amlodipine Norvasc
Pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration.

Luksa J, Josic D, Kremser M, Kopitar Z, Milutinovic S.

Lek Pharmaceutical and Chemical Company d.d., Ljubljana, Slovenia.

Amlodipine, 3-ethyl 5-methyl-2-[(2-aminoethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methy l-3,5-pyridinedicarboxylate, is a chiral calcium antagonist, currently on the market and in therapeutic use as a racemate. The pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration to healthy male human volunteers together with comparative administration of the racemic mixture of both enantiomers were studied. Plasma levels were studied as a function of time and assayed using an enantioselective chromatographic method (coupled chiral and achiral HPLC) with on-line solid-phase extraction and UV absorbance detection. The method was validated separately for the R-(+)- and S-(-)-enantiomer, respectively. Results of the study indicate that the pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration is comparable to that of each enantiomer after administration of the racemate. No racemization occurs in vivo in human plasma after single enantiomer administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9448075&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Efficient inhibition of the development of cardiac remodeling by a long-acting calcium antagonist amlodipine.

Yamazaki T, Komuro I, Zou Y, Kudoh S, Shiojima I, Mizuno T, Hiroi Y, Nagai R, Yazaki Y.

Department of Medicine III, University of Tokyo School of Medicine, the Health Service Center, Japan.

The purpose of the present study was to examine the effects of a long-acting calcium antagonist, amlodipine, on the development of cardiac remodeling. Dihydropyridine calcium antagonists have been used widely for many years in the treatment of hypertension and angina pectoris. It has been reported, however, that a prototype of dihydropyridines, nifedipine, does not reduce mortality of patients with ischemic heart disease, possibly because of reflex stimulation of the sympathetic nervous system. A calcium antagonist, amlodipine, has been reported to have potential benefits by virtue of a gradual onset of action and a long duration of effects. Amlodipine (8 mg/kg per day, once a day) or nifedipine (24 mg/kg per day, three times a day) was administered to spontaneously hypertensive 12-week-old rats for 12 weeks. Left ventricular wall thickness was measured by echocardiography, and relative amounts of myosin heavy chain isoforms were assessed by pyrophosphate gels. Expressions of "fetal type" genes and type 1 collagen gene were examined by Northern blot analysis. Amlodipine and nifedipine both markedly reduced systolic blood pressure. However, the decrease in systolic blood pressure caused by nifedipine continued for no more than 8 hours, whereas the blood pressure-lowering effect of amlodipine continued for more than 16 hours post dose. Amlodipine markedly reduced left ventricular wall thickness, whereas nifedipine only weakly attenuated an increase in the wall thickness. Amlodipine, but not nifedipine, prevented an increase in the relative amount of V3 myosin heavy chain isoform and suppressed an increase in mRNA levels of beta-myosin heavy chain, skeletal alpha-actin, and type 1 collagen. Unlike nifedipine, amlodipine effectively prevented cardiac remodeling secondary to high blood pressure at biochemical levels and morphological levels. These results suggest that a long-acting calcium antagonist is more effective than a short-acting one in preventing organ injury in hypertensive subjects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9449387&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Efficacy of amlodipine in pediatric bone marrow transplant patients.

Khattak S, Rogan JW, Saunders EF, Theis JG, Arbus GS, Koren G.

Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, The University of Toronto, Ontario, Canada.

The calcium antagonist amlodipine may have the potential for expanded use in children owing to its physiochemistry and pharmacokinetic profile that facilitates once-daily dosing in a liquid formulation. Its safety and efficacy have not been previously evaluated in children. A retrospective analysis of 15 pediatric bone marrow transplant patients who had amlodipine incorporated into their antihypertensive drug regimen reveals significantly lower blood pressure as compared with baseline therapy (123.5+/-2.1 mmHg and 117.2+/-2.2 mmHg, systolic blood pressure before and during amlodipine, P<0.05; 81.5+/-1.8 mmHg and 75.5+/-2.6 mmHg, diastolic blood pressure before and during amlodipine, P<0.05). Amlodipine provided improved blood pressure control in this cohort and may provide a valuable pharmacologic alternative for treatment of pediatric hypertension.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9475697&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine lowers blood pressure without increasing sympathetic activity or activating the renin-angiotensin system in patients with essential hypertension.

Sasaguri M, Matsumoto N, Noda K, Koga M, Kinoshita A, Ideishi M, Arakawa K.

Department of Internal Medicine, Fukuoka University, School of Medicine, Japan.

OBJECTIVE: Recent clinical studies suggest that the reflex increase in sympathetic nervous activity accompanying a reduction in blood pressure may contribute to the untoward effects of dihydropyridine calcium antagonists. The aim of this study was to examine whether plasma noradrenaline levels and renin activity are increased with the reduction of blood pressure during the initial phase of administration of the long-acting dihydropyridine calcium antagonist amlodipine. METHODS: The effects of amlodipine on ambulatory blood pressure and on diurnal variations in plasma noradrenaline and renin activity were examined 1, 4, and 7 days after the start of amlodipine administration in eight inpatients with essential hypertension. RESULTS: The 24-h mean systolic and diastolic blood pressure on day 7 was significantly lower than it was 1 day before the start of treatment. There was no change in the mean heart rate. The mean trough to peak ratios of systolic and diastolic blood pressure of seven patients were 61% and 71%, respectively. Diurnal patterns of plasma noradrenaline levels and renin activity 1, 4, and 7 days after the start of amlodipine administration were unchanged. CONCLUSION: The antihypertensive effects of amlodipine were of slow onset and long duration and were not accompanied by an increase in sympathetic activity or activation of the renin-angiotensin system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9476031&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Molecular pharmacology of UK-118, 434-05, a permanently charged amlodipine analog.

Heath B, Xia J, Kass RS.

Department of Pharmacology, Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

We studied the effects of UK-118, 434-05, a permanently charged form of amlodipine, on recombinant smooth muscle and cardiac L-type calcium channels to determine the distinct modulatory properties of the ionized form of amlodipine. We found that the short distance between the permanent charge group and the active dihydropyridine (DHP) ring of UK-118, 434-05 reduces the potency of this compound as an inhibitor of smooth muscle (alpha(1c-b)) L-type channels, and is similar to the effects of other charged DHP derivatives on cardiac (alpha(1c-a)) L-type channels. However, we found surprisingly that the tonic block of cardiac (alpha(1c-a)) L-type channels was more pronounced than the tonic block of smooth muscle (alpha(1c-b)) L-type channels. This result contrasts with the previously reported subunit-specificity of neutral DHP compounds, and suggests that interactions between the amlodipine charge group and site(s) on the L-type channel alpha1 subunit distinguish the action of charged from neutral DHPs and may contribute to amlodipine's unique pharmacological profile.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9488195&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine and vascular hypertrophy.

Stepien O, Iouzalen L, Herembert T, Zhu DL, Marche P.

Laboratory of Pharmacology, Universite Rene Descartes and CNRS URA 1482, Faculte de Medecine Necker, Paris, France.

In both atherosclerosis and arterial hypertension, structural and functional abnormalities result in vascular hypertrophy that is associated with an increased ratio of vascular media thickness to lumen diameter and hyperreactivity of vascular smooth muscle cells (VSMCs), resulting in uncontrolled cell migration and growth in vivo. In culture, VSMCs isolated from the spontaneously hypertensive rat (SHR) also display exaggerated growth and/or proliferation compared to VSMCs isolated from normotensive control Wistar Kyoto (WKY) rats. In vitro studies of cultured VSMCs can therefore be used as a model to investigate the mechanisms whereby a drug such as amlodipine can exert its antihypertensive and antiatherogenic effects. The present in vitro investigations examine the mechanisms whereby amlodipine reduces VSMC growth/proliferation promoted by basic fibroblast growth factor (bFGF), a peptide growth factor likely to participate in the vascular smooth muscle hypertrophy of the SHR. VSMCs from SHR and/or WKY rat aortae were isolated, passaged, and cultured. The influence of amlodipine on VSMC growth/proliferation was studied by measuring DNA synthesis and cell number under experimental conditions, which allowed us to determine the cell cycle phase in which amlodipine exerts its effects. Amlodipine was found to inhibit growth and bFGF-induced DNA synthesis in a concentration-dependent manner. Delayed addition of amlodipine showed that the drug exerts its effect early in the G1 phase, a result that was confirmed by the finding that amlodipine could not inhibit bFGF-induced DNA synthesis in VSMCs arrested at the G1/S boundary. In comparative experiments, the inhibitory effect of amlodipine on both cell growth and DNA synthesis was found to be of similar magnitude in SHR- and WKY-derived VSMCs. It is therefore likely that by modulating cell growth/proliferation induced by bFGF, amlodipine may reduce the vascular hypertrophy of the SHR. Since amlodipine also has been found to inhibit VSMC migration, one may reasonably envisage that these characteristics are important components of the antiatherogenic properties of the drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9488198&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Inhibition of platelet activity in vivo by amlodipine alone and combined with aspirin.

Folts JD.

Department of Medicine, University of Wisconsin Medical School, Madison 53792-3248, USA.

Platelets are known to contribute to the initiation and progression of coronary artery narrowing by atherosclerotic plaques. Platelets also initiate periodic occlusive coronary arterial thrombosis that leads to unstable angina and myocardial infarction. Aspirin is the most widely used platelet inhibitor. However, if blood levels of epinephrine are elevated, some of the platelet inhibition produced by aspirin is diminished. Amlodipine, a second generation dihydropyridine calcium channel blocker, was studied in a widely used dog model of experimental coronary artery thrombosis. Amlodipine 1 mg/kg alone or amlodipine 0.4 mg/kg with 5 mg/kg of aspirin I.V. completely abolished the experimental coronary thrombosis and prevented the exacerbation of coronary thrombosis by epinephrine 0.2 microg/kg/min. This protective effect did not appear until 60 minutes after the amlodipine was given, suggesting a delayed onset of action. Long-acting dihydropyridine calcium channel blockers are used in patients with hypertension, angina, and coronary artery disease. They also may offer the patient some protection against fatal or nonfatal myocardial infarction via their platelet-inhibiting effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9488202&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine releases nitric oxide from canine coronary microvessels: an unexpected mechanism of action of a calcium channel-blocking agent.

Zhang X, Hintze TH.

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

BACKGROUND: Recent studies suggest that amlodipine may reduce mortality in patients with heart failure, especially those with dilated cardiomyopathy. In general, drugs that release NO, such as organic nitrates and ACE inhibitors, have been shown to be of substantial benefit in the treatment of heart failure. METHODS AND RESULTS: We hypothesized that a portion of the beneficial actions of amlodipine may involve the release or action of NO. Coronary microvessels were isolated from the heart of normal dogs and incubated with increasing doses of the calcium channel blockers nifedipine, diltiazem, and amlodipine or the ACE inhibitors enalaprilat and ramiprilat. Neither nifedipine nor diltiazem increased nitrite production at any dose studied. In marked contrast, amlodipine caused a dose-dependent increase in nitrite production from 74+/-5 to 130+/-8 pmol/mg (by 85+/-21%,10(-5) mol/L, P<.05) that was similar in magnitude to that of either of the ACE inhibitors. Amlodipine also increased nitrite production in large coronary arteries and in aorta. N(omega)-Nitro-L-arginine methyl ester, HOE-140, and dichloroisocoumarin essentially abolished the increase in nitrite production, indicating that (1) nitrite production reflected NO formation, (2) nitrite production was dependent on stimulation of the kinin2 receptor, and (3) nitrite production is most likely secondary to the formation of local kinins. CONCLUSIONS: Thus, unlike nifedipine and diltiazem, amlodipine releases NO from blood vessels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9494028&dopt=Abstract amlodipine Norvasc