amlodipine Norvasc
Amlodipine gynaecomastia.

Cornes PG, Hole AC.

Department of Radiotherapy, Royal Marsden Hospital, Sutton SM2 5PT, UK.

We report only the second published confirmed case of gynaecomastia caused by amlodipine (a dihydropyridine calcium channel blocker). Gynaecomastia developed in a 70-year-old male within 3 months of starting amlodipine, and symptoms resolved within 3 weeks of drug withdrawal suggesting a strong relationship between amlodipine and gynaecomastia in this patient. Recent research has suggested possible interesting novel mechanisms for amlodipine gynaecomastia, which are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14965638&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine besylate-excipients interaction in solid dosage form.

Abdoh A, Al-Omari MM, Badwan AA, Jaber AM.

The Jordanian Pharmaceutical Manufacturing Co., Naor, Jordan.

This article studies the compatibility of amlodipine besylate in its solid formulations with various drug excipients. The various factors affecting amlodipine besylate stability were studied using high-performance liquid chromatography (HPLC). It has been found that binary 1:1 mixtures of amlodipine besylate and an excipient are stable at 65 degrees C and 40 degrees C/75% RH. Further investigations were conducted to study the stability of amlodipine besylate in multicomponent mixtures, including mixtures with actual formulations. The study reveals that mixtures of lactose, magnesium stearate, and water induce some instability on amlodipine besylate. The major degradation product confirmed by HPLC-mass spectrometry is amlodipine besylate glycosyl. This is in conformity with the well-known Maillard reaction between primary amines and lactose. Thus, lactose-free amlodipine formulations are recommended from the safety, quality, efficacy, and process cost points of view.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15000463&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis.

Candido R, Allen TJ, Lassila M, Cao Z, Thallas V, Cooper ME, Jandeleit-Dahm KA.

Vascular Division, Baker Heart Research Institute, PO Box 6492, Melbourne 8008, Victoria, Australia.

BACKGROUND: It remains controversial whether specific blockade of the renin-angiotensin system confers superior antiatherosclerotic effects over other antihypertensive agents in diabetes. Therefore, the aim of this study was to compare equihypotensive doses of the angiotensin II subtype 1 (AT1) receptor blocker irbesartan with the calcium antagonist amlodipine on diabetes-induced plaque formation in the apolipoprotein E (apoE)-null mouse and to explore molecular and cellular mechanisms linked to vascular protection. METHODS AND RESULTS: Diabetes was induced by injection of streptozotocin in 6-week-old apoE-null mice. Diabetic animals were randomized to no treatment, irbesartan, or amlodipine for 20 weeks. Diabetes was associated with an increase in plaque area and complexity in the aorta in association with a significant increase in aortic AT1 receptor expression, cellular proliferation, collagen content, macrophage- and alpha-smooth muscle actin-positive cell infiltration, as well as an increased expression of platelet-derived growth factor-B (PDGF-B), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). Irbesartan but not amlodipine treatment attenuated the development of atherosclerosis, collagen content, cellular proliferation, and macrophage infiltration as well as diabetes-induced AT1 receptor, PDGF-B, MCP-1, and VCAM-1 overexpression in the aorta despite similar blood pressure reductions by both treatments. CONCLUSIONS: Diabetes-associated atherosclerosis is ameliorated by AT1 receptor blockade but not by calcium channel antagonism, providing further evidence for the vascular renin-angiotensin system playing a pivotal role in the development and acceleration of atherosclerosis in diabetes.

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amlodipine Norvasc
Early blood pressure normalization independent of the class of antihypertensive agent prevents augmented renal fibronectin and albuminuria in experimental diabetic nephropathy.

Lehfeld LS, Silveira LA, Ghini B, Lopes de Faria JB.

Division of Nephrology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil.

BACKGROUND/AIMS: This study tested the hypothesis that prevention of the development of hypertension, and not the class of antihypertensive agent, inhibits the increase in renal fibronectin and albuminuria in experimental diabetes. METHODS: Four-week-old spontaneously hypertensive rats (SHR), with diabetes induced by streptozotocin, were randomized for no treatment, or treatment with captopril, amlodipine, an association of captopril and amlodipine (Cap+A) or an association of captopril and verapamil (Cap+V) for 12 weeks. RESULTS: Systolic blood pressure increased similarly in control (187 +/- 5 mm Hg, mean +/- SE) and diabetic (186 +/- 4) SHR and was kept within the normal range by amlodipine (131 +/- 3), captopril (127 +/- 3), Cap+A (134 +/- 4) and Cap+V (134 +/- 9, p < 0.0001). In diabetic rats, albuminuria was higher than in control SHR [geometric mean (variance), 1,213 (953-1,708) vs. 512 (213-850), p < 0.0001] and was reduced to a similar extent by amlodipine [573 (353-744), p < 0.0001], captopril [562 (238-771), p < 0.0001], Cap+A [679 (442-971), p < 0.0001] and Cap+V [748 (581-848) microg/24 h, p = 0.0002]. Renal fibronectin increased in diabetic rats (24.0 +/- 3.3 densitometric units, mean +/- SE) compared to control rats (9.6 +/- 1.8, p = 0.0005) and was normalized by amlodipine (9.9 +/- 1.0, p = 0.0001), captopril (11.2 +/- 0.4, p = 0.0016), Cap+A (9.9 +/- 2.0, p = 0.0004) and Cap+V (14.7 +/- 4.9, p = 0.0159). CONCLUSION: In this model, tight blood pressure control rather than the class of antihypertensive agent was the main determinant factor in attenuating of nephropathy. Copyright 2004 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15051931&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Blood pressure and alpha-vascular reactivity in hypertensive rats treated with amlodipine and dietary Ca.

Civantos B, Aleixandre A.

Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain.

It has been suggested that the combination of dietary Ca and Ca2+ channel antagonists could have a synergic antihypertensive effect. In this study, 3-week-old male spontaneously hypertensive rats (SHR) were randomized into four groups of animals. Two of these groups were fed on a normal Ca diet (Ca 1%) and the other two groups were fed on a Ca-enriched diet (Ca 2.5%). One of the groups fed on each diet also received amlodipine (1 mg/kg/day) in their drinking water. Systolic and diastolic arterial blood pressure were measured weekly in the rats, from the 6th week of life until the 25th week of life, by the tail-cuff method, and we also calculated the corresponding pulse pressure values (systolic blood pressure-diastolic blood pressure). Determination of plasma Ca levels by colourimetric methods, and measurement in pithed rats of the pressor responses to the alpha-adrenoceptor agonists methoxamine and B-HT 920 (5-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d)-acepin-dihydrochloride, talixepole) were also performed using 16- and 23-week-old animals from the different groups. The Ca-enriched diet decreased systolic and diastolic blood pressure in SHR. Almodipine also decreased systolic and diastolic blood pressure in SHR, and this drug intensified the antihypertensive effect of the Ca 2.5% diet in the SHR between weeks 13 and 18. Nevertheless, in the 19- to 25-week-old SHR amlodipine antagonized the effect of dietary Ca on arterial blood pressure. A decrease in the pulse pressure was seen only in the 15- to 20-week-old SHR which had been simultaneously treated with dietary Ca and amlodipine. All the treatments used increased calcaemia, and the highest plasma Ca levels were obtained in the animals which had received the combined treatment with Ca and amlodipine. The responses to methoxamine and to B-HT 920 in the pithed 16-week-old SHR were similar in the four groups of animals. The responses to these agonists in the pithed 23-week-old SHR fed on the Ca-enriched diet were smaller than the corresponding responses in 23-week-old SHR of the untreated group. By contrast, the responses to these agonists were slightly higher in the pithed 23-week-old SHR which were treated with amlodipine than in the pithed 23-week-old SHR in the untreated group. Moreover, amlodipine partially reversed the effect of dietary Ca on alpha-vascular reactivity. According to our results, it would seem inadvisable to use dietary Ca with a Ca2+ channel antagonist with the aim of controlling arterial blood pressure.

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amlodipine Norvasc
Oxygen-dependent mechanisms underlying the antiischemic effect of verapamil and amlodipine.

Gatsura SV.

Russian State Medical University, Moscow. svg medicina.ru

Verapamil and amlodipine produced a potent antiischemic effect and reduced the area of myocardial infarction in rats. The observed changes were accompanied by inhibition of lipid peroxidation. In contrast to verapamil, amlodipine in a dose of 50 ng/ml in vitro decreased hemoglobin affinity for oxygen. Moreover, amlodipine in a concentration of 2 ng/ml decreased the content of malonic dialdehyde and activity of superoxide dismutase in the blood.

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amlodipine Norvasc
Amlodipine at high dose increases preproendothelin-1 expression in the ventricles and aorta of normotensive rats.

Krenek P, Morel N, Kyselovic J, Wibo M.

Laboratoire de Pharmacologie, Universite Catholique de Louvain, Avenue Hippocrate 54, B 1200 Brussels, Belgium.

BACKGROUND: High doses of dihydropyridine calcium channel blockers can activate the sympathetic nervous system and the renin-angiotensin system. Both noradrenaline and angiotensin II stimulate preproendothelin-1 gene expression, yet the effects of high doses of dihydropyridines on preproendothelin-1 expression in vivo remain unknown. OBJECTIVES: To investigate the effects of high doses of dihydropyridines on preproendothelin-1 expression in the ventricles and aorta of normotensive rats. METHODS: Sprague-Dawley rats were treated with amlodipine 5 or 20 mg/kg per day (Amlo 5 or Amlo 20) in drinking water for 5 days or 5 weeks. Systolic blood pressure and heart rate were measured by tail-cuff plethysmography. Gene expression was examined by reverse transcriptase polymerase chain reaction. RESULTS: Amlo 5 increased heart rate during the first week only and had no effect on blood pressure and ventricular weight and gene expression. Amlo 20 reduced blood pressure transiently and increased heart rate consistently. It did not change relative left ventricular weight (corrected for body weight) after 5 days, but increased it after 5 weeks; it increased relative right ventricular weight at both time points. Aorta weight (mg/mm) was decreased after 5 weeks of treatment with both dosages of amlodipine. Preproendothelin-1 mRNA levels were increased by Amlo 20 in the ventricles and aorta and, concomitantly, renin mRNA was increased in the kidney. Less consistently, interleukin-6 mRNA also increased in ventricles, whereas cardiotrophin-1 mRNA remained unchanged. The sensitivity of isolated aorta to the contractile effect of noradrenaline was decreased by Amlo 5, but not by Amlo 20. CONCLUSIONS: In Sprague-Dawley rats, high-dose amlodipine, while promoting neurohormonal activation, induced overexpression of preproendothelin-1 mRNA in the ventricles and aorta. Endothelin-1 overexpression could contribute to the lack of inhibitory effect of high-dose amlodipine on ventricular mass in normotensive rats.

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amlodipine Norvasc
Amlodipine and carvedilol prevent cytotoxicity in cortical neurons isolated from stroke-prone spontaneously hypertensive rats.

Yamagata K, Ichinose S, Tagami M.

Laboratory of Nutritional Biochemistry and Center of Excellence Program in the 21st Century, School of Food and Nutritional Sciences, The University of Shizuoka, Shizuoka, Japan. yamagata brs.nihon-u.ac.jp

We previously reported that vitamin E prevents apoptosis in neurons during cerebral ischemia and reperfusion in stroke-prone spontaneously hypertensive rats (SHRSP). In this paper, we analyzed the effects of antihypertensives as well as vitamin E, which were added to neuron cultures after reoxygenation (20% O2) following hypoxia (1% O2). When added after hypoxia before reoxygenation, vitamin E conferred significant protection to neuronal cells. It was also shown that vitamin E conferred complete protection from neural cell death when added hypoxia and again before reoxygenation. At higher concentrations of vitamin E, strong neuroprotection was observed. Moreover, we verified that pretreatment with either amlodipine, carvedilol or dipyridamole consistently prevented cell death during hypoxia and reoxygenation (H/R). On the other hand, nilvadipine, a dihydropyridine-type calcium entry blocker, had no apparent effect on neuroprotection during H/R. The order of neuroprotective potency was vitamin E > dipyridamole > carvedilol > or = amlodipine > nilvadipine. In parallel experiments, we examined whether these antihypertensive agents were more effective when combined with vitamin E and dipyridamole. The results suggested that in our in vitro model system, antioxidants were the most important agents for the reduction of oxygen-free radical damage in cortical neurons. These findings suggest that amlodipine and carvedilol, with their antioxidant properties and antihypertensive activity, would be useful to inhibit neuronal cell death in the treatment of cerebrovascular stroke and neurodegenerative diseases in hypertensive patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15127885&dopt=Abstract amlodipine Norvasc