Vasotec scientific update |
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2010 Jun 1. [Epub ahead of print]
Kitzman DW, Hundley WG, Brubaker PH, Morgan T, Moore JB, Stewart KP, Little WC.
1 Cardiology Section, Dept. of Internal Medicine, Wake Forest Univ. Health Sciences, Winston-Salem, NC;
A Randomized, Double-Blinded Trial of Enalapril in Older Patients with Heart Failure and Preserved Ejection Fraction: Effects on Exercise Tolerance and Arterial Distensibility.
BACKGROUND: -Exercise intolerance is the primary symptom in older patients with heart failure and preserved ejection fraction (HFPEF), however little is known regarding its mechanisms and therapy. METHODS AND RESULTS: -71 elderly stable, compensated HFPEF patients (age 70+/-1 years; 80% women) with controlled blood pressure were randomized into a 12 month follow-up (FU) double-blind trial of enalapril 20 mg per day (E) vs. placebo (P). Assessments included: peak exercise oxygen consumption (VO(2)); six-minute walk test; Minnesota Living with HF Questionnaire (MLHF); MRI; Doppler-echocardiography; and vascular ultrasound. Compliance by pill count was excellent (94%). Twenty-five E vs. 34 P completed 12-month FU. During FU in E compared to P, there was no difference in the primary outcome of peak exercise VO(2) (14.5 +/- 3.2 vs. 14.3 +/- 3.4 ml/kg/min; p=0.99), nor in six-minute walk distance, aortic distensibility (the primary mechanistic outcome), LV mass, or neurohormonal profile. The effect size of enalapril on peak VO(2) was small (0.7%; CI -4.2 to 5.6%). There was a trend to improved MLHF total score (p=0.07). There was also a modest reduction in systolic blood pressure at peak exercise (p=0.02) and a marginal improvement in carotid arterial distensibility (p=0.04). CONCLUSIONS: -In stable, compensated older HFPEF patients with controlled blood pressure, 12 months of enalapril did not improve exercise capacity or aortic distensibility. These data, combined with those from large clinical event trials, suggest that angiotensin inhibition does not substantially improve key long-term clinical outcomes in this group of patients. This contrasts sharply with observations in HF with reduced EF and highlights our incomplete understanding of this important and common disorder.
2010 Apr;61(2):171-9.
Nakagiri A, Sunamoto M, Takeuchi K, Murakami M.
Department of Pharmacotherapeutics, Clinical Pharmacy, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, Japan. anakagir@dwc.doshisha.ac.jp
Evidence for the involvement of NADPH oxidase in ischemia/reperfusion-induced gastric damage via angiotensin II.
Reactive oxygen species are known to be derived from NADPH oxidase in several tissues. Angiotensin II was suggested to be involved in the activation of NADPH oxidase; however, its role in the gastric mucosa is unclear. We examined the roles of angiotensin II receptor and NADPH oxidase in ischemia/reperfusion-induced gastric damage in rats. Under urethane anesthesia, male Sprague-Dawley rat stomachs were mounted in an ex-vivo chamber, had 100 mM HCl applied to them, and then a catheter was passed through the femoral vein. Ischemia/reperfusion was accompanied by blood collection and reperfusion through the catheter. Losartan, candesartan, valsartan, which are AT1 receptor blockers (ARB); PD123319, an AT2 receptor blocker; enalapril, an ACE inhibitor; or diphenylene iodonium, a NADPH oxidase inhibitor, was given i.v. 10 mins, and beta-NADPH, a NADPH oxidase substrate, was given i.v. 5 mins before reperfusion. The gastric damage by ischemia/reperfusion was attenuated by treatment with any of ARB or enalapril, but was not affected by PD123319. The increase in gastric H(2)O(2) production and microvascular permeability by ischemia/reperfusion was also suppressed by treatment with any of ARB or enalapril. In rat gastric mucosa, the NADPH oxidase subunit p47(phox) was detected. Additionally, diphenylene iodonium had similar effects to ARB against ischemia/reperfusion-caused gastric damage, increased H(2)O(2) production, and microvascular permeability. Ischemia/reperfusion activated NADPH oxidase in the gastric mucosa, and the activation was significantly attenuated by treatment with losartan or diphenylene iodonium. These results suggest that ischemia/reperfusion generated reactive oxygen species are derived from NADPH oxidase activation via AT1 receptor in rat stomachs.
2010 Apr 23;16:720-8.
Sharma A, Bettis DI, Cowden JW, Mohan RR.
Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65212, USA.
Localization of angiotensin converting enzyme in rabbit cornea and its role in controlling corneal angiogenesis in vivo.
PURPOSE: The renin angiotensin system (RAS) has been shown to modulate vascular endothelial growth factor and angiogenesis. In this study we investigated (i) the existence of the RAS components angiotensin converting enzyme (ACE) and angiotensin II receptors (AT(1) and AT(2)) in the rabbit cornea using in vitro and ex vivo models and (ii) the effect of enalapril, an ACE inhibitor, to inhibit angiogenesis in rabbit cornea in vivo. METHODS: New Zealand White rabbits were used. Cultured corneal fibroblasts and corneal epithelial cells were used for RNA isolation and cDNA preparation using standard molecular biology techniques. PCR was performed to detect the presence of ACE, AT(1), and AT(2) gene expression. A corneal micropocket assay to implant a vascular endothelial growth factor (VEGF) pellet in the rabbit cornea was used to induce corneal angiogenesis. Rabbits of the control group received sterile water, and the treated group received 3 mg/kg enalapril intramuscularly once daily for 14 days starting from day 1 of pellet implantation. The clinical eye examination was performed by slit-lamp biomicroscopy. We monitored the level of corneal angiogenesis in live animals by stereomicroscopy at days 4, 9, and 14 after VEGF pellet implantation. Collagen type IV and lectin immunohistochemistry and fluorescent microscopy were used to measure corneal angiogenesis in tissue sections of control and enalapril-treated corneas of the rabbits. Image J software was used to quantify corneal angiogenesis in the rabbit eye in situ. RESULTS: Our data demonstrated the presence of ACE, AT(1), and AT(2) expression in corneal fibroblasts. Cells of corneal epithelium expressed AT(1) and AT(2) but did not show ACE expression. Slit-lamp examination did not show any significant difference between the degree of edema or cellular infiltration between the corneas of control and enalapril-treated rabbits. VEGF pellet implantation caused corneal angiogenesis in the eyes of vehicle-treated control rabbits, and the mean area of corneal neovascularization was 1.8, 2.8, and 3.2 mm(2) on days 4, 9, and 14, respectively. Enalapril treatment caused a notable decrease in corneal neovascularization of 44% (1 mm(2)), 28% (2.1 mm(2)), and 31% (2.2 mm(2)) on the three tested time points, respectively. The immunostaining of corneal tissue sections with collagen type IV and lectin confirmed the presence of blood vessels, with enalapril-treated rabbit corneas showing a lesser degree of blood vessel staining. CONCLUSIONS: Corneal cells show expression of tissue RAS components, such as ACE, AT(1), and AT(2). Treatment with ACE inhibitor enalapril markedly decreased corneal angiogenesis in a rabbit model of VEGF-induced corneal neovascularization, suggesting that ACE inhibitors may represent a novel therapeutic strategy to treat corneal angiogenesis.
2010 Feb;38(2):317-22. Epub 2009 Nov 17.
Parker RB, Laizure SC.
College of Pharmacy, Department of Clinical Pharmacy, University of Tennessee, 910 Madison Ave., Memphis, TN 38163, USA.
The effect of ethanol on oral cocaine pharmacokinetics reveals an unrecognized class of ethanol-mediated drug interactions.
Ethanol decreases the clearance of cocaine by inhibiting the hydrolysis of cocaine to benzoylecgonine and ecgonine methyl ester by carboxylesterases, and there is a large body of literature describing this interaction as it relates to the abuse of cocaine. In this study, we describe the effect of intravenous ethanol on the pharmacokinetics of cocaine after intravenous and oral administration in the dog. The intent is to determine the effect ethanol has on metabolic hydrolysis using cocaine metabolism as a surrogate marker of carboxylesterase activity. Five dogs were administered intravenous cocaine alone, intravenous cocaine after ethanol, oral cocaine alone, and oral cocaine after ethanol on separate study days. Cocaine, benzoylecgonine, and cocaethylene concentrations were determined by high-performance liquid chromatography. Cocaine had poor systemic bioavailability with an area under the plasma concentration-time curve that was approximately 4-fold higher after intravenous than after oral administration. The coadministration of ethanol and cocaine resulted in a 23% decrease in the clearance of intravenous cocaine and a 300% increase in the bioavailability of oral cocaine. Cocaine behaves as a high extraction drug, which undergoes first-pass metabolism in the intestines and liver that is profoundly inhibited by ethanol. We infer from these results that ethanol could inhibit the hydrolysis of other drug compounds subject to hydrolysis by carboxylesterases. Indeed, there are numerous commonly prescribed drugs with significant carboxylesterase-mediated metabolism such as enalapril, lovastatin, irinotecan, clopidogrel, prasugrel, methylphenidate, meperidine, and oseltamivir that may interact with ethanol. The clinical significance of the interaction of ethanol with specific drugs subject to carboxylesterase hydrolysis is not well recognized and has not been adequately studied.
2010 Mar-Apr;24(2):342-7.
Ishikawa T, Tanaka R, Suzuki S, Miyaishi Y, Akagi H, Iino Y, Fukushima R, Yamane Y.
Department of Veterinary Surgery, Faculty of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo, Japan.
The effect of angiotensin-converting enzyme inhibitors of left atrial pressure in dogs with mitral valve regurgitation.
BACKGROUND: Despite many epidemiological reports concerning the efficacy of angiotensin-converting enzyme (ACE) inhibitors in dogs with mitral regurgitation (MR), the hemodynamic effects of ACE inhibitor administration have not been fully evaluated. OBJECTIVES: To document left atrial pressure (LAP) in dogs with MR administered ACE inhibitors, in order to obtain interesting information about daily LAP changes with administration of ACE inhibitors. ANIMALS: Five healthy Beagle dogs weighing 9.8 to 14.2 kg (2 males and 3 females; aged 2 years). METHODS: Experimental, crossover, and interventional study. Chordae tendineae rupture was induced, and a radiotelemetry transmitter catheter was inserted into the left atrium. LAP was recorded for 72 consecutive hours during which each of 3 ACE inhibitors--nalapril (0.5 mg/kg/d), temocapril (0.1 mg/kg/d), and alacepril (3.0 mg/kg/d)--were administered in a crossover study. RESULTS: Averaged diurnal LAP was significantly, but slightly reduced by alacepril (P = .03, 19.03 +/- 3.01-18.24 +/- 3.07 mmHg). The nightly drops in LAP caused by alacepril and enalapril were significantly higher than the daily drops (P = .03, -0.98 +/- 0.19 to -0.07 +/- 0.25 mmHg, and P = .03, -0.54 +/- 0.21-0.02 +/- 0.17 mmHg, respectively), despite the fact that the oral administrations were given in the morning. Systolic blood pressure (122.7 +/- 14.4-117.4 +/- 13.1 mmHg, P = .04) and systemic vascular resistance (5800 +/- 2685-5144 +/- 2077 dyne x s/cm5, P = .03) were decreased by ACE inhibitors. CONCLUSIONS AND CLINICAL IMPORTANCE: ACE inhibitors decrease LAP minimally, despite reductions in left ventricular afterload. ACE inhibitors should not be used to decrease LAP.
2009 Jan;157(1):37-45.
Hsu DT, Mital S, Ravishankar C, Margossian R, Li JS, Sleeper LA, Williams RV, Levine JC, McCrindle BW, Atz AM, Servedio D, Mahony L; Pediatric Heart Network Investigators.
Columbia University, New York, NY, USA. dhsu@montefiore.org
Rationale and design of a trial of angiotensin-converting enzyme inhibition in infants with single ventricle.
BACKGROUND: Angiotensin converting enzyme (ACE) inhibitors are known to improve clinical outcome and ventricular function in adults with heart failure. Infants with single-ventricle physiology show abnormalities in ventricular function as well as poor growth. The ability of an ACE inhibitor to preserve ventricular function and improve growth in these infants is unknown. METHODS: The Pediatric Heart Network designed a randomized, double-blind trial to compare outcomes in infants with single-ventricle physiology receiving enalapril or placebo. Neonates < or =45 days old were eligible. The primary outcome is weight-for-age Z-score at 14 months of age. Secondary outcomes include other measures of somatic growth, laboratory and functional measures of heart failure, developmental indices, measures of ventricular size and function, and the relationship of the renin-angiotensin-aldosterone system genotype to the response to enalapril. The incidence and spectrum of adverse events will also be compared between treatment groups. RESULTS: A total of 1,245 neonates were screened and 533 (43%) were eligible. The consent rate was 43%; 230 subjects were enrolled. Parental reluctance to participate was the primary reason for non-consent in 79% of the eligible nonconsenting patients. Randomized patients were older, more likely to be male, and more likely to have hypoplastic left heart syndrome than the eligible patients who did not enroll. CONCLUSIONS: The results of this randomized trial will make an important contribution to the management of infants with single-ventricle physiology by determining whether initiation of ACE inhibition therapy in the neonatal period improves growth, clinical outcome, and ventricular function.
2009;69(17):2477-99. doi: 10.2165/11203980-000000000-00000.
Plosker GL.
Adis, a Wolters Kluwer Business, Auckland, New Zealand. demail@adis.co.nz
Eprosartan: a review of its use in hypertension.
Eprosartan is an angiotensin II receptor antagonist (angiotensin II receptor blocker [ARB]) used in the treatment of hypertension. In large, randomized trials, eprosartan (with or without hydrochlorothiazide [HCTZ]) demonstrated superior antihypertensive efficacy to that of placebo and, when administered at comparable dosage regimens, had similar blood pressure-lowering effects to enalapril. Eprosartan was generally well tolerated in clinical trials and had a lower incidence of persistent dry cough than enalapril. Eprosartan has a neutral effect on metabolic parameters, such as serum lipid levels and glucose homeostasis, and a low propensity for pharmacokinetic drug interactions. The use of eprosartan or other ARBs in combination with HCTZ tends to reverse the potassium loss associated with thiazide diuretics. Independent of its antihypertensive effects, eprosartan was associated with improved clinical outcomes (primary composite endpoint of all causes of mortality and all cardiovascular and cerebrovascular events, including all recurrent events) compared with nitrendipine in a randomized, secondary prevention trial in hypertensive patients with previous cerebrovascular events (MOSES trial). Eprosartan also reduced blood pressure and was associated with a modest improvement in cognitive function in a large observational study in patients > or =50 years of age with newly diagnosed hypertension (OSCAR study). In both of these trials, additional antihypertensive therapy, such as HCTZ, was permitted. Therefore, eprosartan is a useful treatment option in the management of a broad range of patients with hypertension, and its use with HCTZ provides a rational combination regimen.
2009 Nov-Dec;22(6):686-97.
Ong HT.
HT Ong Heart Clinic, Penang, Malaysia. htyl@streamyx.com
Are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers especially useful for cardiovascular protection?
PURPOSE: This article seeks to objectively review the clinical trial evidence to determine whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) have special cardiovascular protective effects. METHODS: An objective review of the clinical trial evidence. RESULTS: Clinical trials in hypertensive patients comparing ACEI and ARB with other drugs generally showed no difference in the primary cardiovascular outcome (United Kingdom Prospective Diabetes Study Group, Captopril Prevention Project, Swedish Trial in Old Patients with Hypertension 2, Japan Multicenter Investigation for Cardiovascular Diseases-B Randomized Trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, Second Australian National Blood Pressure Study Group, Valsartan Antihypertensive Long-Term Use Evaluation). Where the primary, or major secondary, cardiovascular end-point favors one of the treatment arms, it was always the arm with the lower achieved blood pressure that saw the better clinical result as in Losartan Intervention For Endpoint Reduction in Hypertension Study, Captopril Prevention Project, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and Valsartan Antihypertensive Long-Term Use Evaluation. Trials comparing ACEI or ARB against placebo in patients at high risk of cardiovascular events have not showed a consistent result; cardiovascular outcomes were reduced in Heart Outcomes Prevention Evaluation, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease, and the Jikei Heart Study, but were not significantly reduced in Perindopril Protection Against Recurrent Stroke Study, Comparison of Arnlodipine vs Enalapril to Limit Occurrences of Thrombosis Trial, Prevention of Events with ACEIs Trial, Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease Trial, and Prevention Regimen for Effectively Avoiding Second Strokes Trial. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, combining ACEIs with ARBs in high-risk patients did not reduce cardiovascular or renal outcomes compared with ACEI monotherapy alone. This absence of a reduction in cardiovascular outcome from the ACEI and ARB combination arm is further evidence suggesting that these drugs do not have any special cardiovascular protective effect. This objective review thus shows that the rennin-angiotensin antagonists do not have special cardiovascular protective properties. CONCLUSION: The key to reducing cardiovascular outcome is to appropriately control blood pressure as well as to treat all other coronary risk factors.
2009 Nov;15(11):BR334-8.
Jablecka A, Czaplicka E, Olszewski J, Bogdanski P, Krauss H, Smolarek I.
Department of Clinical Pharmacology, University of Medical Sciences, Poznan, Poland.
Influence of selected angiotensin-converting enzyme inhibitors on alloxan-induced diabetic cataract in rabbits.
BACKGROUND: Hyperglycemia enhances cataractogenesis. Elevated glucose level is commonly accompanied by arterial hypertension, for which angiotensin-converting enzyme (ACE) inhibitors (ACEIs) are a widely used intervention. ACE inhibitors exert some endothelial pleiotropic actions and can beneficially modulate glucose control and some other metabolic pathways. The purpose of this study was to evaluate the effect of ACEIs on cataract formation in experimental alloxan-induced diabetes in rabbits and assess the role of the reactive function group of the ACEIs in this process. MATERIAL/METHODS: Two study and two control groups of rabbits were examined. In the study groups and in one of the control groups, diabetes was induced by alloxan. The study groups were assigned to receive captopril or enalapril for six months; the controls received distilled water. Glucose concentration was monitored with a glucometer. A biomicroscope and an ophthalmoscope were used to evaluate lens opacity and cataractogenesis. RESULTS: Six-month administration of ACEI to rabbis resulted in a delay of diabetic cataractogenesis. The rate of cataract formation was significantly lower in the group treated with captopril than in the enalapril group. A difference in morphology of lens opacity formation between the two study groups was observed. CONCLUSIONS: ACEIs delay diabetic cataractogenesis in an experimental animal model. The ACEI functional groups have different influences on the pattern and rate of lens opacity.
2009 Dec;31(6):710-6.
Lima DM, Mundim IM, Jardim PC, Jardim TS, Diniz DG, Lima EM.
Laboratory of Pharmaceutical Technology and Drug Delivery Systems, School of Pharmacy, Federal University of Goiás, Praça Universitária c/1a, Avenida, Goiânia, Goiás, Brazil.
A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using solid phase extraction for the simultaneous determination of plasma concentrations of enalapril and enalaprilate in hypertensive patients treated with different
Enalapril maleate, available on the market in a variety of different pharmaceutical formulations, is commonly used for the control of systemic arterial hypertension. Many therapeutical failures have been reported thus far in clinical practice with respect to switching between different pharmaceutical formulations of the same product during pharmacological therapy. In the present study, plasma concentrations of enalapril and enalaprilate were measured in hypertensive patients undergoing treatment with different pharmaceutical formulations. Materials and methods: Pharmaceutical formulations studied included the reference brand product, a generic formulation, and a third drug product marketed as "similar"; plasma samples were obtained from 30 hypertensive volunteer patients. Drug was extracted from the plasma by solid phase extraction and determined by liquid chromatography-tandem mass spectrometry. The method was validated for the main analytical parameters. Results: The analytical method developed in this study, using liquid chromatography-tandem mass spectrometry, was confirmed as suitable for application in the determination of plasma concentrations in patients and subsequently revealed statistically significant differences in plasma concentrations between the 3 treatment groups. Conclusions: Such differences reinforce the hypothesis that the bioequivalence tests currently proposed by the regulatory authorities to promote interchangeability between pharmaceutical formulations may not in fact represent a definitive parameter for guaranteeing similar plasma concentrations.
2008 Sep;28(9):806-9.
Zhang ZH, Zhang WD, Yao K.
Center of Urology and Nephrology, First Hospital of Tsinghua University, Beijing. zhangzhihong2001@hotmail.com
[Treatment of chronic allograft nephropathy with combination of enalapril and bailing capsule] [Article in Chinese]
OBJECTIVE: To investigate the clinical effect of combined use of enalapril (an angiotensin converting enzyme inhibitor, ACEI) and Bailing Capsule (a Chinese herbal preparation made by fermented cordyceps sinensis, BLC) on renal function in patients with chronic allograft nephropathy (CAN) for seeking an effective therapy to control CAN progression. METHODS: Eighty-four CAN patients were randomly assigned to four groups, the 22 patents in group A treated with combined treatment of enalapril (10 mg/d) and BLC (2.0 g, twice a day); 20 in group B with enalapril alone; 21 in group C with BLC alone; and 21 in group D with the previously used immunosuppressive agents for control. Levels of serum creatinine (SCr), blood urea nitrogen (BUN), clearance of creatinine (CCr), 24 h urinary protein (24 h Upro) and urinary transforming growth factor beta1 (TGF-beta1) in all patients were measured before treatment, and after 6-and 9-month treatment. RESULTS: CCr was improved in patients of group A after 6-month treatment accompanied with decrease of SCr, 24 h Upro and urinary TGF-131 (P < 0.05), the latter 3 indexes were lower than in group D, and there was no difference among group A-C. These indexes in patients of group A, B, and C were further improved after treatment for 9 months (P < 0.01), whereas they worsened in patients of group B (P < 0.05). and the cases of patients with renal function improving or stable condition were more in group A than those in group B. CONCLUSION: Combined treatment of enalapril and BLC has better efficacy than using enalapril or BLC alone in reducing excretion of urinary protein, improving or stabilizing the function of graft kidney, and retarding CAN progression.
2008 Dec;156(6):1154.e1-8.
Napoli C, Bruzzese G, Ignarro LJ, Crimi E, de Nigris F, Williams-Ignarro S, Libardi S, Sommese L, Fiorito C, Mancini FP, Cacciatore F, Liguori A.
Department of General Pathology and Excellence Research Center on Cardiovascular Diseases, and Microbiology Section, 1st School of Medicine, II University of Naples, Naples, Italy. claudio.napoli@unina2.it
Long-term treatment with sulfhydryl angiotensin-converting enzyme inhibition reduces carotid intima-media thickening and improves the nitric oxide/oxidative stress pathways in newly diagnosed patients with mild to moderate primary hypertension.
BACKGROUND: Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors exert antiatherosclerotic effects in preclinical models and antioxidant effects in patients. However, whether ACE inhibitors have any clinically significant antiatherogenic effects remains still debated. OBJECTIVES: In mildly hypertensive patients, we evaluated the effect of the sulfhydryl ACE inhibitor zofenopril in comparison with the carboxylic ACE inhibitor enalapril on carotid atherosclerosis (intima-media thickness [IMT] and vascular lumen diameter) and systemic oxidative stress (nitrite/nitrate, asymmetrical dimethyl-l-arginine, and isoprostanes). METHODS: In 2001, we started a small prospective randomized clinical trial on 48 newly diagnosed mildly hypertensive patients with no additional risk factors for atherosclerosis (eg, hyperlipidemia, smoke habit, familiar history of atherosclerosis-related diseases or diabetes). Patients were randomly assigned either to the enalapril (20 mg/d, n = 24) or the zofenopril group (30 mg/d, n = 24); the planned duration of the trial was 5 years. Carotid IMT and vascular lumen diameter were determined by ultrasonography for all patients at baseline and at 1, 3, and 5 years. Furthermore, nitrite/nitrate, asymmetrical dimethyl-l-arginine, and isoprostane levels were measured. RESULTS: In our conditions, IMT of the right and left common carotid arteries was similar at baseline in both groups (P = NS). Intima-media thickness measurements until 5 years revealed a significant reduction in the zofenopril group but not in the enalapril group (P < .05 vs enalapril-treated group). This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group. CONCLUSIONS: Long-term treatment with the sulfhydryl ACE inhibitor zofenopril besides its blood pressure-lowering effects may slow the progression of IMT of the carotid artery in newly diagnosed mildly hypertensive patients
2008 Oct;27(4):263-6.
Ogunkunle OO, Asinobi AO, Omokhodion SI, Ademola AD.
Department of Paediatrics, College of Medicine, University College Hospital, Ibadan, Nigeria. oogunkunle@comui.edu.ng
Nephrotic syndrome complicating cyanotic congenital heart disease: a report of two cases.
BACKGROUND: Renal complications are said to be common in cyanotic congenital heart disease (CCHD), but have not been documented frequently in Nigerian children. Nephrotic syndrome (NS) is an uncommon complication of CCHD. OBJECTIVES: To report two cases of NS complicating CCHD who presented within months of each other, in order to draw attention to the problem. METHODS: The details of the clinical presentation, course and outcome of two children with CCHD, presenting with features of NS within months of each other, were reviewed. The patients were fully assessed clinically and were further investigated with chest X-ray, ECG ad echocardiography. RESULTS: A 12-year old girl with Fallot's tetralogy underwent a Blalock-Taussig shunt at the age of 2 years, but subsequently defaulted from follow-up. She reappeared 10 years later with features of NS. Echocardiography revealed impaired myocardial function. Despite initial clinical improvement following three plasma exchanges and Enalapril therapy, she suddenly died on the 15th day of admission. The second patient was a 7-year old boy with tricuspid atresia, diagnosed at the age of 10 months, and similarly defaulted, reappearing six years later with features of NS. Oedema regressed with similar treatment, but his renal function deteriorated. He was stable enough to be discharged after six weeks on admission. CONCLUSION: Proteinuria is likely to be more common in Nigerian children with CCHD than has been previously appreciated. Early intervention in patients with CCHD is desirable in order to prevent development of complications which worsen the prognosis. Patients with CCHD should be screened regularly for proteinuria in order to detect and address renal complications early.
2008;6(2-3):157-62. doi: 10.2165/00148365-200806020-00007.
Menzin J, Boulanger L, Tang S, Thakker K, Nissen SE.
Boston Health Economics, Inc., Waltham, Massachusetts, USA. jmenzin@bhei.com
Cost analysis of amlodipine versus enalapril in patients with coronary artery disease and normal blood pressure: findings from the CAMELOT economic substudy.
OBJECTIVES: To analyse 2-year hospitalization and cost data collected during a prospective, double-blind, randomized, controlled trial comparing amlodipine, enalapril and placebo in normotensive patients with coronary artery disease (CAD). METHODS: All patients who were enrolled in the CAMELOT study were included in this economic substudy. Patients with CAD and normal blood pressure were randomized to amlodipine, enalapril or placebo, and followed up for 24 months (between 1999 and 2004). Data on hospitalizations and medication use were obtained from the clinical trial. Costs were assigned from secondary sources. Total costs ($US, year 2004 values) were estimated as the sum of costs associated with cardiovascular hospitalizations, study medications and concomitant cardiovascular medications. Costs and resource use were analysed by treatment arm overall and for selected patient subgroups. Cost differences were evaluated using nonparametric bootstrap techniques. RESULTS: Of 1991 patients enrolled, 663 were treated with amlodipine, 673 were treated with enalapril and 655 were treated with placebo. Significantly fewer patients were hospitalized for cardiovascular reasons in the amlodipine group (16.4%) than in the placebo group (22.7%; p < 0.01), but not compared with the enalapril group (20.1%; p = 0.09). The amlodipine group also had numerically fewer days in hospital per patient (1.1) than the enalapril (1.3) and placebo (1.5) groups. Mean 2-year per-patient costs in the amlodipine group were estimated to be $US 609 and $US 717 lower than for the placebo and enalapril groups, respectively. CONCLUSIONS: These results suggest that use of amlodipine may reduce costs of care among CAD patients with normal blood pressure.
2008 Dec;86(12):827-34.
Ungi I, Pálinkás A, Nemes A, Ungi T, Thury A, Sepp R, Horváth T, Forster T, Végh A.
Department of Cardiology, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Center, University of Szeged, H-6720, Pecsi Street 4, Szeged, Hungary.
Myocardial protection with enalaprilat in patients unresponsive to ischemic preconditioning during percutaneous coronary intervention.
Cardioprotection due to angiotensin enzyme inhibitors is attributed, at least in part, to the inhibition of bradykinin breakdown and the preconditioning effect of the elevated endogenous bradykinin level. We have previously shown that in patients undergoing percutaneous coronary intervention, one 120-second balloon inflation is insufficient to precondition the heart. The objective of the present study was to examine whether the administration of enalaprilat to these patients results in protection. Twenty patients underwent two 120-second coronary artery occlusions separated by a reperfusion interval of 10 min. Ten patients were given 50 microg x min-1 enalaprilat in an intracoronary infusion between the balloon inflations, whereas the others received an infusion of saline. In the latter control patients, there were no significant differences in ST-segment elevation between the consecutive occlusions (peak ST: 1.61 +/- 0.17 vs. 1.61 +/- 0.16 mV; time to reach 0.5 mV ST elevation: 16 +/- 4 vs. 22 +/- 7 s; mean ST: 1.03 +/- 0.12 vs. 1.02 +/- 0.11 mV). In the patients who received enalaprilat before the second balloon inflation, the ST-segment elevation was significantly less pronounced and slower during the second inflation than during the first (peak ST: 1.80 +/- 0.18 vs. 1.41 +/- 0.19 mV; time to reach 0.5 mV ST elevation: 18 +/- 4 vs. 30 +/- 4 s; mean ST: 1.04 +/- 0.11 vs. 0.85 +/- 0.14 mV). We conclude that enalaprilat administered during percutaneous coronary intervention provides protection to patients who do not have a protective response to the initial balloon inflation.
2008 Nov;28 Suppl 5:S38-42.
Bozkurt D, Cetin P, Sipahi S, Hur E, Nar H, Ertilav M, Sezak M, Duman S.
Department of Nephrology, Ege University, Izmir, Turkey.
The effects of renin-angiotensin system inhibition on regression of encapsulating peritoneal sclerosis.
BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a clinical syndrome associated with symptoms of ileus and irreversible sclerosis of both visceral and parietal peritoneum. Peritoneal dialysis (PD) patients rarely develop EPS, a severe life-threatening condition of unknown pathogenesis. Angiotensin II is known to promote fibrosis and inflammation in various tissues. Renin-angiotensin system (RAS) blockade provides advantages in the course of diseases such as hypertension, chronic kidney disease, and proteinuria. We have also previously shown that RAS blockade has beneficial effects on hypertonic (3.86%) PD solution-induced peritoneal alterations. Because it shares the same characteristics as other fibrotic processes, peritoneal fibrosis can benefit from RAS blockade. OBJECTIVE: To determine the advantages of RAS blockade in regression of EPS. METHODS: We divided 56 nonuremic albino Wistar rats into 6 groups: control group (n = 10), daily intraperitoneal (IP) injection of 2 mL isotonic saline for 3 weeks; CG group (n = 10), daily IP injection of 2 mL/200 g chlorhexidine gluconate (CG) for 3 weeks; resting group (n = 10), daily IP injection of CG (0 - 3 weeks) plus peritoneal rest (4 - 6 weeks). After 3 weeks of being injected with CG (0 - 3 weeks), a fourth group (n = 9) was treated with 100 mg/L enalapril (ENA group); a fifth group (n = 10) was treated with 80 mg/L valsartan (VAL group), and a sixth group (n = 7) was treated with 100 mg/L enalapril + 80 mg/L valsartan (ENA+VAL group) in drinking water for an additional 3 weeks (4 - 6 weeks). At the end, a 1-hour peritoneal equilibration test was performed with 25 mL 3.86% PD solution. Dialysate-to-plasma ratio of urea (D/P urea), dialysate WBC count, ultrafiltration volume (UF), and morphological changes of parietal peritoneum were examined. RESULTS: Exposure to CG for 3 weeks resulted in alterations in peritoneal transport (increased D/P urea, decreased UF volume; p < 0.05) and morphology (increased inflammation, neovascularization, fibrosis, and peritoneal thickness; p < 0.05). Peritoneal rest had some beneficial effect only on UF failure and dialysate cell count (p < 0.05). However, RAS blockade was more effective than peritoneal rest with respect to UF volume, vascularity (p < 0.05), and peritoneal thickness (p > 0.05). Dual blockade of RAS had no additional beneficial effects. CONCLUSION: We suggest that RAS blockade either with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be a more effective option than resting in the management of EPS.
2007 Dec;8(4):200-4.
Vittorio TJ, Ahuja K, Kasper M, Turalic H, Tseng CH, Jorde UP, Go C.
Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, NY 10461, USA. t_vittorio@hotmail.com
Comparison of high- versus low-tissue affinity ACE-inhibitor treatment on circulating aldosterone levels in patients with chronic heart failure.
INTRODUCTION: Previous animal studies of chronic heart failure (CHF) suggest that angiotensin-converting enzyme (ACE) inhibitors of differing tissue avidity provide varying levels of renin-angiotensin system (RAS) suppression. Human studies have not consistently confirmed these animal findings. We hypothesised that production of circulating aldosterone (ALDO) would be suppressed to a greater extent in subjects treated with an ACE-inhibitor of higher tissue avidity. We randomised subjects with stable CHF to receive the low-tissue affinity ACE-inhibitor enalapril (ENAL) or the high-tissue affinity ACE-inhibitor trandolapril (TRAN), and assessed circulating ALDO levels at baseline and after eight weeks of treatment. METHODS: Thirty clinically stable subjects with CHF and left ventricular ejection fraction (LVEF) < 40% who were in a steady-state fluid balance were enrolled into a prospective, randomised double-blind trial. After a one month run-in period for standardisation to initial ACE-inhibition with ENAL, baseline circulating ALDO levels were measured and patients were randomised to receive ENAL 40 mg versus TRAN 4 mg (or the maximally tolerated doses) for eight weeks. Final determination of ALDO levels were made at the end of the 8-week study period. RESULTS: Baseline clinical characteristics including age, diabetes, LVEF, serum sodium, potassium and creatinine concentrations, and background medications were similar in both groups. We found no statistically significant difference in circulating ALDO levels between the ENAL and TRAN groups at the end of the 8-week study period. [ENAL (12.6 vs. 13.3 ng/dL); TRAN (12.5 vs. 14.5 ng/dL); p=NS]. CONCLUSION: We found no statistically significant difference in circulating ALDO levels between high- and low-tissue affinity ACE-inhibitor therapy. Further studies assessing ALDO production at the tissue level is warranted.
2007 Aug;3(4):569-78.
Metra M, Nodari S, Bordonali T, Milani P, Lombardi C, Bugatti S, Fontanella B, Verzura G, Danesi R, Dei Cas L.
Section of Cardiovascular Diseases, Department of Experimental and Applied Medicine, University of Brescia Italy.
Bisoprolol in the treatment of chronic heart failure: from pathophysiology to clinical pharmacology and trial results.
Clinical trials have consistently shown the benefits of beta-blocker treatment in patients with chronic heart failure (HF). As a result, bisoprolol, carvedilol, and metoprolol succinate are now indicated for the treatment of all patients with chronic HF who do not have major contraindications. Bisoprolol is the first beta-blocker shown to improve survival in an outcome trial. In the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), all-cause mortality and sudden death were reduced in patients treated with bisoprolol compared with those on placebo (11.8% vs 17.3%; p < 0.0001 and 3.6% vs 6.3%, p < 0.002; respectively) regardless of age, NYHA functional class, and co-morbidities. Further studies have shown both the efficacy of bisoprolol on secondary endpoints and patients subgroups as well its high cost effectiveness. More recently, CIBIS-III has shown similar efficacy and safety of the initiation of HF treatment with either bisoprolol or enalapril, with a tendency to a survival advantage with bisoprolol. Nowadays, the role of bisoprolol, as well as that of carvedilol and metoprolol succinate, in HF treatment is firmly established and research is mainly focused on implementation of treatment and better dosing. This article will summarize evidence for the efficacy of bisoprolol in the treatment of HF.
2007;67(5):445-50.
Trimarchi H, Muryan A, Young P, Forrester M, Iotti A, Pereyra H, Lombi F, Seminario O, Alonso M, Iotti R.
Division of Nephrology, Department of Medicine, Hospital Británico, Buenos Aires, Argentina. htrimarchi@hotmail.com
Dual renin-angiotensin system blockade plus oral methylprednisone for the treatment of proteinuria in IgA nephropathy.
Renin-angiotensin system inhibition is a widely accepted approach to initially deal with proteinuria in IgA nephropathy, while the role of immunosuppressants remains controversial in many instances. A prospective, uncontrolled, open-label trial was undertaken in patients with biopsy-proven IgA nephropathy with proteinuria > 0.5 g/day and normal renal function to assess the efficacy of a combination treatment of angiotensin converting enzyme inhibitors plus angiotensin receptor blockers enalapril valsartan coupled with methylprednisone to decrease proteinuria to levels below 0.5 g/day. Twenty patients were included: Age 37.45 +/- 13.26 years (50% male); 7 patients (35%) were hypertensive; proteinuria 2.2 +/- 1.86 g/day; serum creatinine 1.07 +/- 0.29 mg/dl; mean follow-up 60.10 +/- 31.47 months. IgA nephropathy was subclassified according to Haas criteria. Twelve patients (60%) were class II; seven (35%) were class III and one (5%) class V. All patients received dual renin-angiotensin system blockade as tolerated. Oral methylprednisone was started at 0.5 mg/kg/day for the initial 8 weeks and subsequently tapered bi-weekly until the maintenance dose of 4 mg was reached. Oral steroids were discontinued after 24 weeks (6 months) of therapy but renin-angiotensin inhibition remained unchanged. At 10 weeks of therapy proteinuria decreased to 0.15 +/- 0.07 g/day (P < 0.001) while serum creatinine did not vary: 1.07 +/- 0.28 mg/dl (P = ns). After a mean follow-up of 42.36 +/- 21.56 months urinary protein excretion (0.12 +/- 0.06 g/day) and renal function (serum creatinine 1.06 +/- 0.27 mg/dl) remained stable. No major side effects were reported during the study. Renin-angiotensin blockade plus oral steroids proved useful to significantly decrease proteinuria to < 0.5 g/day in patients with IgA nephropathy without changes in renal function.
2007 Oct;2:13-8.
Mallion JM.
Service de Cardiologie et hypertension artérielle, CHU, Grenoble, France. jmmallion@chu-grenoble.fr
An evaluation of the initial and long-term antihypertensive efficacy of zofenopril compared with enalapril in mild to moderate hypertension.
Angiotensin-converting enzyme inhibitors (ACEIs) are used in the management of a range of cardiovascular disorders and are well established in primary as well as secondary cardiovascular prevention programmes. Over the years, several second- and third-generation ACEIs have been introduced into the clinic. In a comparative study in patients with mild to moderate hypertension, the efficacy and safety of zofenopril 30 mg od (with an up-titration to 60 mg od after 4 weeks in non-responder patients) was compared with enalapril 20 mg od (with an up-titration to 40 mg od after 4 weeks in nonresponders) during 12 weeks of treatment. Both treatments significantly reduced systolic (SBP) and diastolic blood pressure (DBP). BP reduction was significantly greater with zofenopril (30 mg/day) during the initial 4 weeks of treatment compared with enalapril (20 mg/day). A larger proportion of patients needed dose up-titration with enalapril compared with zofenopril to reach preset BP goals. After 12 weeks of treatment and after appropriate dose up-titration, SBP and DBPs were lowered to similar extent in the two treatment groups, resulting in no differences between the groups in terms of response and control rates. A similar number of patients reported adverse events in the two study groups. However, the severity of adverse events were significantly milder with zofenopril compared with enalapril. In mild to moderate hypertensive patients, zofenopril treatment results in a more pronounced lowering of BP compared with enalapril at recommended dose levels. Additionally, at clinical and comparative antihypertensive doses, zofenopril presents a more beneficial adverse event profile compared with enalapril.
2007 Oct 1;231(7):1061-9.
Atkins CE, Keene BW, Brown WA, Coats JR, Crawford MA, DeFrancesco TC, Edwards NJ, Fox PR, Lehmkuhl LB, Luethy MW, Meurs KM, Petrie JP, Pipers FS, Rosenthal SL,Sidley JA, Straus JH.
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA.
Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency.
OBJECTIVE: To determine the efficacy of long-term enalapril administration in delaying the onset of congestive heart failure (CHF). DESIGN: Placebo-controlled, double-blind, multicenter, randomized trial. ANIMALS: 124 dogs with compensated mitral valve regurgitation (MR). PROCEDURES: Dogs randomly assigned to receive enalapril or placebo were monitored for the primary endpoint of onset of CHF for < or = 58 months. Secondary endpoints included time from study entry to the combined endpoint of CHF-all-cause death; number of dogs free of CHF at 500, 1,000, and 1,500 days; and mean number of CHF-free days. RESULTS: Kaplan-Meier estimates of the effect of enalapril on the primary endpoint did not reveal a significant treatment benefit. Chronic enalapril administration did have a significant benefit on the combined endpoint of CHF-all-cause death (benefit was 317 days [10.6 months]). Dogs receiving enalapril remained free of CHF for a significantly longer time than those receiving placebo and were significantly more likely to be free of CHF at day 500 and at study end. CONCLUSIONS AND CLINICAL RELEVANCE: Chronic enalapril treatment of dogs with naturally occurring, moderate to severe MR significantly delayed onset of CHF, compared with placebo, on the basis of number of CHF-free days, number of dogs free of CHF at days 500 and study end, and increased time to a combined secondary endpoint of CHF-all-cause death. Improvement in the primary endpoint, CHF-free survival, was not significant. Results suggest that enalapril modestly delays the onset of CHF in dogs with moderate to severe MR.
Clin Ther. 2004 Aug;26(8):1292-304.
Tomlinson B, Woo J, Thomas GN, Chau YM, Critchley JA.
Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong.
Randomized, controlled, parallel-group comparison of ambulatory and clinic blood pressure responses to amlodipine or enalapril during and after treatment in adult chinese patients with hypertension.
BACKGROUND: Few studies have examined the relative efficacy and tolerability of antihypertensive drug classes in Chinese populations. OBJECTIVE: This study compared the efficacy, tolerability, and duration of antihypertensive effect of amlodipine besylate and enalapril in Chinese patients with hypertension, including elderly patients with isolated systolic hypertension. METHODS: This randomized, double-blind, double-dummy, parallel-group dose-titration study was conducted at the Department of Medicine and Therapeutics, Chinese University of Hong Kong. Chinese patients aged 18 to 80 years with primary hypertension were enrolled. After a 4-week placebo run-in period, patients were randomly assigned to receive active oral, once-daily treatment with amlodipine (5 mg) or with enalapril (5 mg) for 14 weeks. Treatment doses were titrated at weeks 4 and 8 if necessary according to blood pressure (BP) response and if the dose had been tolerated. Patients also underwent 24-hour ambulatory BP monitoring (ABPM) at the end of the placebo run-in, after the first and last doses of active treatment, and 48 hours after discontinuation of treatment to determine the duration of drug action and to mimic the effect of 2 missed doses. RESULTS: Eighty patients were recruited for the study (26 men, 54 women; mean [SD] age, 60.5 [11.6] years) (40 patients per group). Thirty-seven patients in each group completed the active treatment phase. Baseline trough BPs were similar: 167.7 (15.0)/94.6 (9.7) mm Hg in the amlodipine group and 168.6 (11.9)/93.4 (9.5) mm Hg in the enalapril group. After 14 weeks of treatment, amlodipine (mean [SD] final dose, 6.3 [2.3] mg) produced greater reductions than enalapril (mean [SD] final dose, 13.3 [6.6] mg) in trough BP (-20.8 [13.2]/-9.2 [9.0] vs -5.5 [14.9]/-3.2 [10.6] mm Hg, respectively; P < or = 0.01). Most of the effect of amlodipine persisted for 72 hours after the last dose (-18.9 [14.6]/-11.1 [11.7] mm Hg), but enalapril had no significant antihypertensive effect at 72 hours (-1.3 [12.3]/-1.8 [9.1] mm Hg). Similar observations were found with ABPM recordings. Cough was reported in 5 patients (12.5%) and 13 patients (32.5%) in the amlodipine and enalapril groups, respectively, but was thought to be treatment related in only 6 patients (15.0%), all in the enalapril group. One of the patients in the enalapril group withdrew from the study because of cough, and 1 patient in the amlodipine group withdrew because of ankle edema.
Pediatr Int. 2004 Oct;46(5):576-9.
Tanaka H, Suzuki K, Nakahata T, Tsugawa K, Konno Y, Tsuruga K, Ito E, Waga S.
Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Japan.
Combined therapy of enalapril and losartan attenuates histologic progression in immunoglobulin A nephropathy.
BACKGROUND: It has been reported that combined therapy of angiotensin converting enzyme inhibitor and angiotensin receptor blocker significantly decreases proteinuria in immunoglobulin A (IgA) nephropathy. However, histologic alterations following the therapy have not been reported. METHODS: A total of nine Japanese children with severe proteinuric IgA nephropathy who received a prompt immunosuppressive therapy were enrolled the study, four of whom received a combined therapy of angiotensin converting enzyme inhibitor, enalapril and angiotensin receptor blocker, losartan (Group A), while the remaining five did not (Group B). All underwent renal biopsy before and approximately 12 months after the first renal biopsy. RESULTS: At presentation, urine protein excretion and the histologic indices of mean activity index, mean chronicity index and tubulointerstitial scores did not show a statistical difference between the two groups: Group A (2.6 +/- 0.6 g/day; mean activity index, 5.0 +/- 1.0; mean chronicity index, 5.0 +/- 1.0; tubulointerstitial scores, 4.3 +/- 1.0) and Group B (2.2 +/- 0.6 g/day; mean activity index, 4.8 +/- 0.8; mean chronicity index, 4.8 +/- 1.3; tubulointerstitial scores, 3.6 +/- 0.5, respectively). All had normal blood pressure and renal function. Urine protein excretion and the activity index decreased at the second renal biopsy, while the chronicity index and the tubulointerstitial scores slightly increased or remained unchanged. In comparison with Group B, a significant suppression in increasing the chronicity index and the tubulointerstitial scores obtained at the second renal biopsy were observed in Group A [Group A: 4.3 +/- 1.2 and 3.0 +/- 0.0, respectively, vs Group B: 6.0 +/- 0.7 and 4.4 +/- 0.9, respectively (P < 0.05)]. One patient in Group B developed chronic renal insufficiency thereafter. CONCLUSIONS: Although only a small number of patients were examined, these clinical findings suggest that a combined therapy of enalapril and losartan may attenuate histologic progression in at least a proportion of patients with severe proteinuric IgA nephropathy.
N Engl J Med. 2004 Nov 4;351(19):1952-61.
Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J;
Diabetics Exposed to Telmisartan and Enalapril Study Group.
Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy.
BACKGROUND: Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme (ACE) inhibitors in persons with type 2 diabetes. METHODS: In this prospective, multicenter, double-blind, five-year study, we randomly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan (80 mg daily, in 120 subjects) or the ACE inhibitor enalapril (20 mg daily, in 130 subjects). The primary end point was the change in the glomerular filtration rate (determined by measuring the plasma clearance of iohexol) between the baseline value and the last available value during the five-year treatment period. Secondary end points included the annual changes in the glomerular filtration rate, serum creatinine level, urinary albumin excretion, and blood pressure; the rates of end-stage renal disease and cardiovascular events; and the rate of death from all causes. RESULTS: After five years, the change in the glomerular filtration rate was -17.9 ml per minute per 1.73 m2 of body-surface area, where the minus sign denotes a decrement, with telmisartan (in 103 subjects), as compared with -14.9 ml per minute per 1.73 m2 with enalapril (in 113 subjects), for a treatment difference of -3.0 ml per minute per 1.73 m2 (95 percent confidence interval, -7.6 to 1.6 ml per minute per 1.73 m2. The lower boundary of the confidence interval, in favor of enalapril, was greater than the predefined margin of -10.0 ml per minute per 1.73 m2, indicating that telmisartan was not inferior to enalapril. The effects of the two agents on the secondary end points were not significantly different after five years. CONCLUSIONS: Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes. These findings do not necessarily apply to persons with more advanced nephropathy, but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events. Copyright 2004 Massachusetts Medical Society.
Am Heart J. 2004 Nov;148(5):889-94.
Tang WH, Vagelos RH, Yee YG, Fowler MB.
Kaufman Center for Heart Failure, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Impact of angiotensin-converting enzyme gene polymorphism on neurohormonal responses to high- versus low-dose enalapril in advanced heart failure.
BACKGROUND: The impact of angiotensin-converting enzyme (ACE) gene polymorphism on neurohormonal dose response to ACE inhibitor therapy is unclear. METHODS: ACE Insertion (I) or Deletion (D) genotype was determined in 74 patients with chronic heart failure who were randomly assigned to receive either high-dose or low-dose enalapril over a period of 6 months. Monthly pre-enalapril and post-enalapril neurohormone levels (serum ACE activity (sACE), plasma angiotensin II (A-II), plasma renin activity (PRA), and serum aldosterone (ALDO) were compared between genotype subgroups and between patients who received high- or low-dose enalapril within each genotype subgroup. RESULTS: At baseline, predose/postdose sACE and postdose PRA were significantly higher in the DD genotype. At 6-month follow-up, postdose sACE was reduced in a dose-dependent fashion in all three genotypes (P < .05). However, predose and postdose ALDO and A-II levels did not differ between each genotype subgroup at baseline or by enalapril dose within each genotype subgroup. ALDO escape and A-II reactivation were not affected by ACE genotype or enalapril dosage. CONCLUSIONS: Predose sACE were consistently higher in the DD genotype when compared with ID or II subgroups. Despite a dose-dependent suppression of sACE, there were no observed statistically significant differences in ALDO and A-II suppression or escape with escalating doses of enalapril within each subgroup.
Clin Ther. 2004 Sep;26(9):1419-26.
Mugellini A, Dobovisek J, Planinc D, Cremonesi G, Fogari R.
Department of Internal Medicine and Therapeutics, Clinica Medica II, IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
Efficacy and safety of delapril plus manidipine compared with enalapril plus hydrochlorothiazide in mild to moderate essential hypertension: results of a randomized trial.
BACKGROUND: The use of combination therapy is required to achieve blood pressure targets in 40% to 75% of patients with hypertension. There have been few studies comparing the efficacy and tolerability of the new fixed combination of the angiotensin-converting enzyme (ACE) inhibitor delapril 30 mg and the calcium channel antagonist manidipine 10 mg with those of a standard combination of another ACE inhibitor and a diuretic. OBJECTIVE: The aim of this study was to compare the antihypertensive efficacy and tolerability of delapril 30 mg given alone or with manidipine 10 mg with those of enalapril 20 mg given alone or with hydrochlorothiazide (HCTZ) 12.5 mg in patients with mild to moderate essential hypertension. METHODS: This was a multicenter, active-controlled, parallel-group trial. After an initial 2-week placebo run-in period, patients aged 18 to 75 years with diastolic blood pressure (DBP) > or =90 and < or =109 mm Hg were randomized in a 2:1 ratio to receive delapril or enalapril for 8 weeks. After the initial 8 weeks, nonresponders (DBP > or =85 mm Hg) received an additional 8 weeks of treatment with a fixed combination of delapril + manidipine or enalapril + HCTZ; patients whose DBP was normalized continued their initial monotherapy through the end of the study. The primary efficacy variable was the change in sitting DBP at the end of treatment. Secondary efficacy variables were the percentage of patients whose DBP was normalized (DBP Z:85 mm Hg) and the percentage of responders (> or =10-mm Hg reduction in DBP or DBP <85 mm Hg). RESULTS: One hundred sixty patients (84 men, 76 women) were randomized to receive delapril (n = 106) or enalapril (n = 54). After 16 weeks of treatment, the mean (SD) reduction in DBP was similar with the 2 treatments (delapril, -14 [8] mm Hg; enalapril, -15 [8] mm Hg). In the delapril and enalapril groups, DBP was normalized in a respective 55 (51.9%) and 29 (53.7%) patients, and 77 (72.6%) and 38 (70.4%) were responders; there was no significant difference between groups. Tolerability was also similar in both groups--10 (9.4%) patients in the delapril group and 5 (9.3%) in the enalapril group experienced adverse events that were judged related to treatment. CONCLUSIONS: The results of this study suggest that delapril alone or combined with manidipine is well tolerated and as effective as enalapril alone or combined with HCTZ in lowering blood pressure in patients with mild to moderate essential hypertension.
JAMA. 2004 Nov 10;292(18):2217-25.
Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, Berman L, Shi H, Buebendorf E, Topol EJ; CAMELOT Investigators.
Department of Cardiovascular Medicine, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio, USA.
Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.
CONTEXT: The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain. OBJECTIVE: To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS). INTERVENTIONS: Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion. MAIN OUTCOME MEASURES: The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume. RESULTS: Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P = .10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = .02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P = .08), and no progression in the amlodipine group (P = .31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19, P = .07. CONCLUSIONS: Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.
Anadolu Kardiyol Derg. 2004 Dec;4(4):296-300.
Turker H, Donmez A, Zeyneloglu P, Sezgin A, Ulucam M.
Department of Anesthesiology, University of Baskent, School of Medicine, Ankara, Turkey.
Effects of enalaprilat infusion on hemodynamics and renal function in patients undergoing cardiac surgery.
OBJECTIVE: This study was undertaken to evaluate the effect of enalaprilat infusion on hemodynamics and renal function during cardiopulmonary bypass (CPB). METHODS: Thirty adults undergoing CPB were randomly allocated into 2 groups. All patients received the same anesthetic protocol and same dopamine infusion protocol (2 mg/kg(-1)/min(-1)) during the study. In addition to dopamine infusion 15 patients received enalaprilat infusion (0.06 mg/kg(-1)/hr(-1)) during CPB. Blood creatinine, urea levels, and creatinine clearance (CLcr) were measured and cardiac output (CO) was calculated by echocardiography preoperatively and on the 6th postoperative day. Mean arterial pressure (MAP), central venous pressure (CVP), systemic vascular resistance (SVR) measurements were recorded during the operation and during postoperative 24 hours. RESULTS: In the control group postoperative blood creatinine and urea levels were significantly higher and CLcr measurements were significantly lower than the preoperative values (p<0.05). These values did not change in the enalaprilat group. Mean arterial pressure was similar in both groups (p>0.05), but SVR was lower (p<0.05) and CVP was higher (p<0.05) in the enalaprilat group than in the control group. In the enalaprilat group postoperative CO measurements were higher than the preoperative values (p<0.05). CONCLUSION: Our results demonstrate that enalaprilat infusion during CPB improves renal function and CO measurements in the early postoperative period.
J Pharm Biomed Anal. 2005 Mar 9;37(3):627-30. Epub 2004 Dec 25.
Zoppi A, Linares M, Longhi M.
Departamento de Farmacia, Facultad de Ciencias Quimicas, Universidad Nacional de Cordoba, Ciudad Universitaria, 5000 Cordoba, Argentina.
Quantitative analysis of enalapril by (1)H NMR spectroscopy in tablets.
A simple, rapid, accurate and selective (1)H NMR method was developed for quantitative determination of enalapril maleate in pharmaceutical preparations. Spectra were determined in D(2)O, using l-leucine as internal standard. Both synthetic mixtures and commercial dosage forms were assayed, and the results were compared to those obtained using the USP XXIV procedure and were both in close agreement.
Eur J Clin Pharmacol. 2005 Mar 11.
Elung-Jensen T, Heisterberg J, Sonne J, Strandgaard S, Kamper AL.
Departments of Nephrology and Clinical Physiology and Nuclear Medicine, Herlev Hospital, University of Copenhagen, Denmark.
Enalapril dosage in progressive chronic nephropathy: a randomised, controlled trial.
OBJECTIVE: In chronic renal failure, clearance of enalapril is reduced. Hence, a renoprotective effect may be achieved with lower doses than conventionally used. Since marked inter-patient variation in concentrations of enalaprilat has been shown in patients with renal failure despite equivalent dosage of enalapril, a direct comparison of the effect of high versus low plasma concentrations of enalaprilat on the progression of renal failure was undertaken.METHODS: Forty patients with a median glomerular filtration rate (GFR) of 17 (6-35) ml/min/1.73 m(2) were studied in an open-label, randomised trial comparing patients with a high (>50 ng/ml) with patients with a low (<10 ng/ml) target trough plasma concentration of enalaprilat. The dose of enalapril was titrated accordingly. The patients were followed for 12 months or until they needed renal replacement therapy. GFR was measured at 3-month intervals by the plasma clearance of (51) Cr-EDTA, and the individual rates of progression of renal failure were calculated as the slope of GFR versus time plot.RESULTS: In the high-concentration group, the median enalaprilat trough concentration was 92.9 ng/ml (21.8-371.0 ng/ml) and in the low-concentration group it was 9.1 ng/ml (2.5-74.8 ng/ml) at 3 months follow-up (P<0.001). The median daily doses of enalapril were 10 mg (2.5-30 mg) and 1.88 mg (1.25-5 mg) in the high and low groups, respectively (P<0.001). In the high-concentration group, the mean+/-SE decline in renal function was 6.1+/-1.5 ml/min/1.73 m(2) per year and in the low-concentration group it was 4.3+/-14.4 ml/min/1.73 m(2) per year (P=0.48). Five patients in the high-concentration group reached end-stage renal failure whereas none in the low-concentration group did (P=0.04). There were no statistically significant differences in blood pressure level, concomitant antihypertensive therapy or urinary albumin excretion. However, the high-enalaprilat concentration group had an overall higher plasma potassium concentration of 0.42 mmol/l than the low group (P<0.001).CONCLUSION: In patients with moderate to severe renal insufficiency, a low concentration of enalaprilat afforded the same degree of renoprotection, blood pressure control and minimisation of proteinuria as a high concentration, during 12 months of follow-up. The high-dosage treatment was associated with a more pronounced tendency to hyperkalaemia. Thus, there seems to be no indication for increasing the daily dose of enalapril beyond what achieves adequate blood pressure control in this group of patients.
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Drug category:Hypotensive agents
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