1,721,034 research outputs found
Pleiotropic effects of statins in atherosclerosis and diabetes
No full textOBJECTIVE:
To investigate the direct anti-atherosclerotic properties of statins.
RESEARCH DESIGN AND METHODS:
Using in vitro and ex vivo models, the effect of different statins on key events involved in atherogenesis has been investigated. We studied the ability of statins to modulate modified LDL-induced cholesterol esterification, metalloproteinase secretion by macrophages, and arterial myocyte migration and proliferation. The mechanisms underlying the inhibitory effect of statins have also been explored. Finally, the antiproliferative effect of sera from statin-treated patients has been confirmed in a cell culture system.
RESULTS:
Fluvastatin, simvastatin, lovastatin, atorvastatin, and cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cell (SMC) migration and proliferation. Moreover, statins are able to reduce cholesterol accumulation in macrophages in vitro by blocking cholesterol esterification and endocytosis of modified lipoproteins and matrix-degrading enzyme secretion. This in vitro inhibition was completely prevented by mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites (probably through prenylated protein[s]) in regulating these cellular events. The inhibitory effect of statins on SMC proliferation has been shown in different models of proliferating cells, such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits, independently of their ability to reduce plasma cholesterol. Finally, ex vivo studies showed that sera from fluvastatin-treated patients interfere with SMC proliferation.
CONCLUSIONS:
These results suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert a direct anti-atherosclerotic effect in the arterial wall, beyond their effects on plasma lipids that could translate into a more significant prevention of cardiovascular disease. These findings provide a basis for the beneficial effect of statins in clinical trials also involving diabetic patients--a population with a higher absolute risk of recurrent cardiovascular events
Effect of carvedilol on cholesterol esterification and nitric oxide synthesis in cultured macrophages
No full textSafety considerations for statins
No full textPURPOSE OF REVIEW: The hydroxymethyl glutaryl coenzyme A reductase inhibitors or statins offer important benefits for the large populations of individuals at high risk for coronary heart disease. These drugs have a good safety profile. Nevertheless, differences in physicochemical and pharmacokinetic properties between statins may translate into significant differences in long-term safety. This review focuses on long-term adverse effects related to statin use, namely hepatotoxicity and myopathy. Moreover, the most common drugs used in combination with statins in long-term therapies are analyzed in terms of possible drug/drug interactions affecting the safety of statins.
RECENT FINDINGS: The withdrawal of cerivastatin from the global market in 2001, because of severe cases of rhabdomyolysis, highlighted concerns regarding the safety of the entire class. Afterwards, the role of statins and their interactions with other drugs in precipitating this condition have been carefully reviewed. In approximately 60% of the total number of cases, statin-related rhabdomyolysis was found to be related to drug/drug interactions. Recently, all cases of fatal rhabdomyolysis associated with statin use have been reported to the US Food and Drug Administration. This has shown that fatal rhabdomyolysis among statin users is a rare event, the reporting rates being much less than one death per million prescriptions in the case of all statins except cerivastatin.
SUMMARY: The safety and tolerability of the available statins support their use as the first-line treatment of patients at high risk for coronary heart disease, since the clinical benefits greatly outweigh the small risk of myopathy. Nevertheless, clinicians should be aware of the adverse effects possibly related to statin therapy, particularly in patients at high risk for coronary heart disease and requiring long-term multiple-drug therapies
Calcium antagonists and cholesteryl ester metabolism in macrophages
No full textExperimental data indicate that calcium antagonists modify cellular lipid metabolism in the arterial wall as part of their antiatherosclerotic action observed in animal models. In the present study, we investigated the effect of verapamil, nifedipine, and lacidipine (a new dihydropyridine derivative) on cholesteryl ester metabolism in cultured mouse peritoneal macrophages (MPMs). Cholesteryl esters are formed in the cell via acyl-CoA:cholesterol acyltransferase (ACAT), which senses free cholesterol supplied by lysosomal hydrolysis of lipoprotein cholesterol ester. Verapamil inhibited up to 99% the ability of acetyl-low-density lipoprotein (acLDL) to stimulate cholesterol esterification in macrophages, but was less effective in 25-hydroxycholesterol-stimulated MPMs and in cholesterol-loaded cells after acLDL removal. Cells incubated with [3H]cholesterol ester-acLDL and verapamil showed a reduction in the cholesterol/cholesteryl ester ratio. In the same experimental conditions, nifedipine displays minor or no effects on cholesterol esterification and in the cholesterol/cholesteryl ester ratio. On the contrary, the nifedipine-like lacidipine was active in inhibiting cholesterol esterification in macrophages elicited by acLDL. Our data indicate that calcium antagonists of different structure, even within the same class, may have various effects on cholesterol esterification in macrophages in cultur
The calcium antagonist lacidipine modulates the secretion of matrix metalloproteinase-9 by human macrophages
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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