amlodipine Norvasc
An in vitro study of the peroxyl and hydroxyl radical scavenging capacity of the calcium antagonist amlodipine.

Franzoni F, Santoro G, Regoli F, Plantinga Y, Femia FR, Carpi A, Galetta F.

Department of Internal Medicine, University of Pisa, Via Roma, 67, 56100 Pisa, Italy. f.franzoni int.med.unipi.it

Amlodipine has been reported to improve endothelial function in patients with arterial hypertension and to significantly limit the progression of carotid atherosclerosis. The aim of this study was to assess the total antioxidant activity of amlodipine. We measured the in vitro antioxidant activity of amlodipine as its ability to antagonize the oxidation of alpha-keto-gamma-methiolbutyric acid by both hydroxyl and peroxyl radicals. The results are expressed as Total Oxyradical Scavenging Capacity (TOSC) units. Reduced glutathione, uric acid and trolox were used as the reference antioxidants. Amlodipine showed an efficiency as scavenger of peroxyl radicals (TOSC: 5945 +/- 544 units/mg) significantly higher (>50%, P <0.001) than that of GSH (2733 +/- 636 units/mg), and 70% lower (P < 0.0001) than the value obtained with uric acid (18144 +/- 696 units/mg) and trolox (17522 +/- 734 units/mg). Of interest, the scavenging capacity of amlodipine towards hydroxyl radicals (1455 +/- 154 units/mg) was 320% higher (P < 0.00001) than that of GSH (358 +/- 112 units/mg), 20% higher than that of uric acid (1198 +/- 121 units/mg), and 100% higher than that of trolox (759 +/- 143 units/mg). Amlodipine has intrinsic antioxidant activity with both anti-hydroxyl and anti-peroxyl radicals activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15464869&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The calcium channel blocker amlodipine exerts its anti-proliferative action via p21(Waf1/Cip1) gene activation.

Ziesche R, Petkov V, Lambers C, Erne P, Block LH.

Department of Internal Medicine IV, University of Vienna, Austria.

Proliferation of vascular smooth muscle cells (VSMC) contributes to the progression of atherosclerotic plaques. Calcium channel blockers have been shown to reduce VSMC proliferation, but the underlying molecular mechanism remains unclear. p21(Waf1/Cip1) is a potent inhibitor of cell cycle progression. Here, we demonstrate that amlodipine (10(-6) to 10(-8) M) activates de novo synthesis of p21(Waf1/Cip1) in vitro. We show that amlodipine-dependent activation of p21(Waf1/Cip1) involves the action of the glucocorticoid receptor (GR) and C/EBP-alpha. The underlying pathway apparently involves the action of mitogen-activated protein kinase or protein kinase C, but not of extracellular signal-related kinase or changes of intracellular calcium. Amlodipine-induced p21(Waf1/Cip1) promoter activity and expression were abrogated by C/EBP-alpha antisense oligonucleotide or by the GR antagonist RU486. Amlodipine-dependent inhibition of cell proliferation was partially reversed by RU486 at 10(-8) M (58%+/-29%), antisense oligonucleotides targeting C/EBP-alpha (91%+/-26%), or antisense mRNAs targeting p21(Waf1/Cip1) (96%+/-32%, n=6); scrambled antisense oligonucleotides or those directed against C/EBP-beta were ineffective. The data suggest that the anti-proliferative action of amlodipine is achieved by induction of the p21 (Waf1/Cip1) gene, which may explain beneficial covert effects of this widely used cardiovascular therapeutic drug beyond a more limited role as a vascular relaxant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15466360&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
A comparison of the efficacy and duration of action of telmisartan, amlodipine and ramipril in patients with confirmed ambulatory hypertension.

Poirier L, de Champlain J, Larochelle P, Lamarre-Cliche M, Lacourciere Y.

Unite d'hypertension, Centre Hospitalier de l'Universite Laval, Universite Laval, 2705 Boulevard Laurier S-120-A, Sainte-Foy, Quebec, Canada G1V 4G2. luc.poirier crchul.ulaval.ca

OBJECTIVES: The aim of the study was to compare the antihypertensive effects and the duration of action of telmisartan, amlodipine and ramipril in patients with mild-to-moderate hypertension using ambulatory blood pressure (ABP) monitoring. METHODS: After a 2-4-week single-blind, placebo run-in period, qualifying patients were randomized to receive telmisartan 80 mg (n=18); amlodipine 5 mg (n=22); titrated to 10 mg after 4 weeks; or ramipril 2.5 mg (n=17); titrated to 5 mg and 10 mg after 1 and 3 weeks, respectively, administered once daily in the morning (0700 h). Ambulatory blood pressure monitoring was performed at baseline and at the end of the 8-week treatment period. Plasma renin activity was measured over 24 h at the same time points. RESULTS: Telmisartan and amlodipine provided significant reductions from baseline (P<0.0001) and not statistically different reductions between treatments in ABP during daytime (9.3/6.0 and 14.7/9.4 mmHg, respectively) and night-time (12.4/7.7 and 13.3/8.6 mmHg, respectively) at the end of 8 weeks' treatment. In contrast, although ramipril provided significant reductions in ambulatory systolic and diastolic BP from 2-6 h post dose (peak effect), it failed to induce significant reductions in mean daytime (4.5/1.6 mmHg) and night-time (1.8/0.1 mmHg) ambulatory BP. In addition, the greater reductions in ABP with telmisartan and amlodipine were associated with a significant rise in plasma renin activity whereas ramipril only increased renin during the first 4 h of the administration interval. CONCLUSION: The results of the present study confirm the efficacy of both telmisartan and amlodipine in reducing ABP during each period of the 24-h interval. Because ABP reduction with ramipril was restricted to its peak effect, the present data do not support the use of this agent when administered once daily in the morning.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15472494&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Antihypertensive treatment and renal damage: amlodipine exerts protective effect through the polyol pathway.

Bernobich E, Cosenzi A, Campa C, Zennaro C, Sasso F, Paoletti S, Bellini G.

Department of Internal Medicine, University of Trieste, Cattinara Hospital, Italy. e.bernobich fmc.units.it

Besides generating renal damage, hypertension plays an important role in the progression of diabetic nephropathy. The fructose-fed rat is a well-established model both of high blood pressure and renal impairment, which is similar to diabetic nephropathy. To clarify the relationship between hypertension, glucose metabolism, and kidney remodeling, we investigated the renal level of Glut 1 and Glut 5, their relation to fibrosis and the effects of an antihypertensive drug on renal damage. Twenty-four male WK rats were divided into three groups: 8 animals received a fructose-enriched diet, 8 a control diet, and 8 animals a high-fructose diet plus amlodipine (5 mg/Kg). After six weeks of treatment, we observed a significant increase in Glut 5, fibronectin, and sorbitol in fructose-fed rats compared with control and amlodipine-treated animals; there was a positive correlation between Glut 5 and fibronectin levels (r = 0.63). Glut 1 levels were similar in all three groups, whereas collagen IV was higher in fructose-fed rats; amlodipine prevented the increase of collagen IV and sorbitol. Collagen I was statistically higher in the fructose group than in the other two groups. Therefore, prolonged fructose feeding results in renal fibrosis via polyol pathway overactivity that can be prevented by means of an antihypertensive drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15475840&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Platelet morphology and plasma indices of platelet activation in essential hypertension: effects of amlodipine-based antihypertensive therapy.

Nadar S, Blann AD, Lip GY.

Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, Birmingham, UK.

BACKGROUND AND AIM: Platelet abnormalities have been described in hypertension, especially in the presence of target organ damage. Our aim was to study the differences in morphology and indices of platelet activation in treatment-naive patients with essential hypertension as compared to normotensive controls and secondly, to study the effects of amlodipine-based antihypertensive therapy on these indices. METHODS: We recruited 42 previously untreated, newly diagnosed hypertensive patients (25 men; mean age 53 years) for the cross-sectional study, where data were compared with those from 30 normotensive controls (20 men; mean age 57 years). Of the 42 untreated hypertensive patients who were recruited, 27 patients successfully completed, the six-month treatment phase with amlodipine-based antihypertensive therapy. Platelet morphology (volume and mass) was quantified, and plasma markers of platelet activation (betaTG and sPsel) measured in citrated plasma. The mass of P-selectin in each platelet (pPsel) was determined by lysing a fixed number of platelets and then determining the levels of P-selectin in the lysate. RESULTS: Hypertensive patients had significantly higher platelet volume (P = 0.01) and mass (P = 0.003), plasma betaTG and sPsel, and pPsel levels (all P < 0.001) compared to the controls. After a mean treatment time of 6 months, there was a decrease in platelet volume (P < 0.001) and mass (P = 0.02), with lower pPsel, sPsel and BTG levels (all P < 0.001) compared to the untreated state. CONCLUSION: Treatment of uncomplicated essential hypertension using amlodipine-based anti-hypertensive therapy results in a reversal of the platelet morphology abnormalities and indices of platelet activation. This may contribute to a reduction in thrombosis-related complications seen in those whose blood pressure lowering is effective.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15513305&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Ionization, lipophilicity, and molecular modeling to investigate permeability and other biological properties of amlodipine.

Caron G, Ermondi G, Damiano A, Novaroli L, Tsinman O, Ruell JA, Avdeef A.

Dipartimento di Scienza e Tecnologia del Farmaco, Universita di Torino, Via P. Giuria 9, I-10125 Torino, Italy. giulia.caron unito.it

This paper uses a recent approach toward drug discovery, in which in silico tools and experimental data are combined together to study the structural features of amlodipine and their relevance in the peculiar pharmacodynamic and pharmacokinetic profiles of this long acting calcium antagonist. Results reveal for amlodipine two families of conformers (folded and extended) but also demonstrate that protonation is the predominant factor governing amlodipine intermolecular interactions among which ionic forces play a major role.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15519156&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine and glutathione cycle in hypercholesterolaemia.

Mutaf I, Habif S, Turgan N, Parildar Z, Ozmen D, Bayindir O, Uysal A.

Department of Clinical Biochemistry, Ege University School of Medicine, 35100 Bornova, Izmir, Turkey.

OBJECTIVE: Effects of amlodipine on lipid peroxidation and alterations in glutathione and related enzymes in blood and aortic tissue were investigated in a cholesterol-induced atherosclerotic rabbit model. METHODS AND RESULTS: New Zealand white male rabbits were fed with regular chow (group I), chow supplemented with I% cholesterol (group II), regular chow plus amlodipine 5 mg/kg/day p.o. (group III) and I% cholesterol diet supplemented with amlodipine (group IV) for 8 weeks. Cholesterol, malondialdehyde (MDA), reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione peroxidase (GSH-PX) and glutathione reductase (GSH-Rd) were determined in blood samples drawn before and after the experimental period. Aortic tissue was examined morphologically for atherosclerotic changes and tissue cholesterol, MDA, GSSG, GSH-PX, GSH-Rd and glutathione-S-transferase (GST) were measured. After 8 weeks, blood cholesterol, MDA, GSSG and GSH-PX were elevated in groups II and IV; GSH was reduced in group IV; MDA levels were higher in group II than in group IV. Aortic tissue investigations revealed higher cholesterol and MDA concentrations in group II than in group IV. Morphological examination of aortic tissues exhibited endothelial disarrangement and lipid deposition in group II. Histopathological alterations related to atherogenesis were less in group IV than in group II. CONCLUSIONS: Amlodipine reduced the increase in oxidative stress by inhibiting excessive MDA production. Accelerated glutathione redox cycle activity of erythrocytes from animals supplemented with amlodipine suggests that this drug may reduce oxidative stress by enhancing the glutathione system. However, this drug does not seem to affect the glutathione redox cycle in the aortic tissue.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15529551&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Application of oxidants to the spectrophotometric determination of amlodipine besylate in pharmaceutical formulations.

Rahman N, Singh M, Hoda MN.

Analytical Research Division, Department of Chemistry, Aligarh Muslim University, Aligarh, 202002 UP, India. cht17nr_amu yahoo.com

Three new spectrophotometric methods for the determination of amlodipine besylate have been proposed. The first two methods, i.e. A and B, are based on the oxidation of the drug with Fe(III) and the estimation of Fe(II) produced after chelation with either 1,10-phenanthroline or 2,2'-bipyridyl at 500 and 515 nm, respectively. The Beer's law was obeyed in the concentration ranges of 2-10 and 4-14 microg ml(-1) with molar absorptivity of 2.9 x 10(4) and 2.7 x 10(4) l mol(-1) cm(-1) for methods A and B, respectively. The third procedure depends on the interaction of amlodipine besylate with ammonium heptamolybdate tetrahydrate, which resulted in the formation of molybdenum blue (lambda(max) 825 nm). The linear dynamic range and the molar absorptivity values were found to be 15-59 microg ml(-1) and 1.8 x 10(4) l mol(-1) cm(-1), respectively. The results of the proposed procedures were validated statistically and compared with those obtained by the reference method. The proposed methods were applied successfully to the determination of amlodipine besylate in commercial tablets.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15544797&dopt=Abstract amlodipine Norvasc