S. Nomura

DECREASES IN PLASMA LIPID CONTENT AND THROMBOTIC ACTIVITY BY ETHYL ICOSAPENTATE PURIFIED FROM FISH OILS

Abstract The effects of ethyl icosapentate (purified from fish oils) on plasma lipids, activity of coagulation factors VII and X, and content of plasminogen activator inhibitor-1 were examined in 28 patients with familial combined hyperlipidemia. After 8 weeks, ethyl icosapentate at 1800 mg daily significantly decreased plasma total cholesterol and triglyceride levels, activity of coagulation factors VII and X, and content of plasminogen activator inhibitor-1 without deleterious effects on plasma low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and plasma apolipoproteins. Activity of coagulation factors VII and X and the content of plasminogen activator inhibitor-1 correlated with triglyceride levels at week 0 while only coagulation factor VII correlated with total cholesterol at week 0. Changes in coagulation factor activity and content of plasminogen activator inhibitor-1 did not correlate with that of plasma total cholesterol or triglyceride after 8 weeks. Purified ethyl icosapentate would thus appear to have an antiatherogenic effect and could be essential in the control of coronary heart disease by lowering plasma lipid content and increasing antithrombotic action.

Reduction of Plasma Cholesterol Levels and Induction of Hepatic LDL Receptor by Cerivastatin Sodium (CAS 143201-11-0, BAY w 6228), a New Inhibitor of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase, in Dogs

The effects of cerivastatin sodium (BAY w 6228), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on plasma cholesterol concentrations and the induction of hepatic LDL receptors were investigated with beagle dogs and Hep G2 cells. Oral administration of cerivastatin (0.01, 0.03, and 0.1 mg/kg per day) for 3 weeks reduced plasma total and very low-density lipoprotein plus low-density lipoprotein (VLDL + LDL) cholesterol concentrations and increased hepatic LDL receptor binding activity in dogs. Scatchard plot analysis revealed a 1.9-fold increase in the maximum binding capacity of hepatic LDL receptors in cerivastatin-treated animals. Similar results were obtained by administration of pravastatin (1.0 and 5.0 mg/kg/day) for 3 weeks. Binding activity of the LDL receptor, as well as receptor mRNA and protein concentrations, were increased in a dose-dependent manner (0.01–1.0 μM) by exposure of Hep G2 cells to cerivastatin. The results suggest that cerivastatin reduces plasma cholesterol concentrations by increasing hepatic LDL receptor expression. The mechanism of lowering cholesterol concentration by cerivastatin was the same as with the other previously examined HMG-CoA reductase inhibitors, but the effects with cerivastatin were apparent at doses much lower than the effective doses of the other drugs. Cerivastatin, therefore, shows potential for clinical use as a potent and efficacious plasma cholesterol-lowering drug.

Effect of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on hepatic cholesterol 7α-hydroxylase, acyl-coenzyme A: cholesterol acyltransferase, and bile lipid secretion in the hamster with intact enterohepatic circulation

The effects of administration of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on hepatic cholesterol 7 alpha-hydroxylase and acyl-coenzyme A: cholesterol acyltransferase (ACAT) activities and bile lipid secretion were investigated in Syrian golden hamsters. Continuous administration of pravastatin induced no significant changes in hepatic cholesterol content, ACAT and cholesterol 7 alpha-hydroxylase activities, or bile lipid and acid composition. Abrupt withdrawal of pravastatin induced increases in hepatic cholesterol content and ACAT activity and no change in hepatic cholesterol 7 alpha-hydroxylase activity, and increased cholesterol saturation in bile. Hepatic cholesterol 7 alpha-hydroxylase activity paralleled hepatic mRNA levels of this enzyme. These results suggest that a change in hepatic cholesterol metabolism induced by continuous administration of pravastatin maintains a constant net balance of hepatic cholesterol content. In addition, the drug has no deleterious influence on metabolism of bile lipids and acids and related enzymes, except for a transient increase in cholesterol saturation in bile induced by an inappropriate increase in hepatic cholesterol content and a lack of response of cholesterol 7 alpha-hydroxylase activity to changes in hepatic cholesterol content upon abrupt withdrawal of pravastatin.

Amino Acid Transport System of the Guinea Pig Small Intestine is Injured by Hydroxyl Radicals

The mechanism for the damage to the alanine-preferring amino acid transport system (A system) of guinea pig intestinal brush border membrane vesicles induced by active oxygen species was studied in vitro. The transport activity of L-proline, which is a model amino acid for the A system, and the tryptophan fluorescence intensity of intestinal brush border membrane vesicles were decreased, and lipid peroxidation of these membrane vesicles was induced by ultraviolet irradiation, which generated active oxygen species. Thiourea (hydroxyl radical scavenger) protected L-proline transport activity and tryptophan fluorescence intensity of intestinal brush border membrane vesicles and also inhibited lipid peroxidation in these membrane vesicles in the presence of active oxygen radicals. alpha-Tocopherol (singlet oxygen radical scavenger) inhibited lipid peroxidation of intestinal brush border membrane vesicles but protected neither L-proline transport activity nor tryptophan fluorescence intensity in these membrane vesicles in the presence of active oxygen radicals. Catalase and superoxide dismutase showed no protective effect on L-proline transport activity, tryptophan fluorescence intensity, or lipid peroxide formation in intestinal brush border membrane vesicles in the presence of active oxygen radicals.(ABSTRACT TRUNCATED AT 250 WORDS)