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This double-blind study compares the effects of tibric acid at four different doses to that of placebo in type IV hyperlipidemic patients. Fifty patients, divided at random in five groups of 10 patients each, received one of the following treatments: placebo, tibric acid 500 mg, 750 mg, 1,000 mg, or 1,250 mg per 24 hr. The data suggest that the 1,000 mg and the 1 ,250 mg doses are effective in lowering the serum triglyceride levels after 6 wk of treatment; the effect on total cholesterol is less pronounced. No effect is observed on the concentration of serum esterified cholesterol, phospholipids, and free fatty acids. It is also shown that in the dose range studied, the best fitting curve defining the four mean values of triglycerides and total cholesterol obtained with the four active treatments did not deviate significantly from linearity. Due to lack of toxicity, tibric acid may be useful in the treatment of type IV hyperlipoproteinemia.

The effect of chlorophenoxyisobutyrate, a hypolipidemic drug that decreases plasma free fatty acids, triglycerides, and cholesterol, on the partitioning of [14C]-palmitate between hexane and bovine serum albumin was studied at 37°. In this system, hexane served as a hydrophobic trap for free fatty acids displaced from BSA by chlorophenoxyisobutyrate, allowing less than 0.3% to remain in the aqueous phase. As the concentration of chlorophenoxy isobutyrate was raised from 0.4 to 3.2 mM, there was a progressive displacement of palmitate from the [14C]-palmitate-BSA complex into hexane, the magnitude being dependent on the initial V value (moles palmitate bound/mole BSA). Beginning with [14C]-palmitate in hexane, chlorophenoxyisobutyrate (2 mM) decreased the moles palmitate bound/mole of BSA by 16% at V = 0.2, and 34% at V = 3.0.

Summary Investigations on new agents for hyperlipidemia should consider the proper choice of an animal model, and the possible mechanisms of action of the agent. Animal models may include dietary and drug induced hyperlipidemias, as well as genetic or spontaneous forms of atherosclerosis. The activity of various drugs on the models may provide indications on their mechanism of action. Lipoprotein metabolism is somewhat different in the various animal species, an about constant feature being the appearance of abnormal lipoproteins following dietary cholesterol. In some cases these lipoproteins do not markedly differ from those of some types of human disease. Structure-activity relationship of hypolipidemic drugs is not clear due to the variety of compounds tested up to now. In general, clofibrate and its derivatives exert numerous effects both on lipid absorption and transport. Surgical procedures, such as partial ileal bypass, and portocaval shunt, hold promise for cases which respond poorly to diet and drug treatments.

Dietary counseling is recommended as the first step in management of the patient with an abnormally high plasma cholesterol or triglyceride level. If diet alone does not bring about a satisfactory reduction, addition of a lipid-lowering drug should be considered.

A double-blind crossover study in 11 patients suggests that MK-185 may be a useful drug in lowering plasma triglyceride levels, whereas it has minimal effects on cholesterol levels. A good correlation between the hypouricemic and protein bound iodine lowering effects and plasma level of MK-185 was seen. No correlation with the hypolipidemic effect was noted.

An enlargement as well as a remarkable increase in number of peroxisomes was electron microscopically encountered in mouse hepatocytes treated for 7 days with 1, 3-propyl-bis (2-p-chlorophenoxy-2-methylpropanoate) (simfibrate, BCPMP), a hypolipidemic drug, that lowers serum chloesterol and triglycerids. Increase in number of peroxisomes was approximately 3 times of that in control cells. The general size of enlarged peroxisomes was 1.33×1.07μ, and approximately 2.5 times as compared with normal peroxisomes, 0.54×0.46μ, in control hepatocytes.The use of the term “giant peroxisomes (megaloperoxisomes)” is proposed in the present investigation.Giant peroxisomes had protein-riched matrix surrounded by a single membrane, and many of them contained a single nucleoid. Continuities or close associations between giant peroxisomes and the smooth or rough endoplasmic reticulum were frequently observed. Further detailed investigations on the origin of giant peroxisomes and relationship to pharmacological effect of BCPMP will be achieved.

Administration of the hypolipidemic agents, Clofibrate and Nafenopin, to rats reversibly increases liver weight and Z protein concentration; ligandin concentration is depressed but total hepatic content is unaffected. Method for determination of Z protein by radioimmune assay is described.

OVER the past decade considerable insight into the mechanisms involved in normal and abnormal lipid transport as well as the mode of action of hypolipidemic drugs has been achieved.1 This progress ...

The inhibition of lipidemia can be achieved in several ways. The most logical mechanism — interference with lipoprotein metabolism (synthesis, release or catabolism) — has not been approached in a rational manner. There are some effective hypolipidemic drugs but their mechanisms of action are not clear and the search for a more effective compound continues.

The effects of pharmacological agents on bile acid metabolism may be assessed in several ways. The total excretion of bile acids in the bile or feces can be measured, the spectrum of bile acids or their conjugates can be determined, or the synthesis of bile acids can be assessed. To date, most experimental approaches have involved the first of these possibilities.

Reduction of hyperlipoproteinemias is accepted almost universally as one way to retard atherogenesis. An enormous research and development effort is expended each year in the search for hypolipidemic drugs. Rats or mice are generally used in the primary screening and subsequent follow-up testing for hypolipoproteinemic agents. But the lipoproteins of both rats and mice are quite different quantitatively and qualitatively from human lipoproteins. Clearly better animal models simulating the human lipoprotein spectrum are needed for atherosclerosis research, especially in the pharmaceutical industry. The primary requirement for such an animal model is an elevated low density lipoprotein (LDL) level and a high LDL/HDL ratio. Secondary considerations include size, cost, and ease of handling and maintenance of the animal. Size and cost are major considerations for drug screening, since compounds are usually available in only very small quantities and large numbers of animals are required. The purpose of this investigation was to survey the electrophoretic profiles of serum lipoproteins of several animals in an effort to discover a better animal model for human serum lipoproteins suitable for drug evaluations.

Liver and spleen scans using 99mTc-labeled sulfur colloid were performed in 5 patients with hyperlipoproteinemia at the time of clofibrate, nafenopin, or placebo treatment. No clinical or laboratory hepatic abnormalities were detected except in one patient. A shift in colloid distribution was found during treatment with active drugs in 3 patients. This was not present when these patients were treated with a placebo.

Insight into the mechanism of action and efficacy of hypolipidemic drugs has awaited the development of the current concepts of lipid transport (1). Fundamental is the fact that the blood fats-- cholesterol, phospholipid, and triglyceride-- do not circulate free in the plasma. Lipids exist in a soluble form in the blood only because they are bound to protein. These proteins serve as detergents and solubilize the otherwise insoluble lipid. It is as lipid protein complexes or lipoproteins that all fat enters and leaves the blood stream.

Summary The first clinical trials with a new aryloxy-type of hypolipidemic compound, the tetralin-derivative CIBA 13,437-Su, are reported. Various hyperlipidemic syndromes were treated in a total of 88 patients for periods up to 22 months. With daily doses of 4–10 mg/kg, i.e. 300-600 mg per day, serum triglycerides and cholesterol were markedly lowered. The most pronounced effect was observed in hyperlipidemias of Types III, IV, and V of the Fredrickson-Lees classification. The pre- β -fraction appeared to be more readily lowered than the β -fraction, although the rather resistant hypercholesterolemia of Type II responded in all cases, yet to a lesser degree, and these patients received the higher doses. Slight transient increases in serum transaminases were observed in 7 out of 88 patients. The compound was very well tolerated subjectively. The results demonstrate that 13,437-Su is a very potent hypolipidemic agent.

Nafenopin (2-methyl-2[P-(1,2,3,4-tetrahydro-1 naphthyl) phenoxy]- propionic acid, a phenolic ether with hypolipidemic properties, when administered by gavage at 100 mg/kg b wt daily for 1 to 2 weeks, caused a significant increase in the number of microbody profiles and simultaneous increase in catalase activity in livers of male rats. The concentration of catalase protein and the rate of incorporation of H3-δ-aminolevulinic acid into catalase fraction, as determined by immunochemical methods were approximately twice that of controls. The microbody proliferation resulting from nafenopin treatment was comparable to that induced by CPIB.

This is volume 26 of Advances in Experimental Medicine and Biology , presenting the proceedings of the "Fourth International Symposium on Drugs Affecting Lipid Metabolism." It is divided into sections. The first of these (70 pp) deals with protein moieties of the lipoproteins and the synthesis and fate of plasma lipoproteins. This is followed by 20 pages on the metabolism of adipose tissue and the role of hormones and of cyclic 3′5′-AMP. Twelve pages are devoted to biochemical changes in the arterial wall during the genesis and regression of atheromas. The topic selected for the title (newer aspects of drugs that raise or lower plasma lipid values) is covered in 84 pages. Articles report the effects of drugs on free fatty acids, triglycerides, cholesterol (one page; how are the mighty fallen!), and bile acids. The reports on hypolipidemic drugs and lipoprotein metabolism, effects of nicotinic acid, and the combined use of