amlodipine Norvasc
Novel anti-inflammatory actions of amlodipine in a rat model of arteriosclerosis induced by long-term inhibition of nitric oxide synthesis.

Kataoka C, Egashira K, Ishibashi M, Inoue S, Ni W, Hiasa K, Kitamoto S, Usui M, Takeshita A.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Amlodipine (a new class of calcium channel antagonist) has been shown to limit the progression of arteriosclerosis and decrease the incidence of cardiovascular events. The mechanisms underlying the beneficial effects of amlodipine, however, remain unclear. Therefore, we hypothesized that amlodipine attenuates the development of arteriosclerosis through the inhibition of inflammation in vivo. Long-term inhibition of nitric oxide (NO) by administration of a NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), to rats induces coronary vascular inflammation [monocyte infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, increased activity of angiotensin-converting enzyme (ACE)], and arteriosclerosis. Here, we used the rat model to investigate the anti-inflammatory effects of amlodipine in vivo. Treatment with amlodipine markedly inhibited the L-NAME-induced increase in vascular inflammation, oxidative stress, and local ACE and Rho activity and prevented arteriosclerosis. Interestingly, amlodipine prevented the L-NAME-induced increase in MCP-1 receptor CCR2 expression in circulating monocytes. Amlodipine markedly attenuated the high mortality rate at 8 wk of treatment. These data suggest that amlodipine attenuated arteriosclerosis through inhibiting inflammatory disorders in the rat model of long-term inhibition of NO synthesis. The anti-inflammatory effects of amlodipine seem to be mediated not only by the inhibition of local factors such as MCP-1 but also by the decrease in CCR2 in circulating monocytes. Inhibition of the MCP-1 to CCR2 pathway may represent novel anti-inflammatory actions of amlodipine beyond blood pressure lowering.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14592942&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
[Reperfusion syndrome after direct myocardial revascularization on beating heart in patients with ischemic heart disease. Possibilities of prevention with amlodipine]

[Article in Russian]

Tepliakov AT, Dzhavadova GK, Akhmedov ShD, Kandinskii ML, Vesnina ZhV.

Research Insitute of Cardiology of the Research Centre of RAMS Siberian Branch, ul. Kievskaya 111, 634012 Tomsk, Russia.

Possibilities of secondary prevention of reperfusion syndrome with amlodipine was assessed in 46 patients (39 with class III-IV angina after myocardial infarction and 7 with non ST elevation acute coronary syndrome). Twenty six patients received basic therapy, in 20 patients this therapy was supplemented with amlodipine (5-10 mg/day). In all patients complete direct arterial myocardial revascularization on beating heart was carried out. Methods of dynamic control included echocardiography, paired bicycle exercise tests, 6 minute walk test, myocardial scintigraphy with thallium-199. The results evidence for efficacy and feasibility of secondary prevention of reversible myocardial dysfunction with amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14593355&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Exploring the methodological challenges of investigating comparison groups with different underlying characteristics: a case study.

Arocho R, Solis A, Wade S, Goldberg G, Tang S.

Clinical Practice Outcomes Research, Pfizer Inc., Madrid, Spain.

OBJECTIVE: To examine challenges in forming accurate conclusions from claims data when comparing different patient groups, and to stress the need to adjust for confounding variables through application of statistical methods. METHODS: Patients who were 60 or older and began amlodipine or felodipine in 1997 or 1998 were identified from a proprietary managed care claims database. Patients had 6 months of medical and outpatient pharmacy benefits coverage before and after initiating therapy. They were stratified on varying degrees of hypertension severity and on all-condition clinical complexity, and quantified with a proprietary Burden of Illness (BOI) score, defined as the expected resource use for the patient.s combined conditions during the 6 months before therapy. RESULTS: Of the 17,667 patients, 10,469 (59.3%) were female. The 12,389 amlodipine users were similar in age to felodipine users (n=5,278), 73 versus 74, respectively. More amlodipine users were assigned to the 2 most clinically complex quintiles of the BOI distribution (45.5% to 26.9%), with 24.3% of patients in the top quintile (9.7% for felodipine) and twice the prevalence of ischemic heart disease/angina (42.4% versus 19.4%). High-severity hypertension was found among 33.6% of amlodipine users, contrasted with 17.9% for felodipine. A significant difference in the mean average daily dose (ADD) between the amlodipine (5.93 mg) and felodipine (5.8 mg) groups (P=0.0007) was noted. CONCLUSION: These results stress the importance of assessing the impact of potentially confounding variables and the need to address differing patient characteristics through either risk adjustment or stratification in making head-to-head comparisons.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14613401&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Patient adherence with amlodipine, lisinopril, or valsartan therapy in a usual-care setting.

Wogen J, Kreilick CA, Livornese RC, Yokoyama K, Frech F.

The Institute for Effectiveness Research, LLC, 520 U.S. Highway 22, Suite 303, Bridgewater, NJ 08807, USA.

OBJECTIVE: To compare the persistence and compliance in a usual-care setting with 3 drugs (amlodipine, lisinopril, or valsartan) from 3 different pharmaceutical classes.calcium-channel blocker, angiotensin-converting enzyme inhibitor, and angiotensin receptor blocker, respectively, commonly used to treat hypertension. METHODS: This retrospective observational study included a cohort of 142,945 continuously benefit-eligible patients from a pharmacy benefit manager drug claims database who began therapy with lisinopril, valsartan, or amlodipine. Concurrent use of other cardiovascular medications was assessed as a proxy for cardiovascular disease severity. Chronic Disease Score (CDS), derived from pharmacy claims data, was used to classify patient chronic disease burden as mild, moderate, or severe. Drug utilization measures included compliance, persistence, medication possession ratio (MPR), duration of therapy, and drug discontinuation. Multiple linear regression techniques were used to assess the impact of various predictor variables on study outcomes and to compare compliance among treatment groups, adjusted for age, gender, and CDS. RESULTS: The mean age of the study cohort was 63.1 years; 53% were female. Just over one half (51%, n=73,148) received amlodipine, 28% (n=40,238) received lisinopril, and 21% (n=29,669) received valsartan. Significantly more valsartan patients (63%) remained persistent on therapy at 12 months past the index date of the first prescription, compared with amlodipine (53%) and lisinopril (50%) patients (P<0.001). Both crude and adjusted compliance rates also were greatest for valsartan patients, reflected by an adjusted mean MPR of 75%, compared with 67% for amlodipine and 65% for lisinopril (P<0.0001, both comparisons). CONCLUSION: These results suggest that, in a usual-care setting, patients receiving valsartan (relative to amlodipine or lisinopril) appear to be more compliant and persistent with pharmacologic therapy, independent of patient chronic disease burden.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14613440&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Evaluation of a therapeutic conversion from amlodipine to felodipine.

Manzo BA, Matalka MS, Ravnan SL.

Department of Pharmacy Practice, Thomas J. Long, School of Pharmacy and Health Sciences, University of the Pacific, Stockton, California 95211, USA.

STUDY OBJECTIVES: To determine patient satisfaction with and tolerability of a conversion from a long-acting calcium channel blocker, amlodipine, to felodipine. Secondary objectives were to compare the effect of the change on blood pressure and heart rate and the economic impact of the change. DESIGN: Retrospective study. SETTING: Veterans Affairs health care system. PATIENTS: Two hundred eighty-three men who were taking amlodipine to manage hypertension. INTERVENTION: Patients who were converted to felodipine were mailed a survey quantifying subjective symptoms; the survey also included questions specific to the change program. Transitory blood pressure and heart rate measurements retrieved by electronic chart review were evaluated during therapy with both amlodipine and felodipine. MEASUREMENTS AND MAIN RESULTS: Ninety-five percent of patients were satisfied with the conversion process and tolerated the switch from amlodipine to felodipine. Mean systolic and diastolic blood pressures were reduced by 4.4 and 2.6 mm Hg, respectively (p=0.166 and 0.187, respectively). Heart rate was reduced significantly by 4.2 beats/minute (p=0.008). The conversion realized a net annual drug cost savings of approximately dollars 16,000. CONCLUSION: Our patient population was satisfied with the conversion from amlodipine to felodipine, and the new drug was found to be effective, well tolerated, and associated with a modest cost reduction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14620396&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
A calcium channel blocker activates both ecto-5(')-nucleotidase and NO synthase in HUVEC.

Asano Y, Kim J, Ogai A, Takashima S, Shintani Y, Minamino T, Kitamura S, Tomoike H, Hori M, Kitakaze M.

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan. asano medone.med.osaka-u.ac.jp

Since amlodipine, a long-acting Ca channel blocker, increases both NO and adenosine production in canine hearts, we investigated that amlodipine activates both ecto-5(')-nucleotidase responsible for adenosine production and NO synthase (NOS) for NO production in human umbilical venous endothelial cells (HUVECs), and its cellular signaling. We measured activities of ecto-5(')-nucleotidase and NOS in HUVECs in the condition with additions of xanthine (100 microM)+xanthine oxidase (1.6 x 10(-3)U/ml) in the presence or absence of amlodipine (1 x 10(-9)-1 x 10(-6)M). Amlodipine increased both ecto-5(')-nucleotidase and NOS activities. Xanthine+xanthine oxidase deactivated both NOS and ecto-5(')-nucleotidase, and amlodipine increased both activities of NOS and ecto-5(')-nucleotidase by 117+/-33% and 48+/-6%, respectively. Amlodipine phosphorylated p38MAP kinase and that an inhibitor of p38MAP kinase inhibited the amlodipine-induced activation of both NOS and ecto-5(')-nucleotidase. Furthermore, amlodipine increased both adenosine and NO production in the canine ischemic hearts. We concluded that amlodipine activates both NOS and ecto-5(')-nucleotidase via p38MAP kinase in vitro and enhances both NO and adenosine production in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14623316&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Edaravone, a radical scavenger, may enhance or produce antiproliferative effects of fluvastatin, amlodipine, ozagrel, GF109203X and Y27632 on cultured basilar artery smooth muscle cells.

Yamaguchi T, Oishi K, Uchida M, Echizen H.

Departments of Hospital Pharmacy, Nakano General Hospital, Tokyo, Japan. nghph nakanosogo.or.jp

Proliferation of vascular smooth muscle cells stimulated by reactive oxygen species (ROS) may play a pivotal role in the pathogenesis of atherosclerosis. To clarify mechanisms by which ROS promote vascular atherogenesis, effects of fluvastatin, amlodipine, ozagrel (thromboxane synthetase inhibitor), GF109203X (a protein kinase C inhibitor) and Y27632 (a ROCK inhibitor) on the proliferation of guinea-pig basilar artery smooth muscle cells (GBa-SM3) in a 5% FBS culture medium were studied over 3 d in the presence or absence of a free radical scavenger, edaravone. Viability of cells at the end of incubation was measured by the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test. Results demonstrated that fluvastatin and amlodipine by themselves possess antiproliferative effects on the GBa-SM3 cells at 10-100 microM and 0.1-1 microM, respectively. While edaravone possessed no antiproliferative effect by itself at 100 microM, it significantly (p<0.05) augmented the antiproliferative effects of fluvastatin and amlodipine. In addition, ozagrel, GF109203X and Y27632 possessed no appreciable effects on the cell growth by themselves. However, coincubation of edaravone at 100 microM with these agents elicited significant antiproliferative effects for ozagrel, GF109203X and Y27632 at 10-100 microM, 1-10 microM and 0.1-1 microM, respectively. In conclusion, edaravone may have clinically beneficial interactions with fluvastatin, amlodipine and ozagrel regarding the prevention of vascular atherosclerosis. The interactions between edaravone and the inhibitors of protein kinase C and ROCK were suggestive of possible contributions of ROS-triggered intracellular signals associated with these enzymes to vascular atherogenesis, but further studies are required for confirmation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14646175&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine increases endothelial nitric oxide by dual mechanisms.

Berkels R, Taubert D, Bartels H, Breitenbach T, Klaus W, Roesen R.

Institut fur Pharmakologie, Klinikum der Universitat zu Koln, Cologne, Germany. Reinhard.Berkels medizin.uni-koeln.de

Several experimental and clinical studies have demonstrated the antiatherogenic profile of the long-acting calcium antagonist amlodipine. Given the pivotal role of endothelial (dys)function during atherogenesis, we investigated the influence of amlodipine on endothelial nitric oxide (NO) bioavailability. Acute addition of amlodipine to segments of porcine coronary arteries resulted in a significant increase in NO release which could be blocked by the NO synthase inhibitor L-NMMA (N-monomethylarginine). This effect was mirrored by a rise in intracellular cGMP levels in porcine endothelial cell cultures. Long-term (24 h) treatment of porcine endothelial cell cultures with amlodipine (0.1-10 micromol/l) significantly enhanced the basal NO formation in a concentration-dependent manner which was abrogated in the presence of L-NMMA (0.1 mmol/l). In EA.hy 926 endothelial cells, amlodipine treatment for 24 h significantly increased the endothelial NO synthase protein expression. To evaluate whether the observed increase in NO was additionally due to an antioxidative protection of NO, we examined the influence of amlodipine in different in vitro models. In a cell-free system, amlodipine quenched superoxide anions (hypoxanthine/xanthine oxidase assay) at high concentrations (150 micromol/l). Addition of artificial membrane preparations (dimyristoylphosphatidylcholine) to mimic a physiological environment significantly enhanced this antioxidative effect. In a more physiological model of hyperglycemia (30 mmol/l, 20 min) induced formation of reactive oxygen species from native endothelial cells of porcine coronary arteries, amlodipine concentration dependently attenuated the reactive oxygen species release (>60%; 10 micromol/l). We conclude, that amlodipine increases the endothelial NO bioavailability, firstly via enhanced NO formation and secondly by prolonging the half-life of NO through antioxidative properties. This may result in an improved endothelial function. Copyright 2004 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14646355&dopt=Abstract amlodipine Norvasc