Norvasc

Norvasc, with its generic ingredient amlodipine, is a medication used in the treatment of angina and hypertension. It belongs to a group of drugs named calcium channel blockers and its main action is to relax blood vessels by slowing down the movement of calcium through them; thus it causes the blood to flow smoother and reduces the energy uptake by the heart. Since angina results from lack of oxygen in the heart and blood pressure is dependant on relaxed blood vessels, both of these conditions can be kept under control by the use of Norvasc. The medication does not, however, cure either disease – it just keeps them under control. Side effects are mild and include fatigue, headache, nausea and apathy. It can be used alone or in any combination with blood pressure-lowering medications. Recent studies have suggested a different benefit of Norvasc as well – it looks like the drug also inhibits the development of atherosclerosis and possesses properties which can aid its treatment.

Curr Med Res Opin. 2005 Jan;21(1):37-46.
Evaluation of long-term efficacy and acceptability of indapamide SR in elderly hypertensive patients.
Leonetti G, Emeriau JP, Knauf H, Pujadas JO, Calvo-Gomez C, Abate G; European Study Investigators.
Department of Cardiology, Ospedale San Luca, Via Spagnoletto 3, Milan, Italy. gastone.leonetti@unimi.it

OBJECTIVE: To assess the long-term antihypertensive efficacy and acceptability of indapamide SR 1.5 mg in elderly hypertensive patients (> or = 65 years). STUDY DESIGN: Open, 12-month, follow-up study of 444 patients, treated with indapamide SR, who were responders and/or achieved target BP levels following a 3-month, randomised, controlled, double-blind short-term comparison of indapamide SR versus hydrochlorothiazide 25 mg and amlodipine 5 mg. RESULTS: The long-term decrease in systolic blood pressure (SBP)/diastolic blood pressure (DBP) after 12 months follow-up with indapamide SR was -24.0/-13.1 mmHg from baseline (M0). The percentage of patients that achieved target BP levels (DBP < 95 mmHg, SBP < or = 160 mmHg) was 80.1% [84.3% for isolated systolic hypertension (ISH) subgroup], and the response rate (BP < 140/90 mmHg or decrease in supine diastolic BP > or = 10 mmHg or in supine systolic BP > or = 20 mmHg) 81.5%. Blood pressure (BP) remained stable throughout the 12 months follow-up period (M3-M15), whatever the previous treatment received during the 3-month, doubleblind period (M0-M3). Clinical and biological acceptability was good. A low occurrence of withdrawals (7.2%), was reported. CONCLUSION: Over the course of the long-term, 12-month follow-up study, indapamide SR was shown to be an effective and well tolerated antihypertensive therapy, even after a switch from amlodipine or hydrochlorothiazide, in patients aged 65 years-80 years with systolo-diastolic hypertension (SDH) or ISH.

Anal Bioanal Chem. 2005 May 13;
Development and validation of a selective and robust LC-MS/MS method for quantifying amlodipine in human plasma.
Massaroti P, Moraes LA, Marchioretto MA, Cassiano NM, Bernasconi G, Calafatti SA, Barros FA, Meurer EC, Pedrazzoli J.
Clinical Pharmacology and Gastroenterology Unit, Sao Francisco University Medical School, Av. Sao Francisco de Assis 218, 12916-900, Braganca Paulista, SP, Brazil, eduardo.meurer@saofrancisco.edu.br.

A liquid chromatographic-tandem mass spectrometric method (LC-MS/MS) for quantifying amlodipine in human plasma was developed and validated. Sample preparation was based on liquid-liquid extraction using NaOH and a mixture of ethyl acetate/hexane (80/20; v/v). Chromatography was performed on a C-18 analytical column and the retention times were 1.9 and 3.0 min for amlodipine and nimodipine (internal standard), respectively. The ionization was optimized using ESI(+) and enhanced selectivity was achieved using tandem mass spectrometric analysis via two MRM functions, 409-->238 and 418-->343 for amlodipine and nimodipine. The calibration curve ranged from 0.2 to 20.0 ng/mL. The inter-day precision and accuracy and the relative standard deviation (RSD) were <15%. The analyte was shown to be stable over the timescale of the whole procedure. The robustness of the method was demonstrated by the good reproducibility of the results obtained during the analysis of clinical samples.

Ann Pharmacother. 2005 Feb 22.
Anasarca Edema with Amlodipine Treatment (April).
Sener D, Halil M, Yavuz BB, Cankurtaran M, Ariogul S.
Medical Faculty, Department of Internal Medicine, Hacettepe University, Ankara, Turkey.

OBJECTIVE: To report a case of anasarca edema associated with amlodipine use. CASE SUMMARY: A 77-year-old woman with essential hypertension who had not been treated with any other drug was prescribed amlodipine 10 mg/day to control her blood pressure. She developed anasarca edema soon after amlodipine treatment was initiated. Laboratory test results for possible etiologies were negative. Discontinuation of amlodipine resulted in dramatic improvement. DISCUSSION: To our knowledge, as of February 3, 2005, there have been no other reports of amlodipine-related anasarca edema in the English literature, and only one case was described in the Japanese literature. Pretibial edema is the most common adverse effect of amlodipine. Periocular and perioral edema have occurred less frequently, but anasarca edema has not emerged as a problem. An objective causality assessment revealed amlodipine to be a probable cause of anasarca edema. CONCLUSIONS: In rare instances, amlodipine may cause generalized edema, which will resolve upon discontinuation of the drug.

Expert Rev Cardiovasc Ther. 2004 Sep;2(5):675-81.
Amlodipine/atorvastatin: the first cross risk factor polypill for the prevention and treatment of cardiovascular disease.
Frishman WH, Zuckerman AL.
Department of Medicine, New York Medical College, Munger Pavillion 263, Valhalla, NY 10595, USA. William_Frishman@nymc.edu
In 2002, the World Health Organization estimated that over 58% of cardiovascular disease in North America is due to 'both blood pressure and cholesterol higher than optimal'. Unfortunately, less than a third of patients with both conditions are identified, and fewer than one in ten reach the treatment goals for both factors. Adherence to treatment is notably improved when therapy is initiated simultaneously. Combination therapy of amlodipine besylate (Norvasc, Pfizer Ltd) with atorvastatin calcium (Lipitor, Pfizer Ltd), marketed as Caduet (Pfizer Ltd) is the first dual-therapy compound designed to treat hypertension and/or angina and dyslipidemia concurrently with a single daily pill in the full range of dosing combinations. Amlodipine/atorvastatin retains the safety and efficacy of its parent compounds whilst simplifying the management of these comorbid conditions, in what may be considered the first version of a polypill.

J Pediatr. 2004 Sep;145(3):353-9.
A randomized, placebo-controlled trial of amlodipine in children with hypertension.
Flynn JT, Newburger JW, Daniels SR, Sanders SP, Portman RJ, Hogg RJ, Saul JP; PATH-1 Investigators.
Division of Pediatric Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, USA.
OBJECTIVES: Evaluation of the efficacy and safety of amlodipine in hypertensive children. STUDY DESIGN: A randomized, double blinded, placebo-controlled, parallel-group, dose-ranging study was conducted at 49 centers in North and South America. The primary end point was the effect of amlodipine on systolic blood pressure (BP); secondary end points included the effect of amlodipine on diastolic BP, the effect of amlodipine as a function of dose and body size, and evaluation of safety. RESULTS: We enrolled 268 hypertensive children (mean age, 12.1 +/- 3.3 years); 84 (31.3%) had primary hypertension, and 177 (66%) were boys. Amlodipine produced significantly greater reductions in systolic BP than placebo; these were -6.9 mm Hg for 2.5 mg daily (P=.045 vs placebo) and -8.7 mm Hg for 5 mg daily (P=.005 vs placebo). The underlying cause of hypertension had no effect on the response to amlodipine. There was a significant dose-response effect of amlodipine on both systolic and diastolic BP beginning at doses > or =0.06 mg/kg per day. Systolic BP < or =95(th) percentile was achieved in 34.6% of subjects with systolic hypertension. Amlodipine was well tolerated, with just 6 children withdrawn from treatment because of drug-related adverse events. CONCLUSIONS: Amlodipine effectively lowers systolic BP in a dose-dependent manner in hypertensive children who require drug treatment.

Rev Clin Esp. 2004 Aug;204(8):398-404.
Analysis of the effectiveness and costs of amlodipine on the hospitalizations for cardiovascular events in patients with ischemic cardiopathy
Galduf Cabanas J, Cosin Aguilar J, Rodriguez-Padialc L, Zamorano Gomez JL, Fernandez Gonzalez I, Rejas Gutierrrez J.
Departamento de Investigacion y Desarrollo, Euroclin, Pfizer, S.A., Madrid. jonathan.galduf@pfizer.com
OBJECTIVE: Evaluation of the effect of amlodipine on the hospitalizations for cardiovascular events (CVE) and their associated costs in patients with ischemic cardiopathy. METHODS: Data from the multicenter, randomized, double-blind, placebo-controlled PREVENT (Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial) clinical trial were utilized. A tree-type model of decision was used in order to analyze the incremental costs expected from the treatment with amlodipine with regard to placebo. Hospitalization costs were estimated with regard to the DRG weights of the American Medicare adapted for the costs of average stay available in our environment. RESULTS: Amlodipine reduced significantly the incidence of CVE that required hospitalization in contrast to placebo; 0.60 +/- 1.16 versus 0.77 +/- 1.31 (average +/- SD), p < 0.05. The expected direct expenses due to hospitalizations were higher in the placebo group than in the amlodipine group (saving of 205.76 Euro/patient). Total cost for patient in the amlodipine group was 1,723.52 Euro while in the placebo group was 1,929.28 Euro. When the relation cost/price shifted in the sensitivity analysis from 1.20 to 0.66 (cost of every hospitalization ranged between + 20% and -34%), the saving fluctuated from 330.56 Euro to 0. Accordingly, the breakeven point of the cost/price relation it is 0.66, and above this the treatment with amlodipine still generates savings in regard to its cost. CONCLUSIONS: Amlodipine is cost-effective in the treatment of the patients with ischemic cardiopathy, being able to reduce the hospital costs related to ischemic episodes in this type of patients.

Life Sci. 2004 Jul 2;75(7):881-91.
Amlodipine decreases fibrosis and cardiac hypertrophy in spontaneously hypertensive rats: persistent effects after withdrawal.
Sevilla MA, Voces F, Carron R, Guerrero EI, Ardanaz N, San Roman L, Arevalo MA, Montero MJ.
Laboratorio de Farmacognosia y Farmacologia, Facultad de Farmacia, Departamento de Fisiologia y Farmacologia, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca 37007, Spain.
Our objective was to examine the effect of chronic treatment with amlodipine on blood pressure, left ventricular hypertrophy, and fibrosis in spontaneously hypertensive rats and the persistence of such an effect after drug withdrawal. We investigated the effects of treatment with 2, 8 and 20 mg/kg/day of amlodipine given orally for six months and at three months after drug withdrawal. Systolic blood pressure was measured using the tail-cuff method. At the end of the study period, the heart was excised, the left ventricle was isolated, and the left ventricle weight/body weight ratio was calculated as a left ventricular hypertrophy index. Fibrosis, expressed as collagen volume fraction, was evaluated using an automated image-analysis system on sections stained with Sirius red. Age-matched untreated Wistar-Kyoto and SHR were used as normotensive and hypertensive controls, respectively. Systolic blood pressure was reduced in the treated SHR in a dose-dependent way and after amlodipine withdrawal it increased progressively, without reaching the values of the hypertensive controls. Cardiac hypertrophy was reduced by 8 and 20 mg/kg/day amlodipine, but when treatment was withdrawn only the group treated with 8 mg/kg/day maintained significant differences versus the hypertensive controls. All three doses of amlodipine reduced cardiac fibrosis and this regression persisted with the two highest doses after three months without treatment. We concluded that antihypertensive treatment with amlodipine is accompanied by a reduction in left ventricular hypertrophy and regression in collagen deposition. Treatment was more effective in preventing fibrosis than in preventing ventricular hypertrophy after drug withdrawal. Copyright 2004 Elsevier Inc.

Am J Vet Res. 2004 Jul;65(7):1006-13.
Evaluation of a technique of inducing hypertensive renal insufficiency in cats.
Mathur S, Brown CA, Dietrich UM, Munday JS, Newell MA, Sheldon SE, Cartier LM, Brown SA.
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
OBJECTIVE: To compare 2 techniques of inducing combined renal insufficiency and systemic hypertension in cats. ANIMALS: 22 cats 6 to 12 months of age. PROCEDURES: Cats were randomly assigned to 1 of 3 groups. Control (C) group cats had 2 intact kidneys, remnant kidney (RK) group cats underwent unilateral partial renal infarction and contralateral nephrectomy, and remnant-wrap (W) group cats underwent unilateral partial renal infarction and partial abtation and wrapping of the contralateral kidney. Systemic arterial blood pressure (BP) was measured continuously by use of implanted radiotelemetric devices. Renal function was assessed via determination of glomerular filtration rate, measurement of serum creatinine and BUN concentrations, and determination of urine protein-to-creatinine ratio (UP/C). Serum aldosterone concentration and plasma renin activity were measured on day 75. RESULTS: Systolic BP was significantly higher in groups RK and W than in group C, and systolic BP was significantly higher in group W than in group RK. Serum aldosterone concentration and plasma renin activity were significantly higher in group W, compared with groups C and RK. Glomerular filtration rate was significantly lower in groups RK and W, compared with group C. Histologic indices of renal injury and UP/C were significantly higher in group W, compared with groups C and RK. CONCLUSIONS AND CLINICAL RELEVANCE: Hypertensive renal insufficiency in group W was characterized by marked sustained systemic hypertension, decreased renal function, proteinuria, activation of the renin-angiotensin-aldosterone axis, and renal structural injury. Results support the hypothesis that marked systemic hypertension, activation of the renin-angiotensin-aldosterone axis, and proteinuria may damage the kidney of cats with preexisting renal insufficiency.

Lancet. 2004 Jun 19;363(9426):2049-51.
Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.
Weber MA, Julius S, Kjeldsen SE, Brunner HR, Ekman S, Hansson L, Hua T, Laragh JH, McInnes GT, Mitchell L, Plat F, Schork MA, Smith B, Zanchetti A.
State University of New York, Brooklyn, NY, USA.
The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test whether, for the same achieved blood pressures, regimens based on valsartan or amlodipine would have differing effects on cardiovascular endpoints in high risk hypertension. But inequalities in blood pressure, favouring amlodipine, throughout the multiyear trial precluded comparison of outcomes. A technique of serial median matching, applied at 6 months when treatment adjustments intended to achieve control of blood pressure were complete, created 5006 valsartan-amlodipine patient pairs matched exactly for systolic blood pressure, age, sex, and the presence or absence of previous coronary disease, stroke, or diabetes. Subsequent combined cardiac events, myocardial infarction, stroke, and mortality were almost identical in the two cohorts, but admission to hospital for heart failure was significantly lower with valsartan. Reaching blood pressure control (systolic <140 mm Hg) by 6 months, independent of drug type, was associated with significant benefits for subsequent major outcomes; the blood pressure response after just 1 month of treatment predicted events and survival.

Lancet. 2004 Jun 19;363(9426):2022-31.
Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.
Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A; VALUE trial group.
University of Michigan, Ann Arbor, USA. sjulius@med.umich.edu
BACKGROUND: The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test the hypothesis that for the same blood-pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk. METHODS: 15?245 patients, aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a randomised, double-blind, parallel-group comparison of therapy based on valsartan or amlodipine. Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint, defined as a composite of cardiac mortality and morbidity. Patients from 31 countries were followed up for a mean of 4.2 years. FINDINGS: Blood pressure was reduced by both treatments, but the effects of the amlodipine-based regimen were more pronounced, especially in the early period (blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month; 1.5/1.3 mm Hg after 1 year; p<0.001 between groups). The primary composite endpoint occurred in 810 patients in the valsartan group (10.6%, 25.5 per 1000 patient-years) and 789 in the amlodipine group (10.4%, 24.7 per 1000 patient-years; hazard ratio 1.04, 95% CI 0.94-1.15, p=0.49). INTERPRETATION: The main outcome of cardiac disease did not differ between the treatment groups. Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes. The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk.

J Am Coll Cardiol. 2004 Jun 2;43(11):2116-23.
Comparative effects of valsartan versus amlodipine on left ventricular mass and reactive oxygen species formation by monocytes in hypertensive patients with left ventricular hypertrophy.
Yasunari K, Maeda K, Watanabe T, Nakamura M, Yoshikawa J, Asada A.
Department of General Medicine and Cardiology, Graduate School of Medicine, Osaka City University, Osaka, Japan. yasunari@med.osaka-cu.ac.jp
OBJECTIVES: To compare the effects of the angiotensin receptor blocker (ARB) valsartan versus the calcium channel blocker amlodipine, reactive oxygen species (ROS) formation by monocytes, C-reactive protein (CRP), and left ventricular (LV) mass were studied in 104 hypertensive patients with left ventricular hypertrophy (LVH). BACKGROUND: There is evidence that ARBs have blood pressure (BP)-independent effects on LV mass. Whether regression of LV mass by ARBs is correlated to ROS formation by monocytes and CRP is not fully understood yet. METHODS: A cross-sectional and prospective study was performed. Participants were randomly assigned to either the 80-mg valsartan (n = 52) or 5-mg amlodipine (n = 52) group and were treated for eight months. The left ventricular mass index (LVMI) was calculated from two-dimensional M-mode echocardiography. Formation of ROS by monocytes was measured by gated flow cytometry. In addition, CRP, plasma renin activity, plasma aldosterone, and traditional risk factors were assessed. RESULTS: Multiple regression analysis showed a significant correlation between LVMI and ROS formation by monocytes and between LVMI and CRP. Treatment reduced BP to a similar extent in both groups. Valsartan significantly reduced LVMI after eight months, but amlodipine had less effect (16% vs. 1.2%, n = 50, p < 0.01). Formation of ROS by monocytes was reduced to a greater extent with valsartan than with amlodipine (28% vs. 2%, n = 50, p < 0.01). Valsartan but not amlodipine reduced CRP levels. A significant correlation between changes in ROS formation by monocytes and LVMI or between CRP and LVMI was observed. CONCLUSIONS: The ARB valsartan has BP-independent effects on LVH, ROS formation by monocytes, and CRP in hypertensive patients with LVH.

Am J Physiol Renal Physiol. 2004 Jun;286(6):F1136-43. Epub 2004 Mar 02.
Effects of calcium channel blockers on "dynamic" and "steady-state step" renal autoregulation.
Griffin KA, Hacioglu R, Abu-Amarah I, Loutzenhiser R, Williamson GA, Bidani AK.
Loyola Univ. Medical Ctr., 2160 South First Ave., Maywood, IL 60153, USA. kgriffi@lumc.edu
Renal autoregulation (AR) mechanisms provide the primary protection against transmission of systemic pressures and hypertensive renal damage. However, the relative merits of the "step" change vs. "dynamic" methods for the assessment of AR capacity remain controversial. The effects of 48-72 h of orally administered amlodipine (L-type) and mibefradil (T-type) calcium channel blockers (CCBs) on step and dynamic AR in Sprague-Dawley rats were compared. Both CCBs significantly impaired "steady-state step" AR (autoregulatory indexes = approximately 0.5 vs. approximately 0.1 in controls, P < 0.05; n = 9-10/group). By contrast, dynamic AR compensation in separate conscious rats (n = 12) was not significantly altered by either amlodipine (n = 10) or mibefradil (n = 6; fractional gain in admittance approximately 0.4-0.5 in all groups at frequencies in the range of 0.0025-0.025 Hz). However, both CCBs tended to attenuate the myogenic resonance peak along with shifting it to a significantly slower frequency (P < 0.001) during dynamic AR, but no consistent effects were observed on the tubuloglomerular feedback resonance peak. While the reasons for the insensitivity of dynamic vs. steady-state step AR capacity estimates to CCBs remain to be established, the present data indicate that dynamic AR methods may have a limited utility for assessing AR capacity but may provide potentially important insights into the operational characteristics of AR control mechanisms. A strong correlation was also observed between the average conductance and the admittance gain at the heart beat frequency (r = 0.77, P < 0.001), suggesting that such parameters may provide additional and possibly more meaningful indexes of BP transmission in conscious animals during dynamic AR.

Curr Rheumatol Rep. 2004 Jun;6(3):240-7.
Serum uric acid-lowering therapies: where are we heading in management of hyperuricemia and the potential role of uricase.
Bomalaski JS, Clark MA.
Medical College of Pennsylvania Hospital, Drexel University College of Medicine, 3300 Henry Avenue, Philadelphia, PA 19129, USA. johnsbomalaski@msn.com
Although allopurinol has been available for approximately 50 years, hyperuricemia and its sequelae are not only prevalent, but the incidence and costs associated with this disorder continue to increase. However, several new therapies have been developed. Recombinant urate oxidase has been useful in the treatment of tumor lysis hyperuricemia, and pegylated urate oxidase shows promise in patients with hyperuricemia and gout. Febuxostat and Y-700 are new oral xanthine oxidase inhibitors that are in human clinical trials. Tailoring of antilipid therapy in selected hyperuricemic and hyperlipidemic patients with fenofibrate may be of benefit in lowering blood cholesterol and uric acid levels. Similarly, treatment of selected hyperuricemic patients who also are hypertensive with losartan or amlodipine may be beneficial in lowering blood pressure and hyperuricemia. Despite these advances, new treatments for hyperuricemia are needed.

Hypertens Res. 2004 Jun;27(6):379-85.
Comparison between cilnidipine and amlodipine besilate with respect to proteinuria in hypertensive patients with renal diseases.
Kojima S, Shida M, Yokoyama H.
Division of Internal Medicine, National Hospital Organization Shizuoka Medical Center, Japan. skojima@jun.ncvc.go.jp
Unlike other dihydropyridine calcium channel blockers (CCBs), cilnidipine has been reported to exert an N-type calcium-channel-blocking activity and to reduce sympathetic hyperactivity. This study compared cilnidipine and amlodipine with respect to their effects on renal function and proteinuria. Twenty-eight proteinuric hypertensive outpatients (13 men and 15 women, aged 62+/-2 years) who had been maintained on CCBs for more than 3 months were randomly assigned to a group receiving amlodipine besilate (14 patients) or a group receiving cilnidipine (14 patients). CCBs were increased in dosage or other drugs were added until blood pressure decreased below 140/90 mmHg, but no inhibitors of the renin-angiotensin (RA) system were added or changed in dosage. Before and at 6 and 12 months after randomization, the concentrations of urine protein, urine albumin, serum and urine creatinine (Cr), and serum beta2-microglobulin were determined. The amlodipine group showed a significant increase in proteinuria, while the increase was suppressed in the cilnidipine group. The rate of increase in proteinuria at 12 months was 87% (95% confidence interval (CI) -10 to 184) of the baseline value with amlodipine and 4% (95% CI -69 to 77) of baseline with cilnidipine, a significant intergroup difference (p<0.05). The mean blood pressure remained in the 96-99 mmHg range until 12 months after randomization, showing no significant difference between the two groups. The cilnidipine group showed an increase in serum Cr levels (baseline vs. 12 months, 1.36+/-0.20 vs. 1.50+/-0.23 mg/dl, p<0.01). Overall, an inverse correlation existed between the changes in Cr and proteinuria (r= -0.477, p<0.01). These results suggest that cilnidipine results in a greater suppression of the increase in proteinuria and greater reduction in glomerular filtration rate than amlodipine, and that these effects are similar between cilnidipine and RA inhibitors. However, additional large-cohort and longer-term studies will be needed to clarify whether cilnidipine is superior to other CCBs in maintaining renal function.

Int J Clin Pharmacol Ther. 2004 Jun;42(6):330-5.
Bioequivalence study of generic amlodipine in healthy Thai male volunteers.
Rojanasthien N, Teekachunhatean S, Jakob K, Gaupp M, Arnold P, Chaichana N, Martin W.
Division of Clinical Pharmacology, Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. nrojanas@med.cmu.ac.th
SUBJECTS, MATERIAL AND METHODS: To determine the bioequivalence of 10 mg generic amlodipine in healthy male volunteers, the reference and the test formulations were administered as a single oral dose after overnight fasting in a crossover study separated by 2-week washout interval. After dosing, serial blood samples were collected for a period of 144 h. Plasma amlodipine concentrations were determined by LC-MS/MS and the pharmacokinetic parameters were analyzed by non-compartmental analysis. RESULTS: The mean elimination half-life (t1/2) for the test (40 h) and the reference (44 h) were within the values previously reported. The rate of absorption reflected by tmax had a difference of -0.33 h, with a 90% CI of (-1.52)-0.85 (acceptable range +/- 1.3). Although the tmax of the test (5 h) was faster than the reference (6 h), the mean (90% CI) of the AUC(0-infinity) and Cmax ratios Test/Reference were 0.91 (0.87-0.97) and 1.01 (0.93-1.09), respectively. These values were within the range of 0.80-1.25, thus, the study demonstrated the bioequivalence of the 2 formulations.

Nephrol Dial Transplant. 2004 Jun;19(6):1392-7. Epub 2004 Mar 05.
The role of nitric oxide in the regulation of glomerular haemodynamics in humans.
Delles C, Klingbeil AU, Schneider MP, Handrock R, Schaufele T, Schmieder RE.
Department of Medicine IV/4, University of Erlangen-Nuremburg, Erlangen, Germany.
BACKGROUND: According to experimental data, the afferent glomerular arteriole is particularly under control of nitric oxide (NO). By use of pharmacological manoeuvres, we examined whether this finding holds true in the human renal circulation in vivo. METHODS: Seventy-seven volunteers (aged 50+/-9 years) with mild to moderate essential hypertension (n = 57) or arterial normotension (n = 20) were examined. Basal NO activity in the renal circulation was assessed by the change of renal plasma flow (RPF) through systemic infusion of the NO synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg). Hypertensive patients were treated over 8 weeks with either the calcium-channel blocker amlodipine or the AT(1)-receptor blocker valsartan, primarily dilating the afferent and efferent arteriole, respectively. Subsequently, renal haemodynamics and NO activity in the renal circulation were determined again. RESULTS: L-NMMA reduced RPF in normotensive (by 57+/-70 ml/min/1.73 m(2); P<0.01) and hypertensive subjects (by 46+/-56 ml/min/1.73 m(2); P<0.001) with no significant difference between the two groups. The decrease of RPF through L-NMMA was closely related with the glomerular filtration rate (GFR; r = 0.39, P<0.001). Administration of amlodipine increased GFR by 7.1+/-12.1 ml/min/1.73 m(2); (P<0.01) and in parallel reduced the response of RPF to L-NMMA to 19+/-48 ml/min/1.73 m(2); (P<0.05). In contrast, valsartan maintained GFR and left the response of RPF to L-NMMA unchanged. CONCLUSIONS: NO plays an important role in the regulation of human glomerular haemodynamics, probably with a greater contribution to afferent than to efferent arteriolar tone in man.

Am J Cardiol. 2004 May 1;93(9):1124-9.
Statin therapy is associated with lower mortality among patients with severe heart failure.
Mozaffarian D, Nye R, Levy WC.
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. darymd@hotmail.com
Experimental considerations suggest both potential harm and benefit from statin therapy in patients with severe heart failure. However, relations of statin therapy with clinical outcomes in severe heart failure are not well established. Using data from the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, we evaluated associations of statin therapy with total mortality among 1,153 patients with severe heart failure (ejection fraction <30% and New York Heart Association class IIIB or IV symptoms) of ischemic and nonischemic etiologies. Statin therapy was administered to 134 patients (12%) during the study period. Over a 1.3-year mean follow-up, there were 413 deaths (29 deaths/100 person-years). Adjusting for age, gender, diabetes, smoking, heart failure etiology, ejection fraction, and New York Heart Association class, statin therapy was associated with a 62% lower risk of death (hazard ratio 0.38, 95% confidence interval 0.23 to 0.65), or 1 fewer death/5 patients taking statin therapy for 1 year. This association was not greatly altered by additional adjustment for a variety of other patient characteristics, including serum cholesterol levels. After propensity score analyses, statin therapy was still associated with a 48% lower risk of death (hazard ratio 0.52, 95% confidence interval 0.30 to 0.89). Although this observational study does not prove causality, further investigation of potential benefits of statins in patients with severe heart failure appears warranted.

Clin Ther. 2004 May;26(5):715-23.
Randomized, open-label, two-period crossover comparison of the pharmacokinetic and pharmacodynamic properties of two amlodipine formulations in healthy adult male Korean subjects.
Park JY, Kim KA, Lee GS, Park PW, Kim SL, Lee YS, Lee YW, Shin EK.
Department of Pharmacology, Clinical Trial Center, Gil Medical Center, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu, Incheon 405-760, Korea. jypark@gachon.ac.kr
BACKGROUND: Amlodipine, a third-generation dihydropyridine calcium antagonist, is prescribed in the management of angina and hypertension. A newly developed amlodipine formulation (amlodipine camsylate) is associated with similar physical properties, melting point, and solubility-and improved stability against long-term stability test and accelerated temperature test-compared with the conventional formulation (amlodipine besylate). OBJECTIVE: This study was performed to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of a newly developed amlodipine formulation with a conventional formulation in healthy male subjects. METHODS: This randomized, open-label, 2-period crossover comparative study was conducted at the Clinical Trial Center, Gil Medical Center, Gachon Medical School (Incheon, Korea). Eighteen healthy male Korean subjects aged 20 to 40 years were enrolled. All subjects received a single oral dose (5-mg tablet) of a conventional (reference) or newly developed (test) amlodipine formulation. Blood samples for PK analysis of amlodipine were obtained during the 144-hour period after dosing. Systolic and diastolic blood pressure (BP) (SBP and DBP, respectively) and pulse rate (PR) were measured just before each blood sampling. Assessment of safety profiles, including hematology and biochemistry, electrocardiography, urinalysis, and monitoring of adverse events (AEs), was performed. RESULTS: All participants completed both treatment periods. Their mean (SD) age was 22.3 (1.5) years (range, 20-25 years) and their mean (SD) body weight was 67.9 (5.6) kg (range, 57-77 kg). The plasma concentration-time profiles of amlodipine were similar after administration of the 2 formulations. The reference and test formulations were pharmacokinetically equivalent. The 90% CIs for the mean treatment ratios of the log-transformed peak plasma concentration and the area under the plasma concentration-time curve were within the predetermined equivalence range of 80% to 125%. Despite administration of a single dose, significant maximal changes in SBP, DBP, and PR were achieved after drug administration for both formulations compared with baseline values (all, P < 0.001). No significant differences in PD profiles were found between the 2 formulations. No clinically relevant changes were observed in physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study. Neither formulation caused any AEs during the study. CONCLUSIONS: The 2 amlodipine formulations were pharmacokinetically equivalent and showed similar PD characteristics in these healthy male subjects.

Cerebrovasc Dis. 2003;16 Suppl 3:11-7.
Atheroprotective effects of long-acting dihydropyridine-type calcium channel blockers: evidence from clinical trials and basic scientific research.
Mason RP.
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Atherosclerosis is a systemic disease that can ultimately lead to ischaemia and infarction in the heart, brain and peripheral vasculature. According to the "response to injury" hypothesis, endothelial dysfunction is the early event that allows penetration of lipids and inflammatory cells into the arterial wall, contributing to the development of the atherosclerotic lesion. Endothelial dysfunction is causally related to a variety of risk factors for atherosclerosis, including hyperlipidaemia and hypertension. Agents that restore endothelial function and NO bioavailability have beneficial anti-atherogenic activities and can improve cardiovascular outcomes; this has been observed with angiotensin-converting enzyme (ACE) inhibitors, statins and certain dihydropyridine-type calcium channel blockers (CCBs). In the Prospective Randomised Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), the CCB amlodipine provided significant clinical benefits compared with placebo, including a marked reduction in cardiovascular morbidity and a reduction in the progression of carotid atherosclerosis. As these beneficial effects of amlodipine have not been observed with other dihydropyridine-type CCBs, it has been proposed that this agent has distinct anti-atherosclerotic properties related to its strong lipophilicity and membrane location. Experimental support for this hypothesis has been obtained from various in vitro and in vivo models of atherosclerosis. These findings support a broader therapeutic role for third-generation dihydropyridine-type CCBs in the treatment of atherosclerosis. Copyright 2003 S. Karger AG, Basel

Am J Ther. 2003 Nov-Dec;10(6):409-14.
Calcium antagonists and atherosclerosis protection in hypertension.
Hernandez RH, Armas-Hernandez MJ, Velasco M, Israili ZH, Armas-Padilla MC.
Clinical Pharmacology Unit, School of Medicine, Universidad Centroccidental Lisandro Alvarado, Barquisimeto, Venezuela.
Calcium antagonists are effective in hypertensive patients of all ethnic groups, irrespective of age, dietary salt intake, salt-sensitivity status or plasma renin activity profile. Some prospective studies show that the calcium antagonists, nifedipine GITS and nitrendipine, reduce cardiovascular morbidity and mortality at least to the same extent as the diuretics. Other prospective studies are in progress to evaluate the effect of calcium antagonists on cardiovascular morbidity and mortality, and the progression of atherosclerosis in hypertensive patients. Calcium antagonists, especially the highly lipophilic amlodipine, lacidipine and nisoldipine, are shown to possess antioxidant properties. These drugs reduce the oxidation of LDL and its influx into the arterial wall, and reduce atherosclerotic lesions in animals. Platelet production of malondialdehyde, a marker of oxygen free radical formation, is suppressed by amlodipine, lacidipine or nifedipine in hypertensive patients. New evidence from long-term clinical trials of calcium antagonists indicates that these drugs can reduce the rate of progression of atherosclerosis in hypertensive and coronary heart disease patients. In the Regression Growth Evaluation Statin Study (REGRESS), co-administration of calcium antagonist, amlodipine or nifedipine with pravasatin caused a significant reduction in the appearance of new angiographic lesions. In the Verapamil in Hypertension and Atherosclerosis Study (VHAS), verapamil was more effective than chlorthalidone in promoting regression of thicker carotid lesions in parallel with a reduction in the incidence of cardiovascular events. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), amlodipine slowed the progression of early coronary atherosclerosis in patients with coronary artery disease. In a subprotocol of the Intervention as a Goal in the Hypertension Treatment (INSIGHT) study, nifedipine GITS significantly decreased intima-media thickness as compared to co-amilozide (hydrochlorothiazide + amiloride). Preliminary results of the European Lacidipine Study on Atherosclerosis (ELSA) show that lacidipine reduced the intima-media thickness progression rate as compared to atenolol. Thus, selective calcium antagonists are potential antiatherosclerotic agents.

Circulation. 2003 Oct 14;108(15):1831-8. Epub 2003 Sep 29.
Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study.
Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B, Kleiman J, Krause S, Burns D, Williams GH.
University of Michigan Health System, Ann Arbor, Mich, USA.
BACKGROUND: Elevated renin-angiotensin-aldosterone system activity correlates with left ventricular hypertrophy (LVH) and cardiovascular risk, but the relative contributions of angiotensin II and aldosterone remain unclear. This study compared LVH regression during treatment with the selective aldosterone blocker eplerenone, enalapril, and their combination in patients with hypertension. METHODS AND RESULTS: A 9-month, double-blind, randomized study was performed in 202 patients with LVH and hypertension who received eplerenone 200 mg daily, enalapril 40 mg daily, or eplerenone 200 mg and enalapril 10 mg daily. At week 8, hydrochlorothiazide 12.5 to 25 mg and/or amlodipine 10 mg was added if diastolic blood pressure was >90 mm Hg. Change in left ventricular (LV) mass as assessed by MRI was the primary end point. Change in blood pressure, renin-angiotensin-aldosterone system hormones, albuminuria, and safety were also assessed. Eplerenone significantly reduced LV mass from baseline (-14.5+/-3.36 g; n=50) similarly to enalapril (-19.7+/-3.20 g; n=54; P=0.258), but eplerenone/enalapril (-27.2+/-3.39 g; n=49) was more effective than eplerenone alone (P=0.007). All treatments reduced systolic blood pressure and diastolic blood pressure from baseline (eplerenone, -23.8 and -11.9 mm Hg; enalapril, -24.7 and -13.4 mm Hg; and eplerenone/enalapril, -28.7 and -14.4 mm Hg, P=0.048, in systolic blood pressure compared with eplerenone alone). Cough was more common with enalapril than with eplerenone (P=0.033), and elevated potassium was more common with eplerenone. CONCLUSIONS: Eplerenone was as effective as enalapril in LVH regression and blood pressure control. The combination of eplerenone and enalapril was more effective in reducing LV mass and systolic blood pressure than eplerenone alone.

Norvasc
Mil Med. 2003 Jul;168(7):530-5.
A comparative analysis of amlodipine and felodipine in a military outpatient population: efficacy, outcomes, and cost considerations.
Blivin SJ, Pippins J, Annis LG, Lyons F.
Department of Primary Care, Naval Medical Clinic, Quantico, VA, USA.
BACKGROUND: This retrospective study compared the efficacy, tolerability, and cost of two dihydropyridine calcium channel blockers. METHODS: Charts of patients who had been on continuous antihypertensive therapy with amlodipine or felodipine for at least 6 months were reviewed. Analyses include mean changes in blood pressure, percentage of patients achieving blood pressure (BP) < 140/90 mm Hg, average dose, and cost per day of the two calcium channel blockers, average cost of additional medication, total medication cost per day, and cost to achieve BP control. RESULTS: Eighty-seven percent of amlodipine-treated patients achieved BP control compared with 33% of felodipine-treated patients. Total medication cost to achieve BP control was 0.87 dollars per day for patients on amlodipine compared with 1.79 dollars per day for patients on felodipine. CONCLUSIONS: Amlodipine produced BP control in a greater percentage of patients than did felodipine at a lower total cost to achieve BP control. When evaluating the total cost of antihypertensive treatment, the cost of a drug alone can be misleading.

Am Heart J. 2003 Aug;146(2):291-7.
Neurohormones and oxidative stress in nonischemic cardiomyopathy: relationship to survival and the effect of treatment with amlodipine.
Wijeysundera HC, Hansen MS, Stanton E, Cropp AS, Hall C, Dhalla NS, Ghali J, Rouleau JL; PRAISE II Investigators.
Division of Cardiology, University Health Network and Mount Sinai Hospital, Toronto, Ontario, Canada.
OBJECTIVES: The purpose of this study was to assess the effects of amlodipine on neurohormones and oxidative stress in nonischemic cardiomyopathy, and determine the relationship between baseline and posttreatment levels of these markers with survival. BACKGROUND: Neurohormones and oxidative stress are important in the pathophysiology of heart failure. Calcium-channel blockers are associated with poor outcomes in patients with heart failure, in part due to neurohormonal activation. In contrast, amlodipine, a second-generation dihydropyridine, has a more favorable clinical profile. METHODS: In the Prospective Randomized Amlodipine Survival Evaluation 2 (PRAISE-2) trial, a subset of 181 patients with nonischemic cardiomyopathy were randomized to amlodipine (10 mg/day) or placebo. Blood samples were evaluated at baseline, 2 weeks and 26 weeks for norepinephrine, epinephrine, angiotensin II, dopamine, N-terminal pro-atrial natriuretic peptide (Nt-pro-ANP), brain natriuretic peptide (BNP), adrenolutin and malondialdehyde. RESULTS: There was no difference in levels of neurohormones or oxidative stress markers between the amlodipine and placebo groups at the different times. Both Nt-pro-ANP and BNP decreased at 2 weeks and at 26 weeks. Baseline Nt-pro-ANP correlated with survival in multivariate analysis (P =.001). A strong relationship was found between a reduction in BNP at 26 weeks and survival, with a hazard ratio of 0.153 (95% CI 0.051-0.461, P =.017). No relationship was found between markers of oxidative stress and survival. CONCLUSIONS: We conclude that amlodipine does not affect circulating neurohormones and oxidative stress markers in patients with nonischemic cardiomyopathy treated with angiotensin-converting enzyme inhibitors, digoxin and diuretics. In addition, low circulating Nt-pro-ANP and a reduction in BNP over time confers a good prognosis.