amlodipine Norvasc
Interaction of charged and uncharged calcium channel antagonists with phospholipid membranes. Binding equilibrium, binding enthalpy, and membrane location.

Bauerle HD, Seelig J.

Department of Biophysical Chemistry, University of Basel, Switzerland.

The membrane location and the binding mechanism of two Ca2+ channel antagonists, amlodipine and nimodipine, in pure lipid membranes were investigated with deuterium and phosphorus-31 nuclear magnetic resonance, with thermodynamic methods such as high-sensitivity titration calorimetry, and by measuring the membrane surface charge via the zeta-potential. The two drugs exhibit quite different physical-chemical properties. The noncharged nimodipine is strongly hydrophobic, and selective deuteration of the lipid membrane reveals a homogeneous distribution of nimodipine across the whole hydrocarbon layer, but no interaction at the lipid headgroup level. The membrane behavior of the amiphiphilic amlodipine (electric charge z = +1) is distinctly more complex. Deuterium magnetic resonance demonstrates that amlodipine adopts a well-defined position in the bilayer membrane. In particular, the charged ethanolamine side group of amlodipine is located near the water-lipid interface, interacting with the dipoles of the headgroup region according to a nonspecific, electrostatic mechanism and inducing a reorientation of the phosphocholine dipoles toward the water phase. At the level of the hydrocarbon segment, the nonpolar ring system of amlodipine interacts specifically with the cis double bond of the membrane lipid, forming a weak association complex. With increasing amlodipine concentration the deuterium signal of the cis double bond gradually loses intensity, a phenomenon previously observed only in related studies on protein-lipid interactions. The binding equilibrium of amlodipine to phosphatidylcholine membranes was studied by measuring the electrophoretic mobility of lipid vesicles and with a centrifugation assay. Hydrophobic interactions of the nonpolar ring systems and electrostatic repulsions at the membrane surface contribute to the binding energy.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1830218&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
In vitro and in vivo potentiation of chloroquine against malaria parasites by an enantiomer of amlodipine.

Deloron P, Basco LK, Dubois B, Gaudin C, Clavier F, Le Bras J, Verdier F.

Institut National de la Sante et de la Recherche Medicale Unite 13, Claude Bernard Hospital, Paris, France.

A combination of chloroquine and amlodipine, a derivative of 1,4-dihydropyridine calcium channel blocker, was tested against Plasmodium falciparum in vitro and P. yoelii in mice. The dextrorotary enantiomer of amlodipine, practically devoid of calcium channel blocking action, increased chloroquine accumulation inside the infected mouse erythrocytes and potentiated chloroquine action against the resistant strains of P. falciparum in vitro and P. yoelii in mice. Unlike the racemate, the dextrorotary amlodipine was not toxic to the host animal, even at the highest dose of 250 mg/kg. No potentiating effect was noted in the chloroquine-susceptible strains of P. falciparum. The results of this study indicate that chloroquine potentiation of amlodipine is probably independent of calcium channels and that a combination therapy of the dextrorotary enantiomer of amlodipine and chloroquine might be a potentially useful therapeutic strategy against chloroquine-resistant falciparum malaria.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1834011&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The unique binding properties of amlodipine: a long-acting calcium antagonist.

Nayler WG, Gu XH.

Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria.

Amlodipine is a 'second generation', long-acting calcium antagonist. To characterise the binding properties of this drug saturation binding studies were undertaken using (-)[3H]amlodipine and rat cardiac membrane fragments. (-)[3H]Amlodipine bound to a single population of high affinity binding sites with a KD of 1.64 +/- 0.17 nM, a Bmax of 0.45 +/- 0.08 pmol/mg protein and a Hill coefficient approaching unity. Binding was slow and required up to 5 hours to reach asymptote during incubation at 25 degrees C. The specific binding was totally inhibited by (-)amlodipine and (-)D600 and partially inhibited by (+)PN200-110, Bay K8644, (+)D600 and d-cis diltiazem. These results indicate that (-)[3H]amlodipine interacts strongly with the phenylalkylamine as well as the dihydropyridine binding sites. It also interacts with the benzothiazepine binding sites. The inhibition of (-)[3H]amlodipine binding by D600 is stereospecific, (-) greater than (+)D600. Bound (-)[3H]amlodipine dissociated slowly from its binding sites, less than 40% dissociation occurring during 5 hours of incubation (k-1 = 1.53 x 10(-3) min-1). These results indicate that the binding profile of amlodipine differs from that of other dihydropyridine-based Ca2+ antagonists. In addition they explain its slow onset of action, and slowed recovery on withdrawal.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1834847&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Unaltered insulin sensitivity during calcium channel blockade with amlodipine.

Ferrari P, Giachino D, Weidmann P, Shaw S, Riesen W, Neuner N, Keller U, Heynen G.

Medizinische Poliklinik, University of Berne, Switzerland.

The sensitivity of peripheral tissues to insulin is of pathophysiological, therapeutic and possibly also of prognostic relevance. Calcium channel blockers are widely used in the treatment of cardiovascular disorders that are commonly associated with decreased insulin sensitivity (SI). To evaluate the effects of calcium channel blokkade on SI, glucose homoeostasis and lipid profiles, studies were made of SI (determined by the Minimal Model Method of Bergman), basal glucose and insulin levels, serum total triglyceride (Tg) and lipoprotein cholesterol (C) fractions and certain other variables in 38 healthy young men (24 y) during placebo and after 3 weeks of calcium channel blockade with amlodipine 5 mg once daily. Measurements were made after 3 days on a standard diet (2200 kcal.day-1, 45% carbohydrates, 40% fat and 15% proteins) and after an overnight fast. Compared to placebo, amlodipine decreased supine systolic blood pressure (P less than 0.01). Heart rate, body weight and 24 h urinary sodium excretion were unaltered, and so were fasting plasma glucose (placebo vs amlodipine: 4.86 vs 4.83 mmol.l-1, respectively) and insulin levels (7.7 vs 7.9 microU.ml-1), SI (10.5 vs 9.6.10(-4) x min-1 pro microU.ml-1), serum total Tg, C and lipoprotein C fractions. The findings demonstrate unchanged insulin sensitivity and secretion, as well as lipoprotein regulation, during maintenance administration of 5 mg amlodipine daily to healthy young men.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1835931&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine on circadian rhythms in blood pressure, heart rate, and motility: a telemetric study in rats.

Mattes A, Lemmer B.

Zentrum der Pharmakologie, J. W. Goethe Universitat, Frankfurt, Germany.

In male Wistar rats [light(L): 07:00-19:00 h, dark(D): 19:00-07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED50 values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1839243&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The effects of the calcium antagonist amlodipine on blood pressure and platelet aggregation in hypertensive patients.

Hernandez R, Carvajal AR, Armas-de Hernandez MJ, Guerrero-Pajuelo J, Armas-Padilla MC, Barragan O, Machado-de Alvarado I.

Clinical Pharmacology Unit, School of Medicine, Universidad Centro Occidental Lisandro Alvarado, Barquisimeto, Venezuela.

This study examined the antihypertensive efficacy of open-label amlodipine in once-daily doses of 5-10 mg for 12 weeks. Efficacy was assessed by measurement of blood pressure and heart rate in the supine, seated and standing positions and after exercise periodically during the study. Blood pressure was significantly reduced throughout the study with no change in heart rate. During a placebo-washout phase after the 12-week active treatment phase of the study, blood pressure returned to baseline values. After the 4-week placebo-washout phase some patients received a single 10-mg dose of amlodipine followed by an exercise test 6 h later, which showed that amlodipine lowered blood pressure without blunting the normal physiological response to exercise. In these patients amlodipine also significantly reduced ex vivo platelet aggregation induced by collagen or ADP.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1839438&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Vascular and myocardial effects of amlodipine: an overview.

Nayler WG, Gu XH.

Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.

Amlodipine is a long-acting dihydropyridine calcium antagonist with vascular selectivity. Although structurally related to nifedipine, amlodipine differs in several important respects, including its slow rate of onset and slow recovery. These effects probably reflect the relatively slow rate of association and dissociation of amlodipine with its binding site. The interaction of amlodipine with the calcium antagonist binding site associated with the slow Ca2+ channels differs from that of other dihydropyridines in that it involves the binding domains for the phenylalkylamine- and benzothiazepine-based antagonists, as well as for the dihydropyridines. The prolonged duration of action of amlodipine makes it suitable for use in conditions where calcium channel blockade is required on a 24-h basis. To determine whether amlodipine has a vascular protective effect, amlodipine was given orally to either cholesterol-fed rabbits or stroke-prone hypertensive rats. In the cholesterol-fed rabbits amlodipine (1 or 5 mg/kg/day) produced a significant, dose-dependent reduction in the incidence of atheromatous lesions in the thoracic aorta over an 8-week period. In stroke-prone rats the administration of amlodipine at a dose of 5 mg/kg/day reduced the incidence of mortality over a 30-week treatment period. In spontaneously hypertensive rats amlodipine (5 mg/kg/day) caused a fall in systolic blood pressure, accompanied by a significant (P less than 0.01) reduction in cardiac hypertrophy. When administered intravenously (0.25 mg/kg) 5 h before hearts were excised and made globally ischaemic for short periods (the 'stunned' heart) amlodipine pretreatment improved functional recovery associated with reperfusion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1839439&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Anti-anginal efficacy of intravenous amlodipine assessed by means of atrial pacing.

Hogg KJ, Hornung RS, Hillis WS, Gupta S, Grant P, Singh SP.

Department of Materia Medica, Stobhill General Hospital, Glasgow, UK.

The anti-anginal efficacy of amlodipine was investigated in patients with angina pectoris by means of atrial pacing during cardiac catheterization. Intravenous administration of amlodipine significantly increased the time to pacing-induced angina and reduced the area of ST-segment change for an equivalent pacing rate, suggesting an improvement in this functional marker of ischaemia. In addition, a significant reduction in the double product suggests that amlodipine reduced myocardial oxygen consumption.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1839443&dopt=Abstract amlodipine Norvasc