The inhibitory mechanisms of amlodipine in human vascular smooth muscle cell proliferation.
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The abnormal proliferation of vascular smooth muscle cells (VSMCs) is closely related to vascular diseases. There is growing evidence that calcium antagonists inhibit VSMC growth/proliferation, yet their molecular mechanisms remain to be determined. Recent reports suggest that p42/p44 mitogen-activated protein kinases (MAPKs) play an important role in cell growth and proliferation induced by growth factors. This study was designed to determine whether these MAPKs are involved in VSMC proliferation induced by basic fibroblast growth factor (bFGF) and to examine the inhibitory effect of amlodipine. Human VSMCs were obtained from inner mammary artery. p42/p44 MAPKs activity was measured by immunoblotting assay using anti-p42/p44 phospho-MAPK antibody. 1) bFGF (20 ng/ml) significantly activated p42/p44 MAPKs with a peak time of 5-15 min, which was maintained for 3 h. PD98059 (100 nM-10 microM), a specific inhibitor of MAPK kinase, inhibited bFGF-induced p42/p44 MAPKs activation in a dose-dependent manner. 2) Amlodipine (1-100 nM) dose-dependently inhibited p42/p44 MAPKs activation by bFGF. 3) Amlodipine (10 nM) could inhibit both short-term and long-term p42/p44 MAPKs activation by bFGF. Our results indicate that bFGF could activate p42/p44 MAPKs. Amlodipine, which could inhibit bFGF-induced human VSMC proliferation, inhibited both short-term and sustained p42/p44 MAPKs activation by bFGF, suggesting that bFGF-induced VSMC proliferation may be related to p42/p44 MAPKs activation, and that the antiproliferative effect of amlodipine may be related to its inhibition of p42/p44 MAPKs activation. (+info)
Circadian rhythm and sudden death in heart failure: results from Prospective Randomized Amlodipine Survival Trial.
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OBJECTIVE: The purpose of this study was to address the timing of sudden death in advanced heart failure patients. BACKGROUND: Sudden death is a catastrophic event in cardiovascular disease. It has a circadian pattern prominent in the early AM, which has been thought to be due to a surge of sympathetic stimulation. We postulated that the distribution of events in advanced heart failure, with chronic sympathetic activation, would be more uniform implicating other potential mechanisms. METHODS: We analyzed data from Prospective Randomized Amlodipine Survival Trial (PRAISE). Sudden deaths were analyzed by time of death in 4-h and 1-h blocks for uniformity of distribution in the entire cohort, and in the prespecified ischemic and nonischemic stratum. Further analyses were undertaken in the treatment groups of amlodipine and placebo, and among those receiving background therapy of aspirin and warfarin. RESULTS: Sudden deaths in the overall cohort showed a nonuniform distribution with a PM peak but not an AM peak. The ischemic stratum also showed a PM peak, but sudden deaths within the nonischemic stratum were uniformly distributed. Neither amlodipine treatment nor aspirin or warfarin use altered the distribution. CONCLUSIONS: Sudden death in advanced heart failure did not show an AM peak, suggesting that circadian sympathetic activation did not strongly influence these events. The PM peak noted is likely complex in origin and was not affected by antiischemic or antithrombotic medications. (+info)
Efficacy of candesartan cilexetil alone or in combination with amlodipine and hydrochlorothiazide in moderate-to-severe hypertension. UK and Israel Candesartan Investigators.
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This multicenter study evaluated the efficacy of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, used alone or in combination with amlodipine or in combination with amlodipine and hydrochlorothiazide in the treatment of patients with moderate-to-severe essential hypertension. After a 2-week, single-blind, placebo run-in period, patients entered a 12-week, open-label, dose-titration period. The candesartan cilexetil dose was increased from 8 to 16 mg once daily; amlodipine (5 mg once daily), hydrochlorothiazide (25 mg once daily), and additional medication were also added sequentially if necessary. Patients then entered a final 4-week, parallel-group, double-blind, randomized, placebo-controlled withdrawal period of candesartan alone. A total of 216 patients were recruited. After a 2-week run-in period on placebo tablets, mean sitting blood pressure (BP) was 175/108 mm Hg. At the end of the 12-week dose-titration/maintenance period, mean sitting BP fell to 141/88 mm Hg. In 67 patients who were randomized to placebo and had their candesartan withdrawn, there was a highly significant increase in mean systolic/diastolic BP (13/6 mm Hg) compared with those patients who continued with candesartan (ANCOVA, P:<0.0001). In conclusion, candesartan cilexetil is an effective BP-lowering drug when used alone or in combination with amlodipine or amlodipine plus hydrochlorothiazide in the treatment of moderate-to-severe essential hypertension. The drug was well tolerated throughout the investigation period. (+info)
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. (+info)
Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators.
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BACKGROUND: The results of angiographic studies have suggested that calcium channel-blocking agents may prevent new coronary lesion formation, the progression of minimal lesions, or both. METHODS AND RESULTS: The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) was a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to test whether amlodipine would slow the progression of early coronary atherosclerosis in 825 patients with angiographically documented coronary artery disease. The primary outcome was the average 36-month angiographic change in mean minimal diameters of segments with a baseline diameter stenosis of 30%. A secondary hypothesis was whether amlodipine would reduce the rate of atherosclerosis in the carotid arteries as assessed with B-mode ultrasonography, which measured intimal-medial thicknesses (IMT). The rates of clinical events were also monitored. The placebo and amlodipine groups had nearly identical average 36-month reductions in the minimal diameter: 0.084 versus 0.095 mm, respectively (P:=0.38). In contrast, amlodipine had a significant effect in slowing the 36-month progression of carotid artery atherosclerosis: the placebo group experienced a 0.033-mm increase in IMT, whereas there was a 0. 0126-mm decrease in the amlodipine group (P:=0.007). There was no treatment difference in the rates of all-cause mortality or major cardiovascular events, although amlodipine use was associated with fewer cases of unstable angina and coronary revascularization. CONCLUSIONS: Amlodipine has no demonstrable effect on angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events but is associated with fewer hospitalizations for unstable angina and revascularization. (+info)
Using administrative data to compare the relative effectiveness of amlodipine vs nifedipine CC.
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OBJECTIVE: To describe an approach for using claims data to compare the effectiveness of 2 similar drugs used for similar indications within a health maintenance organization. STUDY DESIGN: A database study comparing the effectiveness of amlodipine and nifedipine CC in the initial treatment of hypertension. PATIENTS AND METHODS: The claims records of Pennsylvania Medicaid patients between 18 and 64 years of age with continuous eligibility in 1994 were studied. Pharmacy, hospital, and outpatient claims data were merged, and adult patients receiving the target drugs for the specified indication were identified. The effectiveness of the 2 agents used were compared based on the concept that a change in dispensed medication suggested either an adverse event or lack of effectiveness. Adherence rates, adverse events, and pharmacy and nonpharmacy costs associated with the 2 agents were also compared. RESULTS: Patients receiving amlodipine and nifedipine CC as initial treatment for hypertension had similar demographic characteristics and numbers of comorbid conditions. More patients started on nifedipine CC switched to another calcium channel blocker (15.8% for nifedipine CC vs 10.3% for amlodipine). More patients started on amlodipine switched to another class of antihypertensive agent (13.2% for amlodipine vs 7.3% for nifedipine CC). Patients in both groups received adjunctive antihypertensive drugs at a similar frequency (35% for nifedipine CC vs 42%, for amlodipine). Rates of adherence were similar. In adherent patients, there was no difference in rates of reported adverse events. The nonpharmacy costs were similar between groups. Patients in the amlodipine group also had a trend toward higher overall pharmacy charges (all medications) and higher charges for antihypertensive medications other than the study drugs ($302 vs $188, P = .054). CONCLUSIONS: Claims data are often the best available evidence for comparing the effectiveness of pharmaceuticals in real clinical practice. While these comparisons have inherent limitations, the accuracy of the assessment can be maximized by limiting the assessment to agents with the same specific indications. Other important elements include comparison of crossover rates to other pharmaceuticals in the same class; rates of addition of other pharmaceuticals in the same class, adherence, adverse events, and overall healthcare charges. (+info)
Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine.
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AIMS: To determine whether repeated once daily administration of grapefruit juice altered the pharmacokinetics or pharmacodynamics of the calcium antagonist amlodipine. METHOD: S The effects of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral and intravenous amlodipine were assessed in 20 healthy men in a placebo-controlled, open, randomized, four-way crossover study using single doses of amlodipine 10 mg. For 9 days beginning with the day of administration of amlodipine, grapefruit juice (or water control) was given once daily, and blood samples, blood pressure and heart rate measures were obtained. Plasma concentrations of amlodipine and its enantiomers were determined in separate assays by GC-ECD. RESULTS: Oral amlodipine had high systemic availability (grapefruit juice: 88%; water: 81%). Pharmacokinetic parameters of racemic amlodipine (AUC, Cmax, tmax, and kel) were not markedly changed with grapefruit juice coadministration. Total plasma clearance and volume of distribution, calculated after intravenous amlodipine, were essentially unchanged by grapefruit juice (CL 6.65 ml min-1 kg-1, juice vs 6.93 ml min-1 kg-1, water; Vdss 22.7 l kg-1, juice vs 21.0 l kg-1, water). Grapefruit juice coadministration did not greatly alter the stereoselectivity in amlodipine oral or intravenous kinetics. The sum of S(-) and R(+) enantiomer concentrations correlated well with total racemic amlodipine concentration (r2 = 0. 957; P = 0.0001). Coadministration of grapefruit juice with either route of amlodipine administration did not significantly alter blood pressure changes vs control. CONCLUSIONS: Grapefruit juice has no appreciable effect on amlodipine pharmacodynamics or pharmacokinetics, including its stereoselective kinetics. Bioavailability enhancement by grapefruit juice, noted with other dihydropyridine calcium antagonists, does not occur with amlodipine. Once daily grapefruit juice administration with usual oral doses of amlodipine is unlikely to alter the profile of response in clinical practice. (+info)
Successful management of intractable coronary spasm with a coronary stent.
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Although the long-term survival of patients suffering from coronary spasm is usually excellent, serious complications can develop, such as disabling pain, myocardial infarction, ventricular tachyarrhythmias, atrioventricular block and sudden cardiac death. A 40-year-old man who had intractable chest pain from coronary artery spasm suffered ventricular fibrillation and an acute anterior myocardial infarction upon first admission. The patient underwent a coronary angiogram, which revealed a spontaneous focal spasm at the proximal left anterior descending coronary artery (LAD). He was treated by the combination of nitrate and calcium channel blocker, but continued to complain of severe chest pain despite intensive medical therapy and he had to be treated in the emergency room 5 times during an 8-month follow-up period. An ergonovine coronary angiogram was performed and an intracoronary ultrasound examination, which revealed a focal spasm at the same site of the proximal LAD with a small amount of localized eccentric atheromatous plaque. A coronary artery stent was placed in the proximal LAD and his symptoms resolved. A follow-up coronary angiogram was performed 3 years after stenting and the stent remained patent without any in-stent restenosis or spasm. (+info)