amlodipine Norvasc
Disparate effects of angiotensin II antagonists and calcium channel blockers on albuminuria in experimental diabetes and hypertension: potential role of nephrin.

Davis BJ, Cao Z, de Gasparo M, Kawachi H, Cooper ME, Allen TJ.

Department of Medicine, University of Melbourne, Repatriation Campus, Heidelberg West, Victoria 3081, Australia.

OBJECTIVE AND DESIGN: To explore the effects of various antihypertensive regimes which achieve similar blood pressure control using a range of agents including the angiotensin II type 1 receptor antagonist, valsartan, as monotherapy or in combination with two subclasses of calcium channel blockers (CCBs) (the dihydropyridine, amlodipine and the phenylalkylamine, verapamil) on the progression of renal disease and the expression of the podocyte slit pore protein, nephrin in an accelerated model of diabetic nephropathy. RESULTS: Valsartan treatment reduced systolic blood pressure as assessed by radiotelemetry (135 +/- 3 versus diabetic 153 +/- 6 mmHg) as well as retarding the increase in albumin excretion rate by approximately 50%. Combination therapy of valsartan with either amlodipine or verapamil was equally effective in reducing blood pressure to valsartan monotherapy (valsartan + amlodipine 129 +/- 4 valsartan + verapamil 133 +/- 6 mmHg;) but was not as effective at reducing albuminuria. A reduction in glomerulosclerosis was observed with valsartan monotherapy with less reduction in injury with the valsartan + amlodipine combination, despite a similar reduction in blood pressure. The decrease in nephrin, in diabetic rats was attenuated by valsartan monotherapy, but not by other treatments. CONCLUSIONS: The results of this study demonstrate that despite a similar reduction in blood pressure, the addition of the CCB amlodipine to the AII antagonist failed to provide similar renoprotection to that observed with an equihypotensive regimen of valsartan as monotherapy. Furthermore, the depletion in glomerular nephrin expression in diabetic animals was only abrogated by valsartan treatment, the therapy which was most effective at retarding the development of albuminuria in this model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12544453&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Efficacy and safety of a therapeutic interchange from high-dose calcium channel blockers to a fixed-dose combination of amlodipine/benazepril in patients with moderate-to-severe hypertension.

Hilleman DE, Reyes AP, Wurdeman RL, Faulkner M.

Creighton University School of Pharmacy and Allied Health Professions, 2500 California Plaza, Omaha, NE 68178, USA.

BACKGROUND: Recent hypertension trials have demonstrated the importance of achieving goal blood pressures to reduce the risk of target organ damage. In patients with moderate to severe hypertension, the use of high-dose monotherapy and/or combinations of drugs are necessary to achieve these goals. Fixed-dose combination products may be useful in these patients by reducing the number of daily doses required to control blood pressure. OBJECTIVE: The objective of the present study was to evaluate the efficacy and safety of a therapeutic interchange between high-dose calcium channel blocker therapy and a fixed-dose combination of amlodipine/ benazepril (Lotrel; Novartis Pharmaceuticals, USA) in patients with moderate to severe hypertension. METHODS: A total of 75 patients were switched from amlodipine (n = 25), felodipine (n = 25), and nifedipine-GITS (n = 25) to amlodipine/benazepril. Twenty-eight of the 75 patients (37%) were taking either a beta-blocker or a diuretic in addition to the high-dose calcium channel blocker prior to the switch. Blood pressure control, side effects and the cost of the therapeutic interchange were evaluated in the year following the therapeutic interchange. RESULTS: Sixty-six of the 75 (88%) patients were successfully switched with maintenance of blood pressure control and without the development of new dose-limiting side effects. Reasons for treatment failure after the therapeutic interchange included loss of blood pressure control in five patients and the development of new dose-limiting side effects in four patients. These side effects included cough in three patients and rash in one patient. After accounting for differences in drug acquisition cost and costs related to the switch (clinic and emergency room and laboratory tests), a cost savings of $16030 for all 75 patients was realised in the first year. The per patient-per year cost savings was $214. CONCLUSIONS: Our data indicate that a therapeutic interchange from selected high-dose calcium channel blockers to a fixed-dose combination of amlodipine/ benazepril can be successfully accomplished in the majority of patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11494095&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Benidipine dilates both pre- and post-glomerular arteriole in the canine kidney.

Yue W, Kimura S, Fujisawa Y, Tian R, Li F, Rahman M, Nishiyama A, Fukui T, Abe Y.

Department of Pharmacology, Kagawa Medical School, Japan.

The aim of the present study was to determine the effects of benidipine on renal function and whether benidipine may dilate the efferent arteriole as well as the afferent arteriole of the canine kidney. The effects of benidipine on the renal segmental vascular resistance were estimated using Gomez's formula with some modification. The renal hemodynamic action of benidipine was also compared with that of amlodipine. Intrarenal arterial injection of benidipine at a dose of 3 microg/kg resulted in a significant increase in renal blood flow (RBF), urine flow and urinary excretion of sodium, but not in glomerular filtration rate (GFR). Amlodipine at a dose of 300 microg/kg also increased RBF, urine flow and urinary excretion of sodium to a significant degree equivalent to that by benidipine. However, in contrast to benidipine, amlodipine significantly increased GFR. After the administration of benidipine, autoregulation of RBF and GFR was relatively maintained and the renal perfusion pressure (RPP)-RBF relation shifted upward; that is, RBFs at 75 and 50 mmHg were maintained at a higher level than those of the control. In contrast to benidipine, amlodipine diminished the autoregulation of RBF and GFR. RBFs at 75 and 50 mmHg were not different from those of the control. The afferent and efferent arteriolar resistance (Ra and Re) were calculated based on the RPP-RBF and RPP-GFR relations. Benidipine reduced both Ra and Re, but amlodipine selectively reduced Ra. Benidipine increased RBF but not GFR via the dilation of both afferent and efferent arterioles. Thus, benidipine has unique renal hemodynamic actions which differ from those by most calcium antagonists.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11510756&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Pharmacist-managed hypertension therapy conversion.

Yanchick JK.

Drug Therapy Monitoring Unit, Reynolds Army Community Hospital, Department of Pharmacy, Building 4300, Fort Sill, OK 73503-6300, USA.

The cost of treating hypertension represents a substantial percentage of total pharmacy expenditures at medical centers and by managed care organizations in the United States. The present study evaluated improvements in blood pressure control and cost savings achieved by switching 543 hypertensive patients from nifedipine gastrointestinal therapeutic system (GITS) to amlodipine and concurrently instituting an educational program directed at prescribers, nursing and pharmacy staff, and patients and family members. Before the switch, 543 patients were being treated with nifedipine GITS: 259 with 30 mg/d, 209 with 60 mg/d, and 75 with 90 mg/d. The total annual cost of primary antihypertensive therapy for this patient population was $184,698. All patients were switched from nifedipine GITS to 5 mg of amlodipine. The pharmacist saw patients at the time of the switch and at 2, 4, and 6 to 8 weeks after the change in antihypertensive therapy. Patients who did not achieve systolic blood pressure < or = 140 mm Hg or diastolic blood pressure < or = 90 mm Hg by 6 to 8 weeks after the switch were titrated to 10 mg/d amlodipine. After the conversion, 417 patients were receiving amlodipine 5 mg/d and 126 patients were ultimately titrated to 10 mg/d. Measurements made during the first 6 to 8 weeks of treatment indicated that amlodipine therapy significantly reduced blood pressure. Overall, amlodipine produced further mean reductions in blood pressure, from 140/82 to 130/76 mm Hg (p < 0.00005). The mean reduction from the time of the switch to 6 to 8 weeks was from 138/81 to 129/74 mm Hg for the patients who received 5 mg/d amlodipine (p < 0.00001) and from 147/85 to 133/79 mm Hg for the patients ultimately titrated to 10 mg/d amlodipine (p < 0.05). The total annual cost for primary antihypertensive therapy after the conversion was $136,854. We observed that conversion from nifedipine GITS to amlodipine enhanced blood pressure control and saved $47,844 in the annual cost of primary antihypertensive medication. For the 543 patients undergoing the switch, annual cost savings was $47,844. When the cost of additional antihypertensive agents discontinued after the switch to amlodipine was added to the analysis, the net annual cost savings increased to $49,578, a 27% reduction in yearly drug costs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11603236&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Photodegradation monitoring of amlodipine by derivative spectrophotometry.

Ragno G, Garofalo A, Vetuschi C.

Department Scienze Farmaceutiche, Universita della Calabria, 87036 (CS), Arcavacata di Rende, Italy.

A derivative spectrophotometric method for the simultaneous determination of amlodipine and its pyridine photodegradation product has been developed. The analytes concentrations were linearly correlated with spectral measurements in the 3rd order UV derivative spectrum through equations obtained by simple and multiple regression analysis. The recovery values were estimated to range from 95 to 99% and the quantitation limit of the photoproduct was found to be equivalent to an impurity level of 1%, with respect to the content of amlodipine. The method could usefully be applied to routine quality control of pharmaceutical formulations containing amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11682206&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine on unitary non-L-type high voltage-activated Ca2+ channel currents in differentiated PC12 cells.

Hirano Y, Orikabe M, Hiraoka M.

Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Japan. hirano.card mri.tmd.ac.jp

Effects of amlodipine on unitary non-L-type high voltage-activated Ca2+ channels (Cav2 channels) were investigated in cell-attached patches of nerve growth factor (NGF)-differentiated PC12 cells. Cav2 channels, mainly composed of N-type channel in our experimental condition, were defined in this study as high voltage-activated Ca2+ channels obtained after selection of patches without L-type channel "mode 2" activity in the presence of 1 microM BayK8644, or L-type channel block by 5 microM nifedipine. At a test potential of +20 mV, they had a unitary current amplitude of approximately 0.5 pA and open time constants of approximately 0.4 ms and approximately 1.1 ms when fit assuming double exponential components. As bath application of amlodipine was ineffective to modify Cav2 channels in the sealed patch, we analyzed the channel activity when giga-seal formation was obtained in the presence of amlodipine (10 microM both in the pipette and bath solution). Amlodipine did not modify the unitary current amplitude but suppressed the channel open probability (NPo) when holding potential was depolarized, shifting the voltage-dependent inactivation curve towards negative potentials by 25mV. Amlodipine-induced suppression of NPo was mainly due to the decreased ratio of sweeps with channel openings (availability) and was not associated with changes in open time constants. These results were consistent with the view that amlodipine prevented channel openings through the high-affinity binding to the inactivated state, as often observed when dihydropyridines block L-type Ca2+ channels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11683521&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Long-term administration of amlodipine prevents decompensation to diastolic heart failure in hypertensive rats.

Nishikawa N, Masuyama T, Yamamoto K, Sakata Y, Mano T, Miwa T, Sugawara M, Hori M.

Department of Internal Medicine and Therapeutics (A8), Suita, Japan.

OBJECTIVES; We assessed the effects of long-term amlodipine administration in a diastolic heart failure (DHF) rat model with preserved systolic function as well as the relationship between changes in left ventricular (LV) myocardial stiffening and alterations in extracellular matrix. BACKGROUND: Although the effect of long-term administration of amlodipine has been shown to be disappointing in patients with systolic failure, the effect is unknown in those with DHF. METHODS: Dahl salt-sensitive rats fed a high-salt diet for seven weeks were divided into three groups: eight untreated rats (DHF group), eight rats given high-dose amlodipine (10 mg/kg/day; HDA group) and seven rats given low-dose amlodipine (1 mg/kg/day; LDA group). RESULTS: High-dose administration of amlodipine decreased systolic blood pressure and controlled excessive hypertrophy, without a decrease in the collagen content, and prevented the elevation of LV end-diastolic pressure at 19 weeks. Low-dose administration of amlodipine with subdeppressive effects did not control either hypertrophy or fibrosis; however, it prevented myocardial stiffening and, hence, the elevation of LV end-diastolic pressure. The ratio of type I to type III collagen messenger ribonucleic acid levels was significantly lower in both the HDA and LDA groups than in the DHF group. CONCLUSIONS: Long-term administration of amlodipine prevented the transition to DHF both at the depressor and subdepressor doses. Amlodipine did not decrease the collagen content, but attenuated myocardial stiffness, with inhibition of the phenotype shift from type III to type I collagen. Thus, amlodipine may exert beneficial effects through amelioration of collagen remodeling in the treatment of DHF.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11691537&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Preferential renal and mesenteric vasodilation induced by barnidipine and amlodipine in spontaneously hypertensive rats.

Janssen BJ, Kam KL, Smits JF.

Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Universiteit Maastricht, P.O. Box 616, Maastricht 6200 MD, The Netherlands. b.janssen farmaco.unimaas.nl

Barnidipine is a stereoselective single isomer formulation of a long-term acting dihydropyridine calcium antagonist (CaA). In anaesthetised animals, the antihypertensive response to barnidipine is accompanied by a diuretic effect. The aim of the present study was to examine whether barnidipine increased renal blood flow in a conscious animal model for essential hypertension. We compared the regional specific hemodynamic effects of barnidipine with those obtained with its racemic mixture and amlodipine. Male adult spontaneously hypertensive rats (SHR) were instrumented with Doppler flow probes and catheters to measure renal (RVR), mesenteric (MVR) and hindquarter (HQVR) vascular resistance changes. One week after surgery, barnidipine, its racemic mixture, and amlodipine were intravenously administered at three doses (n> or =10 per dose) causing comparable reductions in mean arterial pressure (MAP). At doses of 3, 10 and 30 microg/kg barnidipine reduced MAP (+/- SEM) by 8+/-2, 26+/-3 and 45+/-4 mmHg. Equipotent effects on MAP were achieved by the racemic mixture of barnidipine at 10, 30 and 100 microg/kg, and by amlodipine at doses of 100, 300 and 1000 microg/kg. Following the 3 microg/kg and 10 microg/kg dose, barnidipine reduced MVR (% +/- SEM) by 4+/-4 and 19+/-4, and RVR by 8+/-2 and 15+/-4, respectively. In contrast, HQVR remained unaltered. Similar data were obtained for the racemic mixture of barnidipine and for amlodipine, although for the latter the changes in RVR were half of those found after barnidipine. After the highest doses of barnidipine, its racemic mixture as well as amlodipine, HQVR fell more than 25% whereas RVR and MVR remained unaltered. Analysis of the dynamic response to the CaAs revealed that the reductions in vascular resistance were associated with decreased myogenic-like oscillations in blood flow. We conclude that, in conscious SHR, the single isomer barnidipine reduces MAP at doses which are three times lower than its racemic mixture and 30 times lower than amlodipine. In contrast to short-acting CaAs such as nifedipine and isradipine, which reduce mainly HQVR and do not reduce RVR (Nievelstein et al.; Eur J Pharmacol 113:187-198, 1985), the three long-term acting CaAs preferentially dilated the mesenteric and renal vascular bed. In view of the elevation of RVR in essential hypertension, the reduction of RVR may contribute to the long-term antihypertensive effects of barnidipine and amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11692224&dopt=Abstract amlodipine Norvasc