amlodipine Norvasc
Concentration dependency of modulatory effect of amlodipine on P-glycoprotein efflux activity of doxorubicin--a comparison with tamoxifen.

Darvari R, Boroujerdi M.

Epic Therapeutics Inc., 220 Norwood Park South, Norwood, MA 02062, USA.

Modulators of P-glycoprotein (P-gp) can enhance or limit the permeability of a number of therapeutic agents that are considered substrates of this efflux pump protein. The modulatory effect of amlodipine (4-dihydropyridine calcium antagonist) on P-gp efflux activity has not been fully elucidated. We have studied the concentration dependency of its modulatory effect and compared it qualitatively with tamoxifen (a non-esteroid anti-estrogen). The investigation was conducted on transmembrane efflux of doxorubicin at a fixed concentration of 5 microM across a Caco-2 monolayer in the presence of various concentrations of amlodipine or tamoxifen. The maximum flux of doxorubicin from basolateral to apical (ba) occurred at 4.5 microM amlodipine and at 0.02 microM tamoxifen. At higher concentrations, the apical to basolateral (ab) flux and the net flux of doxorubicin (ba - ab) declined steadily in a concentration-dependent manner. We analysed the observed net flux data by fitting different mathematical models to the data. A composite sigmoidal Emax/Imax (stimulatory/inhibitory) model was found to be the most appropriate to define the system. The observed and calculated parameters supported the modulatory role of both compounds and clearly indicated that the stimulation and inhibition of transmembrane efflux occurred simultaneously in the presence of amlodipine or tamoxifen. It was concluded that amlodipine, similar to tamoxifen, modulated the transporter-dependent transmembrane flux of the P-gp substrate in a concentration-dependent manner.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15285842&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Comparison of the effects of amlodipine and verapamil on autonomic activity in hypertensive patients.

Sahin I, Kosar F, Altunkan S, Gunaydin M.

Department of Internal Medicine, Faculty of Medicine, Inonu University, TR-44069 Malatya, Turkey.

Background: Many studies have shown that autonomic activation is one of the major factors in the etiology of hypertension. Furthermore, sympathovagal imbalance may be responsible for arrhythmias and sudden cardiac death. The aim of the present study was to compare and to evaluate the effects of short-term therapy with amlodipine and verapamil on heart rate variability (HRV) in patients with essential hypertension. Methods: Forty patients with essential hypertension (11 men and 29 women, mean age 50.5+/-10.4 years) were included in the study. Patients with cardiac, metabolic, or any other systemic disease were excluded. Patients were randomized to receive either amlodipine (10 mg; n=20) or verapamil (240 mg; n=20). Patients underwent 24-h Holter monitoring assessment before treatment and after the 4-week treatment period. Standard deviation of normal RR intervals (SDNN), standard deviation of all 5-min mean normal RR intervals (SDANN), square root of the mean of the sum of the squares of differences between adjacent RR intervals (r-MSSD), and pNN50 (time domain variables) and TF, high-frequency power (HF), low-frequency power (LF), and sympathovagal balance (LF/HF; frequency domain variables) were analyzed before and after treatment. Results: Blood pressure (BP) was reduced to a similar degree, from 182/104 to 128/85 mmHg with verapamil and from 174/100 to 124/86 mmHg with amlodipine (verapamil p<0.001; amlodipine p<0.001). This study revealed that amlodipine had no significant effect on any of the time or frequency domain parameters. In contrast, in patients on verapamil, there were significant increases in all time domain parameters, and the LF/HF ratio was significantly decreased (p<0.05). Conclusions: These results suggest that verapamil may have additional positive effects on sympathico-parasympathetic control beyond lowering blood pressure compared with amlodipine, even after short-term treatment in hypertensive patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15288676&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Comparative effects of candesartan and amlodipine in a monkey atherosclerotic model.

Takai S, Jin D, Sakaguchi M, Muramatsu M, Ishii K, Kirimura K, Sakonjo H, Miyazaki M.

Department of Pharmacology, Osaka Medical College, Takatsuki, Japan. Pha010 art.osaka-med.ac.jp

Angiotensin II receptor blockers could prevent the development of atherosclerosis beyond reducing blood pressure in monkeys fed a high-cholesterol diet. However, it has been unclear whether hypotensive effects improve atherosclerosis in primates. We investigated whether antihypertensive agents, an angiotensin II receptor antagonist, candesartan, and a calcium channel blocker, amlodipine, prevent areas of atherosclerotic lesions in the aorta of monkeys fed a high-cholesterol diet. Seventeen male monkeys fed a high-cholesterol diet for 6 months were grouped as follows: a high-cholesterol diet group (n=5), a candesartan-treated group (1 mg/kg per day, n=6) and an amlodipine-treated group (5 mg/kg per day, n=6). Candesartan and amlodipine showed a similar hypotensive effect by decreasing the systolic blood pressure approximately 20 mmHg, while these agents did not affect serum cholesterol levels. The ratio of atherosclerotic area to total area in thoracic aorta was significantly decreased by treatment with candesartan, but the ratio tended to be decreased by treatment with amlodipine. Although the angiotensin-converting enzyme activity in plasma was not changed by treatment with candesartan or amlodipine, the angiotensin-converting enzyme activity in the thoracic aorta was obviously reduced by treatment with candesartan, but not with amlodipine. Therefore, a blockade of angiotensin II action rather than a hypotensive effect may play an important role in preventing the development of atherosclerosis in primates. Copyright 2004 Lippincott Williams & Wilkins

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amlodipine Norvasc
Fosinopril and amlodipine in the treatment of isolated systolic hypertension.

[Article in English, Serbian]

[No authors listed]

The aim of this study was to assess the therapeutic effects of fosinopril (F) and amlodipine (A) on regulation and circadian rhythm of blood pressure, and to evaluate left ventricle mass index (LVMI) in patients over 60 years of age with isolated systolic hypertension, after three months of administration period. After one-week placebo run-in period, 60 patients were randomized into two groups, each including 30 patients, to receive either fosinopril or amlodipine for three months. Clinical, echocardiographic examinations and 24 h ambulatory blood pressure measurements were performed at baseline, and after 3 months of therapy. The goal blood pressure was < or = 140/90 mmHg. It was accomplished in more than two thirds of cases (F 76.6%, and A 79.9%), with lower drug doses needed in the group treated with F. In 13 patients goal values were not accomplished, therefore the therapy was prolonged for one additional month, with combination of two drugs. In 10 of these patients (76.9%), adequate regulation of blood pressure was achieved. Both fosinopril and amlodipine efficiently control blood pressure by once-a-day administration, both significantly influencing its circadian rhythm and resulting in regression of myocardial hyperthrophy. Adequate control of blood pressure and beneficial effects on circadian rhythm of blood pressure are achieved with lower doses of fosinopril.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15327190&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Calcium channel blockers, either amlodipine or mibefradil, ameliorate renal injury in experimental diabetes.

Ma G, Allen TJ, Cooper ME, Cao Z.

Danielle Alberti Memorial Centre for Diabetes Complications, Baker Medical Research Institute, Melbourne, Victoria, Australia.

BACKGROUND: Diabetic nephropathy is associated with increased albuminuria and accumulation of extracellular matrix proteins within the kidney. Clinical studies have shown some beneficial effects of calcium channel blockers (CCB) on diabetic nephropathy, even though they are generally considered to be less renoprotective than agents that interrupt the renin angiotensin system. However, effects of CCBs on renal injury, and in particular, expression of extracellular matrix proteins in a model of normotensive diabetic nephropathy, are poorly characterized. METHODS: Experimental diabetes was induced by injection of streptozocin in Sprague-Dawley rats. Amlodipine, a CCB which blocks the L channel, and mibefradil, a CCB blocking the T as well as the L channels, were given to diabetic rats for six months. Albumin excretion rate (AER), pathologic injury, and expression of the extracellular matrix proteins, collagen I, and fibronectin were assessed. RESULTS: Increased AER in diabetic rats (13.2 x//1.3 mg/d, geometric mean x// tolerance factor) was attenuated by either amlodipine (3.2 x// 1.4 mg/d) or mibefradil (2.6 x// 1.4 mg/d). Increased glomerulosclerosis and tubulointerstitial injury in diabetic animals were attenuated by amlodipine and mibefradil. There was increased collagen accumulation in the kidney of diabetic rats as assessed by picro-sirius red staining. Gene expression of both collagen I and fibronectin were also increased in the kidneys from diabetic animals, as assessed by reverse transcription-polymerase chain reaction (RT-PCR). These markers of fibrosis were attenuated by treatment with either amlodipine or mibefradil. Blood pressure in diabetic rats (136 +/- 2 mm Hg) was modestly reduced by amlodipine (126 +/- 3 mm Hg) but not by mibefradil treatment (134 +/- 3 mm Hg). CONCLUSION: Calcium channel blockers attenuated albuminuria, pathologic injury, and accumulation of extracellular matrix proteins in this normotensive model of diabetic nephropathy. These findings suggest that CCBs may be useful in preventing pathologic injury in the diabetic kidney.

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amlodipine Norvasc
Simple and rapid HPLC method for determination of amlodipine in human serum with fluorescence detection and its use in pharmacokinetic studies.

Bahrami G, Mirzaeei Sh.

Department of Pharmacology, Biomedical Research Center, Medical School Kermanshah, University of Medical Sciences, Kermanshah 67184 69914, Iran. gbahrami kums.ac.ir

A fast, sensitive and specific high performance liquid chromatographic method using fluorescence detection is described for analysis of amlodipine in human serum. Amlodipine is extracted from serum by ethyl acetate and involves precolumn derivatization with 4-chloro-7-nitrobenzofurazan (NBD-Cl) and reverse-phase chromatography on C18 column. The mobile phase was sodium phosphate buffer (pH 2.5) containing 1 ml/l triethylamine and methanol at flow rate of 2.8 ml/min. Propranolol was used as internal standard. The standard curve was linear over the range 0.25-16 ng/ml of amlodipine in human serum. The within-day and between-day precision studies showed good reproducibility with coefficients of variation less than 12% for all the analytes. The limit of quantification was 0.25 ng/ml of serum. The method has been applied to a bioequivalence study after administration of 10 mg amlodipine in 12 normal subjects.

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amlodipine Norvasc
Plasma atrial natriuretic peptide levels in elderly hypertensives: effects of blood pressure reduction with amlodipine.

Lennox S, Penney M, Woodhouse K.

University Department of Geriatric Medicine, Cardiff Royal Infirmary (West Wing), Newport Road, Cardiff CF2 1SZ, UK.

Atrial natriuretic peptide (ANP) is a hormone of relatively recent discovery concerned with sodium homeostasis. Increased levels of ANP are found in the elderly and in hypertensives, but the mechanisms for this are unclear. This study determined the effect of amlodipine, a calcium antagonist, which is the only class of antihypertensive agent that has little or no influence on the renin-angiotensin system (Bauer and Reams, 1988) on plasma ANP in a group of 18 elderly hypertensives and a placebo (vit B complex) on a further group of 6 elderly hypertensives. The mean pre-treatment plasma ANP was 62.7 pg/ml (range 18-148.7 pg/ml) and 52.0 pg/ml (range 15.0-148.4 pg/ml) after treatment with amlodipine (not statistically significant). However, systolic blood pressure fell from a mean of 181.6 mmHg to 151.1 mmHg and diastolic blood pressure fell from a mean of 101.6 mmHg to 83.6 mmHg after treatment with amlodipine ( [Formula: see text] ). In the group treated with vit B complex, the mean plasma ANP level was 68.4 pg/ml (range 31.4-119.5 pg/ml) before treatment and 63.6 pg/ml (range 29.2-127.3 pg/ml) after treatment. This was not statistically significant and there was no significant change in blood pressure. These findings reinforce the theory that raised plasma ANP levels found in elderly hypertensives are a function of the aging process itself or of age-related physiological changes rather than the result of hypertension.

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amlodipine Norvasc
Influence of serum cholesterol on atherogenesis and intimal hyperplasia after angioplasty: inhibition by amlodipine.

Kahn MB, Boesze-Battaglia K, Stepp DW, Petrov A, Huang Y, Mason RP, Tulenko TN.

Department of Surgery, Thomas Jefferson University College of Medicine, Philadelphia, Pennsylvania 19107, USA.

The objectives of the present study were to determine whether serum hypercholesterolemia (HC) promotes the development of spontaneous and angioplasty-induced lesions and whether amlodipine inhibits these lesions and cellular processes underlying their genesis. Rabbits were fed normal, 0.5%, or 2% cholesterol diets for 9 wk, which resulted in the development of increasing HC. After week one, balloon dilation of the abdominal aorta was performed while the thoracic aorta was not disturbed and monitored for the development of spontaneous lesions. Lesion size increased with the degree of HC and was accompanied by increased collagen synthesis and smooth muscle cell (SMC) proliferation at each site. Amlodipine (5 mg/kg p.o.) inhibited lesion size by 50% (P < 0.01) at both sites in cholesterol-fed animals but not at angioplasty sites in animals on a normal diet. Local collagen synthesis was inhibited at both sites by amlodipine in the diet animals. The increase in HC was accompanied by a 1.7-fold increase in basal Ca2+ uptake in SMCs in the thoracic aorta, which was not altered by amlodipine, nifedipine, Ni2+, or La3+, revealing an uninhibitable calcium leak during atherogenesis. In culture, cholesterol enrichment increased SMC proliferation, collagen synthesis, and the secretion of a soluble SMC mitogen, which were inhibited by amlodipine (10(-9) M). Finally, in SMC membranes, amlodipine uniquely restored the cholesterol-expanded membrane bilayer width without any effect on membrane fluidity. This study establishes a causal role between serum HC and the development of spontaneous and angioplasty-induced lesions and the ability of amlodipine to disrupt this action by a novel remodelling action on the SMC membrane.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15388506&dopt=Abstract amlodipine Norvasc