Failure of alpha-phenylbutyrate and beta-phenylvalerate in treatment of hypercholesterolemia.

Sodium alpha-phenylbuty-ratc and sodium beta-phenyl-n-valerate have been administered to a carefully controlled group of hypercholesterolemic patients. Prior reports that these compounds are effective in the treatment of hypercholesterolemia are not confirmed. Two patients developed toxic reactions requiring cessation of treatment. The ineffectiveness of these drugs, despite their inhibitory effect on the synthesis of cholesterol from acetate, is discussed in terms of recent biochemical information concerning their site of action. RECENTLY a number of studies have appeared describing the therapeutic use of certain aromatic acids and their derivatives in hypercholesterolemia.1-' Cottet and co-workers were first to report significant lowering of serum cholesterol following administration of the sodium salt or the amide of alpha-phenylbu-tyric acid,l* and the sodium salt of beta-phenyl-valeric acid.4 (Also called phenylethylpropionic acid, sodium salt.) Following these reports we initiated a series of studies in an attempt to establish the mechanism of action of these compounds. It was found that a-phenylbutyrate or j3-phenyl-valerate strongly inhibited the rate of conversion of acetate-i-C'4 to cholesterol and fatty acids both in vitro and in vivo.5 On the other hand, little or no effect of phenylbutyrate administration on the serum cholesterol in rats could be demonstrated.6 In the present paper we report our observations on the effects of sodium phenylvalerate and sodium phenylbutyrate in a small but carefully controlled series of 14 patients. Dietary intake, especially that of cholesterol and other fats, was maintained as constant as possible, including the use of liquid formula diets in 6 patients for periods up to 3 months. * In the European studies these compounds are referred to as phenylethylacetic acid, sodium salt, or phenylethylacetamide (the latter compound is a product of Theraplix, Inc., Paris, under the designation 4128TH or Hyposterol). 391 METHODS A total of 14 adult patients were selected for study. Two patients were normocholesterolemic; the remaining 12 patients all had hypercholesterolemia of long standing. Ten patients had clear sera and normal or slightly elevated serum triglycerides. Half of these patients had demonstrable tendon xan-thomata. Two patients had slightly turbid sera and definitely elevated triglyceride values. One of the 2 had tuberous xanthomata. Three patients were given a therapeutic trial with 2 different compounds. Six of the patients were hospitalized throughout the control and treatment periods. The remaining patients were followed weekly in the outpatient clinic. All patients were ambulatory. Many had clinical evidence of coronary artery disease, but no signs or symptoms of congestive …