amlodipine Norvasc
Using administrative data to compare the relative effectiveness of amlodipine vs nifedipine CC.

Lenert LA, Linde-Zwirble W, Newbold R 3rd, Korenblat BM, Doherty J, Smith ME.

Health Services Research and Development, Veterans Affairs San Diego Healthcare System, and the University of California, San Diego, CA, USA. llenert ucsd.edu

OBJECTIVE: To describe an approach for using claims data to compare the effectiveness of 2 similar drugs used for similar indications within a health maintenance organization. STUDY DESIGN: A database study comparing the effectiveness of amlodipine and nifedipine CC in the initial treatment of hypertension. PATIENTS AND METHODS: The claims records of Pennsylvania Medicaid patients between 18 and 64 years of age with continuous eligibility in 1994 were studied. Pharmacy, hospital, and outpatient claims data were merged, and adult patients receiving the target drugs for the specified indication were identified. The effectiveness of the 2 agents used were compared based on the concept that a change in dispensed medication suggested either an adverse event or lack of effectiveness. Adherence rates, adverse events, and pharmacy and nonpharmacy costs associated with the 2 agents were also compared. RESULTS: Patients receiving amlodipine and nifedipine CC as initial treatment for hypertension had similar demographic characteristics and numbers of comorbid conditions. More patients started on nifedipine CC switched to another calcium channel blocker (15.8% for nifedipine CC vs 10.3% for amlodipine). More patients started on amlodipine switched to another class of antihypertensive agent (13.2% for amlodipine vs 7.3% for nifedipine CC). Patients in both groups received adjunctive antihypertensive drugs at a similar frequency (35% for nifedipine CC vs 42%, for amlodipine). Rates of adherence were similar. In adherent patients, there was no difference in rates of reported adverse events. The nonpharmacy costs were similar between groups. Patients in the amlodipine group also had a trend toward higher overall pharmacy charges (all medications) and higher charges for antihypertensive medications other than the study drugs ($302 vs $188, P = .054). CONCLUSIONS: Claims data are often the best available evidence for comparing the effectiveness of pharmaceuticals in real clinical practice. While these comparisons have inherent limitations, the accuracy of the assessment can be maximized by limiting the assessment to agents with the same specific indications. Other important elements include comparison of crossover rates to other pharmaceuticals in the same class; rates of addition of other pharmaceuticals in the same class, adherence, adverse events, and overall healthcare charges.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11066620&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of Ca2+ antagonists on motor activity and the dopaminergic system in aged mice.

Kurosaki R, Akasaka M, Michimata M, Matsubara M, Imai Y, Araki T.

Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Science and Medicine, Aoba-yama, Aoba-ku, Sendai 980-8578, Japan.

We investigated the effects of the Ca(2+) antagonist nilvadipine on the dopaminergic system and motor activity in aged mice, in comparison with an other Ca(2+) antagonist, amlodipine. Furthermore, we examined the close correlation between the dopaminergic system and motor activity during the aging process. Striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents were measured in 2-, 4-, 8-, 18- and 36-week-old mice. Behavioral tests (pole and catalepsy test) were performed with 4- and 36-week-old mice. Nilvadipine or amlodipine was administered intraperitoneally twice a day for 3 consecutive days to 30-36-week-old mice. The striatal dopamine, DOPAC and HVA contents were examined and behavioral tests were performed 1h after the last injection of each Ca(2+) antagonist. The dopamine, DOPAC and HVA contents in 2-week-old mice were significantly decreased in the striatum, as compared with 4-week-old animals. Thereafter, age-related increases in the dopamine, DOPAC and HVA contents were observed from 4 to 18 weeks old. However, in 36-week-old mice, the dopamine and DOPAC contents were reduced in the striatum, as compared with 18-week-old animals. Age-related decreases in motor function between 5- and 36-week-old mice were observed in both pole test and catalepsy tests. On the other hand, nilvalipine treatment produced a significant and dose-dependent increase in the striatal dopamine and DOPAC contents in 30-36-week-old mice. In contrast, no significant changes were observed in the striatal dopamine content in amlodipine-treated mice, although this drug showed a significant and dose-dependent increase in the striatal DOPAC and HVA content. In our behavioral study, nilvadipine also showed a significant and dose-dependent inhibition against motor deficits in 30-36-week-old mice. In contrast, amlodipine showed no significant effect on motor deficits in 30-36-week-old mice.The present study demonstrated that nilvadipine has a protective effect against the deficits in both the striatal dopaminergic system and motor activity in aged mice. Our study also suggested that the beneficial effect of nilvadipine against motor abnormalities may be mediated by a protective effect against the reduced activity of the dopaminergic system in aged mice. These results suggested that nilvadipine may offer a new approach for the treatment of hypobulia in aged humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12498965&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine increases nitric oxide synthesis in cytokine-stimulated cultured vascualar smooth muscle cells.

Ikeda U, Shimpo M, Ohki R, Takahashi M, Yamamoto K, Ikeda M, Minota S, Shimada K.

Department of Cardiology, Jichi Medical School, Utsunomiya University, Tochigi, Japan. uikeda jichi.ac.jp

OBJECTIVE: If calcium channel blockers affect nitric oxide synthesis in the vascular tissue, they could influence disease progression in coronary arteries. We investigated the effects of the calcium channel blocker amlodipine on nitric oxide synthesis by measuring the production of nitrite, a stable metabolite of nitric oxide, in vascular smooth muscle cells. METHODS: We measured the production of nitrate in cultured rat vascular smooth muscle cells with the Griess reagent Inducible nitric oxide synthase protein and mRNA expression were assayed by Western blotting and reverse transcription-polymerase chain reaction, respectively. The levels of NF-kappaB proteins in nuclear extracts were analyzed by gel retardation assay. RESULTS: Incubation of cultures with interleukin-1 , (10 ng/ ml) for 24 h caused a significant increase in nitrite generation. Interleukin-1 l-induced nitrite production by vascular smooth muscle cells was significantly increased by amlodipine in a dose-dependent manner. This augmentative effect of amlodipine was completely abolished in the presence of N(G)-monomethyl-L-arginine or actinomycin D. Amlodipine-induced nitrite production was accompanied by increased inducible nitric oxide synthase mRNA and protein accumulation. Interleukin-1 , induced NF-kappaB activation in vascular smooth muscle cells, and addition of amlodipine further increased this NF-kappaB activation. The effect of amlodipine on nitrite production was maintained in the presence of the calcium channel agonist Bay K 8644. CONCLUSION: Amlodipine enhances nitric oxide synthesis in cytokine-stimulated cultured vascular smooth muscle cells by L-type calcium channel-independent mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11081772&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Calcium channel blockers reduce blood pressure in part by inhibiting vascular smooth muscle carbonic anhydrase I.

Puscas L, Gilau L, Coltau M, Pasca R, Domuta G, Baican M, Hecht A.

University of Medicine Oradea, Romania. ccam teli.netcompsj.ro

Calcium channel blockers are a group of drugs used for the treatment of hypertension. Carbonic anhydrase (CA) I detected in vascular smooth muscle and in other cells in the organism has a major role in the acid-base balance and in vascular processes. Our previous work has proven that verapamil inhibits CA activity by a direct mechanism of action. Starting from our results in this article we studied in vitro and in vivo the effect of calcium channel blockers (verapamil and amlodipine) on erythrocyte CA I, on vascular smooth muscles CA I, and on arterial blood pressure values in human and in animals. Our in vitro and in vivo results have proved that verapamil and amlodipine are strong CA I inhibitors both in human erythrocytes and also in vascular smooth muscles in animals. In humans, calcium channel blockers studied here progressively reduce arterial blood pressure in hypertensive subjects, in parallel with progressive lowering of erythrocyte CA I activity in the normal range in normotensive subjects. From our point of view verapamil and amlodipine possess a dual mechanism of action: the first well-known action consists of their action on calcium channels. The second mechanism, suggested by us, directly acts on the vascular smooth muscle CA I isozyme, so that its inhibition should ensure an adequate pH for calcium ions transport through the channels, having as result vasodilation. This double mechanism could explain the hypotensive effect of verapamil and amlodipine, with a mechanism that partially dependent on CA I inhibition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11101200&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine.

Loke KE, Messina EJ, Shesely EG, Kaley G, Hintze TH.

Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.

OBJECTIVES: Our aim was to investigate the potential therapeutic role of endothelial nitric oxide synthase (eNOS) in the modulation of cardiac O(2) consumption induced by the angiotensin converting enzyme (ACE) inhibitor ramiprilat and amlodipine. METHODS: Three different groups of mice were used; wild type, wild type in the presence of N-nitro-L-arginine methyl ester (L-NAME, 10(-4) mol/l) or genetically altered mice lacking the eNOS gene (eNOS -/-). Myocardial O(2) consumption was measured using a Clark-type O(2) electrode in an air-tight stirred bath. Concentration-response curves to ramiprilat (RAM), amlodipine (AMLO), diltiazem (DIL), carbachol (CCL), substance P (SP) and S-nitroso-N-acetyl-penicillamine (SNAP) were performed. The rate of decrease in O(2) concentration was expressed as a percentage of the baseline. RESULTS: Baseline O(2) consumption was not different between the three groups of mice. In tissues from wild type mice, RAM (10(-5) mol/l), AMLO (10(-5) mol/l), DIL (10(-4) mol/l), CCL (10(-4) mol/l), SP (10(-7) mol/l) and SNAP (10(-4) mol/l) reduced myocardial O(2) consumption by -32+/-4, -27+/-10, -20+/-6, -25+/-2, -22+/-4 and -42+/-4%, respectively. The responses to RAM, AMLO, CCL and SP were absent in tissues taken from eNOS -/- mice (-7.1+/-4.3, -5.0+/-6.0, -5.2+/-5.1 and -0.4+/-0.2%, respectively). In addition, L-NAME significantly (P<0.05) inhibited the reduction in O(2) consumption induced by RAM (-9.8+/-4.4%), AMLO (-1.0+/-6.0%), CCL (-8.8+/-3.7%) and SP (-6.6+/-4.9%) in cardiac tissues from wild type mice. In contrast, NO-independent responses to the calcium channel antagonist, DIL, and responses to the NO donor, SNAP, were not affected in cardiac tissues taken from eNOS -/- (DIL: -20+/-4%; SNAP: -46+/-6%) or L-NAME-treated (DIL: -17+/-2%; SNAP: -33+/-5%) mice. CONCLUSIONS: These results suggest that endogenous endothelial NO synthase derived NO serves an important role in the regulation of myocardial O(2) consumption. This action may contribute to the therapeutic action of ACE inhibitors and amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11121799&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Ameliorating effects of amlodipine on plasma and myocardial catecholamines in BIO 53.58 Syrian hamsters, a model of dilated cardiomyopathy.

Yamada S, Urayama A, Kimura R, Watanabe H, Ohashi K.

Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan. yamada ys7.u-shizuoka-ken.ac.jp

Our previous study has shown that the concentrations of norepinephrine, epinephrine and dopamine in the plasma of BIO 53.58 hamsters (a model of dilated cardiomyopathy: DCM) at 18 weeks of age (severe cardiomyopathic stage) were twice those of age-matched F1B control and conversely the myocardial norepinephrine level was decreased. The present study was undertaken to examine the effect of amlodipine on catecholamine concentration, myocardial receptors and histopathological changes in BIO 53.58 hamsters. Oral administration of amlodipine (10 mg/kg/day) for 7 weeks in 11 week-old-BIO 53.58 hamsters brought about marked decreases in the concentrations of norepinephrine, epinephrine and dopamine in the plasma, compared with those in vehicle-treated BIO 53.58 hamsters. This was accompanied by a concomitant increase in the concentration of myocardial catecholamine concentration. In other words, the concentrations of catecholamines in plasma and myocardium of amlodipine administered BIO 53.58 hamsters approximated to the control level in age-matched F1B. In addition, amlodipine administration caused a significant reduction of calcium deposition with a tendency toward a decrease in the myocardial necrosis, and it had little effect on the affinity and number of specific binding for (+)-[3H]PN 200-110, (-)-[125I]iodocyanopindolol (CYP) and [3H]prazosin in the myocardium. In conclusion, the present study shows that administration of amlodipine in BIO 53.58 hamsters may exhibit ameliorating effect on plasma and myocardial catecholamines with a significant reduction of calcium deposition. These data may offer further support for the use of amlodipine in patients with DCM.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11125842&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of long-term treatment with calcium antagonists on periarterial nerve function in the mesenteric artery of spontaneously hypertensive rats.

Nakatsuma A, Kawasaki H, Kurosaki Y, Futagami K, Araki H, Gomita Y.

Department of Clinical Pharmaceutical Science, Graduate School of Natural Science and Technology, Okayama University, Japan.

The effect of long-term treatment with dihydropyridine calcium antagonists (amlodipine, pranidipine, nicardipine) on the periarterial nerve function was investigated in the perfused mesenteric vascular bed isolated from spontaneously hypertensive rat (SHR). Male 8-week-old SHR received amlodipine (0.01% and 0.02%) and nicardipine (0.1%) in drinking water and pranidipine (0.0035% and 0.035%) in rat chow for 7 weeks. Mean blood pressure in SHR was significantly lowered by long-term treatment with each calcium antagonist. In mesenteric vascular preparations treated with each calcium antagonist, vasoconstriction induced by periarterial nerve stimulation (PNS; 4, 8 and 12 Hz) was significantly smaller than that in non-treated SHR. The PNS (8 Hz)-evoked norepinephrine (NE) overflow in the perfusate was significantly decreased by amlodipine and pranidipine treatment, whereas nicardipine-treatment significantly enhanced the overflow of NE. In preparations with active tone produced by methoxamine and guanethidine, the PNS-induced vasodilation mediated by calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves was not affected by these drugs. These results suggest that long-term treatment of SHR with long-acting drugs, amlodipine and pranidipine, reduces sympathetic adrenergic nerve function but calcium antagonists have no effect on CGRPergic nerve function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11128038&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Reduction of blood pressure variability by amlodipine in baroreceptor denervated rats.

Van Vliet BN, Chafe LL.

Faculty of Medicine, Memorial University of Newfoundland, St John's, Canada.

To determine the effect of the calcium blocker amlodipine on the variability of mean arterial pressure (MAP), amlodipine besylate was acutely administered to sino-aortic baroreceptor-denervated (SAD) rats (0, 1, 3, 10 mg/kg s.c.), and chronically administered to SAD and sham-denervated rats (0, 50, 150, 500, and 1,500 mg x kg(-1) feed, 4 days per dose). Acute amlodipine administration caused significant dose-dependent reductions of the mean MAP level and short-term MAP variability at the 3 and 10 mg/kg dose levels, respectively. Chronic administration produced dose-dependent reductions in short-term MAP variability, becoming significant at the 150 and 500 mg x kg(-1) feed dose level in SAD and Sham groups, respectively. Day-night differences in blood pressure were significantly attenuated or reversed at the 500 and 1,500 mg x kg(-1) feed dose levels. Amlodipine had little or no effect upon the 24 h MAP level, long-term MAP variability, and only modestly reduced the MAP response to hexamethonium. These results demonstrate that amlodipine can reduce MAP variability independent of changes in the mean blood pressure level.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11131042&dopt=Abstract amlodipine Norvasc