amlodipine Norvasc
Effects of circadian rhythms, posture, and medication on renin-aldosterone interrelations in essential hypertensives.

Lamarre-Cliche M, de Champlain J, Lacourciere Y, Poirier L, Karas M, Larochelle P.

Institut de Recherches Cliniques de Montreal (IRCM), Canada. lamarrm ircm.qc.ca

BACKGROUND: The aldosterone-to-renin ratio (ARR) is frequently used to screen primary hyperaldosteronism. This study, part of a clinical trial, was designed to measure the influence of circadian rhythms, antihypertensive drugs, and body posture on plasma renin, on aldosterone, and on their interrelation. METHODS: In a prospective, randomized, open-label, parallel-designed protocol, 57 essential hypertensives (41 men, 16 women) were randomized to a morning dose of telmisartan (80 mg), ramipril (10 mg), or amlodipine (10 mg) for 8 weeks. At baseline and after 8 weeks of therapy, blood pressure (BP), plasma renin (in nanograms per liter), and plasma aldosterone (in picomoles per liter) concentrations were assessed in the supine position every 4 h for 24 h and after 10 min of standing at 9 am. RESULTS: There was no significant association between renin, aldosterone, the ARR and demographic factors, or BP. Circadian variations of plasma renin and aldosterone were clearly present. Aldosterone variations were of greater relative amplitude with earlier-occurring peaks than renin. The ARR exhibited statistically and clinically significant circadian variations with the low and peak values averaging 55.9 +/- 32.3 and 161.84 +/- 85.4 pmol/L/ng/dL, respectively. Telmisartan, ramipril, and amlodipine significantly decreased the ARR. Telmisartan had the greatest influence on the ARR. Posture had a clinically significant but statistically nonsignificant effect on the ARR. CONCLUSIONS: Renin, aldosterone, and their interrelation are influenced by circadian rhythms, telmisartan, ramipril, and amlodipine in patients with essential hypertension. Telmisartan has a greater impact on these parameters than ramipril and amlodipine. Measurement of the ARR in treated hypertensive patients should take these influences into account.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15691618&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Anasarca Edema with Amlodipine Treatment (April).

Sener D, Halil M, Yavuz BB, Cankurtaran M, Ariogul S.

Medical Faculty, Department of Internal Medicine, Hacettepe University, Ankara, Turkey.

OBJECTIVE: To report a case of anasarca edema associated with amlodipine use. CASE SUMMARY: A 77-year-old woman with essential hypertension who had not been treated with any other drug was prescribed amlodipine 10 mg/day to control her blood pressure. She developed anasarca edema soon after amlodipine treatment was initiated. Laboratory test results for possible etiologies were negative. Discontinuation of amlodipine resulted in dramatic improvement. DISCUSSION: To our knowledge, as of February 3, 2005, there have been no other reports of amlodipine-related anasarca edema in the English literature, and only one case was described in the Japanese literature. Pretibial edema is the most common adverse effect of amlodipine. Periocular and perioral edema have occurred less frequently, but anasarca edema has not emerged as a problem. An objective causality assessment revealed amlodipine to be a probable cause of anasarca edema. CONCLUSIONS: In rare instances, amlodipine may cause generalized edema, which will resolve upon discontinuation of the drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15728328&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Immunomodulating effects of second-generation calcium channel blockers on experimental heart transplantation.

Lapointe N, Chen H, Qi S, Xu D, Daloze P, Dumont L.

Departement de Pharmacologie, Faculte de Medecine, Universite de Montreal, Montreal, Que., Canada.

The administration of second-generation calcium channel blockers (CCBs) to counteract the adverse effects of conventional immunosuppression gains more and more acceptance. Since these newly developed molecules differ in their chemical structure and possess specific pharmacokinetic profiles, we hypothesized that exposure to clinically relevant concentrations may have a significant immunomodulatory potential. The effects of various second-generation CCBs, felodipine, amlodipine, mibefradil and clentiazem, on cardiac allograft survival were therefore evaluated. Inbred male Lewis rats were used as recipients and Brown-Norway rats as donors. After abdominal implantation of the donor heart, allograft recipients were exposed to felodipine (31 microg/kg/day), amlodipine (25 microg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). Other allograft recipients were treated with low-dose cyclosporine (CsA) alone (2 mg/kg/day) or with low-dose CsA combined with amlodipine (25 microg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). All drugs were given daily by gavage. Median survival time of untreated cardiac allografts was 6.5 days. When given alone, not all the second-generation CCBs elicited a positive effect: the dihydropyridines felodipine and amlodipine were ineffective (median survival time was 6.5 and 7.0 days, respectively), the T- and L-type CCB mibefradil had a significant but minor impact (median survival time = 9.0 days, p <0.0015) while the benzothiazepine clentiazem produced the most significant result (median survival time = 16.0 days, p <0.0033). Neither amlodipine nor mibefradil modified the extent of survival provided by low-dose CsA (median survival time = 9.0 days), while clentiazem had a significant positive effect. These data indicate that second-generation CCBs differ in their immunomodulatory potential. These observations of pharmacodynamic specificity appear to be related to differences in their chemical structure as well as their interaction with other sites than the calcium channel.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10352354&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
NO modulates myocardial O2 consumption in the nonhuman primate: an additional mechanism of action of amlodipine.

Forfia PR, Zhang X, Knight DR, Smith AH, Doe CP, Wolfgang EA, Flynn DM, Wolin MS, Hintze TH.

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

Recent evidence from our laboratory and others suggests that nitric oxide (NO) is a modulator of in vivo and in vitro oxygen consumption in the murine and canine heart. Therefore, the goal of our study was twofold: to determine whether NO modulates myocardial oxygen consumption in the nonhuman primate heart in vitro and to evaluate whether the seemingly cardioprotective actions of amlodipine may involve an NO-mediated mechanism. Using a Clark-type O2 electrode, we measured oxygen consumption in cynomologous monkey heart at baseline and after increasing doses of S-nitroso-N-acetylpenicillamine (SNAP; 10(-7)-10(-4) M), bradykinin (10(-7)-10(-4) M), ramiprilat (10(-7)-10(-4) M), and amlodipine (10(-7)-10(-5) M). SNAP (-38 +/- 5.8%), bradykinin (-19 +/- 3.9%), ramiprilat (-28 +/- 2.3%), and amlodipine (-23 +/- 4.5%) each caused significant (P < 0.05) reductions in myocardial oxygen consumption at their highest dose. Preincubation of tissue with nitro-L-arginine methyl ester (10(-4) M) blunted the effects of bradykinin (-5.4 +/- 3.2%), ramiprilat (-4.8 +/- 5.0%), and amlodipine (-5.3 +/- 5.0%) but had no effect on the tissue response to SNAP (-38 +/- 5.8%). Our results indicate that NO can reduce oxygen consumption in the primate myocardium in vitro, and they support a role for the calcium-channel blocker amlodipine as a modulator of myocardial oxygen consumption via a kinin-NO mediated mechanism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10362689&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Stability of amlodipine besylate in two liquid dosage forms.

Nahata MC, Morosco RS, Hipple TF.

College of Pharmacy, Ohio State University, Columbus 43210, USA. nahata.1 osu.edu

OBJECTIVE: To determine the stability of amlodipine besylate in two liquid dosage forms under refrigeration and at room temperature. DESIGN: Commercially available amlodipine tablets (Norvasc-Pfizer) were used to prepare two suspensions: one in extemporaneously prepared 1% methylcellulose in syrup (1:1), and another in equal volumes of commercially available OraPlus/OraSweet. Each suspension containing amlodipine 1 mg/mL was stored in 10 plastic prescription bottles; 5 were stored at 4 degrees C and 5 at 25 degrees C. Samples were collected immediately after preparation (day 0) and on days 7, 14, 28, 42, 56, 70, and 91. Amlodipine concentration was measured by stability-indicating HPLC method (n = 15). SETTING: Research laboratory at Children's Hospital. MAIN OUTCOME MEASURES: Physical and chemical stability (> 90% of the initial concentration) of amlodipine in the two extemporaneously prepared suspensions during storage in plastic prescription bottles at 4 degrees C and 25 degrees C. RESULTS: Observed mean concentrations exceeded 90% of the initial concentrations in both suspensions for 91 days at 4 degrees C and 56 days at 25 degrees C. No noticeable change in physical appearance or odor was observed; pH changed slightly in the methylcellulose-containing formulation stored at 25 degrees C. CONCLUSION: Amlodipine was stable in two suspensions when stored in plastic prescription bottles for 91 days at 4 degrees C or 56 days at 25 degrees C. These formulations may be considered for pediatric or elderly patients who are unable to swallow tablets. The liquid dosage form would also permit accurate administration of amlodipine doses to infants and young children based on their body weight.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10363465&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Pharmacokinetics of phenytoin: unaltered by enalapril and amlodipine in rhesus monkeys.

Badyal DK, Garg SK, Bhargava VK, Majumdar S.

Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh.

A cross over single and multiple dose study was carried out to find out pharmacokinetic interactions between diphynylhydantoin (DPH) (35 mg/kg, p.o.) and antihypertensives enalapril (1.6 mg/kg; p.o.) and amlodipine (0.4 mg/kg, p.o.) in rhesus monkeys. Neither the plasma concentrations nor the pharmacokinetic parameters of DPH were altered by coadministration of enalapril or amlodipine, suggesting that enalapril and amlodipine can be safely administered to epileptic patients receiving phenytoin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10365321&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine on native cardiac Na+ channels and cloned alpha-subunits of cardiac Na+ channels.

Inoue Y, Hisatome I, Tsuboi M, Ahmmed GU, Yatsuhashi T, Uchida K, Yamanouchi Y, Santo Y, Miake J, Tanaka Y, Hamada T, Watanabe M, Igawa O, Yoshida A, Shigemasa C, Makita N, Sato R.

First Department of Medicine, Tottori University Faculty of Medicine, Yonago, Japan.

The inhibitory effects of amlodipine besilate (CAS 11470-99-6) on the native Na+ current (INa) and cloned human cardiac Na+ channel alpha subunit (hH1) were studied by whole cell patch clamp techniques. Amlodipine produced tonic block of INa in a concentration- and holding potential (HP)-dependent manner with hyperpolarization of H infinity. Amlodipine produced phasic blockade of INa, which was dependent on HP and pulse duration. Amlodipine produced tonic blockade of hH1 in a concentration-dependent manner with 1 : 1 stoichiometry, and phasic blockade of hH1 which was dependent on the pulse duration. Amlodipine blocked INa in a voltage- and frequency-dependent manner via affinity to the resting as well as inactivated conformations of the alpha subunit.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10367100&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Comparison of binding affinities of omega-conotoxin and amlodipine to N-type Ca2+ channels in rat brain.

Qu YL, Sugiyama K, Ohnuki T, Hattori K, Watanabe K, Nagatomo T.

Department of Pharmacology, Niigata College of Pharmacy, Japan.

AIM: To compare the binding affinities of omega-conotoxin (CTX) and amlodipine to N-type Ca2+ channels in rat brains. METHODS: Whole rat brains were homogenized in HEPES buffer 50 mmol.L-1 (pH 7.4) and centrifuged at 40,000 x g to obtain the membrane-entriched fraction. 125I-omega-conotoxin (125I-omega-CTX) was used as a radioligand. Using radioligand binding assay Kd and Bmax values of the radioligand were determined by Scatchard analysis. The IC50 value for each drug was obtained from displacement experiments. RESULTS: No differences in Bmax values of 125I-omega-CTX binding sites between frozen and fresh tissues were observed. Values of Kd and Bmax of N-type Ca2+ channels were 0.02 +/- 0.01 nmol.L-1 and 1029 +/- 108 pmol/g protein, respectively. The pKi values of omega-CTX and amlodipine were 9.57 and less than 4, respectively. The pKi values of propranolol, prazosin, atropine, and histamine were very low. CONCLUSION: The binding affinity of the L-type Ca(2+)-antagonist amlodipine to N-type Ca2+ channels in the rat brain was very low.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10374627&dopt=Abstract amlodipine Norvasc