Clofibrat

BeschreibungResearchers in France observed in 1953 that structures derived from dehydrocholic acid, phenylethyl acetic acid, and certain other disubstituted acetic acids exhibited hypocholesterolemic properties in rats and humans. Several years later, Thorp and Waring discovered clof ibrate as an effective compound for lowering lipids in animal models, with minimal toxicity. Its mode of action was initially attributed to seasonal variations in adrenal and thyroid function, and the administration of androsterone was found to potentiate the hypocholesterolemic effect of this compound. Subsequently, several clinical trials were performed which showed that clofibrate decreases lipid levels in hypercholesterolemic patients, mainly as the result of a reduction in the very-low-density lipoprotein (VLDL), and less in the low-density lipoprotein (LDL) fraction, and that the coadministration of androsterone was not necessary for its hypolipidemic effect. Despite reported hepatomegaly in rats following long-term treatment with clofibrate, this drug was approved in the United States in 1967 for the treatment of hyperlipidemias. Clofibrate can be chemically synthesized by the condensation of phenol with ethyl 2-chloro-2-methylpropionate in the presence of a dehydrochlorinating agent, followed by chlorination and purification. It can also be synthesized by the condensation of p-chlorophenol with acetone and chloroform followed by esterifying the resultant acid to give clofibrate.

VerwendenClofibrate is a lipid-lowering agent (antilipidemic) used for controlling high cholesterol (anticholesteremic) and triacylglyceride levels in the blood. It increases lipoprotein lipase activity to promote the conversion of VLDL to LDL, thereby reducing VLDL levels. It is indicated only in subjects with increased concentrations of VLDL and intermediate-density lipoproteins (IDL) who have failed to respond adequately to gemfibrozil or nicotinic acid. Clofibrate is of limited utility for patients with either familial hypercholesterolemia or polygenic hypercholesterolemia, as comparatively more effective drugs are available for lowering the concentration of LDL in these patients.Clofibrate has no effect on hyperchylomicronemia, nor does it affect concentrations of high-density lipoproteins (HDL). Thus, clofibrate appears to have specific efficacy only in patients with familial type-III hyperlipoproteinemia. There is no substantial evidence proving efficacy of clofibrate in preventing deaths from coronary artery disease. Clofibrate has been used to prevent or control polydipsia, polyuria, and dehydration in a limited number of patients with mild to moderate neurohypophyseal diabetes insipidus. A 5-year multicenter study reported failure of clofibrate in reducing or preventing mortality in cardiovascular disorders, which has provided a setback for the prophylactic use of this drug.