Yoshiya Hata

Dose-dependent hypolipidemic effect of an inhibitor of HMG-CoA reductase, pravastatin (CS-514)) in hypercholesterolemic subjects A double blind test

The hypolipidemic effect of a new HMG-CoA reductase inhibitor, pravastatin, was examined. The reductions of serum cholesterol and LDL-cholesterol were dose-dependent and significant differences were observed between placebo and 10 or 20 mg groups (P less than 0.01), and 10 and 20 mg (P less than 0.05) groups. The reduction rate of cholesterol after 8 weeks during medication was 16.1% in the 10 mg group, 20.5% in the 20 mg group compared to baseline serum cholesterol levels. LDL-cholesterol decreased by 23.9% in the 10 mg group, and 29.8% compared to baseline LDL-cholesterol in the 20 mg group. The lowering of total cholesterol was entirely attributed to a reduction in LDL-cholesterol.

Clinical efficacy of fluvastatin for hyperlipidemia in Japanese patients

The objective of the study was to evaluate the efficacy and safety of fluvastatin in patients with hypercholesterolemia, including heterozygous familial hypercholesterolemia, in a 1-year study (a 12-week open assessment, followed by 40 weeks of active treatment). Of the 337 patients enrolled in the study, the effects of fluvastatin were analyzed in 296 patients at baseline and at 12 weeks. Of these, 265 were receiving 20 mg/day fluvastatin at week 12 and in 20 patients the dose had been increased to 30 mg/day; 11 patients violated the dosing protocol. A total of 229 patients continued into the 40-week, long-term phase, and 212 patients were analyzed at baseline and after 24 and 52 weeks. At the end of treatment, 153 evaluable patients were still taking 20 mg/day fluvastatin, 1 was taking 10 mg/day, and 48 patients were taking 30 mg/day, and 10 were taking 40 mg/day. In the 20 mg/day fluvastatin group, low density lipoprotein cholesterol (LDL-C) levels decreased by 24.1% at week 12 and by 29.3% at week 52. In those patients requiring the higher doses, the corresponding reductions in LDL-C were 20.2% (week 12) and 26.7% (week 52). Total cholesterol was also reduced at week 12 by 17.0% (20 mg/day) and 15.7% (20-30 mg/day), and at week 52 by 20.4% (< or = 20 mg/day) and 19.2% (> or = 30 mg/day). Throughout the study, fluvastatin was generally well tolerated and no serious clinical adverse events were observed. In conclusion, long-term treatment of hypercholesterolemia with fluvastatin at dosages of 20-40 mg daily can be considered both safe and effective.

Effect of beraprost, a stable prostacyclin analogue, on red blood cell deformability impairment in the presence of hypercholesterolemia in rabbits

We evaluated the effects of orally administered beraprost, a stable prostacyclin analogue, on the rheological behavior of red blood cells (RBC) in the presence of hypercholesterolemia. Rabbits fed a cholesterolrich diet were administered various doses of beraprost or pravastatin. We evaluated rheological behavior of RBC by assessing RBC deformability, using a positive-pressure filtration method. The maximum pressure generated by passing a suspension of RBC through a membrane filter was used as an index of RBC deformability. After animals were fed cholesterol for 16 weeks, the maximum pressure increased significantly from 172 +/- 15 mm Hg at baseline to 261 +/- 18 mm Hg (p < 0.01, n = 24). The reduction in RBC deformability associated with hypercholesterolemia improved dose dependently during 1-h incubation with various doses of beraprost. In ex vivo study, beraprost markedly restored RBC deformability 3 h after its oral administration to 218 +/- 17 mm Hg (n = 9) at a low dose and to 215 +/- 20 mm Hg (n = 9) at a high dose. The effect persisted for at least 2 h. Pravastatin failed to reduce the increased maximum pressure. Findings suggest that beraprost treatment may improve the microcirculation by restoring RBC deformability in the presence of hypercholesterolemia.

Disproportionally High Concentrations of Apolipoprotein E in the Interstitial Fluid of Normal Pulmonary Artery in Man

‘Apoprotein E is one of the apolipoproteins present in blood plasma.’.’ It is primarily synthesized in the liver and secreted into plasma as a peptide of 299 amino acids with a molecular weight of 34,200.2.3 As it has become clear that apo E is synthesized not only in the liver, but also in other organs such as brain, lung, spleen, kidney, adrenal, ovary, testis, and muscle in several different specie^,^ considerable attention has been drawn to the physiological functions of apo E in the body. Recently, Mahley classified them into three ~a tegor ies ,~ i) Distribution of lipids through systemic circulation among cells of different organs. Plasma lipoproteins with E are the vehicles for this process. Chylomicron and the remnants convey dietary triglycerides to peripheral tissues and dietary cholesterol to the liver.5 Very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) deliver endogenously synthesized lipids to peripheral organs.’ High density lipoprotein (HDL) with E transports excess cholesterol in reverse from peripheral tissues to the liver.“ ii) Redistribution of lipids via interstitial fluid among cells within t i s s ~ e s . ~ ” Apo E appears to carry cholesterol from cells with excess cholesterol to those requiring it within the tissue. Recent studies have shown that the coordinated storage and redistribution of cholesterol are mediated by apo E, for instance, in injured and regenerating peripheral nerve cells.4 iii) Regulation of cellular activities at cell site such as growth, repair, migration, hormone secretion, and immune response^.^.^ In smooth muscle cells, for instance, apo E production goes parallel with growth arrest, cell differentiation, and migration in tissue.’ In ovary cells, it exerts a permissive effect on hormone secretion,’ and on T lymphocytes, it stimulates immune activation and proliferation into the t i s s ~ e . ~ These indicate that apo E has an expanding role not only in delivery of lipids among organs, but also in redistribution of them within tissues, and moreover they determine biological functions of various cells from several tissues. In arterial tissues, the accumulation of cholesteryl ester leads to formation of foam cells in the intima,’”.’’ whose cholesterol moiety originates from serum LDL.” There-

Cholesteryl Ester-Rich Lipid Inclusions in the Development of Experimental Atherosclerosis in Rabbits

The fundamental cellular and biochemical processes that occur in human and experimental atherosclerosis are proliferation of smooth muscle cells, accumulation of intra- and extracellular lipids, and deposition of such intercellular ground substances as collagen, elastin and proteoglycans (Ross and Glomset 1973). Of these changes, we focus our attention on the arterial wall lipids, since they are of particular importance in initiation and development of atherosclerosis for the following seven reasons; (i) the arterial wall is a catabolic site of serum low density lipoproteins (LDL) carrying the major portion of cholesteryl esters, (ii) the derangement of catabolic process of LDL in arterial tissue leads to accumulation of lipids in situ, (iii) the arterial lipid contents are related to both the serum lipid level and the severity of lesions, (iv) in experimental animals atherosclerosis can be induced by cholesterol feeding, (v) it regresses when serum cholesterol is lowered both in man and animals, (vi) the other risk factors alone can not produce atherosclerosis without hypercholesterolemia and (vii) there is no atherosclerosis without accumulation of lipids in arterial tissues.

The Lipids in Human Atherosclerosis — Morphological Demonstrations of Five Forms of Atheroma Lipids

In the development of atherosclerosis in mammals including man, arterial tissue undergoes three fundamental changes: proliferation of smooth muscle cells, deposition of intra- and extracellular lipids, and accumulation of extracellular matrix of collagen, elastin and proteoglycans (1). Among these processes, the accumulation of lipids in atherosclerosis is featured by accretion of cholesteryl esters, particularly oleate in the early lesions of fatty streak (2–6), while cholesteryl linoleate accumulates in addition to oleate with a marked increase in free cholesterol and phospholipids in the intermediate lesions of fibrous plaque and in the advanced lesion of complicated lesions (2,3, 4,6–9).