Lee A. Bricker

Long-term oral administration of probucol (4,4'-(isopropylidenedithio) bis(2,6-di-t-butylphenol)) (DH-581) in the management of hypercholesterolemia.

Fifty patients who received a new hypocholesterolemic agent, probucol, in a dosage of 0.5 gm twice daily, were studied for one year. Mean pretreatment serum cholesterol and triglyceride values were 329 mg/100 ml and 360 mg/100 ml respectively. Baseline lipoprotein electrophoreses showed 17 Fredrickson phenotypic patterns of type 2, 6 of type 3, 10 of type 4, 3 of type 5, and 14 non‐definitive patterns. After twelve months of treatment with probucol, the mean serum cholesterol level was 263 mg/100 ml (a minus 20 per cent change) and the mean triglyceride level was 293 mg/100 ml (a minus 19 per cent change) for all patients. The median baseline cholesterol level was 311 mg/100 ml and the median cholesterol value during twelve months of therapy was 252 mg/100 ml, a reduction of 19 per cent. The median baseline triglyceride level was 174 mg/100 ml and the median triglyceride value during twelve months of therapy was 147 mg/100 ml, a reduction of 16 per cent. Significant changes were noted in the serum lipoprotein patterns; the majority of type 2 and type 3 changed to the non‐definitive pattern, but the majority of type 4 and type 5 remained unchanged. Seven patients had xanthelasmas, but all these lesions decreased in size and 3 lesions disappeared during probucol therapy. Side effects were minimal. About a third of the patients had mild transient flatulence or slight transient eosinophilia. There was no effect on prothrombin time.

Autonomous cholesterol and fatty acid synthesis in hepatomas: deletion of the adenosine 3',5'-cyclic monophosphate control mechanism of normal liver.

Summary Rat hepatoma slices incubated with cAMP (5×10 −3 M) or dibutyryl cAMP (3×10 −4 M), and acetate-2- 14 C, demonstrated unsuppressible cholesterol and fatty acid synthesis, compared to controls. This observation contrasts sharply with that of the marked suppression in lipogenesis brought about by cyclic nucleotides in normal liver and indicates a deletion in hepatomas of this regulatory mechanism in lipogenesis.

Weekly treatment of diet/drug-resistant hypercholesterolemia with the heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) system by selective plasma low-density lipoprotein removal☆

Heparin-induced extracorporeal low-density lipoprotein (LDL) precipitation (HELP) weekly therapy was evaluated for safety and efficacy in selectively reducing LDL cholesterol levels. Weekly treatments (25) were given to high-risk hypercholesterolemic patients (n = 33) with screening LDL cholesterol levels > 160 mg/dl despite prior diet and drug therapy. Lipids, lipoprotein cholesterol, apolipoproteins A-l and B, and fibrinogen were measured on plasma samples before and after treatment. Mean plasma volume treated was 2.66 liters and mean treatment duration 1.7 hours. Therapy complications were infrequent and were primarily vascular access problems or hypotension. Treatment goals were > 30% LDL cholesterol reduction with each treatment. In 98% of 686 HELP treatments, LDL cholesterol levels were reduced > or = 30%. Mean LDL cholesterol levels were reduced 111.0 mg/dl (54%) with a time-averaged decrease of 39% over a 25-week course. Mean HDL cholesterol was reduced only 6.2 mg/dl (15%). Total cholesterol (134.4 mg/dl; 47% decrease) and apolipoprotein B (88.7 mg/dl; 53% decrease) levels were also reduced. Fibrinogen decreased 158.2 mg/dl (58%) without bleeding complications. HELP therapy can safely and selectively remove plasma LDL cholesterol, producing consistent reductions in LDL cholesterol, total cholesterol and apolipoprotein B levels.

An abnormality of hepatic lipogenesis in a mutant strain of acatalasemic mice

Abstract Previous work demonstrating a relationship between acatalasemia and hypolipidemia prompted the present investigation, in which an in vitro assessment of rates of sterol and fatty acid synthesis was undertaken. A mutant strain of mice harboring the acatalasemic defect was studied, together with normal control animals and mice heterozygous for the abnormality. Incubation of liver slices from homozygous animals with [ 14 C]acetate demonstrated an approximately 80 % mean depression in rates of incorporation of isotope into cholesterol (as digitonin-precipitable sterol) and de novo fatty acid, and less but still significant depression in heterozygotes. Formation of metabolic 14 CO 2 was not significantly reduced by the presence of the acatalasemic defect. The data indicate that the hypolipidemia of acatalasemia is closely related to a diminished rate of lipogenesis in the liver of the affected animal.

A Peptide Inhibitor of Glucagon-Responsive Adenylate Cyclase in Liver

The effects of a peptide inhibitor of adenylate cyclase produced by the isolated, perfused rat liver under hypocalcemic conditions were studied. This inhibitory peptide non-competitively abolished the activation of adenylate cyclase in particulate preparations of rat liver by glucagon, epinephrine, and parathyroid hormone, as well as cyclic AMP production in glucagon-stimulated rat liver slices. Higher concentrations of inhibitor also decreased basal adenylate cyclase activity and its fluoride-responsiveness. The data suggest that this substance is normally present in liver, but is released only under hypocalcemic conditions. The peptide does not crossreact in the radioimmunoassay of glucagon, insulin, or parathyroid hormone. Its inhibitory effects are not duplicated by somatostatin, angiotensin I, renin substrate, or the desoctadecapeptide of insulin.

Negative Feedback in Sterol Biosynthesis and Lipoprotein Release by the Perfused Rat Liver

Summary A high cholesterol diet (5%) given to rats over a 3- to 4-wk period markedly suppressed incorporation of acetate-2-14C in the perfused liver into both stored hepatic cholesterol and into sterol released into the perfusion medium. Perfused livers from low cholesterol-fed rats incorporated radioacetate into sterols at rates at least 50 times those observed in livers of high cholesterol-fed rats. In all animals, during the 3-hr perfusion period, only a small fraction of newly synthesized sterol was released from liver, the remainder being stored within it. Newly synthesized sterol was not detectable in the circulating perfusate until 45–55 min had elapsed. The data demonstrate the cholesterol feedback phenomenon in the perfusion fluid of the perfused rat liver, the quantitative relationship between stored and released new sterols, and the minimal appearance time required for newly synthesized lipoprotein to appear in the circulation of this perfused system.