amlodipine Norvasc
Venodilator effects of pranidipine, a 1,4-dihydropyridine Ca2+ channel antagonist, in rats: comparison with nifedipine and amlodipine.

Hirano T, Ohura M, Orito K, Fujiki H, Miyakoda G, Mori T.

2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Japan.

The effects of pranidipine, a dihydropyridine Ca2+ channel antagonist, on mean circulatory filling pressure, an index of body venous tone, were compared with those of other dihydropyridines (nifedipine and amlodipine) and nitroglycerin in anaesthetized hexamethonium- and norepinephrine-treated rats. In this study, the compounds were used at doses having a equi-hypotensive effect. Intravenous bolus injection of pranidipine (10 and 30 microg/kg) significantly decreased mean circulatory filling pressure in a dose-dependent manner, as did nitroglycerin (30 and 100 microg/kg). Nifedipine (30 and 100 microg/kg), however, did not affect mean circulatory filling pressure. Amlodipine (1000 and 3000 microg/kg) decreased mean circulatory filling pressure only at the higher dose. These results suggest that pranidipine has a greater venodilator effect than nifedipine and amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9145772&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Semi-preparative chromatographic purification of the enantiomers S-(-)-amlodipine and R-(+)-amlodipine.

Luksa J, Josic D, Podobnik B, Furlan B, Kremser M.

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

Pharmacokinetic studies of optically pure compounds after single enantiomer administration are becoming increasingly important. The process of racemization in vivo can diminish all expected advantages of single enantiomer treatment. Amlodipine, one of the calcium channel blockers, currently used in therapy as a racemate, is one of such drugs under study. In order to administer single enantiomers of amlodipine to healthy volunteers both were chromatographically purified and characterised. The two optical isomers of amlodipine, active S-(-)- and non-active R-(+)-amlodipine, were purified using chromatographic procedure adopted from the analytical separation. Enantiomers were successfully converted to benzenesulphonic salt without any racemization. All semi-preparative purifications were monitored with complementary analytical methods, HPLC and CE, along with the determination of optical activity so that the final product was sufficiently defined for further in vivo studies. The analytical method developed for the determination of plasma concentrations of each enantiomer of amlodipine in these studies is also briefly described.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9210441&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Cost containment for treating hypertension in African Americans: impact of a combined ACE inhibitor-calcium channel blocker.

Kountz DS.

Division of Primary Care, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, USA.

The use of calcium channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors has increased dramatically over the last 10 years and now accounts for 60% to 70% of all new antihypertensive prescriptions. Even though these two classes are efficacious, they are costly. Combined ACE inhibitor/CCB therapy (amlodipine-benazepril) was introduced in 1995. An analysis was done to assess the potential financial impact of substituting this agent for patients being treated with on ACE inhibitor/CCB combination. A pharmaceutical profile review of prescriptions during October 1995 was performed on 219 randomly selected patients enrolled in a Medicaid managed care program. Eighty-four profiles were analyzed; 24% of patients were on a combination ACE inhibitor/CCB regimen with an average monthly cost of $135. If the single agent amlodipine-benazepril with an average monthly cost of $45 (all strengths) was substituted, the savings would be considerable: $1080 per patient per year and $1,080,000 annualized for the calculated number of hypertensives on combination therapy in our network of 15,000 patients. Therapeutic substitution is one method of achieving cost containment in managed care. The cost differential between separately prescribed CCBs and ACE inhibitors and amlodipine-benazepril is significant. Compliance also should be enhanced as the patient would need to take only one pill daily. Once a patient has been maintained on a stable dose of a CCB/ACE inhibitor, substitution with amlodipine-benazepril should be considered.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9220694&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Use of 1H-NMR spectroscopy to determine the enantioselective mechanism of neutral and anionic cyclodextrins in capillary electrophoresis.

Owens PK, Fell AF, Coleman MW, Kinns M, Berridge JC.

Pharmaceutical Analysis Research Unit, School of Pharmacy, University of Bradford, UK.

One-dimensional (ID) and two-dimensional (2D) 1H nuclear magnetic resonance (NMR) techniques have been used to investigate the chiral recognition process in capillary electrophoresis (CE) for seven different cyclodextrins (CDs) with the calcium channel blocker amlodipine as a model compound. These include five neutral CDs (alpha-CD, beta-CD, gamma-CD, hydroxypropyl-beta-CD and hydroxyethyl-beta-CD) and two anionic CDs (sulphobutyl-ether-beta-CD and carboxymethyl-beta-CD) where mixtures of amlodipine with each of the seven CDs were examined by 1D NMR in deuterated phosphate buffer at pD 3.4. The resonance shift of signals with added CD, relative to the CD-free position (shift displacement, delta delta) and shift non-equivalence (delta delta *) of enantiomeric signals shifted relative to each other after addition of CD were examined for non-overlapped protons of amlodipine. The possible correlations of NMR shift non-equivalence data with chiral separation in CE for amlodipine have been critically assessed. Qualitative differences in the 1D NMR shifts and enhanced enantioselectivity in CE were observed for amlodipine with sulphobutyl-ether-beta-CD. Further experiments on the through-space interactions using 2D rotating frame nuclear Overhauser effect spectroscopy (ROESY) indicated that there was no association between internal glucopyranose hydrogen atoms and the aromatic hydrogens of amlodipine. This gives evidence for the aromatic ring not being included in this CD. Moreover, data from spin-lattice relaxation times (T1) measured for amlodipine in the free state and after addition of the anionic sulphobutyl-ether-beta-CD indicate that the aromatic moiety of amlodipine is not included into the sulphobutyl-ether-beta-CD cavity. There is evidence that it interacts with the sulphobutyl side chains, and may adopt a preferred orientation outside the sulphobutyl-ether-beta-CD toroid itself.

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amlodipine Norvasc
Preservation of endogenous antioxidant activity and inhibition of lipid peroxidation as common mechanisms of antiatherosclerotic effects of vitamin E, lovastatin and amlodipine.

Chen L, Haught WH, Yang B, Saldeen TG, Parathasarathy S, Mehta JL.

Department of Medicine, University of Florida College of Medicine, Gainesville 32610, USA.

OBJECTIVES: We sought to document the common mechanisms of the antiatherogenic effects of the cholesterol-lowering hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin, the dihydropyridine Ca2+ blocker amlodipine and the antioxidant vitamin E. BACKGROUND: Vitamin E, HMG-CoA reductase inhibitors and Ca2+ blockers each inhibit atherosclerosis in hypercholesterolemic animals. METHODS: New Zealand White rabbits were fed regular chow (Group A), chow with 1% cholesterol (Group B), 1% cholesterol diet plus lovastatin (Group C), 1% cholesterol diet plus vitamin E (Group D) or 1% cholesterol diet plus amlodipine (Group E) for 12 weeks. The extent of aortic atherosclerosis was measured by planimetry of the sudanophilic area. Malondialdehyde (MDA) and superoxide dismutase (SOD) in blood were measured as indexes of lipid peroxidation and antioxidant activity, respectively. RESULTS: Group A rabbits showed no atherosclerosis, whereas Group B rabbits had 17.4 +/- 9.3% (mean +/- SD) of the aorta covered with atherosclerosis, and Groups C, D and E rabbits had significantly less atherosclerosis. Plasma SOD activity was lower in Group B than in Group A (6.9 +/- 1.1 vs. 12.8 +/- 1.5 U/ml, p < 0.01) and was preserved in the groups given lovastatin, vitamin E or amlodipine with a high cholesterol diet. The serum MDA level was higher in Group B rabbits than Group A rabbits (12.1 +/- 2.6 vs. 1.2 +/- 0.1 nmol/ml, p < 0.01) and increased minimally in rabbits given lovastatin, vitamin E or amlodipine with a high cholesterol diet. In in vitro experiments, both lovastatin and amlodipine preserved SOD activity and reduced the oxidizability of low density lipoproteins by rabbit leukocytes. CONCLUSIONS: This study suggests that a reduction in lipid peroxidation and preservation of SOD may be common mechanisms of antiatherosclerotic effects of lovastatin, vitamin E and amlodipine.

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amlodipine Norvasc
Voltage and pH dependent block of cloned N-type Ca2+ channels by amlodipine.

Furukawa T, Nukada T, Suzuki K, Fujita Y, Mori Y, Nishimura M, Yamanaka M.

First Department of Internal Medicine, Teikyo University, Itabashi-ku, Tokyo, Japan.

1. Two types of Ca2+ channel alpha1-subunits were co-expressed in Xenopus oocytes with the Ca2+ channel alpha2- and beta1-subunits. The Ba2+ current through the alpha1C alpha2beta and the alpha1B alpha2beta channels had electrophysiological and pharmacological properties of L- and N-type Ca2+ channels, respectively. 2. Amlodipine had a strong blocking action on both the L-type and N-type Ca2+ channels expressed in the oocyte. The potency of the amlodipine block on the N-type Ca2+ channel was comparable to that on the L-type Ca2+ channel. At -100 mV holding potential, the IC50 values for amlodipine block on the L-type and N-type Ca2+ channel were 2.4 and 5.8 microM, respectively. 3. The blocking action of amlodipine on the N-type Ca2+ channel was dependent on holding potential and extracellular pH, as has been observed with amlodipine block on the L-type Ca2+ channel. A depolarized holding potential and high pH enhanced the blocking action of amlodipine. 4. The time course of block development by amlodipine was similar for L-type and N-type Ca2+ channels. However, it was slower than the time course of block development by nifedipine for the L-type Ca2+ channel.

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amlodipine Norvasc
Prevalence of amlodipine-related gingival hyperplasia.

Jorgensen MG.

Department of Dentistry, Naval Medical Center, San Diego, CA, USA.

Calcium channel blockers are known to contribute to gingival hyperplasia. The vast majority of reports discuss patients taking the drug nifedipine. During the past few years a newer calcium channel blocker, amlodipine, has been used with increasing frequency. To date, six cases have been published indicating that amlodipine may also promote gingival hyperplasia; however, no data have been reported regarding the prevalence of this phenomenon. The purpose of this study was to examine a large group of patients taking amlodipine and determine the prevalence of gingival hyperplasia. One hundred fifty dentate patients who had been taking amlodipine, 5 mg per day for at least 6 months, volunteered to undergo a screening examination for gingival hyperplasia. Mild hyperplasia (< 1/3 clinical crown) was found in five patients-a prevalence of 3.3%. This is significantly less (P < .001) than rates reported for patients taking nifedipine, and not significantly different from rates previously reported in control groups of cardiac patients not taking calcium channel blockers. The results from this group of patients indicated that amlodipine, 5 mg per day, did not induce gingival hyperplasia.

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amlodipine Norvasc
A calcium-channel blocker, amlodipine, attenuates insulin antinatriuresis but does not modulate insulin-mediated attenuation of cardiovascular reactivity in healthy man.

Stenvinkel P, Ottosson-Seeberger A, de Potocki K, Alvestrand A.

Department of Clinical Science, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden.

BACKGROUND: Insulin exerts an antinatriuretic effect when administered acutely in vivo. Interestingly, insulin fails to reduce sodium excretion in rats receiving verapamil. The present study was undertaken in order to investigate whether the calcium-channel blocker amlodipine attenuates the antinatriuretic effect of insulin in humans. METHODS: Eight healthy lean men (32 +/- 2 years) were investigated on three different occasions; i.e. time-control, insulin infusion alone, and insulin infusion following pretreatment with amlodipine (5 mg x 1 during 10 days). During the experiments renal haemodynamics (insulin and PAH clearances) and segmental tubular sodium handling (sodium and lithium clearances) were investigated. The cardiovascular reactivity was also assessed by a graded noradrenaline infusion at the end of each experiment. RESULTS: Insulin infusion alone was accompanied by a significant 50% reduction in urinary sodium excretion. Following amlodipine pretreatment, euglycaemic insulin infusion was associated with an attenuated antinatriuretic response and the cumulative sodium excretion following 135 min of insulin infusion was significantly higher (24 +/- 4 vs 18 +/- 3 mmol; P < 0.05) as compared to insulin infusion alone. No significant differences in the proximal and distal tubular sodium handling respectively, were seen following CCB pretreatment. The results also show that the doses of noradrenaline required to increase the basal mean arterial blood pressure by 10 mmHg (262 +/- 38 vs 150 +/- 25 ng/kg/min; P < 0.05) and by 20 mmHg (431 +/- 36 vs 250 +/- 38 ng/kg/ min; P < 0.05) respectively, were significantly higher during the insulin infusion than during the time-control experiment. Pretreatment with amlodipine did not further modulate the cardiovascular reactivity. CONCLUSION: Pretreatment with a calcium-channel blocker, amlodipine, attenuates the antinatriuretic effects of insulin leading to a significantly higher cumulative sodium excretion at the end of insulin infusion, which may be of clinical importance. Moreover, insulin attenuates the cardiovascular reactivity to a graded noradrenaline infusion, suggesting that insulin causes vasodilatation in healthy man.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9269636&dopt=Abstract amlodipine Norvasc