amlodipine Norvasc
Simvastatin acts synergistically with ACE inhibitors or amlodipine to decrease oxygen consumption in rat hearts.

Mital S, Magneson A, Loke KE, Liao J, Forfia PR, Hintze TH.

Division of Pediatric Cardiology, College of Physicians and Surgeons, Columbia University, New York, USA.

Statin drugs, which are cholesterol-lowering agents, can upregulate endothelial nitric oxide synthase (eNOS) in isolated endothelial cells independent of lipid lowering. We investigated the effect of short-term simvastatin administration on NO-mediated regulation of myocardial oxygen consumption (MV(O2)) in tissue from rat hearts. Male Wistar rats were divided into (a) control group (n = 14), and (b) simvastatin group (n = 10, 20 mg/kg/day by oral gavage). After 2 weeks, left ventricular myocardium was isolated to measure MV(O2) using a Clark-type oxygen electrode, and aortic plasma nitrates and nitrites (NOx) were measured. Baseline plasma NOx levels (19+/-2.6 in control vs. 20+/-2.5 microM/L in simvastatin) and baseline MV(O2) (288+/-23 in control vs. 252+/-11 nmol/g/min; p = 0.09) were not significantly different between the two groups. NO-dependent regulation of MV(O2) in response to bradykinin, ramipril, or amlodipine was augmented in simvastatin rats compared with controls (p < 0.05). Decrease of MV(O2) from baseline in response to highest doses in control versus simvastatin groups was as follows-bradykinin, -28+/-5% vs. -44+/-6%; ramipril, -35+/-5% vs. -50+/-8%; and amlodipine, -32+/-9% vs. -42+/-3%. Response to highest dose of NO donor S-nitroso N-acetyl penicillamine (SNAP) was not significantly different in the two groups (-55+/-5% vs. -52+/-7%). Treatment with Nw-nitro-L-arginine methyl ester, inhibitor of NO synthesis, attenuated the effect of bradykinin, ramipril, and amlodipine on MV(O2) (p < 0.05). In conclusion, short-term administration of simvastatin in rats potentiates the ability of angiotensin-converting enzyme (ACE) inhibitors and amlodipine to cause NO-mediated regulation of MV(O2).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10942168&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Antireproductive effect of the calcium channel blocker amlodipine in male rats.

Almeida SA, Teofilo JM, Anselmo Franci JA, Brentegani LG, Lamano-Carvalho TL.

Department of Morphology, Stomatology and Physiology, Dental School of Ribeirao Preto, University of Sao Paulo, Brazil.

The purpose of the present study was to investigate whether treatment of male rats with the calcium antagonist amlodipine, used in the treatment of hypertension and angina, interferes with the reproductive function of male rats. Amlodipine treatment (0.04 mg amlodipine besylate/rat/day for 30 days) decreased plasma follicle-stimulating hormone and testosterone but not luteinizing hormone or prolactin concentrations (measured by double-antibody radioimmuno-assay). A significant reduction (23%) was observed in sperm density (sperm suspension collected from the cauda epididymidis) as well as in the amount of mature spermatids (14%) and Sertoli cells (9%) counted in seminiferous tubule cross-sections (400 x magnification). The results reveal the deleterious effects of subacute amlodipine treatment on the reproductive function of male rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10987190&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine inhibits thapsigargin-sensitive CA(2+) stores in thrombin-stimulated vascular smooth muscle cells.

Stepien O, Marche P.

Departement de Pharmacologie, Universite Rene Descartes, 75015 Paris, France.

Ca(2+) channel blockers, such as amlodipine, inhibit vascular smooth muscle cell (VSMC) growth through interactions with targets other than L-type Ca(2+) channels. The effects of amlodipine on Ca(2+) movements in thrombin- and thapsigargin-stimulated VSMCs were therefore investigated by determining the variations of intracellular free Ca(2+) concentration in fura 2-loaded cultured VSMCs. Results indicated that 10-1,000 nM amlodipine inhibited 1) thrombin-induced Ca(2+) mobilization from a thapsigargin-sensitive pool and 2) thapsigargin-induced Ca(2+) responses, including Ca(2+) mobilization from internal stores and store-operated Ca(2+) entry. These effects of amlodipine do not involve L-type Ca(2+) channels and could not be reproduced with 100 nM isradipine, diltiazem, or verapamil. The inhibition by amlodipine of Ca(2+) mobilization appears therefore to be a specific property of the drug, in addition to its Ca(2+) channel-blocking property. It is suggested that amlodipine acts in this capacity by interacting with Ca(2+)-ATPases of the sarcoplasmic reticulum, thus modulating the enzyme activity. This mechanism might participate in the inhibitory effect of amlodipine on VSMC growth.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10993788&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Retrospective evaluation of the conversion of amlodipine to alternative calcium channel blockers.

Parra D, Beckey NP, Korman L.

Patient Support Service, Department of Veterans Affairs Medical Center, West Palm Beach, Florida 33410-6400, USA.

STUDY OBJECTIVE: To evaluate the effectiveness, safety, and costs associated with a formulary conversion from amlodipine to alternative calcium channel blockers. DESIGN: Retrospective study. SETTING: Veterans Affairs Medical Center. PATIENTS: One hundred patients with hypertension who were receiving amlodipine. INTERVENTION: Data from a random sample of 100 patients who were taking amlodipine and converted to a formulary calcium channel blocker from February 1, 1999-October 30, 1999, were entered into an Excel database for evaluation of the conversion. MEASUREMENTS AND MAIN RESULTS: Patients were required to have a diagnosis of hypertension and have had two consecutive clinic visits with blood pressure measurements (and no changes in antihypertensive therapy) before conversion. End points were changes in average systolic blood pressure, diastolic blood pressure, and mean arterial pressure (MAP) from the two clinic visits before and after conversion. In addition, data were collected and analyzed with regard to adverse drug reactions, average dosage of the alternative calcium channel blocker, number of additional antihypertensives begun or discontinued, and number of dosage changes in antihypertensives within the two visits after conversion, and the overall cost impact of conversion. Average systolic blood pressure was reduced from 141.6 +/- 15.1 to 139.2 +/- 15.3 mm Hg after the conversion (NS). Average diastolic blood pressure was significantly reduced from 74 +/- 9.5 to 72.6 +/- 10.1 mm Hg after conversion (p=0.032), as was MAP (97.0 +/-q 9.3 to 94.8 +/- 10.0 mm Hg, p=0.026). Five patients had other changes in therapy made concurrently at the time of conversion, and 19 had changes after conversion. When these patients were excluded from analysis, the reduction in systolic blood pressure after conversion was significant (141.4 +/- 14.5 to 137.7 +/- 14.3 mm Hg, p=0.022), as were reductions in diastolic blood pressure (74.4 +/- 9.4 to 71.7 +/- 9.8 mm Hg, p=0.014) and MAP (96.7 +/- 9.1 to 93.7 +/- 9.3 mm Hg, p=0.007). Of patients who had postconversion changes in therapy, 8 (42%) were converted to diltiazem ER, nifedipine CC, or doses of felodipine that were 50% of the original dose of amlodipine. The overall cost impact of the conversion was a net savings of $14,858/year for each 100 patients converted. CONCLUSION: Conversion from amlodipine to other calcium channel blockers resulted in statistically significant reductions in diastolic blood pressure and MAP, and was safe as well as cost-effective. Conversion to calcium channel antagonists other than felodipine or less than equal dosages of felodipine may require dosage titration. When converting patients from amlodipine, dosages usually should be equal to those of felodipine; if converting to other calcium channel antagonists, the need for adjustments should be anticipated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10999500&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
[Membrane biophysical interaction of amlodipine and antioxidant properties]

[Article in French]

Mason RP, Trumbore MW, Mason PE.

Departement de Medecine et de Biochimie, MCP Hahnemann University School of Medicine, Pittsburg, Pennsylvania, USA. Mason pgh.auhs.edu

OBJECTIVE: To assess the potential benefits of the antioxidant activity of certain pharmacological agents that may be beneficial in the treatment of cardiovascular disease, including coronary heart disease and heart failure, by reducing irreversible cell injury due to oxyradical damage. METHODS: The antioxidant activities of representative calcium antagonists were examined and correlated with the molecular membrane interactions of the compounds, as measured by radioligand binding assays and high resolution differential scanning calorimetry. RESULTS: The results of these experiments show a direct relationship between the antioxidant activities of the calcium antagonists and their affinity for the membrane lipid bilayer, as well as their ability to modulate membrane thermodynamic properties (amlodipine > verapamil >> diltiazem). The charged 1,4-dihydropyridine calcium antagonist amlodipine had the highest affinity for the membrane bilayer (Kp10(4)) and produced the largest changes in membrane thermodynamic properties, including a reduction in the thermal phase transition temperature (-11%), enthalpy (-14%) and cooperative unit size (-59%), relative to control phosphatidylcholine liposomes. CONCLUSIONS: These findings indicate that lipophilic calcium antagonists inhibit lipid peroxidation in cellular membranes as a result of modulating physicochemical properties of the membrane lipid bilayer, independently of calcium channel inhibition. The antioxidant activity of highly lipophilic calcium antagonists, such as amlodipine, may contribute to new cytoprotective mechanisms of action in cardiovascular disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11002854&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Nephrotoxicity of high- and low-osmolar contrast media. The protective role of amlodipine in a rat model.

Duan SB, Liu FY, Luo JA, Wu HW, Liu RH, Peng YM, Yang XL.

Department of Medicine, the Second Affiliated Hospital, Hunan Medical University, Changsha, P. R. of China.

PURPOSE: To evaluate the nephrotoxicity of high- and low-osmolar contrast media (HOCM, LOCM) on kidneys in Sprague-Dawley rats. The protective role of amlodipine was studied. MATERIAL AND METHODS: Forty rats of both sexes were randomly divided into 5 groups (n=8/group) and glycerine for inducing renal failure was given to all rats except controls. RESULTS: In diatrizoate-injected rats, blood urea nitrogen (BUN) and serum creatinine (SCr) were increased; levels of phospholipase A2 (PLA2), lipid peroxide (LPO) and calcium were also increased in renal tissues. There was no significant difference between LOCM (iohexol) animals and glycerol controls either in the renal levels of PLA2, LPO and calcium or in the levels of BUN and SCr. The histologic changes were milder in the LOCM animals than in the HOCM animals. In the group pretreated with amlodipine, no increase in the levels of BUN or SCr was discovered and the renal content of PLA2, LPO and calcium were significantly lower than in the HOCM group; the renal injuries induced by diatrizoate were alleviated. CONCLUSION: The HOCM, diatrizoate, was more toxic to rat kidneys than the LOCM iohexol; PLA2, LPO and calcium load played a role in producing renal function impairment induced by diatrizoate meglumine; amlodipine protected the renal tissue from nephrotoxicity induced by diatrizoate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11016776&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Treatment of hypertensive children with amlodipine.

Flynn JT, Smoyer WE, Bunchman TE.

Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, USA. jtflynn umich.edu

Amlodipine, a long-acting dihydropyridine calcium channel blocking agent, was administered to 55 children (age: 11.5 +/- 5.4 years) with hypertension, 49 of whom (89%) had secondary hypertension. Efficacy was assessed by comparing pretreatment blood pressure (BP) to follow-up BP obtained in our outpatient Pediatric Nephrology clinic. Thirty-two (58%) patients achieved BP control with amlodipine alone, and 31 (55%) patients received amlodipine twice daily. Eleven patients received amlodipine as a suspension. Mean amlodipine dose was 0.16 +/- 0.12 mg/kg/day; there was an inverse relationship between patient age and amlodipine dose. Follow-up BP were significantly lower than pretreatment BP: systolic BP fell from 129 +/- 12 to 122 +/- 12 mm Hg (P = .004), and diastolic BP fell from 78 +/- 13 to 70 +/- 19 mm Hg (P = .003). A small, clinically insignificant increase in heart rate (from 91 +/- 19 beats/min to 99 +/- 26 beats/min; P = .02) occurred during amlodipine treatment. Adverse effects reported included dizziness (three patients), fatigue (two patients), flushing (two patients), and leg edema (one patient). All improved with dose reduction. We conclude that amlodipine provides effective BP control without significant adverse effects in children with hypertension, and can be used as monotherapy in most children. Young children appear to require significantly higher doses per kilogram of body weight than older children. Twice-daily dosing may be required in many children to achieve BP control. Detailed pharmacokinetic studies are needed to confirm these observations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11041159&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Improvement in the histopathology of hearts from cardiomyopathic BIO TO-2 hamsters following long-term administration of amlodipine and cilnidipine.

Urayama A, Yamada S, Hirano K, Kimura R, Watanabe H, Ohashi K.

Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan.

The effect of long-term administration of amlodipine and cilnidipine was examined on the histopathology and 1,4-dihydropyridine (DHP) calcium channel antagonist receptors in the left ventricle of BIO TO-2 hamsters, a model of dilated cardiomyopathy (DCM). Oral administration of amlodipine (3 and 10 mg/kg/d, 19 weeks) in 7 week-old BIO TO-2 hamsters produced a significant reduction in calcium deposition and necrosis with little change in the cavity area and fibrosis. A reduction of calcium deposition and necrosis in the myocardium of BIO TO-2 hamsters was also seen following similar administration of cilnidipine (10 mg/kg/d). The long-term administration of amlodipine (3 and 10 mg/kg/d) caused a significant increase (36.6 and 21.7%, respectively) in the Bmax for specific (+)-[3H]PN 200-110 binding in the myocardium from BIO TO-2 hamsters, compared with that in control hamsters. In conclusion, the present study has shown that long-term administration of amlodipine and cilnidipine improves calcium deposition and necrosis in the myocardium from BIO TO-2 hamsters. Thus, these data suggest that both agents may be effective pharmacological treatments of DCM.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11041249&dopt=Abstract amlodipine Norvasc