Liporprotein lipids of four patients with normolipidemic dysbetalipoproteinemia (group-N) were compared with those of ten patients with primary type III hyperlipoproteinemia (group-H) and those of 24 normal subjects (group-C) with total cholesterol (TC) less than 230mg/dl, triglyceride (TG) less than 160mg/dl and positive apoE-3 or apoE-4.
Serum TC levels of group-N (143±30, mean±SD, mg/dl) were significantly lower than those of group-H (388±150mg/dl) and group-C (174±26mg/dl). Group-N showed significantly higher VLDL-TC (32±12mg/dl) and IDL-TC (15±9mg/dl) levels, and significantly lower LDL-TC (36±14mg/dl) levels than group-C. In group-H, VLDL-TC (207±143mg/dl) and IDL-TC (51±21mg/dl) levels were much higher than in group-N, and LDL-TC levels (54±20mg/dl) were intermediary between those of group-N and group-C. Group-N had higher VLDL-TG and lower LDLTG levels than group-C.
The ratio of VLDL-TC/TG was significantly different among group-H, group-N and group-C, 0.42±0.08, 0.29±0.05 and 0.16±0.06, respectively. The ratios of VLDL-TC/LDL-TC in group-H (5.73±7.40) and group-N (0.95±0.38) were significantly higher than in group-C (0.17±0.11). But there were only small differences in these two ratios between group-N and group-C. The ratios of IDL-TC/LDL-TC in group-H (1.02±0.5) and group-N (0.40±0.10) were higher than in group-C (0.07±0.03). The distribution of this ratio in group-N (from 0.30 to 0.52) was apparently higher than that in group-C (below 0.14).
VLDL-TC and IDL-TC levels were positively correlated with serum TC levels in a patient (T.K.) with primary type III hyperlipoproteinemia, whose serum TC levels changed between 175 and 555mg/dl. The IDL-TC/LDL-TC ratio of this patient was much higher than normal range even when her serum TC level, VLDL-TC/LDL-TC ratio and VLDL-TC/TG ratio fell in the normal ranges.
Conclusions: 1) Dysbetalipoproteinemia showed hypo-, normo- and hyperlipidemia. 2) In normolipidemic dysbetalipoproteinemia, VLDL- and IDL-cholesterol levels increased, LDL-cholesterol level decreased, and VLDL-TC/TG ratio elevated as in primary type III hyperlipoproteinemia due to the impaired VLDL metabolism and the accumulation of remnant lipoproteins caused by deficiency of apoE-3. 3) These patients may have higher risk for atherosclerosis than normal subjects with apo E-3 or apoE-4 because of accumulation of remnant lipoproteins.

View full abstract

It is said that two types of arterial lesions are known to be responsible for cerebral thrombosis: One is atherosclerosis, which affects “cortical arteries” called by Kameyama. The other type of lesion is fibrinoid necrosis, which affects “perforating arteries”. Therefore, patients with cerebral thrombosis are classified into 2 sub-groups namely the cortical artery (C) group and the perforating artery (P) group, based on the findings of computerized tomography and angiography.
Serum lipoproteins and albumin concentrations were determined serially after onset of the stroke in patients with cerebral hemorrhage (H group) as well as cerebral thrombosis.
In this study, total serum cholesterol (TC) was devided into two subfractions: α-cholesterol (α-C) and β-choleserol (β-C). HDL (α) farction was obtained by a phosphotungustate-Mg precipitation method, and the concentrations of total (α-C) and esterified cholesterol (α-CE) of this fraction were determined by enzymatic methods. Apolipoproteins were determined according to a single immuno-diffusion technique.
The results were as follows.
1) In the acute stage; within 4 days after onset of the stroke, the mean values of TC and α-C concentration and β/α-cholesterol (β/α-C) ratio in the H as well as in the P group were almost same levels as those of age-matched healthy controls.
In the C group, there were increases of TC and decreases of α-Clevels, and the mean value of β/α-C ratio was significantly higher than that of the controls.
2) In the convalescent stage; 4-8 weeks after onset of the stroke, the α-C and α-CE as well as apo A concentrations and LCAT activities were significantly lower in the C group than in the P group.
In contrast, the mean values of apo B and β/α-C ratio were significantly higher in the C group than in the P group.
3) There were significant differences of the α-C concentration and the β/α-C ratio between in the acute stage and the convalescent stage of cerebral thrombosis.
4) The mean values of serum albumin concentration in each stage of stroke were significantly lower than those of age-matched controls.
Hypercholesterolemia was observed in 46 percentage of patients with stroke and hypocholesterolemia in only a few patient.
The results were suggested that these lipoprotein abnormalities might be due to the pathogenetic differences of cerebrovascular diseases.
Hypoalbuminemia rather than hypocholesterolemia was more important risk factor to stroke in Japanese rural community.

View full abstract

Blood HDL-cholesterol and coagulofibrinolytic factors were determind periodically in 15 patients with myocardial infarction and 22 patients with cerebral thrombosis in acute phase for 28th hospital days. Antithrombin III (ATIII) and HDL-choresterol remained to be lower in both diseases than that of normal. And ATIII in both was decreasing progressively in 2 to 5 days after onset, then gradually returned to the previous level. This change was to be more significant in myocardial infarction than cerebral thrombosis. But HDL-cholesterol in both didn't fluctate during acute phase.
The decrease of ATIII and increase of fibrinogen and α₁-antitrypsin in both were thought to be as the reflection induced by acute illness and these coagulation changes would more promote the thrombogenic tendency in acute phase of myocardial infarction rather than cerebral thrombosis.

View full abstract

Effects of aerobic exercise on coronary risk factors were assessed in patients with obesity, hyperlipoproteinemia, or glucose tolerance abnormality.
METHODS: Aerobic exercise program was prescribed on patients with obesity (18 males and 3 females, age: 22-64, mean 46.1±2.33 (S.E.) years), hyperlipoproteinemia (28 males, 5 females, 27-57, 43.0±1.62 years, Type IIa 16, IIb 11, IV 3, low HDL-cholesterol 3 cases), non-insulin dependent diabetes (5 males, 3 females, 37-64 years) or impaired glucose tolerance (12 males, 1 female, 40-57 years) (mean 50.3±1.31 years). Physical fitness classification of the patients was determined by submaximal treadmill stress testing following Balke's protocol. In some cases, their oxygen uptake was directly indicated continuously employing Waters Oxygen Consumption Computer MRM-1, during the treadmill testing. In accordance with the category of fitness, aerobics exercise program was prescribed following Cooper, K. H. (1970, 1977), Cooper, M. and Cooper, K. H. (1972). The prescription was designed to be selected among the equivalent exercise programs of walking, running, cycling, swimming, stationary running/cycling, rope skipping and other various sports. After completing several weeks' program, traedmill test was performed and the program was renewed to be compatible with the new fittness category. Body weight, serum lipids level, oral 75g glucose tolerance test (OGTT) and oxygen uptake determined by treadmill testing were assessed before and on the exercise program to compare the differences statistically.
RESULTS: 1) Body weight: Improvement in obesity index was observed concomitantly with increase in oxygen uptake (obesity index: before program+(18.9±1.83)%, on program+(15.8± 5.86)%, P<0.05, oxygen uptake: before program 7.9±0.55 METS, on program 9.5±0.60 METS, P<0.01). 2) Serum lipids level: Decrease in serum total cholesterol (TC) level was observed concomitantly with increase in oxygen uptake (TC: before program 276.1±12.17, on program 240.3±11.10mg/dl, P<0.01, oxygen uptake: before program 7.5±0.73, on program 8.9±0.81 METS, P<0.01). 3) OGTT: Decrease in blood sugar level on OGTT at 120 minutes (OGTT BS 120′) and sigma BS (∑BS) were observed concomitantly with increase in oxygen uptake (OGTT BS 120′: before program 162.9±9.51, on program 118.6±9.68mg/dl, P<0.01, ∑LBS: before program 931.6±48.04, on program 806.6±25.41mg/dl, P<0.01, oxygen uptake: before program 6.8±0.75, on program 8.5±0.91 METS, P<0.01).
COMMENT: Beneficial effects of aerobics exercise on coronary risk factors were suggested.

View full abstract

The apoprotein C composition of very low density lipoprotein (VLDL) were studied in 30 male patients with angiographically defined coronary artery disease (CAD). The tetramethylurea soluble VLDL apoproteins were separated by polyacrylamide gel electrophoresis and the relative proportions of apo CII, CIII₁ and CIII₂ were determined.
The CAD group had significantly lower apo CII/CII+CIII ratio (%apo CII) andhigher plasma triglyceride (TG) level than the age-matched control group. There were good correlations between the plasma TG level and % apo CII in each group. The regression lines were Y=-0.0614X+24.48 for the CAD males, and Y=-0.0319X+25.65 for the control males. The regression slope for the CAD group was steeper than the control group. The intercepts at 100mg/dl plasma TG were 22.3% apo CII for the CAD males, and 22.5 for the control males. However, the intercepts at 300mg/dl plasma TG were 10.1% apo CII for the CAD males, and 16.1 for the control males, and the difference was significant.
Twenty-two male relatives of the CAD patients were also investigated. They had no significant differences in VLDL apoprotein C composition from the controls.
These results suggest that hypertriglyceridemia associated with decreased % apo CII is related to coronary atherogenesis. Decreased % apo CII in VLDL might have inhibitory effects on lipoprotein lipase activity and this would disturb VLDL catabolism and accumulate VLDL remnant particles or intermediate density lipoproteins.

View full abstract

To clarify the effects of γ-orizanol on lipid metabolism, high cholesterol diets (1% cholesterol in normal chow diet containing 0, 0.5%, 2 % γ-orizanol) were administered to rats for 5, 9 and 13 weeks, and the changes of serum lipoproteins and the enzyme activities of arterial wall involved in lipid metabolism were examined.
γ-orizanol affects the levels of lipoproteins so as to lower the LDL-cholesterol and to increase HDL cholesterol levels. By administering high cholesterol diet, acid and neutral cholesterol esterase (CEase) in the arterial wall were not changed significantly. But the ratio of LDL cholesterol to acid CEase activity, which may imply the tendency of cholesterol ester deposition in lysosome were increased in high cholesterol diet groups and were decreased in high cholesterol plus γ-orizanol diet groups.
AcylCoA cholesterol acyl transferase (ACAT) activity were increased by the high cholesterol diet, and was decreased by α-orizanol containing diet. As a result, the ratio of ACAT activity of Neutral CEase, which might indicate the tendency of cholesterol ester deposition in microsome, was increased in high cholesterol diet groups, and was decreased in high cholesterol plus α-orizanol diet groups.
From these results, it was suggested that α-orizanol might work as an antiatherogenic agent by improving the cholesterol ester metabolism in the arterial wall, as well as serum lipoprotein levels.

View full abstract

300mg of γ-oryzanol per day was administered to 17 hyperlipemic patients with or without diabetes daily for 16 weeks. Serum lipids (cholesterol, triglyceride, phospholipid, HDL-cholesterol, cholesterylester, β-lipoprotein, lipid peroxide) were analysed every 4 weeks. Both serum cholesterol and β-lipoprotein were decreased in 8 or 16 weeks. HDL-cholesterol was slightly increased, but lipid peroxide level was unchanged. Serum triglyceride level was very variable. There was no side effect but one bothered with skin eruption.

View full abstract

Daily 600mg of clinofibrate were administered to 28 patients with hyperlipidemia and the effect of the drug on serum lipoproteins and their apolipoproteins were investigated.
Serum total cholesterol, triglyceride, beta-lipoprotein, VLDL-LDL cholesterol and VLDL-LDL/HDL cholesterol ratio decreased significantly at 6 and 12 weeks after the drug administration. Serum HDL cholesterol increased at 6 and 12 weeks but apo A protein increased at only 12 weeks after. However, free fatty acid and free cholesterol were not affected by clinofibrate.
Percentage of alph-lipoprotein to total lipoprotein increased and that of pre beta-lipoprotein decreased reciprocally by the treatment. While, beta-lipoprotein ratio showed no significant change. The same tendency was observed in the profile of serum lipoprotein separated by ultra-centrifugation except slight decrease of beta-lipoprotein: the decrease of VLDL and the increase of HDL.
Every component of VLDL fraction decreased up to 60 per cent of the premedication levels by the treatment and triglyceride content in LDL fraction decreased markedly. Apoprotein, triglyceride and phospholipids in HDL fraction increased about 20 per cent of the pretreatment values.
Neither apo AI/AII and apo C ratio to total apoprotein in HDL nor composition of apo C protein in VLDL were affected by the drug administration. But apo E/C ratio in VLDL fraction showed the tendency to increase.

View full abstract

The aim of this report is to investigate the effect of eicosapentaenoic acid (EPA) on platelet aggregation (PA) and fatty acid composition of plasma and platelet phospholipid in rats compared to the non-EPA fed controls. Rats were fed a fish oil diet or a free EPA diet and the fish oil diet was composed of 6% of the total diet. In the case of the free EPA diet, 500mg of the free EPA diet was given per kilogram of body weight every day.
The concentration of EPA of the total fatty acids of the fish oil diet and the free EPA diet was 15% and 73% respectively.
We measured PA and fatty acid composition in rats 8 days after the feeding of the fish oil diet and 7 and 14 days after the feeding in the case of the free EPA diet. ADP- and collagen-induced PA were studied by the turbidometric method, and fatty acids were analysed by gas-liquid chromatography.
In the case of the feeding of the fish oil diet, collagen-induced PA was decreased significantly in the EPA fed rats compared to the controls (P<0.05). ADP-induced PA showed no significant difference between the two groups. Lipid analysis of plasma demonstrated that the ω3 acids, especially EPA, were increased significantly in the EPA fed rats compared to the controls and that the ω6 acids, especially arachidonic acid (AA), were decreased significantly. In the case of the feeding of the free EPA diet, collagen-induced PA was increased 7 days after the feeding, and decreased 14 days after the feeding compared to the controls, but the decrease was not significant. ADP-induced PA showed no significant difference between the two groups. Lipid analysis of platelet phospholipid demonstrated that EPA was increased in the EPA fed rats 7 and 14 days after the feeding compared to the controls, but AA was decreased significantly in the EPA fed rats only 14 days after the feeding.
These results show that after feeding of EPA, PA decreases and fatty acid composition of plasma and platelet changes, but the effect of EPA on PA and fatty acid composition may be influenced by the composition of total fatty acids of the diet and the duration of feeding.

View full abstract

Inhibitors of cholesterol absorption (Moristerol) and of cholesterol synthesis (Amotril) were administered serially to 13 cholesterol-fed subjects in order to study the effects of those drugs on the cholesterol induced changes in plasma lipoprotein profiles.
Seven hundred fifty mg, of cholesterol was continuously administered per day throughout 6 weeks. Moristerol was administered at a dosis of 6.0gr./day between third and fourth week and Amotril was administered next at a dosis of 1.5gr./day between fifth and sixth week. Fasting plasma was collected every two weeks and cholesterol levels in plasma VLDL, LDL, HDL, HDL₂ and HDL₃ were estimated. VLDL was separated by ultracentrifugation and HDL was collected with heparin-Mn⁺⁺ precipitation method. Separation of HDL₂ from HDL₃ was performed by the ultra-centrifugation of the dialysed HDL fraction against NaCl solution (d=1.125).
Cholesterol induced changes in plasma lipoprotein cholesterol levels were very variable in individuals. Moristerol tended to return the cholesterol induced changes in plasma lipoprotein levels to the preloading levels as we expected. Amotril tended to increase HDL cholesterol and to decrease LDL cholesterol levels. However, we could not find any special interreationship between lesterol the tendencies in lipoprotein changes on cholesterol load with and without Amotril.

View full abstract

Probucol is a drug that has been shown to reduce serum cholesterol levels, while its mechanism of action is still unknown.
In this study, probucol was administered to 5 or 6 healthy male volunteers in various dosages and plasma probucol concentrations and serum lipids were measured (short-term administration study).
Probucol was also administered to hyperlipidemic patients (3 type IIa patients, 1 type IIb patient) for the long period of time and plasma probucol concentrations and serum lipids were measured (longterm administration study).
In short-term administration study, the more the dose of probucol (250mg, 500mg and 1, 000mg) increased, the longer the time to reach maxi-mum levels (4-12h, 24-48h and 48-72h) and the longer half lives (29h, 44h and 216h) were obtained. With the increase in dose of probucol, the maximum probucol levels (0.01-0.18μg/ml, 0.87-6.77μg/ml and 8.40-16.9μg/ml) also increased and there was dose-dependent relationship between dosage of probucol and plasma probucol concentration.
The response in rise of plasma probucol levels was variable depending on the subjects and some subjects showed rapid increase in plasma probucol concentration regardless of dose of probucol ad-ministration. The reproducibility in this response was seen in each subject.
In short term administration study, decreases of total cholesterol (TC), triglyceride (TG), phospholipid (PL), free fatty acid (FFA) and HDL-cholesterol (HDL-C) were not significant, possibly due to the low initial plasma lipids level.
In long term administration study, probucol significantly reduced TC, TG, PL and HLD-C levels of serum except LDL-C, however, there were not significant correlations between plasma probucol concentrations and serum lipids changes.

View full abstract

Transport of probucol by various human plasma lipoproteins was investigated in this study. In the single administration study, blood samples were collected from 4 healthy volunteers before and 4, 5, 8, 12 and 24 hours after a single oral administration of 500mg of probucol with 100g of cream. In the long-term study, fasting blood samples were obtained from 5 hypercholesterolemic patients (4 type IIa, 1 type IIb) who had been under the treatment with 750mg to 1000mg of probucol per day for 23±9 months. The plasma was separated into d<1.006 fraction, LDL, HDL and d>1.21 fraction by the ultracentrifugation. Lipids and probucol levels in each lipoprotein fraction were measured by the enzymatic methods and the high pressure liquid chromatography (HPLC), respectively. The fatty acid composition of plasma and the cream were analyzed by gas-liquid chromatography. The results are summarized as follows.
a) On single administration study
Probucol was transported in plasma almost exclusively by the lipoprotein fractions. Plasma Probucol levels reached a peak at 12 to 24 hours after the administration of 500mg of probucol. The highest concentration in plasma probucol was observed 7 to 8 hours after the point when the greatest changes in plasma fatty acid compositions due to the intake of cream were recognized. This delay might be explained by the possibility that probucol is absorbed through the different way from the fatty acids of the cream, for example, through the portal system, or requiring longer time for the intestinal absorption of probucol than that of cream. The different turnover of fatty acids from cream and probucol in vivo may be also concerned to this delay. The probucol level in HDL was significantly higher than that in VLDL 12 hours after the administration but was significantly lower than that in VLDL and LDL 24 hours after. The Probucol in LDL reached the plateau at 12 hours after the administration and stayed even after. 24 hours
b) On long-term study
Probucol level in the fasting plasma of 5 hypercholesterolemic patients was approximately 9 times higher than the peak level of probucol seen in a single administration study. Plasma probucol in patients with type IIa and type IIb was distributed mainly in LDL and VLDL, respectively. Probucol level in plasma and lipoproteins did not show any significant correlation to the lipids level in plasma and lipoprotein fractions.

View full abstract

The distribution of probucol, a new cholesterol-lowering drug, in serum lipoprotein fractions was studied in six healthy volunteers receiving a single and repeated oral dose of probucol.
Serum lipoprotein fractions were separated by ultracentrifugation, and concentrations of probucol and serum lipids in those fractions were determined.
The following results were obtained.
1) A single oral administration of 500mg-probucol
The concentration of probucol in serum reached at 6 hour after administration a peak level of 3.2±1.0μg/ml, which lasted for 18 hours and then gradually decreased. Probucol was found to distribute mainly in chylomicron and VLDL fractions in the early stage of its absorption, and then its distribution percentages increased relatively in LDL and HDL fractions at 48 hour after administration. The distribution patterns of probucol in lipoprotein fractions was found to be in parallel with that of triglyceride rather than that of cholesterol and phospholipid.
2) Consecutive oral administration of 500mg-probucol twice daily for 14 days
The concentration of probucol in serum reached a peak level of 40.8±17.9μg/ml at 1 hour after the last medication on 14th day.
The distribution patterns of probucol in lipo- protein fractions on 14th day were almost the same with those after a single oral administration.
Since we could not detect probucol in the bottom fraction (d>1.21), we considered that probucol was transported in serum by lipoproteins.
The results gained indicated that probucol, after absorption, was carried by chylomicrons to the liver and then released in the circulation with VLDL, from which it was transferred to LDL and HDL fractions.

View full abstract

The mode of action of probucol in reducing serum cholesterol was studied in normal and cholesterol-fed mice.
Probucol did not affect intestinal absorption of radioactive cholesterol in normal and cholesterol-fed mice.
In normal mice, probucol treatment resulted in inhibition of incorporation of [¹⁴C]-acetate into cholesterol in the liver, while it stimulated the incorporation in the small intestines. Incorporation of [¹⁴C]-mevalonate into cholesterol was not affected by the treatment. These results were consistent with the finding that the HMG-CoA reductase activity was decreased in the liver but increased in the intestinal tissues of the treated mice. In cholesterol-fed mice, probucol treatment gave no effect on cholesterol synthesis in the liver, while it increase the intestinal cholesterol synthesis. Over-all effect of this drug on cholesterol synthesis was not significant, although it tended to be inhibitory in normal mice and stimulatory in cholesterol-fed mice.
On the other hand, probucol treatment resulted in acceleration of the clearance of [¹⁴C]-cholesterol-derived radioactivity from the circulation, and also in a significant increase in fecal excretion of the radioactivity, cholesterol and bile acids without changes in lipid composition of the bile. Cholesterol content in and radioactivity distribution among the tissues were not affected by probucol. Hepatic cholesterol 7α-hydroxylase activity was increased by probucol.
These findings indicate that probucol lowers serum cholesterol mainly by increasing catabolic excretion of cholesterol into bile.

View full abstract

The effect of Probucol on serum lipids and lipoprotein was studied in 51 patients with primary hypercholesterolemia in multiple open study. After 1 month of placebo period the patients received 4×250mg of Probucol per day for 4 months. Total and VLDL+LDL cholesterol were significantly reduced with Probucol (23-24% and 22-23 respectively). The concentration of serum triglyceride was not significantly altered. The concentration of HDL cholesterol was reduced under Probucol treatment (25-31%). The Total chol-HDL-chol ratio during Probucol was increased (22%). In general, the subjective and objective tolerance of the drug was excellent.

View full abstract

Probucol, newly developed hypocholesterolemic agent, was given to 130 patients (47 males and 83 females) whose serum cholesterol values were mostly 230mg% or higher with an exception of 9 patients whose values were less than that. The administration was continued for 16 weeks and then placebo was given for 4 weeks more. The results are as follows.
The serum cholesterol level significantly decreased already at the fourth week of the Probucol administration stage. The overall rate of decrease at the end of the sixteenth week was approximately 17%. Though the level slightly increased by giving placebo for succeeding 4 weeks, the final value still showed a statistically significant decrease from the initial level.
With reference to a triglyceride level, similar results were obtained.
Decrease in HDL-C level was around 20 during 16 weeks and, even after administration of placebo for succeeding 4 weeks, the decrease was kept still in 15% showing a significant difference from the initial HDL-C level.
Concerning atherogenic index (TC-HDL-C/HDL-C), there was no significant change.
Difference in the effects of Probucol against the patients with hyperlipemia and those with hypertension, diabetes mellitus and ischemic heart diseases was then tested but there was found no significant difference so far as changes in serum cholesterol, HDL-C and AT were concerned.
Patients with hypertension were divided into two groups—one administered with thiazide agents and another with non-thiazide ones—and the tests were conducted. As a result, there was a slight inclination that AI in the latter group was rather higher though there was no significant difference as compared with that in the former group.
With reference to diabetes mellitus, the patients were divided into three groups—the first group being treated by dieting, the second one with sulfonylurea, and the third with insulin. There was, however, no significant difference among those groups.
As to side effects, 5 cases showed nausea, epigastrial distress, etc. which corresponded to 3.8 of the total patients tested.

View full abstract

To determine the optimal dose of probucol in Japanese, we conducted a multi-central cooperative study on two doses of 750mg and 1000mg a day. The two doses were randomly allocated to 112 subjects with hyperlipidemias from 11 centers, out of whom 7 were excluded from the study because they were unsuited for the protocol, and 5 dropped out. The rest 100 cases completed the study, 54 being on 750mg and 46 on 1000mg a day. Their fasting blood samples were collected to a central laboratory and determined for serum total cholesterol, triglycerides and HDL-cholesterol.
The effect of probucol was analysed in this study in terms of the unit dose effect and the rate of effective case in each group. The unit dose effects were for total cholesterol 4.5mg/dl/100mg (the unit omitted hereafter) from 750mg group and 4.0 from 1000mg group. For triglycerides 4.1 from 750mg and 2.7mg from 1000mg group. For HDL-cholesterol 1.0 from 750mg group and 0.8 from 1000mg group, respectively.
The rate of effective case was for total cholesterol 91% in 750mg group and 94% in 1000mg group, for triglycerides 67% in 750mg and 70% in 1000mg group, and for HDL-cholesterol 9% in 750mg group and 14% in 1000mg group, respectively.
These data indicated that probucol was more efficient in a daily dosis of 750mg in terms of the effect exerted by the unit amount of the drug, while it was more effective in 1000mg administration in terms of the numbers of cases whose unit dose effect became positive. Taking together, the magnitude of effects and the nature of drug, we considered that the unit dose effect was the more important determinant and that the daily dosis of 750mg was the favorable dose for use compared with 1000mg administration.

View full abstract

The hypocholesterolemic agent-Probucol- was administered to the hyperlipidemic patients, investigating efficacy, safety, and usefulness of probucol clinically. 54 patients who have been hypercholesterolemic (type IIa, and/or type IIb) were given total 750mg of probucol three times a day orally. Serum total cholesterol (TC), phospholipid (PL), triglyceride (TG), and HDL-cholesterol (HDL-ch) were measured. Routine blood examinations and clinical findings were also observed every two or four weeks.
(Results and Discussion)
1) TC decreased significantly 4 weeks after administration, continuing until 16 weeks with maximal reduction of 18.7% in 16 weeks.
2) The ratio of TG reduction was also observed through trial. However, the significant reduction was observed both in 12 and in 14 weeks with maximal reduction of 12.6%.
3) Though the average values of HDL-ch were reduced through trial, there were no significant reduction.
4) Side effects of probucol were observed in 3 cases, in which one patient complained of urticaria and ceased to take drug, while other two patients were able to take medicine continuously.
5) There were no unfavorable findings both in the routine blood examinations and in clinical signs.
From these results, it was supposed that probucol was effective in lowering TC and partly TG in hyperlipidemic patients and that efficacy, safety, and usefulness were recognized clinically.

View full abstract

Ninety nine patients with hyperlipidemia were given probucol (dose: 1000mg/day) for 16 weeks. Mean serum total cholesterol levels were reduced significantly from 305±6mg/dl (mean±S.E.) to 252±5mg/dl (p<0.001) after 16 weeks and its percent change was 15.6%. Mean serum triglyceride levels were reduced significantly from 224±24mg/dl to 159±11mg/dl (p<0.05) after 16 weeks and its percent change was 13.9%. Mean serum HDL-cholesterol levels were reduced significantly from 49.4±1.4mg/dl to 37.2±1.3mg/dl (p<0.001) after 16 weeks and its percent change was 23.6%. However, no significant change of the atherogenic index (total cholesterol-HDL-cholesterol/HDL-cholesterol) was found.
Clinical laboratory data revealed no significant change. Side effects were observed in 9 patients out of ninety nine patients (9.1%).

View full abstract

The effect and safety of a new cholesterol- lowering drug, probucol, was investigated in 49 hypercholesterolemia patients in Kyushu multicentral cooperative study (10 hospitals). The patients were allocated to either 750mg or 1000mg per day for 16 weeks. Both doses of probucol lowered serum cholesterol, LDL-cholesterol and HDL-cholesterol and phospholipid significantly without influencing on serum tryglyceride levels. No relationship among two doses of probucol and the degree of cholesterol lowering have been found in this study. And at all doses employed, the drug was well tolerated and no changes attributable to therapy were observed in the laboratory parameters evaluated.

View full abstract

In order to elucidate the mechanism of ethanol induced hypertriglyceridemia, we studied 3 cases with hypertriglyceridemia due to alcohol drinking.
We investigated changes in the levels of plasma cholesterol, triglyceride, HDL-Ch, Apo A-I, Apo A-II and post heparin lipolytic activity (LPL and H-TGL) during low energy diet with high fat or low fat content and isocaloric replacement of dietary carbohydrate by 100g of ethanol.
Results are shown in the following.
1) A case showed a definite increase of the level of plasma triglyceride after alcohol drinking even during low energy, low fat diet.
2) During low energy, low fat diet, the levels of total cholesterol, LDL-Ch and HDL-Ch tended to decrease. However, after replacing dietary carbohydrate by 100g of ethanol, the level of HDL-Ch tended to increase or remained stable, while the levels of total cholesterol and LDL-Ch tended to decrease.
3) Plasma LPL activity has increased after alcohol drinking for 5-9 days.
From these results above, we conclude the effects of ethanol on lipid metabolism are quite different from that of carbohydrate and ethanol has a tendency to increase HDL-Ch possibly by stimulation of LPL activity.

View full abstract

In patients (Pt) with arteriosclerotic aneurysms (AA), the fasting levels of serum lipids, except for triglycerides (TG), were raised as they were in Pt with arteriosclerosis obliterans (ASO). Particularly, in AA without ischemic heart disease (IHD), only the TG levels were low as compared with ASO without IHD. Likewise, glucose tolerance and IRI responses to 100g oral glucose tolerance test (OG-TT) were not lowered or otherwise abnormal. Unlike AA without IHD, in AA complicated by IHD, the OGTT total blood sugar levels (∑BS) was high, the OGTT insulinogenic index (30min) (ΔIRI/ΔBS) was low, and TG levels tended to be high, similar to ASO.
In Pt with Buerger's disease (TAO) without arteriosclerosis of the fundus oculi (AS), TG levels were high, and the glucose tolerance and IRI responses were not diminished. However, in TAO with AS, TG levels were lower than in TAO without AS, and total cholesterol levels, β-lipoprotein levels and phospholipid levels were lower than in ASO with Scheie Grade 1 AS (S.1). Also in TAO with AS, early IRI responses (low ΔIRI/ΔBS) were delayed and glucose tolerance (high ∑BS) was diminished as in ASO.
The TAO with AS patients were younger than those with ASO and ASO with S.1. The blood pressure did not differ but the average age was higher in TAO with AS patients than TAO without AS patients. In 8% of TAO, although the average age was the same as TAO without AS, stenosis and narrowing of arterioles were seen in the fundus oculi.
Between the various degrees of AS in ASO, differences in serum lipids, glucose tolerance and blood pressure were observed. In ASO with S.2 patients, the total cholesterol-HDL cholesterol ratio was lower and systoric blood pressure higher than in ASO with S.1 patients. In ASO with S.3 patients glucose tolerance and early IRI responses were not diminished as they were in ASO with S.1 and S.2 patients.

View full abstract

Hypolipidemic agents have been given considerable attention with regard to their effects on platelet aggregability. One such agent, probucol was studied with regard to serum lipids and platelet aggregability.
Twenty patients with hypercholesterolemia were given a daily dose of 750mg of probucol for 8 weeks and blood samples were taken before, 4 weeks and 8 weeks after treatment. Serum levels of total cholesterol (TC), triglyceride (TG), phospholipid (PL), free fatty acid (FFA) and HDL-cholesterol were analyzed. Platelet aggregation was also studied using 3μM of ADP, 1μg/ml of adrenaline and 2μg/ml of collagen. Plasma levels of thromboxane B₂ (TXB₂) and 6-keto PGF_1α were measured by radioimmunoassay. Four weeks after the withdrawal of probucol, serum lipids and platelet aggregation were studied. The mean serum levels of cholesterol decreased from 264±9mg/dl to 220±13 after 4 weeks of treatment and an even further reduction was observed after 8 weeks (204±9, p<0.01). HDL-cholesterol levels also decreased and in parallel with total cholesterol concentrations. Both TG and FFA exhibited a gradual but not statistical decrease during treatment. Changes in the percent of TG and PL fell significantly, as compared with the levels before treatment (p<0.05). Platelet aggregation, as induced by collagen was slightly suppressed after treatment, however, there were no statistical differences pre and post treatments. The levels of TXB₂ in the plasma remained unchanged, however, there was a statistically significant increase in plasma 6-keto PGF_1α levels 4 weeks after treatment, as compared to the concentrations before the treatment.
In light of these findings, the possibility that probucol has an effect not only lipid metabolism but also the vessel wall to produce increases in prostacyclin production has to be considered.

View full abstract