Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial is the first angiographic clinical trial to be designed to test whether an agent can slow or even reverse the progression of early coronary atherosclerosis in patients with documented disease. In addition, a subset of patients are undergoing carotid ultrasound examinations, providing a unique opportunity to assess and correlate disease progression in 2 arterial beds.
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PMID:Rationale, design, and baseline characteristics of the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT). 935 86

It is well known that the atherogenic dyslipidemias of either elevated serum LDL or reduced HDL levels correlate with the degree and severity of atherosclerosis. However, how this leads to atherogenesis is poorly understood. A role for cellular oxidative stress mediated by oxidized LDL has gained widespread acceptance, but this pathway is unlikely to be the sole atherogenic signal. Recent evidence obtained from arterial smooth muscle cells (SMC) and endothelial cells (EC) is consistent with another pathway that may explain, in part, the early alterations contributing to the initiation of cellular atherogenic modifications. This pathway involves enrichment of the cell plasma membrane with cholesterol. In SMC, in vitro (cell culture) and in vivo (cholesterol feeding) experiments demonstrate that cholesterol enrichment of the SMC membrane occurs rapidly and is associated with an increase in membrane bilayer width, calcium permeability, and cell proliferation. Removal of excess membrane cholesterol with human HDL restores these alterations, suggesting that this membrane structural 'defect' mediates these changes in cell function. In vitro, the increased calcium permeability is inhibitable by calcium channel blockers (CCBs), but in vivo, a calcium 'leak' pathway develops that is virtually uninhibitable. It is not surprising that the literature on the application of CCBs for atheroprotection is not wholly convincing. However, with the advent of the new third generation of CCBs, new hope arises. One of the first CCBs of this generation is amlodipine (Norvasc), a charged dihydropyridine that has a remarkable pharmacologic profile. First, it is markedly lipophilic allowing it to partition readily into cell membranes. Second, in the membrane it has the ability to re-order, or restore, the 'swollen' membrane bilayer back to normal in atherosclerotic SMC. Third, it has potent antioxidant properties. Fourth, it appears to inhibit the expression of a variety of genes implicated in atherogenesis. Fifth, it is a CCB. Amlodipine has demonstrated atheroprotection in both rabbit and subhuman primate models of this disease. We propose that cellular alterations induced by enrichment of the cell membrane with cholesterol, which appears to modulate SMC to the atherosclerotic phenotype, are inhibitable by amlodipine through a combination of its varied pharmacologic properties. The potential for atheroprotection with amlodipine is currently being investigated in a human trial (PREVENT trial) and the results of this trial will determine the relevance of the preclinical findings to humans.
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PMID:Cholesterol, calcium and atherosclerosis: is there a role for calcium channel blockers in atheroprotection? 948 96

Calcium antagonists are currently considered first-choice agents for treating hypertension. They are also active antianginal drugs. Their protective effects against ischaemia and their antiatherogenic potential, which have been demonstrated in various experimental models, may contribute to their preventive effect against the early atherosclerotic processes. However, their effects on survival and cardiovascular events have been inconsistent and controversial. Recent studies have suggested that mortality may be increased by short-acting agents. The effects of certain long-acting calcium antagonists may be different. In early clinical trials, nifedipine and nicardipine did not alter the progression of significant coronary artery narrowing, but did reduce the development of new atherosclerotic lesions. Nevertheless, the number of cardiovascular events was not decreased. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) showed a higher incidence of angina and more frequent cardiovascular events in patients treated with isradipine. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), after 3 years' follow-up, progression of significant atherosclerotic lesions and the development of new lesions were not significantly altered by treatment with amlodipine. However, it would appear that quantitative angiography may not be appropriate for monitoring the progression of atherosclerosis. Because of arterial remodelling, angiographic images may not show changes in the arterial lumen, in arteries where intravascular ultrasound may detect important atherosclerotic plaques. High resolution B-mode ultrasonography of the carotid artery may be more informative, since carotid intima media thickness is strongly correlated with cardiovascular risk factors, the prevalence of cardiovascular disease, and the presence of atherosclerotic lesions at other arterial sites. In the PREVENT trial, carotid ultrasonography showed that intima media thickness was stabilised in the amlodipine group, while progression was uninterrupted in the placebo group. The mechanism of amlodipine in slowing the progression of intima media thickness may be related to its antiatherogenic effect, as well as to its effect on cellular growth and hyperplasia of the arterial wall. It is interesting to note that, as a secondary objective of the PREVENT trial, patients treated with amlodipine had fewer ischaemic events than those treated with placebo. The beneficial effects of amlodipine on arterial thickening and on the prevention of ischaemic events suggest that amlodipine may be recommended for the management of all patients with stable angina. A larger trial with a longer follow-up period should be performed in order to confirm the promising results of PREVENT.
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PMID:[Effects of calcium antagonists on atherosclerosis progression and intima media thickness]. 1100 57

Coronary artery disease (CAD) results from atherosclerosis, a systemic vascular disorder that is the leading cause of death and disability throughout much of the developed world. Because cellular changes associated with vulnerable atherosclerotic plaque are characterized by a loss of normal calcium regulation, there is strong interest in a potential antiatherosclerotic role for calcium channel blockers. This hypothesis has been supported by investigational studies conducted in well-defined cellular and animal models of atherosclerosis. In addition, several clinical studies have tested the benefit of calcium channel blockers among patients with mild-to-moderate CAD. More recent trials have shown reductions in cardiovascular events after treatment with amlodipine, a long-acting, dihydropyridine-type calcium channel blocker. The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) demonstrated that patients with documented CAD treated with amlodipine experienced marked reductions in cardiovascular events compared with patients receiving placebo. Amlodipine also was associated with significant slowing of carotid atherosclerosis, an important surrogate marker for CAD, independent of blood pressure modification. These results have renewed interest in potential plaque stabilization properties of third-generation calcium channel blockers and their possible therapeutic role in CAD.
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PMID:Mechanisms of plaque stabilization for a charged calcium channel blocker in coronary artery disease. 1156 Jan 91

Coronary artery disease (CAD) is the result of atherosclerosis, a vascular disorder characterized by abnormalities in vasoconstriction and endothelial function, ultimately leading to partial or complete vessel occlusion. Because the atherosclerotic plaque is marked by changes in calcium regulation, there has been interest in a potential antiatherosclerotic role for calcium antagonists. In support of this hypothesis, a recent clinical study demonstrated in patients with CAD that treatment with the lipophilic dihydropyridine-type calcium antagonist amlodipine resulted in significantly fewer cardiovascular procedures and events. The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) evaluated the effects of amlodipine on the development and progression of atherosclerotic lesions in coronary and carotid arteries in 825 patients with documented CAD. The results of PREVENT showed that patients receiving amlodipine had marked reductions in hospitalization for revascularization and unstable angina compared with placebo in a population consisting of either normotensive or controlled hypertensive patients. Ultrasound approaches determined that amlodipine therapy was also associated with significant slowing in carotid atherosclerosis-an important surrogate marker for CAD-over the 3-year period. This vascular-wall benefit associated with amlodipine treatment was not related to changes in blood pressure. The findings from PREVENT were consistent with a second reported study known as the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES). These clinical results have led to an interest in potential plaque-stabilization properties of this lipophilic calcium antagonist. In this article, cellular and molecular mechanisms of action that may contribute to a beneficial role for a calcium antagonist in the treatment of atherosclerosis will be reviewed.
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PMID:Mechanisms of atherosclerotic plaque stabilization for a lipophilic calcium antagonist amlodipine. 1170 16

Coronary artery disease (CAD) is the consequence of atherosclerosis, a vascular disorder that is the leading cause of death and disability throughout much of the developed world. Certain cellular changes in the vulnerable atherosclerotic plaque are characterized by a loss of normal calcium regulation. This observation has led to interest in a potential antiatherogenic role for calcium channel blockers (CCBs), independent of their effects on vasodilation. The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) demonstrated that treatment with amlodipine, a third-generation CCB, in patients with documented CAD produced marked reductions in cardiovascular events as compared with placebo, without a reduction in coronary luminal loss. Amlodipine therapy was also associated with significant slowing in carotid atherosclerosis, an important surrogate marker for CAD, independent of blood pressure changes. The findings from PREVENT were remarkably consistent with another study known as the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES). A reduction in the progression of carotid atherosclerosis has also been recently reported for lacidipine, another third-generation dihydropyridine CCB. These clinical findings have led to a renewed interest in potential plaque stabilization properties of certain CCBs, as will be systematically reviewed in this article. It is also probable that vascular protective agents, such as amlodipine may work in a synergistic fashion with other established treatments, including HMG-CoA reductase inhibitors, to effectively improve outcomes in patients who are at risk for or have established CAD.
Atherosclerosis 2002 Dec
PMID:Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodipine: review of the evidence. 1241 68

Atherosclerosis is a systemic disease that can ultimately lead to ischaemia and infarction in the heart, brain and peripheral vasculature. According to the "response to injury" hypothesis, endothelial dysfunction is the early event that allows penetration of lipids and inflammatory cells into the arterial wall, contributing to the development of the atherosclerotic lesion. Endothelial dysfunction is causally related to a variety of risk factors for atherosclerosis, including hyperlipidaemia and hypertension. Agents that restore endothelial function and NO bioavailability have beneficial anti-atherogenic activities and can improve cardiovascular outcomes; this has been observed with angiotensin-converting enzyme (ACE) inhibitors, statins and certain dihydropyridine-type calcium channel blockers (CCBs). In the Prospective Randomised Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), the CCB amlodipine provided significant clinical benefits compared with placebo, including a marked reduction in cardiovascular morbidity and a reduction in the progression of carotid atherosclerosis. As these beneficial effects of amlodipine have not been observed with other dihydropyridine-type CCBs, it has been proposed that this agent has distinct anti-atherosclerotic properties related to its strong lipophilicity and membrane location. Experimental support for this hypothesis has been obtained from various in vitro and in vivo models of atherosclerosis. These findings support a broader therapeutic role for third-generation dihydropyridine-type CCBs in the treatment of atherosclerosis.
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PMID:Atheroprotective effects of long-acting dihydropyridine-type calcium channel blockers: evidence from clinical trials and basic scientific research. 1274 May 51

Calcium antagonists are effective in hypertensive patients of all ethnic groups, irrespective of age, dietary salt intake, salt-sensitivity status or plasma renin activity profile. Some prospective studies show that the calcium antagonists, nifedipine GITS and nitrendipine, reduce cardiovascular morbidity and mortality at least to the same extent as the diuretics. Other prospective studies are in progress to evaluate the effect of calcium antagonists on cardiovascular morbidity and mortality, and the progression of atherosclerosis in hypertensive patients. Calcium antagonists, especially the highly lipophilic amlodipine, lacidipine and nisoldipine, are shown to possess antioxidant properties. These drugs reduce the oxidation of LDL and its influx into the arterial wall, and reduce atherosclerotic lesions in animals. Platelet production of malondialdehyde, a marker of oxygen free radical formation, is suppressed by amlodipine, lacidipine or nifedipine in hypertensive patients. New evidence from long-term clinical trials of calcium antagonists indicates that these drugs can reduce the rate of progression of atherosclerosis in hypertensive and coronary heart disease patients. In the Regression Growth Evaluation Statin Study (REGRESS), co-administration of calcium antagonist, amlodipine or nifedipine with pravasatin caused a significant reduction in the appearance of new angiographic lesions. In the Verapamil in Hypertension and Atherosclerosis Study (VHAS), verapamil was more effective than chlorthalidone in promoting regression of thicker carotid lesions in parallel with a reduction in the incidence of cardiovascular events. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), amlodipine slowed the progression of early coronary atherosclerosis in patients with coronary artery disease. In a subprotocol of the Intervention as a Goal in the Hypertension Treatment (INSIGHT) study, nifedipine GITS significantly decreased intima-media thickness as compared to co-amilozide (hydrochlorothiazide + amiloride). Preliminary results of the European Lacidipine Study on Atherosclerosis (ELSA) show that lacidipine reduced the intima-media thickness progression rate as compared to atenolol. Thus, selective calcium antagonists are potential antiatherosclerotic agents.
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PMID:Calcium antagonists and atherosclerosis protection in hypertension. 1462 78