amlodipine Norvasc
Amlodipine versus diltiazem CR in the reduction of the total ischemic burden: the Circadian Anti-Ischemia Program in Europe (CAPE) II trial--clinical rationale and methodology.

Deanfield JE.

Great Ormond Street Hospital for Children, London, England, UK.

The Circadian Anti-ischemia Program in Europe (CAPE) trial was a large, 10-week, double-blind study of the antiischemic effects of the third-generation calcium antagonist, amlodipine, in patients with chronic stable angina. The study showed that, compared with the addition of placebo to conventional medical therapy (if any), the addition of amlodipine significantly reduced the total ischemic burden. Both symptomatic and asymptomatic ischemic events were reduced, over 24 hours, with no change in the heart rate profile. The next logical step is to compare amlodipine with other agents, as monotherapy and in combination therapy, which is the basis for the CAPE II trial. This European multicenter project will recruit patients with coronary artery disease and chronic stable angina in order to compare the efficacy of the intrinsically long-acting amlodipine with an artificially extended-release formulation of diltiazem, a calcium antagonist with a short plasma half-life. The impact of these agents will also be compared during irregular dosing periods. An agent with an intrinsically long half-life, such as amlodipine, may maintain better clinical efficacy than a short-acting drug with a prolonged delivery system in these circumstances. The CAPE II trial will investigate whether this results in improved management of the circadian pattern of transient myocardial ischemia. In addition, basic therapy will be augmented by the addition of a beta-blocker to amlodipine and the addition of a nitrate to diltiazem to evaluate which of these frequently prescribed treatment approaches results in optimal ischemia suppression. Both the subjective endpoints of angina and patient well-being, as well as the objective measures of myocardial ischemia in exercise testing and ambulatory electrocardiography (ECG) monitoring, will be employed. Answers to these issues will help to define the optimal medical approach to ischemia suppression in patients with coronary artery disease and will complement the findings from large-scale prognosis trials currently being performed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9800053&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effect of amlodipine on the growth of vascular smooth muscle cells of spontaneously hypertensive rats.

Tang J, Liu Z, Ren D, Wu C.

Department of Cardiology, Tongji Hospital, Tongji Medical University, Wuhan.

The effect of anti-hypertensive drug amlodipine on regression of cardiovascular hypertrophy due to hypertension was studied by using cultured smooth muscle cells derived from arteries of spontaneously hypertensive rats (SHR) and measuring [3H]-TdR and [3H]-Leucine binding. 48 h after adding amlodipine, [3H]-TdR binding in arterial smooth muscle cells from SHR in vitro was reduced by 50.5% and [3H]-Leucine binding was reduced by 56.2% as compared with neuropeptide Y (NPY)-treated group. However, there was no significant change in cell number. The results showed that amlodipine could effectively inhibit increase of DNA and protein synthesis of vascular smooth muscle cell (VSMC) due to NPY. It indicates that amlodipine is of great significance on regression of genesis and development of cardiovascular hypertrophy due to hypertension.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9812770&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effect of nilvadipine on the voltage-dependent Ca2+ channels in rat hippocampal CA1 pyramidal neurons.

Ishibashi H, Murai Y, Akaike N.

Department of Physiology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.

Effects of nilvadipine on the low- and high-voltage activated Ca2+ currents (LVA and HVA ICa, respectively) were compared with other organic Ca2+ antagonists in acutely dissociated rat hippocampal CA1 pyramidal neurons. The inhibitory effects of nilvadipine, amlodipine and flunarizine on LVA ICa were concentration- and use-dependent. The apparent half-maximum inhibitory concentrations (IC50s) at every 1- and 30-s stimulation were 6.3x10-7 M and 1.8x10-6 M for flunarizine, 1.9x10-6 M and 7.6x10-6 M for nilvadipine, and 4.0x10-6 M and 8.0x10-6 M for amlodipine, respectively. Thus, the strength of the use-dependence was in the sequence of nilvadipine>flunarizine>amlodipine. Nilvadipine also inhibited the HVA ICa in a concentration-dependent manner with an IC50 of 1.5x10-7 M. The hippocampal CA1 neurons were observed to have five pharmacologically distinct HVA Ca2+ channel subtypes consisting of L-, N-, P-, Q- and R-types. Nilvadipine selectively inhibited the L-type Ca2+ channel current which comprised 34% of the total HVA ICa. On the other hand, amlodipine non-selectively inhibited the HVA Ca2+ channel subtypes. These results suggest that the inhibitory effect of nilvadipine on the neuronal Ca2+ influx through both LVA and HVA L-type Ca2+ channels, in combination with the cerebral vasodilatory action, may prevent neuronal damage during ischemia. Copyright 1998 Published by Elsevier Science B.V.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9824683&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The protective action of amlodipine on cardiac negative inotropism caused by prolonged incubation in vitro.

Bravo G, Hong E, Larios F.

Departamento de Farmacologia y Toxicologia, CINVESTAV-IPN, Mexico, D.F. Mexico.

The mechanism of the antihypertensive action of the 1,4-dihydropyridine Ca2+ antagonist amlodipine was studied in isolated ventricular strips and aortic rings from Wistar rats after oral treatment with amlodipine 15 mg/kg/day for one week. The contractions evoked by electrical stimulation of isolated strips from right ventricles pretreated with amlodipine (5 nM) were unaffected during the first hour after mounting, but they decreased in magnitude after prolonged incubation (4 hr). However, the decrease in response of these preparations after prolonged incubation was less than that observed in strips prepared from untreated rats. A negative inotropic effect of amlodipine was observed at concentrations higher than 300 nM. In the presence of lower concentrations of amlodipine (5 nM-30 nM) after prolonged incubation, the contractions of ventricular strips were significantly more sustained than in the absence of amlodipine. Likewise, the decrease in contractility evoked by increasing the stimulation frequency from 1 to 3 Hz was reduced in amlodipine treated rats. The recovery of contractility was improved when stimulation frequency was returned to 1 Hz. On the other hand, when rat ventricular strips pretreated with amlodipine (5 nM) were exposed to isoprenaline (3 microM), the contractions evoked by isoprenaline were enhanced. The isoprenaline effect was not altered with 300 nM amlodipine, but with 3 microM became weak and was significantly lower than in strips treated with isoprenaline alone. In addition, treatment with amlodipine produced a marked decrease in the contractions evoked by 100 mM KCl solution in isolated aortic rings when compared to untreated rats. This inhibition was produced in a time-dependent manner with an IC50 equal to 30 and 3 nM after 2 and 45 min of contraction, respectively. Ex vivo results show that amlodipine treatment decreased aortic contractility without producing a negative inotropic effect although there was an occupation of cardiac Ca2+ channels. These results suggest that a protective effect of amlodipine on cardiac negative inotropism is produced by prolonged incubation in vitro.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9825763&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Vascular and cardiac effects of amlodipine in acute heart failure in dogs.

Isaac DL, Belenkie I, Manyari DE, Tyberg JV.

Department of Medicine, University of Calgary, Alberta. dlisaac ucalgary.ca

BACKGROUND: Amlodipine improves exercise capacity in patients with chronic congestive heart failure (HF), but the mechanisms of this effect are unknown. OBJECTIVE: To test the hypothesis, in a canine model of acute, ischemic HF, that amlodipine increases vascular capacitance and reduces cardiac filling pressures. METHODS: Amlodipine was given to 13 anesthetized, splenectomized dogs (six controls and seven with HF). Aortic, left ventricular end-diastolic (LVEDP) and portal venous (Pportal) pressures, cardiac output, portal flow (ultrasonic probe) and intestinal blood volume (IBV, 99mTc blood-pool scintigraphy) were measured. Intestinal vascular conductance (= 1/resistance) and vascular capacitance (CAP) were measured before and 15 mins after repetitive 150 micrograms/kg dosages of amlodipine (maximum cumulative dosage, 1000 micrograms/kg). Pportal-IBV curves were obtained by impeding portal flow (pneumatic cuff), and change in CAP was defined by the change in IBV at Pportal = 7.5 mmHg. HF was induced by microsphere embolization of the left coronary artery. RESULTS: CAP increased in the control group (+ 28%, P < 0.01) but decreased (-9%, P < 0.05) in the HF group. Left ventricular stroke work increased in the control group (P < 0.05), while it decreased (P < 0.05) in the HF group, suggesting a negative inotropic effect. In the control group, LVEDP increased after amlodipine was given (P < 0.05) but did not change significantly in the HF group. CONCLUSIONS: In the acute experimental HF model, amlodipine failed to increase intestinal vascular CAP or decrease filling pressures, and may have had a negative inotropic effect. The experiment failed to demonstrate a beneficial hemodynamic effect of amlodipine in acute HF, and the mechanism of benefit of this agent in chronic HF remains unclear.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9854519&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine potentiates metalloproteinase activity and accelerates elastin degradation in a model of aneurysmal disease.

Boyle JR, Loftus IM, Goodall S, Crowther M, Bell PR, Thompson MM.

Department of Surgery, Leicester University, U.K.

AIMS: Abdominal aortic aneurysms are characterised by changes in the extracellular matrix of the arterial media, in particular a reduction in elastin concentration. These changes are mediated by increased levels of endogenous matrix metalloproteinases (MMPs). Recently, calcium channel blockers have been shown to increase the proteolytic activity of MMP-2 secreted by vascular smooth muscle cells. It may therefore by hypothesised that calcium antagonists may potentiate the activity of MMPs in aneurysmal disease and thus accelerate AAA expansion. In this study, the ability of amlodipine--a calcium antagonist--to influence elastin degradation, was assessed in a previously described model of aneurysmal disease. METHODS: Porcine aortic segments (n = 8) were pre-incubated in exogenous pancreatic elastase for 24 h prior to culture in standard conditions for 6 days with 10 and 100 micrograms/l amlodipine. Control segments were cultured both with and without amlodipine and without elastase. At the termination of culture MMPs were extracted from the tissue and quantified by a combination of substrate gel enzymography and immunoblotting. The volume fractions of elastin and collagen were determined by stereological analysis of EVG stained sections. RESULTS: Gel enzymography demonstrated significantly increased MMP-9 activity in the amlodipine treated segments, median 4.218 vs. 2.809 arbitrary units (p < 0.01) and this elevated activity was reflected in a significant destruction of medial elastin 27.0 vs. 40.5% (p < 0.05). CONCLUSION: Therapeutic ranges of amlodipine significantly enhanced elastin degradation and potentiated MMP-9 activity within the aortic organ cultures.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9854552&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Quality of life and calcium channel blockade with nifedipine GITS versus amlodipine in hypertensive patients in Spain. Gastrointestinal Therapeutic System.

Testa MA, Turner RR, Simonson DC, Krafcik MB, Calvo C, Luque-Otero M.

Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

OBJECTIVE: Compliance with hypertension treatment is affected by treatment-related factors (complexity, side effects), efficacy and compound-specific effects that impact on quality of life. This study examined the differences in quality of life produced by two once-daily calcium channel blockers using different delivery systems: nifedipine gastrointestinal therapeutic system (GITS) and amlodipine. DESIGN: This was a double-blind, double-dummy, randomized clinical trial comparing nifedipine GITS (30 mg) and amlodipine (5 mg) for 24 weeks following a placebo run-in. Clinical, laboratory evaluations and quality-of-life data were assessed at screening, baseline randomization and three times during active therapy. SETTING: The study was conducted in 13 medical clinics in Spain. PATIENTS: The sample comprised 430 screened and 356 randomized patients with mild to moderate hypertension (diastolic blood pressure 95-114 mmHg). MAIN OUTCOME MEASURES: Change in systolic and diastolic blood pressure and in health-related quality of life were the main outcome measures. RESULTS: There were no significant differences between active treatment groups in the blood pressure changes (systolic blood pressure: nifedipine GITS -15.5 mmHg; amlodipine -15.7 mmHg). Spontaneous adverse events consistent with calcium channel blockage were not different. The nifedipine GITS group improved in all quality-of-life measures except Sexual Symptom Distress and showed a significantly greater improvement than amlodipine in overall Quality of Life (P< 0.05), General Perceived Health (P < 0.026) and its subscale Vitality (P < 0.019). The amlodipine group declined in overall Quality of Life, General Perceived Health, Vitality and Sleep Disturbance, and significantly in Sexual Symptom Distress (P < 0.045). However, this group improved in self-reported Cognitive Functioning (P=0.036), Mental Acuity (P < 0.005) and Detachment/disorientation (P=0.01). CONCLUSIONS: These results suggest compound-specific effects on quality of life that may be due to differences in the delivery system. Nifedipine GITS is short-acting (2 h half-life) and is delivered continuously over a 24 h period, while amlodipine has a half-life of 40 h, which may produce more sustained low-level effects. While a more beneficial profile was observed for nifedipine, amlodipine demonstrated potential positive effects on cognitive functioning.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9869019&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Kinin-mediated coronary nitric oxide production contributes to the therapeutic action of angiotensin-converting enzyme and neutral endopeptidase inhibitors and amlodipine in the treatment in heart failure.

Zhang X, Recchia FA, Bernstein R, Xu X, Nasjletti A, Hintze TH.

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

Increasing evidence suggests that angiotensin-converting enzyme (ACE) inhibitors can increase vascular nitric oxide (NO) production. Recent studies have found that combined inhibition of ACE and neutral endopeptidase (NEP) may have a greater beneficial effect in the treatment of heart failure than inhibition of ACE alone. Amlodipine, a calcium channel antagonist, has also been reported to have a favorable effect in the treatment of patients with cardiac dysfunction. The purpose of this study was to determine whether and the extent to which all of these agents used in the treatment of heart failure stimulate vascular NO production. Heart failure was induced by rapid ventricular pacing in conscious dogs. Coronary microvessels were isolated from normal and failing dog hearts. Nitrite, the stable metabolite of NO, was measured by the Griess reaction. ACE and NEP inhibitors and amlodipine significantly increased nitrite production from coronary microvessels in both normal and failing dog hearts. However, nitrite release was reduced after heart failure. For instance, the highest concentration of enalaprilat, thiorphan, and amlodipine increased nitrite release from 85 +/- 4 to 156 +/- 9, 82 +/- 7 to 139 +/- 8, and 74 +/- 4 to 134 +/-10 pmol/mg (all *p <.01 versus control), respectively, in normal dog hearts. Nitrite release in response to the highest concentration of these two inhibitors and amlodipine was reduced by 41% and 31% and 32% (all #p <.01 versus normal), respectively, in microvessels after heart failure. The increase in nitrite induced by either ACE or NEP inhibitors or amlodipine was entirely abolished by Nw-nitro-L-arginine methyl ester, HOE 140 (a B2-kinin receptor antagonist), and dichloroisocoumarin (a serine protease inhibitor) in both groups. Our results indicate that: 1) there is an impaired endothelial NO production after pacing-induced heart failure; 2) both ACE and NEP are largely responsible for the metabolism of kinins and modulate canine coronary NO production in normal and failing heart; and 3) amlodipine releases NO even after heart failure and this may be partly responsible for the favorable effect of amlodipine in the treatment of heart failure. Thus, the restoration of reduced coronary vascular NO production may contribute to the beneficial effects of these agents in the treatment of heart failure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9918584&dopt=Abstract amlodipine Norvasc