0-24h) were less than 20%, indicating that this agent is a moderately variable drug. Although AUC(0-24h) was within the protocol-defined range of 80% to 125%, the lower limit of the 90% confidence interval for C(max) fell outside of the 70% to 143% range. Absence of a food effect on the pharmacokinetic profile of 50 mg of M100240 could therefore not be demonstrated. This finding is not surprising based on the documented food effect with the sulfhydryl-containing ACE inhibitor, captopril. Clinical significance of this pharmacokinetic food effect is unlikely, as the magnitude of pharmacodynamic response is probably better correlated with AUC than a single-point determination of C(max). Single oral doses of 50 mg of M100240 were safe and well tolerated under fed and fasted conditions.

M100240 is an acetate thioester of MDL 100,173-a dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor-in phase II development. The pharmacokinetics of M100240 and MDL 100,173 were compared in young and elderly subjects. Pharmacokinetic data were obtained from 12 young (ages 18-45 years, 10 male, 2 female) and 12 elderly (ages 65-85 years, 7 male, 5 female) healthy subjects in a parallel-group, open-label study. Following an overnight fast, subjects received a single 25-mg oral dose of M100240. Serial plasma concentrations of M100240 and MDL 100,173 were determined using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, and pharmacokinetic parameters were calculated with noncompartmental methods. Single-dose treatment with M100240 was well tolerated in both groups of subjects, with no clinically significant changes in vital signs, ECG recordings, or laboratory safety parameters. M100240 was rapidly absorbed and converted to MDL 100,173, with M100240 concentrations no longer detectable at 3 to 4 hours postdose in both groups. The pharmacokinetics of the pharmacologically active MDL 100,173 were similar for both groups. Although maximum concentrations of M100240 were generally higher in elderly versus young subjects (C(max) 0.48 ng/mL vs. 0.17 ng/mL), systemic availability of M100240 was quite low and variable with plasma, and this apparent difference in parent drug exposure is unlikely to have important clinical implications. No age-related differences in the pharmacokinetic parameters of MDL 100,173 (C(max) 8.16 vs. 9.62 ng/mL, t(max) 1.25 vs. 1.5 h, AUC((0-last)) 81.6 vs. 72.2 ng x h/mL) were observed between young and elderly subjects, respectively. In conclusion, there are no age-related differences in the pharmacokinetics of MDL 100,173 between young and elderly subjects.

Background: Most patients with hypertension require two or more antihypertensive medications to achieve blood pressure (BP) goals. This double-blind study compared the efficacy and safety of high-dose combinations of amlodipine besylate (5 mg and 10 mg) and benazepril hydrochloride (40 mg) to benazepril hydrochloride (40 mg) alone in hypertensive patients not adequately controlled with benazepril hydrochloride (40 mg) monotherapy., Methods: After a 2-week washout period and a 4-week lead-in period with benazepril 40 mg daily, patients with a mean sitting diastolic BP > or =95 mm Hg (i.e., nonresponders to benazepril 40 mg) were randomly assigned to active treatment with either a combination of amlodipine 5 mg and benazepril 40 mg for 4 weeks followed by a forced titration to amlodipine 10 mg and benazepril 40 mg for an additional 4 weeks, or to benazepril 40 mg alone for 8 weeks., Results: The mean reduction in sitting BP from baseline (on benazepril) to endpoint (after 8 weeks of treatment) was 17/14 mm Hg with amlodipine/benazepril and 5/7 mm Hg with benazepril (P <.0001). The percentage of patients who met the diastolic BP response criteria (<90 mm Hg at endpoint or > or =10 mm Hg decrease from baseline) was 80% in the amlodipine/benazepril group and 45% in the benazepril group (P <.0001). The incidence of adverse events was infrequent and comparable for both treatment groups., Conclusion: High-dose amlodipine/benazepril combination therapy (5 mg/40 mg and 10 mg/40 mg) is an effective, safe, and well-tolerated treatment option for hypertensive patients who do not respond adequately to benazepril alone.

Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE) has gained increasing interest in the treatment of hypertension, heart failure, and renoprotection. Specifically, M100240, the thioester of the dual ACE/NEP inhibitor MDL100,173, has been evaluated in the management of hypertension. A model-based analysis, including simulations, was employed to characterize the relationship between individual M100240 drug exposure and neurohormonal response and to optimize the dose selection for future clinical studies. Sixty-two healthy subjects and 189 hypertensive patients were studied after oral once-daily administration of 2.5, 5, 10, 25, or 50 mg M100240. Pharmacokinetic-biomarker and blood pressure response models were fitted to the data with the computer program NONMEM. A direct inhibitory E(max) model adequately described the relationship between MDL100,173 concentration and ACE activity. No clear concentration or dose-dependent NEP or blood pressure responses were evident. Given a target 90% ACE inhibition, simulation reveals that (1). 50 mg M100240 once daily produces adequate ACE inhibition 24 hours postdose in only 20% of subjects, and (2). higher and/or more frequent doses on the order of 25 mg three times daily or 50 mg twice daily are required to achieve the target ACE inhibition in at least 50% of patients over 24 hours. Insufficient blood pressure-lowering effects were observed in healthy subjects and hypertensive patients due to inadequate ACE and NEP inhibition with once-daily oral doses of up to 50 mg of M100240. Divided doses might provide target ACE inhibition in more patients.

Background: In this study, we evaluated whether a combination of an angiotensin-converting enzyme (ACE) inhibitor, benazepril (B), with an angiotensin type I receptor antagonist (AT1RA), irbesartan (I), is as effective or more than drugs as monotherapy in controlling renal damage in obese Zucker rats (OZR), a model of metabolic syndrome., Methods: During six months, G1 (OZR receiving no treatment); G2 (OZR with B 10 mg/kg/day); G3 (OZR with I 50mg/kg/day); and G4 (OZR with B 5mg/kg/day + I 25 mg/kg/day). Kidneys were processed for light microscopy (LM) and immunohistochemistry, including antibodies against interstitial alpha-smooth-muscle-actin (alpha-SMA), plasminogen activator inhibitor-1 (PAI-1), transforming growth factor-beta(1)(TGF-beta 1), and collagen (COL) I, III, and IV., Results: All treated groups presented similar reduction in blood pressure compared with untreated OZR. However, animals from G4 (B + I) showed better control on proteinuria together with a higher creatinine clearance. Additionally, G4 showed a significant (P < 0.05) lower kidney weight; smaller glomerular area; lower glomerulosclerosis score; lower percentage of tubular atrophy, interstitial fibrosis, and interstitial alpha-SMA; lower tubular PAI-1 score; lower percentage of COL I, III, and IV in renal interstitium; and lower wall/lumen ratio in renal vessels, when compared with the other groups. OZR treated with B and/or I showed a better outcome (P < 0.01) in the carbohydrate and lipid metabolism in comparison with untreated OZR., Conclusion: These results suggest that combined therapy using B and I is more effective than therapy with either drug at monotherapy for controlling renal damage in this animal model. In addition, data presented here reaffirm the benefit of interacting against renin-angiotensin-system (RAS) in the metabolic syndrome.

Background: The Seventh Report of the Joint National Committee (JNC 7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends initial combination therapy for patients whose blood pressure (BP) is >20/10 mm Hg above goal. This study evaluated the efficacy and safety of initial combination therapy versus that of monotherapy in patients with stage 2 hypertension, who by definition meet the JNC 7 recommendation for initial combination antihypertensive therapy., Methods: This multicenter, double-blind, 12-week study randomized 364 patients with stage 2 hypertension to fixed-dose combination therapy with amlodipine besylate/benazepril HCl (5/20 mg/d titrated to 10/20 mg/d) or amlodipine besylate monotherapy (5 mg/d titrated to 10 mg/d)., Results: Significantly more patients randomized to combination therapy (74.2%) compared with those randomized to monotherapy (53.9%; P <.0001) achieved the primary end point (reductions in systolic BP > or =25 mm Hg, if baseline systolic BP was <180 mm Hg, or > or =32 mm Hg, if baseline systolic BP was > or =180 mm Hg). Significantly more patients randomized to combination therapy compared with monotherapy attained BP goals of <140/90 mm Hg (61.0% v 43.3%; P =.0007) and < or =130/85 mm Hg (35.7% v 19.1%; P =.0004). Among patients with baseline systolic BP > or =180 mm Hg, combination therapy resulted in significantly greater reductions in systolic BP compared with monotherapy (-42.3 v -30.4 mm Hg; P =.001). More than 90% of patients in each group were titrated to the higher dose. Both treatments were well tolerated., Conclusions: Combination therapy was well tolerated and resulted in significantly greater BP reductions and attainment of BP goals compared with monotherapy in patients with stage 2 hypertension. This evidence supports the recommendation of combination therapy as first-line treatment in stage 2 hypertension.

Background: The availability of treatment for IgA nephropathy (IgAN) is limited. Method. A prospective randomized controlled clinical trial was performed to evaluate the effects of therapy with urokinase (UK) and benazepril (BZ, an angiotensin-converting enzyme inhibitor) or BZ alone on severe IgAN. We divided 71 cases of IgAN, Lee's grade >/=III and with fibrinogen deposits, into two groups to be treated for 12 months with either UK + BZ or BZ alone., Results: There was no significant difference between the two groups in baseline clinical and histopathological data. After 12 months of treatment, 25 of 35 patients (71.4%) in the UK + BZ group and 16 of 36 (44.4%) in the BZ-alone group had a >/=50% decrease in 24-h urinary protein excretion compared with the baseline (chi(2) test, P<0.05). Proteinuria significantly decreased at 6 and 12 months of treatment in both groups compared with baseline (P<0.01 in the UK + BZ group, P<0.05 in the BZ group), and the therapeutic efficiency of UK + BZ was better than that of BZ alone (P<0.05 at 6 and 12 months). The endogenous creatinine clearance rate (Ccr) was stable in the UK + BZ group, while Ccr declined significantly at 6 and 12 months in the BZ-alone group compared with baseline (P<0.05, respectively). The Ccrs of the two groups at 12 months of treatment were statistically different (P<0.05)., Conclusions: Combined therapy with UK and BZ was more effective than with BZ alone in reducing proteinuria and protecting renal function in patients with severe IgAN.

The effects of the combined use of angiotensin converting enzyme inhibitor (ACEI) benazepril and angiotensin II type 1 receptor antagonist (AT1RA) valsartan on apoptosis and the expression of apoptosis-related proteins Fas and FasL in the kidney of rats with adriamycin-induced nephritic glomerulosclerosis was investigated. Uninephrectomy and the injection of adriamycin induced the rat model of glomerulosclerosis. Benazepril (6 mg/kg), valsantan (20 mg/kg), or benazepril (3 mg/kg) plus valsantan (20 mg/kg) was respectively delivered daily by gavage to the rats in three treatment groups for 12 weeks. Apoptosis was examined by means of terminal-deoxynucleotidyl transferase mediated d-UTP nick end labeling (TUNEL). Immunohistochemistry was adopted to detect the expression of Fas and FasL. Software of pathological analysis quantitated the levels of Fas and FasL. The results showed that as compared with those in the control group, the kidneys in the model group had more severe glomerulosclerosis, much more apoptotic cells and higher levels of expression of Fas and FasL. The degree of glomerulosclerosis, the number of apoptotic cells and the levels of expression of Fas and FasL were reduced by benazepril and valsartan. The combined use of benazepril and valsartan had the best therapeutic effect. It was concluded that benazepril and valsartan could suppress the excessive apoptosis of kidney cells by lowering the expression of the apoptosis-related proteins Fas and FasL, so as to postpone the process of glomerulosclerosis. The combined use of benazepril and valsartan has better therapeutic effect.

Although recent clinical studies have indicated that angiotensin II receptor blocker is as effective in treating heart failure as an angiotensin-converting enzyme inhibitor, it is unknown whether their effects are different. Dahl salt-sensitive rats were treated with an angiotensin-converting enzyme inhibitor benazepril, and an angiotensin II receptor blocker candesartan from 11 weeks old. We examined cardiac geometry and function by echocardiography, and histology and gene expression by high-density oligonucleotide arrays using Affymetrix U34 (Affymetrix, Santa Clara, CA, U.S.A.). Dahl salt-sensitive rats fed a high salt diet showed a marked increase in blood pressure and developed concentric hypertrophy at 11 weeks, followed by left ventricle dilation and congestive heart failure by 20 weeks after birth. Although both medications had only a mild antihypertensive effect, they strongly suppressed the development of cardiac hypertrophy, fibrosis and heart failure to the same extent. Gene expression pattern examined by Affymetrix GeneChip (Affymetrix) is quite different between the two drug groups, indicating that angiotensin II receptor blocker and angiotensin-converting enzyme inhibitor prevent heart failure by different mechanisms.

Adhering to medication regimens has the potential to significantly improve clinical outcomes for persons with high blood pressure. A patient-related factor likely to affect adherence to treatment is the convenience of the prescribed drug regimen. The authors hypothesized that medication adherence would be superior and cost benefits would accrue in subjects who receive a once-daily, single-capsule, fixed-dose combination product for blood pressure control, compared with subjects who receive a similar regimen of separate components. A managed care organization that provides benefits for members enrolled in various health plans provided the data for this retrospective analysis. The database was used to assess medication adherence patterns for two groups of hypertensive subjects. Group 1 included subjects who had been prescribed the single-capsule, fixed-dose combination of amlodipine besylate/benazepril HCl. Group 2 comprised subjects who had been prescribed a regimen including an angiotensin-converting enzyme inhibitor and a dihydropyridine calcium channel blocker as separate drugs. Adherence was measured by the medication possession ratio, and medical resource utilization by the two groups was assessed during the study period. Group 1 (n=2754) and Group 2 (n=2978) were balanced with regard to age (mean, 53 years; range, 18-64 years) and sex (men, 50%; women, 50%). The overall medication possession ratio for Group 1 was significantly higher than that for Group 2 (80.8% vs. 73.8%; p<0.001). The average annual cost of cardiovascular-related care per subject was significantly lower in Group 1 compared with Group 2 (p<0.001). Subjects receiving the once-daily, single-capsule, fixed-dose combination of amlodipine/benazepril HCl demonstrated significantly better medication adherence and required fewer medical resources than did subjects receiving an angiotensin-converting enzyme inhibitor and a dihydropyridine calcium channel blocker as separate components.

[4S-[4alpha,7alpha(R*),12bbeta]]-7[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid (M100240) is an acetate thioester of MDL 100,173-a dual angiotensin-converting enzyme/neutral endopeptidase inhibitor currently in phase II development. The mass balance of [(14)C]M100240 was assessed following oral administration of [(14)C]M100240. Healthy male subjects were given a single 25-mg dose of [(14)C]M100240 (50 microCi) as an oral solution under fasting conditions. Blood samples and excreta were collected postdose. (14)C-radioactivity was measured by liquid scintillation counting. Plasma concentrations of M100240 and MDL 100,173 were determined by LC/MS/MS methods. Pharmacokinetic parameters were calculated. About 98% of the total radioactive dose was recovered within 7 days of oral administration, with most of the radioactivity recovered within 72 hours. Of the recovered radioactive dose, 49.4% and 48.5% were recovered in the urine and feces, respectively. Unchanged M100240 and MDL 100,173 were not detected in the excreta. On average, 76% of the total radioactivity in the blood was associated with the plasma fraction. M100240 accounted for less than 0.06% of the (14)C-radioactivity in plasma and MDL 100,173 accounted for 15.8% (AUC( infinity )) of (14)C-radioactivity in plasma after oral dosing. These data suggest that the drug was absorbed but rapidly converted to its metabolites either presystemically or postsystemically. Up to 78% of the total radioactivity was identified as MDL 100,173. The apparent terminal elimination half-life of MDL 100,173 was longer than that of (14)C-radioactivity, attributable to assay sensitivity and the saturable binding phenomenon commonly associated with angiotensin-converting enzyme inhibitors. M100240 undergoes extensive metabolism in humans, and its metabolites are excreted relatively equally in feces and urine.

Objective: The aim of this study was to compare the effects of benazepril and amlodipine in monotherapy versus in combination with plasma t-PA and PAI-1 activity in hypertensive type-2 diabetic patients., Methods: After an initial 6-week wash-out, single-blind placebo period, 38 patients, 17 men and 21 females, were randomly assigned to receive benazepril 10 mg o.d. or amlodipine 5 mg o.d. or their combination o.d. at the same dosage for 6 weeks in three crossover periods each separated by a 2-week placebo wash-out period (3x3 latin square). At the end of the placebo run-in period and of each treatment period, BP, plasma PAI-1 and tPA activity were evaluated., Results: Both benazepril and amlodipine were similarly effective in reducing systolic blood pressure (SBP) (-17.6 mmHg with benazepril and -19.8 mmHg with amlodipine; P<0.001 versus placebo), and diastolic blood pressure (DBP) (-11.1 mmHg, -13.2 mmHg, respectively). Combination therapy produced greater reduction in SBP/DBP values (-28.3/-20.5 mmHg; P<0.001 versus placebo, P<0.01 versus benazepril and amlodipine). Benazepril monotherapy significantly decreased plasma PAI-1 activity (-8.4 IU/ml, P<0.05) while it did not influence t-PA activity (+0.02 IU/ml). Amlodipine monotherapy produced a significant increase in t-PA activity (+0.27 IU/ml, P<0.05) while it did not influence PAI-1 activity (+0.8 IU/ml). The amlodipine/benazepril combination produced both a significant decrease in plasma PAI-1 activity (-8.7 IU, P<0.05) and a significant increase in t-PA activity (+0.26 IU/ml, P<0.05)., Conclusions: These data suggest that in hypertensive type-2 diabetic patients, a population with an impaired fibrinolysis, the benazepril/amlodipine combination, may improve the fibrinolytic balance more than the single drugs.

Current recommendations for the treatment of hypertension clarify the need to achieve lower blood pressure levels in the general population (<140/90 mm Hg) and in specific high-risk patient groups such as patients with diabetes or chronic renal disease (<130/80 mm Hg). Further, it is evident that to reach appropriate blood pressure control, most patients with high blood pressure will require two or more antihypertensive agents. There is scarce clinical trial outcome evidence to guide clinicians in the selection of optimal combinations of antihypertensive classes for high-risk hypertensive patients. A new clinical trial, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), is the first large clinical trial to directly compare cardiovascular mortality and morbidity rates for two fixed-dose combination therapies. Results from ACCOMPLISH should provide much-needed guidance for selecting optimal combination therapy for high-risk hypertensive patients.

The disposition and effect of benazepril and its active metabolite, benazeprilat, were evaluated in cats using a pharmacokinetic/pharmacodynamic model. Cats received single 1 mg/kg doses of intravenous 14C-benazeprilat and oral 14C-benazepril.HCl, and single and repeat (eight daily) oral administrations of 0.25, 0.5 and 1.0 mg/kg nonlabelled benazepril.HCl. The pharmacokinetic endpoints were plasma concentrations of benazepril and benazeprilat, and recovery of radioactivity in faeces and urine. The pharmacodynamic endpoint was plasma angiotensin-converting enzyme (ACE) activity. Benazeprilat data were fitted to an equation corresponding to a single-compartment model with a volume equal to the blood space (Vc = 0.093 L/kg). Within this space, benazeprilat was bound nonlinearly to ACE, which was mainly tissular (89.4%) rather than circulating (10.6%). Free benazeprilat was eliminated quickly from the central compartment (t1/2 approximately 1.0 h; Cl approximately 0.125 L/kg/h), elimination being principally biliary ( approximately 85%) rather than urinary ( approximately 15%). Nevertheless, inhibition of ACE was long-lasting (t1/2 16-23 h) due to high affinity binding of benazeprilat to ACE (Kd approximately 3.5 mmol/L, IC50 approximately 4.3 mmol/L). Simulations using the model predict a lack of proportionality between dose of benazepril, plasma benazeprilat concentrations and effect due to the nonlinear binding of benazeprilat to ACE. For example, increasing the dose of benazepril (e.g. above 0.125 mg/kg q24 h) produced only small incremental inhibition of ACE (either peak effect or duration of action).