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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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