amlodipine Norvasc
Doxorubicine-congestive heart failure-increased big endothelin-1 plasma concentration: reversal by amlodipine, losartan, and gastric pentadecapeptide BPC157 in rat and mouse.

Lovric-Bencic M, Sikiric P, Hanzevacki JS, Seiwerth S, Rogic D, Kusec V, Aralica G, Konjevoda P, Batelja L, Blagaic AB.

Department of Pharmacology, Medical Faculty, University of Zagreb, Croatia.

Overall, doxorubicine-congestive heart failure (CHF) (male Wistar rats and NMRI mice; 6 challenges with doxorubicine (2.5 mg/kg, i.p.) throughout 15 days and then a 4-week-rest period) is consistently deteriorating throughout next 14 days, if not reversed or ameliorated by therapy (/kg per day): a stable gastric pentadecapeptide BPC157 (GEPPPGKPADDAGLV, MW 1419, promisingly studied for inflammatory bowel disease (Pliva; PL 10, PLD-116, PL 14736)) (10 microg, 10 ng), losartan (0.7 mg), amlodipine (0.07 mg), given intragastrically (i.g.) (once daily, rats) or in drinking water (mice). Assessed were big endothelin-1 (BET-1) and plasma enzyme levels (CK, MBCK, LDH, AST, ALT) before and after 14 days of therapy and clinical status (hypotension, increased heart rate and respiratory rate, and ascites) every 2 days. Controls (distilled water (5 ml/kg, i.g., once daily) or drinking water (2 ml/mouse per day) given throughout 14 days) exhibited additionally increased BET-1 and aggravated clinical status, while enzyme values maintained their initial increase. BPC157 (10 microg/kg) and amlodipine treatment reversed the increased BET-1 (rats, mice), AST, ALT, CK (rats, mice), and LDH (mice) values. BPC157 (10 ng/kg) and losartan opposed further increase of BET-1 (rats, mice). Losartan reduces AST, ALT, CK, and LDH serum values. BPC157 (10 ng/kg) reduces AST and ALT serum values. Clinical status of CHF-rats and -mice is accordingly improved by the BPC157 regimens and amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15153646&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Adherence to calcium channel blocker therapy in older adults: a comparison of amlodipine and felodipine.

Menzin J, Lang K, Elliott WJ, Boulanger L, Arocho R, Tran MH, Friedman M.

Boston Health Economics, Inc., Waltham, MA, USA. jmenzin bhei.com

The efficacy of dihydropyridine calcium channel blockers for treating hypertension appears to be similar, but a variety of factors, including patient characteristics, tolerability and pharmacokinetic properties, may influence treatment adherence and outcome. We aimed to evaluate treatment adherence in clinical practice among older hypertensive adults (50+ years) prescribed amlodipine or felodipine for the first time as part of the California Medicaid (Medi-Cal) program. We used a retrospective, matched, cohort-analysis design. Over 1 year, patients prescribed amlodipine were 21% less likely to discontinue study treatment than those prescribed felodipine. Discontinuation tended to occur early, with 20% and 30% of amlodipine and felodipine patients, respectively, discontinuing treatment after one prescription. A non-significant difference in favour of amlodipine was demonstrated for anti-anginal medication use among patients taking these drugs at baseline. This study suggests that use of amlodipine may be associated with improved adherence, compared with felodipine, among older out-patients in the Medi-Cal program.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15174215&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Antitumor effects of amlodipine, a Ca2+ channel blocker, on human epidermoid carcinoma A431 cells in vitro and in vivo.

Yoshida J, Ishibashi T, Nishio M.

Department of Pharmacology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan. yayuyo kanazawa-med.ac.jp

Amlodipine, a dihydropyridine Ca(2+) channel blocker, is reported to inhibit proliferation of human epidermoid carcinoma A431 cells, and specifically attenuates Ca(2+) responses evoked by thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+)-ATPases. In this study, we further examined the possible mechanism of the antiproliferative action of amlodipine and its antitumor effect on A431 xenografts in nude mice. Amlodipine reduced BrdU incorporation into nucleic acids in serum-starved A431 cells, and the reduction was diminished by uridine 5'-triphosphate (UTP), a phospholipase C (PLC)-linked agonist. Fluorometric measurement of intracellular free Ca(2+) concentration revealed that amlodipine blunted the UTP-induced Ca(2+) release from the internal Ca(2+) stores and consequently Ca(2+) influx through Ca(2+)-permeable channels on the plasma membrane. Although amlodipine alone caused Ca(2+) release from thapsigargin-sensitive Ca(2+) stores, such an effect was not reproduced by other dihydropyridine Ca(2+) channel blockers, including nicardipine and nimodipine, despite their antiproliferative effects in the cells. Daily intraperitoneal administration of amlodipine (10 mg/kg) for 20 days into mice bearing A431 xenografts retarded tumor growth and prolonged the survival of mice. Our results suggest a potential antitumor action for amlodipine in vitro and in vivo, which may be in part mediated by inhibiting Ca(2+) influx evoked by the passive depletion of internal Ca(2+) stores and by PLC-linked agonist stimulation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15178352&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine decreases fibrosis and cardiac hypertrophy in spontaneously hypertensive rats: persistent effects after withdrawal.

Sevilla MA, Voces F, Carron R, Guerrero EI, Ardanaz N, San Roman L, Arevalo MA, Montero MJ.

Laboratorio de Farmacognosia y Farmacologia, Facultad de Farmacia, Departamento de Fisiologia y Farmacologia, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca 37007, Spain.

Our objective was to examine the effect of chronic treatment with amlodipine on blood pressure, left ventricular hypertrophy, and fibrosis in spontaneously hypertensive rats and the persistence of such an effect after drug withdrawal. We investigated the effects of treatment with 2, 8 and 20 mg/kg/day of amlodipine given orally for six months and at three months after drug withdrawal. Systolic blood pressure was measured using the tail-cuff method. At the end of the study period, the heart was excised, the left ventricle was isolated, and the left ventricle weight/body weight ratio was calculated as a left ventricular hypertrophy index. Fibrosis, expressed as collagen volume fraction, was evaluated using an automated image-analysis system on sections stained with Sirius red. Age-matched untreated Wistar-Kyoto and SHR were used as normotensive and hypertensive controls, respectively. Systolic blood pressure was reduced in the treated SHR in a dose-dependent way and after amlodipine withdrawal it increased progressively, without reaching the values of the hypertensive controls. Cardiac hypertrophy was reduced by 8 and 20 mg/kg/day amlodipine, but when treatment was withdrawn only the group treated with 8 mg/kg/day maintained significant differences versus the hypertensive controls. All three doses of amlodipine reduced cardiac fibrosis and this regression persisted with the two highest doses after three months without treatment. We concluded that antihypertensive treatment with amlodipine is accompanied by a reduction in left ventricular hypertrophy and regression in collagen deposition. Treatment was more effective in preventing fibrosis than in preventing ventricular hypertrophy after drug withdrawal. Copyright 2004 Elsevier Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15183079&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Different effects of calcium channel blockers on matrix metalloproteinase-2 expression in cultured rat cardiac fibroblasts.

Yue H, Uzui H, Shimizu H, Nakano A, Mitsuke Y, Ueda T, Lee JD.

First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

The cardiac effects of calcium channel blockers (CCBs) related to cardiac remodeling are inconsistent. Matrix metalloproteinases (MMPs) contribute to tissue remodeling. Cardiac fibroblasts play an important role in the regulation of collagen degradation by MMPs. Using gelatin zymography, Western blotting, Griess reagent, and a calcium kit-fluo 3, we investigated the effects of nifedipine, verapamil, diltiazem, and amlodipine on MMP-2 expression and further elucidate the mechanisms in cultured rat cardiac fibroblasts. Nifedipine increased and amlodipine decreased the expression of MMP-2; however, neither verapamil nor diltiazem altered MMP-2 expression. Nifedipine also increased nitrite production, and this increase was blunted by a nitric oxide (NO) synthases inhibitor (L-NAME). Nifedipine-induced MMP-2 expression was also blunted by L-NAME. An NO donor (sodium nitroprusside) induced MMP-2 expression. Data indicated that nifedipine might increase MMP-2 expression through a possible NO-dependent pathway. Amlodipine had no influence on nitrite production. The amlodipine-induced decrease of MMP-2 expression was abolished by two protein tyrosine kinase inhibitors, genistein and herbimycin A, indicating that amlodipine might decrease MMP-2 expression through a possible protein tyrosine kinase pathway. None of the four CCBs could alter the fluoscence intensity of fluo 3, indicating that the effects of CCBs on MMP-2 expression were independent of the variation in intracellular C2+ concentration. Our findings revealed that different CCBs exerted different effects on MMP-2 expression in cardiac fibroblasts.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15243304&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Evaluation of synergism between the aminoglycoside antibiotic streptomycin and the cardiovascular agent amlodipine.

Asok Kumar K, Mazumdar K, Dutta NK, Karak P, Dastidar SG, Ray R.

Division of Microbiology, Department of Pharmaceutical Technology, Jadavpur University, Calcutta, India.

Amlodipine, a cardiovascular drug, exhibited remarkable antibacterial action in vitro against 504 bacterial strains belonging to both Gram positive and Gram negative genera, as well as in vivo against a mouse-virulent bacterium. Based on such findings, the present study was undertaken to determine whether the efficacy of this non-antibiotic drug could be enhanced in the presence of any antibiotic. Twelve bacterial strains, sensitive to amlodipine as well as to 6 antibiotics, viz., benzyl penicillin, streptomycin, chloramphenicol, tetracycline, erythromycin and ciprofloxacin were chosen. Disc diffusion test with amlodipine and streptomycin revealed marked synergism between the combination, compared with their individual effects. The synergism was found to be statistically significant (p<0.01). To assess the degree of synergy, the checkerboard analysis was performed. The fractional inhibitory concentration (FIC) index of this combination turned out to be 0.24, which confirmed synergism. This antibiotic-non-antibiotic pair was then administered to mice, challenged with S. typhimurium to determine whether this was effective in vivo. Statistical analysis of the mouse protection tests suggested that the combination was highly synergistic (p<0.001), according to Student's t-test. This synergistic drug combination may help us in enhancing the scope of prolonged antibiotic therapy in various types of infections, and might open a new therapeutic approach to combat drug resistance in bacterial diseases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15256751&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
A fatal case of amlodipine poisoning.

Johansen SS, Genner J.

Department of Forensic Chemistry and Department of Forensic Pathology, Institute of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark. sys.stybe forensic.ku.dk

A fatal overdose of amlodipine, a calcium channel blocker, in a 50-year-old man is described. Biological samples obtained at autopsy were screened for common drugs and narcotics. The amlodipine determination was made by HPLC with diode-array detection and a post-mortem blood concentration of 2.3 mg/kg was determined. The only other drug detected was a blood alcohol concentration of 0.008%. The presence of amlodipine was confirmed in other tissues and in the stomach content. The overdose is assumed to be an accumulation of amlodipine due to the long half-life of this drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15275013&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
[Cost-efectiveness of Ibersartan in type II diabetic nephropathy with hypertension. A Spanish perspective]

[Article in Spanish]

Palmer AJ, Annemans L, Roze S, Lamotte M, Rodby RA, de Alvaro F; Grupo de Estudio Colaborativo IDNT.

Hospital La Paz, Servicio de Nefrologia, Madrid.

BACKGROUND: In the Irbesartan Diabetic Nephropathy Trial (IDNT), treatment with irbesartan demonstrated 23% and 20% reductions in the combined endpoint of doubling of serum creatinine (DSC), end-stage renal disease (ESRD) or death in patients with hypertension, type 2 diabetes and overt nephropathy compared to amlodipine and control respectively. A simulation model was developed to project long-term cost consequences of the IDNT in the Spanish setting. METHODS: A Markov model simulated progression from nephropathy to DSC, ESRD and death in patients with hypertension, type 2 diabetes and overt nephropathy. Treatment-specific probabilities were derived from IDNT. Country-specific ESRD-related data were retrieved from published sources. Delay in onset of ESRD, life expectancy and mean lifetime costs were calculated for patients with baseline age 59 years. Future costs were discounted at 6% per annum, and clinical benefits were discounted at 0% and 6% per annum. Extensive sensitivity analyses were performed. RESULTS: Onset of ESRD was delayed with irbesartan by 1.41 and 1.35 years versus amlodipine and control respectively. When a 25-year (lifetime) horizon was considered, delay in ESRD onset led to anticipated improvements in life expectancy (discounted at 6% shown in brackets) of 0.46 (0.21) years versus amlodipine and 0.75 (0.37) years versus control. Irbesartan was associated with cost savings of 13,673 Euro and 7,632 Euro patient versus amlodipine and control respectively. The results were robust under a wide range of plausible assumptions. CONCLUSIONS: Treating patients with hypertension, type 2 diabetes and overt nephropathy using irbesartan was both cost- and life-saving compared to amlodipine and control in the Spanish setting.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15283313&dopt=Abstract amlodipine Norvasc