Thin films of fibrin-agar mixture induced significant morphological changes in porcine aortic endothelial cells in vitro. These cells became spindle-shaped, piled up and consequently the intercellular spaces widened. These morphological changes became more significant with higher concentration of fibrin. Films of fibrinogen-agar mixture or thrombin-agar mixture induced no such morphological changes, thereby suggesting that fibrin itself injures the endothelial cells. Despite the lack of morphological effects of fibrinogen degradation product D or E on cultured endothelial cells, lower molecular weight fibrinogen degradation products separated by Sephadex G-25 chromatography did induce injury to the endothelial cells.
As damage to the endothelial cells is a key event in initiation of atherosclerosis, fibrinogen and its metabolites probably play important roles.

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The effect of isocaloric high and low carbohydrate diets with the same amount of cholesterol and the same P/S ratio on the properties of HDL subfractions was investigated in four normal volanteers. After three week feeding of basal diet, high and low carbohydrate diets were fed for three weeks successively. One subject was fed in the reverse order. At the end of each diet period, the plasma was obtained and HDL was prepared by ultracentrifugation. The protein and lipid composition of HDL₂ and HDL₃ were not different between the two diet periods. In high carbohydrate diet ingestion as compared with low carbohydrate diet ingestion:
1) HDL mass (concentration) was lower, and especially the ratio of HDL₂ to HDL₃ was significantly smaller. 2) HDL₂ size of each subject was larger, while HDL₃ size was unchanged. 3) Apo C-II and E contents in HDL₂ was significantly higher. 4) Apo E/(Apo C-II+Apo C-III) ratio was significantly higher. 5) Apo C-II and Apo E contents, and Apo E/(Apo C-II+Apo C-III) ratio in HDL₂ were increased in parallel with increase in HDL₂ size. 6) Apo E in HDL exclusively concentrated on HDL₂ fraction when HDL was fractionated by ultracentrifugation. Apo E content seemed to be closely related to the size of HDL not only in total HDL, but also in HDL₂ fraction.Apo E has ability to bind to Apo E receptor of hepatocyts. Apo C-II, which is believed to inhibit the binding of lipoprotein to Apo E receptor was increased in HDL₂ of high carbohydrate diet period. But the ratio of Apo E/Apo C's was increased as well as Apo E in HDL₂ by high carbohydrate diet. These results suggest that decrease in HDL₂ mass by high carbohydrate diet ingestion might be due to accelerated clearance of HDL₂ by the liver because of absolutely and relatively increased Apo E content, and there is some possibility that increase in size of HDL₂ might have preferable effect on its catabolism.

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Various types of swine coronary arteriosclerosis were produced by combination of intimal brushing and high fat diet. Intimal brushing of coronary arteries were carried out by inserting minute brush used for exfoliative bronchial cytology into the Cournand 6F catheter.
Morphological and histochemical study of coronary sclerotic lesions revealed following results:
1) Internal elastic lamina of coronary arteries play a great role in controlling the permeability of coronary arterial wall. Destruction of internal elastic lamina induces remarkable sclerotic changes of intima and outer-media.
2) Adhesion of thrombi and hyper-permeability still observed in areas of intimal damage even after the recovery of endothelial cells. Intactness of whole layer is necessary for coronary artery to do its physiological functions.
3) Sclerotic changes of coronary artery observed only in branches of intimal brushing. Intimal damage played a main role in this experimental model.

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The presence of both smooth muscle cell-derived foam cells and blood-borne monocyte-derived foam cells in atherosclerotic plaques was recently shown clearly. We tried to find out blood-borne monocytes just penetrating into the aortic intima, examine the time when they transform into foam cells and investigate the fate of foam cells in the way of observation with electron microscope of the aortic regions having no obvious atherosclerotic lesions of 25 human autopsy cases between 1 month to 80 years old with mild atherosclerotic lesions. We found that monocytes adhering to endothelium had a few lipid droplets. A group of foam cells having many lipid droplets were observed in the intima. So we agree with Gerrity's opinion that blood-borne monocytes transform into foam cells through endocytosis of lipid in aortic intima. On the other hand, we observed that foam cells loading many lipid droplets having atrophic intracytoplasmic organella and, moreover, found ruptured foam cells, so we consider that foam cells may be inactive cells just going to die.

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Fifty-seven areas, taken from arteries of 25 cases, were electron microscopically examined for evidence of fibrin on arterial wall, that is, fibrinolytic-thrombogenetic theory for atherogenesis.
Only deposits giving characteristic fibrils for fibrin were accepted, and on this basis 24 of the 57 areas examined shown fibrin on the arterial walls.
From the point of ultrastructural aspect of fibrin existence on the arterial walls, the following three patterns of fibrin deposit fashion were classified. And their sequences were proved to be attributable for thrombogenic theory.
Type I: Untouched to the endothelium
Type II: Interacted with the endothelium
Type III: Deposits on the intima

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Vital-microscopic observations on the microcirculatory system in transparent chambers installed in the ear lobe of normal male rabbits fed ad libitum 1.5% cholesterol-supplemented diet and given two times a day tobacco smoke from 5mm length cigarette during 4 weeks, were as follows.
Adhesiveness of circulating leukocytes especially to venular walls was remarkably enhanced even in the first day of cholesterol feeding and the increased adhesiveness persisted throughout the experiment period: masses of adhering leukocytes sometimes looked like parietal microthrombi but no platelets appeared to participate in forming the thrombuslike structure. After about 1 week's cholesterol feeding, abnormal grouping of circulating erythrocytes and swelling of venular endothelia were developed concurrently with the increased adhesiveness of leukocytes: sludging or rouleau formation occurred even in flowing blood.
After about 2 weeks' cholesterol feeding, in addition to the changes in behaviors of intravascular cellular elements, interstitial tissues surrounding the vascular net became markedly proliferated in the shape of sponges or broccoliflowers: the contour of vasculatures was obscure due to the proliferation at the end of the experiment.
A transient increase in adhesiveness of intravenular leukocytes was induced by single inhalations of tobacco smoke either with or without filtration of total particulate matters. Inhalations of both kinds of tobacco smoke combined with cholesterol feeding appeared to accelerate the cholesterol-induced microcirculatory changes.

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Mono dansyl cadaverine is known as the in-hibitor of fibrin cross linking reaction.
In 1971, it was found to be an efficient inhibitor of the second phase of both ADP and norepine-phrine-induced aggregation of human platelet.
We found, this substance also inhibits the first phase of ADP, norepinephlline, collagen, arachidonic acid and thrombin.
By in-vitro study, monodansyl cadaverine in-hibits insulin effect in the rat liver and antagonize for binding of the insuline on the human platelet.
By in-vitro study, monodansyl cadaverine in-hibited the effect of Angiotensin II, not increasing the blood pressure in rabbits.

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The importance of circulating platelet aggregates in the genesis of various arterial insufficiency has been stressed. Various approaches have been used to study platelet abnormality. In 1974 Wu and Hoak devised a simple method to determine these aggregates. It has been developed using a plateletcount ratio technique.
We applied this method to study of normal subjects and patients with arterial insufficiency and diabetes mellitus.
The mean platelet-aggregte ratio were signi-ficantly lower (p<0.05) in patients with cerebral bleeding, infarction, stable angina chronic ischemu myocardial damage and uncontrolled diabetes mellitus than in normal control.
The specificity and validity of the method were demonstrated by in-vitro experiments comparing with light scattering aggregometer. From the result of these studies, this method seems to be useful for follow-up evolution of patient who has arterial insufficiency.

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Plasmalogen is the minor component of serum phospholipids which is characterized by having fatty aldehyde residue in β-position of glycero-phosphate. In this study the concentrations of serum plasmalogens have been determined in 135 normal subjects and 75 patients with ischemic heart disease. In patients with ischemic heart disease the serum level of plasmalogens were significantly lower than normal subjects. In a further study significantly decreased concentration were found in serum HDL fraction in patients suffering from ischemic heart disease as compared with normal subjects. It is suggested that serum plasmalogens could be in some way involved in the antiatherogenic effect.

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Polyunsaturated fatty acid compositions were analyzed using gas liquid chromatograph (Shimazu GC-RIA with solventless injector) equipped with a hydrogen flame ionization detector. A standard mixture of fatty acid was purchased from Applied Science, Inc. Tow types of columns were used for the present measurement. One was a 300cm glass coiled column, 3mm i.d., packed with liquid of 5% Advance-DS, 5% Shinchrom E71, 5% or 10 Thermon 3000, the other was a glass capillary column (Shinwa Kako Co.) coated with films of DEGS (BCL type) or Thermon 3000 (WCOT type).Packed type column chromatography could not separate the fatty acid compositions of C20:0, C20:1, C20:3 and C20:4, whereas the glass capillary type column chromatography could clearly identify the individual compositions in the fatty acid. Especially, by means of the glass capillary column with Thermon 3000, the _{Δ8, 11, 14}C20:3 was separated from _{Δ11, 14, 17}C20:3. This indicates a possible usage of the latter composition as the internal standard in the gas liquid chromatography. Therefore, the glass capillary column chromatography seems to be more appropriate to qualitative and quantitative analysis of fatty acid compositions.
The above technique was applied to analyze blood samples of a healthy young man who was leaded with daily ingestion of canned mackerel meat rich in eicosapentaenoic acid (EPA) for 8 consecutive days. During the ingestion of mackerel meat, cholesterol, phospholipid triglyceride and β-lipoprotein in the plasma showed a progessive decrease, while plasma HDL-cholesterol remained unchanged. Plasma arachidonic acid did not exhibit any significant change during and after the meat ingestion. Platelet arachidonic acid, on the other hand, tended to increase for the second half of the ingestion period with its maximum value on the 2nd postingestion day. Plasma EPA reached its peak concentration on the 4th ingestion day. A sharp increase in platelet EPA was observed during the ingestion period. Collagen induced platelet aggregation was reduced with the ingestion of mackerel meat. However, ADP induced platelet aggregation was not affected by mackerel meat.
These results lead us to the conclusion that EPA rich fish meat seems to play some roles in reducing the plasma lipid levels and in preventing the platelet aggregation.

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The comparative study on the lipid and food composition in Okinawa Prefecture and Taiwan was done and the following results were obtained.
1) There is no remarkable difference of the average temperature in year between Naha City and Taipei City, therefore it is presumed that the difference of weather does not scarcely influence on the structure of diseases and the composition of food between both.
2) It was observed that there were no remark-able differences as for the level of total cholesterol and triglyceride.
3) It was found that the amount of fat intake which will influence the lipid level was almost same between Okinawa Prefecture and Taipei.

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Isolated dog cardiac microsomes (CSR) showed Ca²⁺ uptake by adding ATP, which was measured with the optical density change of Arsenazo III (Ca²⁺-sensitive dye) using Hitachi dual wave length spectro photometer at 30°C. Maximal Ca²⁺-uptake (18.5±1.4nmol/mg) was attained at 1min after adding 0.1mM ATP to 1 mg/ml of CSR in the presence of 50μM Arsenazo III. This Ca²⁺-uptake was inhibited by 0.5mM Nicomol (about 39%) and Nicotinic Acid Amid (about 28%) but not by Nicotinic Acid. It was suggested that the Nicomol and Nicotinic Acid Amid possibly delay the cardiac muscle contraction and relaxation.

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The inhibitory effects of HDL and HDL subfractions on the in vitro complex formation between plasma LDL and arterial elastin were studied. When a definite amount of LDL was incubated with delipidated elastin in the presence of increasing concentrations of HDL, HDL₂, HDL₃, HDL with E or HDL without E, the binding of LDL to elastin decreased progressively. The magnitude of inhibitory effects of HDL₃ or HDL without E was greater than those of HDL₂ or HDL with E, respectively. Although little effects were observed in the cases of apo HDL₂ or apo HDL₃ alone, the binding ability of LDL was significantly inhibited by addition of sonicated phospholipid-apoprotein complexes. Particularly, the inhibitory effect of phospholipid complex with apo HDL₃ was higher than that with HDL₂. In contrast with the inhibitory effect, the binding ability of HDL2 or HDL with E to delipidated elastin was significantly higher than that of HDL₃ or HDL without E. These results suggest that the inhibitory effects of HDL and HDL subfractions are not due to the competitive binding to arterial elastin.

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We investigated the metabolism of Phospholipid transported by Low Density Lipoprotein (LDL-PL) using Smooth Muscle Cell (SMC) compared with Cholesterol Ester transported by LDL (LDL-CE). LDL-PL was labeled with 1-linoleoyl-2-[¹⁴C] linoleoyl phosphatidylcholine and LDL-CE was labeled with cholesteryl-[¹⁴C]-oleate.
LDL linearly incorporated into SMC up to 18 hours and the amount of hydrolysis of LDL-PL and LDL-CE depended on incubation time. The LDL metabolism, which was measured as incorporation of radiolabeled FFA, showed almost the same as that of exogenous FFA added to the incubation medium.
Next, intercellular localization of radiolabeled lipids produced by the incubation of LDL-CE and LDL-PL was investigated. Most of radiolabeled PL or CE was observed in lysosomal fraction, when LDL-PL or LDL-CE was incubated, respectably. These results suggest that incorporated LDL was initially incorporated into lysosome and hydrolyzed.
It is well known that accumulated PL which was observed in atheromatous lesions was produced de novo synthesis in the cell. So, we investigated the effect of LDL on the regulation of PL metabolism in SMC. The incorporation into lipids from acetate in the presence of LDL was examined. Synthesis in SMC was not induced by the incorporation of LDL.

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A possibility of the regression of coronary sclerosis related to undernutritional state, was morphologically examined using 102 autopsied hearts. The materials consisted of 42 cases with malignancies, 36 with chronic hepatic diseases and 24 with miscellaneous conditions. The coronary artery was macroscopically examined for grade of narrowing and extent of sclerotic lesion using multiple cross sectioning method. Scores 1, 2, 3, 4 and 5 were given for minimal, 25%, 50%, 75% and 100 % narrowing or occlusion of the lumens at 30 cross sections with equal interval and the narrowing index was calculated as a sum of the maximal score in 3 major branches. The sclerotic area index was given by numbers of segments with any sclerotic lesions at the 30 cross sections. Histological examination was performed using 2 to 3 paired blocks from 3 major branches. One of them was embeded into paraffine and stained with H-E, azan, trichrome Masson, alcianblue and Weigertvan Gieson methods after usual thin-sectioning. Another block was embeded into carbowax or directly cut using frozen section for Sudan III stain. Fatty deposition, fibroelastosis of intima, fibrosis of media and ground substance accumulation, were microscopically estimated using -, + and ++ grading.
The sclerotic area index was 6.5, 7.7 and 6.6 in malignancies, hepatic diseases and miscellaneous conditions respectively, and the narrowing index was 4.0, 4.1 and 3.6 as the same order. Lower blood pressure than 150/90mmHg and lower serum cholesterol level than 150mg/dl made a reduction of the sclerotic area index by 32 and 17%, and of the narrowing index by 24% and 3%. But lower body weight and lower serum albumin level gave no significant effect to the sclerosis.
Fatty deposition in the sclerotic lesion was less in malignancies and low blood pressure group. Ground substance accumulation was more in hepatic diseases, low cholesterol group and low albumin groups. Intimal fibroelastosis was more prominent in higher blood pressure group.
In relation of clinical course from the onset of symptoms, lipids deposition was reduced after 2 months, and ground substance accumulation was also reducing gradually with some delay to the lipids movement.
The ground substance was more deposited in the right coronary artery than in the other branches with an inverted relation to lipids deposition.

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It is widely accepted that ear lobe crease (ELC) is closely associated with coronary heart disease. In the present study, attempts were made to confirm the significant association of ELC with cerebral infarction as well as coronary heart disease in Japanese people, and to investigate the relationship of ELC with known risk factors for atherosclerotic vascular diseases.
There was no ELC in 53 healthy controls under 50 years of age. ELC was found in 18.3% of 104 patient controls, in 66.5% of 48 patients with coronary heart disease and in 44.4% of 36 patients with cerebral infarction. When cerebral infarctions were subdivided, the frequencies of ELC were equally higher in patients with cerebral infarctions in the distribution of perforating as well as cortical arteries.
The frequency of ELC increased with advancing age. It was found that ELC was significantly associated with smoking and male sex. However, no significant association was observed between ELC and either hypertension, plasma levels of total cholesterol, HDL-cholesterol, triglyceride and uric acid, or calcification of thoracic aorta.

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The relationship between coronary atherosclerosis and serum lipoproteins were examined in 51 patients undergoing coronary angiography suspected on ischemic heart disease.
The degree of coronary sclerosis was assigned to coronary angiogram according to the method of Friesinger. Lipid concentrations in blood serum were mesured by enzymatic method and lipoprotein subfractions were mesured after ultracentrifugation.
Plasm apoprotein concentrations were mesured by SRID method.
Result:
1) TC, TG and FFA were increased in coronary artery disease (CAD) group than healthy (n-CAD) group. High density lipoprotein (HDL) cholesterol and apo A-I were significantly lower in CAD group. Atherogenic index was good correlation in apo B/apo A-I ratio than LDL-C/HDL-C.
2) VLDL was significantly lower in coronary sinus than aorta but LDL and HDL were not higher in coronary sinus.
3) In liporptein subfractions, TG was significantly higher in CAD group. It was suspected the relation to the coronary sclerosis.
4) HDL₂ was significantly lower than HDL₃in CAD group.

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To investigate the distribution of probucol in human serum lipoprotein fractions, 26 patients with type II hyperlipoproteinemia received a single dose or multiple doses of probucol ranged from 125 to 1, 000mg/day. Serum lipoprotein fractions were separated by ultracentrifugation, and probucol and lipid concentrations were determined.
The results: (1) In type IIa patients, serum probucol levels at 6 hr after a single dose administration of 500-750mg were 317±154ng/ml (n=2), and probucol levels in the lipoprotein fractions were high in the order of LDL, VLDL, chylomicron and HDL. After repeated oral doses, serum probucol levels were 30.92±3.32 μg/ml (n=12), and about 58% of probucol in the serum distributed in the LDLL fraction.
(2) In type IIb patients, serum probucol levels at 6hr after a single administration of 750mg were 1, 177±827ng/ml (n=3), and distributed mainly in VLDL and LDL fractions. After repeated oral administration, more than 80% of probucol (18.69±5.77μg/ml, n=9) distributed in VLDL and LDL fractions.
Since less than 4% of probucol was detected in the bottom fraction of the serum (d>1.21), probucol in type IIa and IIb patients was transported by serum lipoproteins as in the normolipidemic subjects. The results further suggested that probucol was largely contained in the increased lipoproteins of hyperlipidemic patients.

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The effects of long-term (12 months) probucol treatment on serum lipids, lipoprotein lipids and skin xanthomas were studied in 17 heterozygous patients with familial hypercholesterolemia (FH). Probucol was administered for 12 months in a dose of 1.0g per day. Serum lipids and lipoprotein determinations were performed at 1, 3, 6 and 12 months of treatment.
Following results were obtained.
(1) The total cholesterol (CHOL) levels decreased from 345±17 (Mean±SE) mg/dl to a minimum of 271±15mg/dl (a decrease of 22%, p<0.001).
(2) The LDL-CHOL levels decreased from 272±17mg/dl to a minimum of 223±13mg/dl (a decrease of 17%, p<0.001).
(3) The HDL-CHOL levels decreased from 40±2 mg/dl to a minimum of 23±2 mg/dl (a decrease of 40%, p<0.001).
(4) The VLDL-CHOL/VLDL-TG ratio increased from 0.43±0.03 to 0.50±0.03 (p<0.05).The LDL-CHOL/LDL-TG ratio decreased from 6.86±1.09 to 4.04±0.36 (p<0.05).
(5) The LDL-CHOL/HDL-CHOL ratio increased from 7.16±0.64 to 10.35±0.96 (p<0.001).
(6) A reduction of tuberous xanthomas and xanthelasma was noticed in three of 6 heterozygous patients with FH.
These data suggest that probucol is an effective hypolipidemic agent for heterozygous patients with FH.

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We describe a method for simultaneous determination of cholesterol, bile acids and lecithin (analyzed as their component fatty acids) in bile by gas-liquid chromatography.
The method will provide more convenient and precise way for drowing biliary lithogenic indices, as compared to conventional method by which individual lipid is measured separately. Clinofibrate (600mg/day) and Cholestyramine (12g/day) were given to 11 patients with hyperlipidemia for 3 to 6 months to evaluate their effect on biliary lipids and biliary bile acid composition. After administration of Clinofibrate, the ratio of molar concentration of cholesterol in bile decreased and that of phospholipids and total bile acids increased slightly. The lithogenic index showed a tendency to decline, but was not affected significantly by Clinofibrate administration. Clinofibrate did not change the bile acid composition. Administration of Cholestyramine decreased the ratio of molar concentration of cholesterol and phospholipids in bile and slightly increased that of total bile acids.
In bile acid composition, cholic acid increased and chenodeoxycholic acid decreased significantly.

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It is reported that the enzyme activities involved cholesterol ester metabolism in the arteriosclerotic arterial wall of rat were modified so as to increase the cholesterol ester deposition in the cells. To clarify the effect of hypolipidemic drug, clinofibrate on the distorted lipid metabolism in the arteriosclerotic rats, high cholesterol diet containing Vitamin D₂ and propylthiouracil (arteriosclerotic diet) were administered to rats and the enzyme activities involved in lipid metabolism were studied. By administering clinofibrate in addition to atherosclerotic diet, plasma cholesterol have reduced about 30%. The most reduced fraction was very low density lipoproteins and the next was low density lipoproteins. Lipoprotein lipase activity, which is released from adipose tissue by the treat-ment of heparin, and VLDL-triolein hydrolysis by adipose tissue stromal vessels were increased in clinofibrate-administered rats compared with arteriosclerotic rats. Acid, neutral cholesterol esterase activity and acyl-CoA cholesterol acyl transferase (ACAT) activity were increased in clinofibrate administered rats. But the ratios of ACAT/neutral cholesterol esterase was decreased, in clinofibrate-administered rats compared with arteriosclerotic rats. From these results, clinofibrate administration cause modification of enzyme activity so as to reduce the cholesterol ester in the arterial wall as well as lowering plasma VLDL or LDL cholesterol levels.

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Eighty one essential hypertensives with glucose intolerance were treated with INDAPAMIDE newly synthesized as an antihypertensive agent. The effect of the drug on blood pressure and on glucose tolerance were observed. Blood pressure was lowered safely 75.9% in effectiveness score, and for actual pressure drop 16.8% at systolic and 16.9% at diastolic without any impropriety.
At the 6th and 12th month of the INDAPAMIDE treatment 50 g of o-GTT were performed and compaired to the control of before INDAPAMIDE; resulting in no evidence of deterioration in glucose intolerance was observed. With other clinical laboratory data and amelioration in clinical symptomes, it is concluded that INDAPAMIDE is a safe and reliable antihypertensive agent and it is useful even for hypertensives with glucose intolerance.

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An important topic in the treatment of diabetic patients is the prevention of the outbreak and progressive development of both macro- and microangiopathy. For this reason, we conducted long-term administration of Dextran sulphate (DS) over a period of 8 years and studied the changes in lipids, coagulation and fibrinolytis and their relationship to diabetic angiopathy.
We selected our 79 subjects from diabetics with stable conditions who showed abnormally high values for at least 2 of the following items: total cholesterol (TC), triglyceride (TG) or β-lipoprotein. The subjects were randomly divided into 3 groups of which 37 patients served as controls, 21 were administered a daily dose of 900 mg of DS and 21 a daily dose of 1, 800 mg of DS.
Our results show that diabetics with hyperlipidemia exhibit prolongation of ELT and high antiplasmin levels. During the 8 year treatment period with DS, an improvement was observed in lipid levels (TG, β-lipoprotein) and the fibrinolytic system (ELT, antiplasmin) and this improvement tended to be especially marked in the 1, 800 mg group. The onset and mortality rate due to complications of diabetic angiopathy during this 8 year period were lower in the DS-treated group than in the controls.

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The effect of antioxidants on lipid peroxidation were investigated using cultured aortic smooth muscle cells (5 cell lines) from 5 albino rabbits.
5 μg and 10 μg/ml of vitamin E and 2, 000 ng/ml of coenzyme Q₁₀ were used as antioxidants. As the lipid peroxide of cells was generated in the time dependent manner with cell proliferation, it remained within the cells and did not accumurate in the media. Although ethanol which is vitamin E solvent showed suppressive effect on cell proliferation, the addition of 10 μg/ml vitamin E increased it up to the control level. On the other hand, the intracellular lipid peroxide formation expressed per DNA was inhibited by 10 μg/ml vitamin E, not by 5 μg/ml. Fatty acid analysis also howed that ethanol decreased the ratio of oleate/stearate in the cells and the addition of 10 μg/ml vitamin E increased it up to the control. Coezyme Q₁₀ showed no difference in the cell proliferation and lipid peroxide formation compared to control.

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Enhanced platelet aggregation (PA) is thought to play an important role in progression of arteriosclerosis with relation to lipids and we have previously reported that PA in patients with arteriosclerosis is enhanced in the chronic state. The aim of this report is to investigate the effects of a hypolipidemic drug, niceritrol, pentaerythritol tetranicotinate, on PA and plasma lipids in patients with arteriosclerosis. We measured PA and plasma total cholesterol, triglycerides, phospholipid, HDL cholesterol, LDL cholesterol and VLDL cholesterol in 20 patients (mean age 61.4 years) with arteriosclerosis including some patients with a chronic state of ischemic heart disease and a chronic state of cerebrovascular disorders before, 4 weeks after and 8 weeks after oral administration of niceritrol 750 mg/day.
Three types of induced PA (ADP, collagen and adrenaline) were studied by the turbidometric method. All of these three types of induced PA were decreased significantly 4 weeks after and 8 weeks after treatment with oral niceritrol. Plasma total cholesterol and triglycerides were decreased gradually after treatment, but plasma phospholipid was increased. Plasma HDL cholesterol and LDL cholesterol were also decreased after treatment. Correlation of change of collagen- or adrenalineinduced PA to the change of plasma total cholesterol between the value before administration and the value after 8 weeks of administration of niceritrol was positive and statistically significant. Correlation of change of all of these three types of induced PA to the change of plasma LDL cholesterol between the value before administration and the value after 8 weeks of administration of niceritrol was also positive and statistically significant.
These results suggest that niceritrol may have beneficial actions in the treatment of patients with arteriosclerosis who show enhanced PA and that its antiaggregating action may be related to its
hypolipidemic action.

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Seventy three patients with hyperlipidemia were examined. The clinical effects and side effects of Pentaerythritol tetranicotinate were examined in 73 patients with diabetes under the good chemical control, hypertension, ischemic heart disease. The hyperlipidemia was diagnosed in the patients either whose cholesterol level was over 220mg/dl or whose triglyceride level was over 180mg/dl. Significant reductions of cholesterol and triglyceride level were found in this study. On the other hand, a significant increase of HDL-cholesterol was also observed by the administration of this drug. There-fore, the atherogenic index significantly decreased. The remarkable changes of SGOT, SGPT, uric acid and fasting blood sugar were not observed through the period of treatment. In the diabetic patients, the glucose tolerance before and after the treatment was not changed. As for the side effects, in 7 patients flushing, in 3 patients los of appetite, and in 2 cases the increase of uric acid were observed, respectively. But these side effect were not serious and the administration could continue.

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Diets high in cholesterol (Ch) have been shown to cause significant elevations in plasma Ch in several animals including man. Elevated plasma Ch has been shown to be an independent risk factor for coronary heart disease.
Consistent features of Ch-induced hypercholesterolemia in several animals are the occurrence of β-VLDL in the d<1.006g/ml fraction, an increase in the IDL and LDL, a decrease in the typical HDL and the appearance of HDLc.
Plasma lipoprotein abnormalities are common in the patients with diabetes mellitus. They are of considerable clinical interest because of the higher incidence of atherosclerosis in the diabetics.
Recently we have found that Ch-fed diabetic rat had marked elevations of plasma Ch and triglyceride (TG) and had higher concentrations of lipoproteins of VLDL (d<1.006g/ml), IDL (1.006<d<1.019g/ml) and LDL (1.019<d<1.063g/ml) as compared with Ch and propylthiouracil (PTU)-fed non-diabetic rat. Insulin treatment was highly effective to improve hyperlipoproteinemia of Ch-fed diabetic rat as well as 17α-ethinyl estradiol treatment.
The present study was designed to investigate the effect of niceritrol (pentaerythritol tetranicotinate) on plasma lipids and plasma lipoproteins of Ch-fed rat, diabetic rat and Ch-fed diabetic rat. Non-diabetic control rats and streptozotocininduced diabetic rats were fed on the diet containing 1% Ch, 1% lard and 0.3% sodium taurocholate
for 4 weeks. In non-diabetic rats, 0.1% PTU was added. Niceritrol-treated rats were fed on the diet containing 0.5% niceritrol. Ch and PTU-fed rats had features of plasma lipoproteins as described previously. Niceritrol treatment significantly decreased the Ch-rich IDL and LDL (IDL-Ch: 189±40.2mg/100ml vs 87±19.9mg/100ml, p<0.01, LDL-Ch: 101±8.6mg/100ml vs 69±4.9mg/100ml, p<0.001). Plasma Ch also decreased, but there was no significant difference as compared with Ch and PTU-fed rats (325±44.4mg/100ml vs 230±27.9mg/100ml). HDL-Ch was significantly increased by niceritrol treatment in Ch and PTU-fed rats (16±3.1mg/100ml vs 53±4.1mg/100ml, p<0.001). Diabetic rats were hypertriglycedemic due to high concentrations of TG-rich lipoproteins (VLDL). Niceritrol treatment significantly decreased the plasma and VLDL TG (plasma TG: 228±35.2mg/100ml vs 103±16.5mg/100ml, p<0.01, VLDL-TG: 211±35.3mg/100ml vs 96±16.3mg/100ml, p<0.05). However, niceritrol did not affect the plasma lipids and plasma lipoproteins in Ch-fed diabetic rats. Since it has been shown that 17α-ethinyl estradiol improves the hyperlipoproteinemia of Ch-fed diabetic rat provably by increasing the number of apo B, E receptor of hepatocytes, it was suggested that niceritrol would not affect the activity of apo B, E receptor in hepatocytes.

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As compared to effects of hypolipidaemic agents on HDL-cholesterol and HDL-phospholipids in man, plasma lipids and lipoprotein-lipids were assessed before and at 4, 8, 12, and 16 weeks during treatment. Pantethine (600mg/day), niceritrol (750mg/day) and alminium clofibrate (1, 500mg/day) was given for 16 weeks to 41, 29 and 48 patients respectively. Plasma triglycerides was markedly reduced in patients with type IIb and IV hyperlipidaemia by niceritrol and alminium clofibrate. HDL-cholesterol significantly increased in pantethine group and alminium clofibrate group. There were, although, no significant changes in HDL-cholesterol levels in patients with type IV hyperlipidaemia treated by these agents. HDL-phospholipids significantly increased in pantethine group and alminium clofibrate group. It was significantly decreased in niceritrol group. Various changes were found in HDL-cholesterol/HDL-phospholipids ratio in these three agent groups. That increased in niceritrol groups, and decreased in pantethine group. There was found no significant changes in alminium clofibrate group.
The results indicate there is no correlations between the falls in plasma triglycerides and the changes in HDL-cholesterol. This would suggest different mechanisms for action of hypolipidaemic agents on plasma lipid and HDL. It is found that lipid component of HDL would change by hypolipideamic agents.

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In the present study, the effect of probucol (500mg×2, daily) on serum lipids and lipoproteirs level were studied in 9 patients with familial hypercholesterolemia (FH) during 3-4 months. The diagnosis of FH was established according to the criteria both of Fredrickson et al and of Makuchi et al. Thickness of Achilles tendon was over 9mm in all patients and the xanthomas were observed in 4 of 9 patients.
Before and 3-4 months after treatment of probucol the measurement of serum triglyceride (TG), total cholesterol (TC) and apolipoprotein (Apo) A-I and A-II were made. At the same time, serum VLDL, LDL, HDL₂ and HDL₃ were separated by successive ultracentrifugation. Thereafter, TG, TC and protein of each lipoprotein fraction were measured.
TG and TC were determined by enzymatic method, Apo A-I and A-II were done by single immunodiffusion assay, and protein was done by dye-binding method.
All data were expressed as mean ±S.E. and statistically analized by Student's t-test.
The results were as follows:
1) VLDL-TG levels were slightly increased, although no significance was found between VLDL-TG level before and after treatment.
2) The levels of serum TC were 388±37mg/dl and 308±28mg/dl (-21%, p<0.05) before and after probucol administration, respectively. LDL-cholesterol (LDL-C) levels decreased from 325±37mg/dl before treatment to 262±32mg/dl (-19%, p<0.05) after treatment. HDL-C values significantly decreased from 42±5mg/dl to 26±4mg/dl (-38%, p<0.01), and especially HDL₂-C showed significant fall (-48%, p<0.01).
3) Serum Lecithin: Cholesterol Acyltransferase (LCAT) activities were not changed.
4) The concentrations of Apo LDL decreased from 139±18mg/dl to 106±17mg/dl (-29%), but it was not significant statistically. Apo A-I levels decreased significantly from 92±10mg/dl to 66±10mg/dl (-28%, p<0.01). On the other hand, Apo A-II levels were unchanged.
These observations suggested that probucol would be a useful drug to improve serum and LDL cholesterol levels in FH. However, we should take care to use this drug because of its effect on HDL metabolism.

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Drug therapy is often required in the control of hypercholesterolemia. But, none of the drugs are entirely satisfactory. For example, clofibrate increases biliary cholesterol saturation and gallstone incidence. It is well known that probucol decreases serum cholesterol. But, the mechanism of probucol is not yet clear. The purpose of this study was to evaluate the effect of probucol on biliary lipids and the likelihood of inducing gallstone.
We studied six patients with familial hypercholesterolemia (F. H. C.) and six healthy subjects, who had never suffered from liver and biliary diseases. The patients with F. H. C. were examined before and after probucol treatment (500mg×2, daily) for 16 weeks. Biliary bile acids were determined by using high-performance liquid chromatography (HPLC).
No free bile acids were found in any of the samples examined. The value of deoxycholic acid was significantly lower (6.9±2.1μmol/ml) (Mean±S. E.) in patients with F. H. C. than that (17.6±3.8μmol/ml) in healthy subjects. The value of other bile acids, cholic acid/chenodeoxycholic acids, and glicine-conjugates/taurine-conjugates ratio in F. H. C. did not significantly differ from those in healthy subjects. Probucol did not significantly change biliary bile acid composition.
Serum cholesterol level decreased significantly from 396.7±39.5mg/dl to 311.0±38.0mg/dl by probucol treatment.
Probucol did not influence biliary lipid composition, cholesterol saturation, and lithogenic index. We suppose that probucol does not have an isolated increase in biliary cholesterol secretion. But, in patients, whose serum cholesterol decreased more effectively by probucol treatment, biliary cholesterol molar % and lithogenic index were tending upward. More detail follow up study must be needed.

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Probucol (1g/day) was administered for 6 months to 10 hypercholesterolemic patients. Total serum cholesterol fell by 13%, LDL cholesterol by 12%, HDL₂ cholesterol by 20% and HDL₃ cholesterol by 14%. The serum, LDL and HDL free cholesterol levels were significantly reduced during probucol treatment. The ratio of total cholesterol to free cholesterol in serum, VLDL and LDL was significantly increased. Thus, probucol appeared to reduce especially free cholesterol in VLDL and LDL fractions.

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A population study of 16, 940 persons aged 20 years showed the following results.
1) Mean serum cholesterol level (±SD) was 164±31mg/dl. Mean serum cholesterol level (169±31mg/dl) of female subjects was higher than that (160±31mg/dl) of male subjects. Normal range (mean±2SD) of serum cholesterol was 164±62mg/dl.
2) Incidence of hypercholesterolemia above 230mg/dl was 2.31%, while that of hypercholesterolemia above 250mg/dl was 1.0% and that of hypercholesterolemia above 300mg/dl was 0.22%.
3) Incidence of familial hypercholesterolemia in Japan was estimated to be 0.21%.
4) Incidences of familial type III and type V hyperlipoproteinemia were estimated to be 0.004% and 0.003%, respectively.

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Long-term therapy with cholestyramine, a strong basic anion exchange resin, involving 168 cases of type II hyperlipidemic patients resulted in the following observations:
1) The lowering of the serum total cholesterol (TC) level was seen in the second week of the cholestyramine therapy and the statistically significant decrease lasted for the entire 52-week administration period thereafter. The mean reduction rate of TC during the therapy was 14.6% overall.
2) No difference was noted in TC lowering effect of cholestyramine between the group at daily dosage of 8g (109 cases) and the group at daily dosage of 12g (59 cases). Thus the daily dosage of 8g taken twice a day was confirmed to be more beneficial considering the facile administration schedule.
3) No difference in drug efficacy was observed between the 91 cases of type IIa and the 77 cases of type IIb hyperlipidemic patients, and larger rate of decrease was obtained in the group with higher TC levels at pretherapy. The drug was also comfirmed to be effective with familial hypercholesterolemia.
4) During the therapy, serum triglyceride and HDL-cholesterol levels tended to increase, while β-lipoprotein and phospholipid levels slightly decreased.
5) The most frequent side effects were gastrointestinal symptoms such as constipation and abdominal distention, and in most cases continuation of the therapy was possible. In a few cases, increases of serum GOT and GPT levels manifested, but most of them were of minor nature.
In conclusion, cholestyramine is considered to be a safe and highly beneficial drug even against serious cases of type II hyperlipidemic patients including familial hypercholesterolemic patients who have been considered difficult to cure.

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