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PubMed1991

Probucol partially prevents development of diabetes in NOD mice.

We examined the hypothesis that the hypocholesterolemic agent, probucol (4,4'-(isopropylidenedithiol) bis (2,6-di-tert-butyl-phenol)), can attenuate development of hyperglycemia in NOD mice. The female NOD mice were fed 1% probucol containing (PROB) or standard diet (CONT) from 5 weeks of age. Development of hyperglycemia was checked by urine glucose levels using stick paper for 35 weeks. At 40 weeks of age, all animals were sacrificed and plasma glucose and serum immunoreactive insulin (IRI) levels were measured. At 40 weeks of age, 80.0% of mice showed hyperglycemia (greater than 200 mg/dl) or death in CONT group. In contrast, only 46.7% showed hyperglycemia in PROB group. Plasma glucose levels of PROB group tended to be lower than those of CONT group. The percentage of Thy 1.2-positive splenocytes were significantly lower in PROB group than that in CONT group. In addition, the splenocytes positive with Lyt. 2 were also reduced by probucol administration. These data suggest that probucol can partially prevent development of diabetes in NOD mice. It is possible that the observed changes of T-cell subsets in the spleen may be involved in the prevention of diabetes.

Aging↗
PubMed1991

Lipoprotein composition and HDL particle size distribution in women with non-insulin-dependent diabetes mellitus and the effects of probucol treatment.

To further characterize the spectrum of potentially atherogenic disturbances in lipoprotein composition in non-insulin-dependent diabetes mellitus (NIDDM), we have studied a subset of women with NIDDM before and after treatment with the lipophilic lipid-lowering drug probucol (1 gm day), which we have shown corrects certain compositional abnormalities these women share with subjects who have hypercholesterolemia. Before treatment, the NIDDM group had a somewhat higher plasma triglyceride level (154 +/- 58.3 mg/dl, vs control, 80.0 +/- 21 mg/dl [mean +/- SD]; p less than 0.025) than controls but their cholesterol and high-density lipoprotein cholesterol (HDL-C) levels did not differ from control levels. A number of significant disturbances, however, were present in the surface and core lipid composition of their lipoproteins. Although the cholesterol content of NIDDM low-density lipoprotein (LDL) was similar to that of controls, its content of sphingomyelin and phosphatidylinositol plus phosphatidylserine and sphingomyelin-to-lecithin ratio all were significantly reduced. Moreover, their very-low-density lipoprotein (VLDL) and HDL2 tended to have reduced amounts of free (unesterified) cholesterol (FC) relative to lecithin, and their HDL2 and HDL3 tended to be triglyceride enriched. Probucol therapy resulted in significant decreases in total plasma cholesterol (-15%), FC (-28%), HDL-C (-22%), and triglyceride (-16%) and in apoproteins A-I, B, and E (apo A-I, B, and E), without changing diabetic control (before probucol: hemoglobin A1, cholesterol, 10.7% +/- 2.7%; after probucol: 10.9% +/- 3.0%).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMedDate not supplied

[Pravastatin vs. probucol in the treatment of hypercholesterolemia. A double-blind study].

This 16-week, double-blind study compared the efficacy and safety of pravastatin, a new HMG-CoA reductase inhibitor, with probucol in the treatment of hyperlipidemia in 26 patients at the Instituto Nacional de Cardiología "Ignacio Chávez" in Mexico City. Patients had to have a low-density lipoprotein-cholesterol (LDL-C) level in the 75th (or greater) percentile for age and sex greater than 150 mg/ on 2 occasions, and a triglyceride level less than 350 mg/dl. The patients, aged 21 to 75 years, were randomly assigned to receive either pravastatin, 40 mg once daily at bedtime (n = 15), or probucol, 500 mg twice daily (n = 11). Complete lipid profiles were obtained at 4-week intervals. By the end of the study, mean changes in total cholesterol (CT) and LDL-C in the pravastatin group were -28% and -37%, respectively, p less than 0.001 vs baseline. In the pravastatin group, there was a mean increment in HDL-cholesterol (HDL-C) of 9% and consequently a significant reduction in the LDL-C/HDL-C ratio. However, in the probucol group HDL-C levels dropped -21%, p less than 0.01, and no significant change in the LDL-C/HDL-C ratio was observed, accounting for the significant difference in LDL-C/HDL-C ratios between the 2 groups. Both drugs were well tolerated. One pravastatin patient discontinued because of adverse effects (nausea/vomiting and mild muscle pain). These results suggest that once daily administration of pravastatin is an effective therapy for hypercholesterolemia and that it produces a more favorable response in LDL-C/HDL-C ratio than probucol.

Adult↗
PubMed1975

Treatment of severe and mild hypercholesterolaemia with probucol and neomycin.

Administration of probucol to 23 patients with familial xanthomatotic hypercholesterolaemia reduced the serum cholesterol level during the 9-month study by 9%, while in 15 patients with less severe hypercholesterolaemia the decrease was on an average 15%. A reduction of more than 10% was obtained in 57% of the former and 80% of the latter subjects. In a double blind trial a greater reduction was obtained in serum cholesterol by probucol than by placebo. Neomycin lowered the serum cholesterol more effectively than probucol in subjects with severe type II abnormality and was at least equally effective in less severe type II patients. Probucol increased transiently the faecal bile acid and dietary cholesterol excretion, while neomycin enhanced the faecal elimination of cholesterol as neutral sterols.

Clinical Trials as Topic↗
PubMed1985

Effect of probucol on triton induced hyperlipidemias in CFY rats.

The two phases of triton test have been used to find out the effect of probucol to evaluate whether it is effective cholesterol lowering agent prophylactically or therapeutically. Probucol is shown to be a better accelerator for lipid clearance in triton hyperlipidemia than clofibrate. The clearance rate of VLDL is more than that of LDL. In the first phase of triton test probucol has more effect on cholesterol synthesis than triglycerides while in the second phase of triton test probucol has more effect as a clearing agent on triglycerides than on cholesterol.

Animals↗
PubMed1980

[A long-term (9 years) clinical study of the safety and efficacy of probucol, and an analysis of morbidity and mortality rates (author's transl)].

The lowering effect of probucol on plasma cholesterol was confirmed in 1 133 patients. The study covered 9 years and approximately 4 000 patient-years. The daily dosage of probucol was 1 g divided into two 500 mg doses. On average, plasma cholesterol values decreased from 300 mg/dl to about 240 mg/dl. There was no tendency to escape. The study also included measurements of plasma probucol in patients under long-term treatment. The drug was generally well tolerated; the only complaints were episodes of loose stools or diarrhea which did not usually oblige to interrupt treatment. The morbidity and mortality rates in these 1 133 patients were compared with those of two major epidemiological surveys: the Coronary Drug Project and the WHO studies. Statistical analysis was impossible, as our long-term trial did not include patients under placebo. However, no unexpected overall excess of mortality was observed with long-term probucol treatment; there was no increase in morbidity, nor in sudden deaths or deaths from coronary disease. These findings apply equally to patients with or without a history of coronary disease prior to their entry into the trial.

Adult↗
PubMed1982

Safety and effectiveness of probucol as a cholesterol lowering agent.

Monitored clinical studies conducted in 1133 patients, involving 3928 patient years of experience with probucol, have shown that it is an effective cholesterol lowering agent and is well tolerated during long term administration (some patients treated for as long as nine years). The incidence of morbidity and mortality in patients treated with probucol is in the expected range. Although a possibly protective action is suggestive against certain endpoints, the lack of long term parallel placebo groups does not allow for a statistical contrast of the results. Therefore, it is preferable to limit conclusions to observing that no excess of cardiac deaths, sudden deaths or cardiac morbidity occurred in probucol treated men with or without ischemic heart disease compared with men not receiving probucol.

Adult↗
PubMed1980

[Experimental pharmacology of probucol (author's transl)].

The experimental studies carried out so far have uniformly demonstrated that probucol lowers plasma cholesterol levels in all animal species. The drug has low toxicity and has been well tolerated during long-term treatment (up to 8 years in monkeys) in most species. In some dogs, however, probucol seemed to increase myocardial sensitivity to catecholamins, but this has not been found in other species. The pharmacokinetics of probucol show a rather slow turnover and are characterized by storage of the drug in adipose tissues, which may explain why the hypocholesterolaemic effect is progressively obtained. The main channel of excretion is the bile. No other pharmacological action has been described with probucol, which in the present state of knowledge appears to be a predominantly cholesterol-lowering agent.

Adipose Tissue↗
PubMed1980

[Effects of probucol on skin cholesterol concentrations in patients with type II hyperlipoproteineamia (author's transl)].

Twenty patients (14 male and 6 female) with hyperlipoproteineamia (type IIa in 10 and type IIb in 10) were given probucol 500 mg b.d. during 6 months. Eleven patients had xanthoma tendinosum and 4 had xanthelasma. The mean plasma cholesterol and plasma triglyceride levels were 435 +/- 100 mg/dl and 210 +/- 138 mg/dl respectively. Normal diet was continued throughout. Skin biopsies were performed on the forearm before and after treatment. The skin fragments were freeze-dried, and free (FCh) and esterified (ECh) cholesterol concentrations were measured by gas chromatography after preliminary thin layer chromatography on silica gel. FCh and ECh were found to be significantly increased before treatment when compared with skin concentrations in 10 control subjects; FCh ranged from 2.25 to 1.58 microgram/mg (p < 0.001) and ECh from 0.44 to 0.16 microgram/mg of dry tissue (p < 0.001). After 6 months' treatment with probucol, there was no significant change in FCh (2.25 to 2.16 microgram/mg), but a significant rise was observed in ECh (0.44 to 0.66 microgram/mg; p < 0.01). This effect suggests that probucol interferes with cholesterol synthesis and transport in human tissues, which might help to comprehend the action of this and other drugs on xanthelasma, xanthoma tendinosum and atherosclerosis. In one of the patients, a xanthelasma was considerably reduced in size following probucol treatment.

Adult↗
PubMed1980

[Comparative study of the effects of probucol, fenofibrate and clofibrate on liver ultrastructure in rats (author's transl)].

The effects on rat liver of probucol (250 or 500 mg/kg/24 h), clofibrate (250 mg/kg/24 h) and fenofibrate (100 mg/kg/24 h) were compared after 28 days' treatment. Th bodyweight of animals treated with probucol 250 mg/kg/24 h has increased, as compared with a control group of untreated animals. The increase in liver weight and live weight/bodyweight ratio was greater in rats treated with clofibrate or fenofibrate than in rats treated with probucol. Cholesterol and triglyceride plasma levels were lower in clofibrate-treated animals. There were no changes in SGOT and SGPT in any of the three groups. Alkaline phosphatases were increased only in rats treated with clofibrate (these enzymes were not assayed in rats which received fenofibrate). Electron microscope study of liver sections showed the following changes in clofibrate--and fenofibrate-treated rats as compared with the control group: increase in smooth-surfaced endoplasmic reticulum, ribosome detachment, slight glycogen depletion and increase in the number of peroxysomes. In the probucol-treated group, apart from an occasional increase in smooth-surfaced endoplasmic reticulum, liver cells were identical with those of the control group; in particular, there was no increase in the number of peroxysomes.

Animals↗
PubMed1994

The effect of probucol on the development of non-insulin dependent diabetes mellitus in Otsuka Long Evans Tokushima Fatty (OLETF) rats.

The effect of probucol which acts as a scavenger of free radicals, on preventing the development of non-insulin dependent diabetes mellitus (NIDDM) in a model rat (Otsuka Long Evans Tokushima Fatty [OLETF]) was examined. Sixteen male OLETF rats aged 5 weeks were divided into two groups. One group were fed standard laboratory chow and the other group were fed the chow containing 1% probucol. At 12, 16, 24 weeks of age, an oral glucose tolerance test (OGTT) was performed. At 24 weeks of age, the cumulative incidences of diabetes mellitus in both groups were 100%. After two weeks, insulin-mediated glucose uptake was measured using a euglycemic clamp technique. There was no significant difference in glucose infusion rates between both groups. At the end of the experiment, plasma lipid concentrations were measured. The serum total cholesterol levels were significantly lower in rats fed probucol containing chow (66.3 +/- 3.7 mg/dl) than those of rats fed standard laboratory chow (78 +/- 6.4 mg/dl). On the other hand, the serum triglyceride level were not significantly different between them. Histological studies on the pancreas of both groups showed enlarged fibrotic islets and mononuclear cell infiltration in the periinsular area, though to a modest extent. These results demonstrated that probucol was not effective in preventing the development of NIDDM in this model animal. Considering these data, inflammatory destruction of pancreatic beta cells by free radical may not be involved in the development of NIDDM.

Animals↗
PubMedDate not supplied

Probucol improves antioxidant activity and modulates development of diabetic cardiomyopathy.

To examine the role of free radicals in diabetic cardiomyopathy, myocardial antioxidants as well as lipid peroxide content were examined in rats made diabetic with a single injection of streptozotocin (65 mg/kg i.v). At 4 wk, the left ventricular peak systolic (LVSP) as well as aortic pressures were depressed in the diabetic group. Hearts from diabetic animals showed about a 100% increase in thiobarbituric acid reactive substances (TBARS), indicating increased lipid peroxidation. This was accompanied by about a 50% decrease in superoxide dismutase (SOD) and 60% decrease in glutathione peroxidase (GSHPx) enzyme activities. Catalase activity in these hearts showed a small but significant increase. Treatment with probucol (10 mg/kg i.p., on alternate days), a known lipid-lowering drug with strong antioxidant properties, was initiated 1 d after the induction of diabetes and was continued for 4 wk. In probucol-treated diabetic animals, LVSP was not different from controls. Probucol treatment caused a small but significant improvement in serum insulin and decrease in glucose levels as well as increased myocardial SOD, GSHPx, and catalase activities with a concomitant decrease in TBARS in the diabetic animals. These data provide evidence that diabetic cardiomyopathy is associated with an antioxidant deficit, and a better cardiac function due to treatment with probucol may be related to the improved insulin levels as well as maintenance of the antioxidant status of the heart.

Animals↗
PubMed1996

Influence of native and modified lipoproteins on migration of mouse peritoneal macrophages and the effect of the antioxidants vitamin E and Probucol.

Macrophage-derived foam cells are a key component of the atherosclerotic plaque. Stimulation of the migration of foam cells back to the blood potentially offers an approach to plaque regression. However, information on the natural and synthetic factors influencing macrophage migration remains limited. The aim of the present study was to determine the effects of different lipoproteins and antioxidants on the migration of mouse peritoneal macrophages and macrophage-derived foam cells. The migration of cells was determined in vitro by using a Boyden chamber. Cellular content of cholesterol and cholesteryl esters was measured by HPLC. The native lipoproteins, VLDL, LDL, and HDL, and the chemically modified lipoproteins acetylated LDL (acLDL) and oxidized LDL (oxLDL), all acted as chemoattractants for macrophages that had not been lipid-loaded. The antioxidants vitamin E and Probucol had chemoattractive and chemokinetic effects on the migration of unloaded mouse peritoneal macrophages. Foam cells (lipid-laden macrophages) showed decreased mobility with increased cellular lipid content. However, as macrophages accumulated higher amounts of cholesterol and cholesteryl esters, the additional decrease of cell migration was relatively minor. Simultaneous incubation of macrophages with acLDL and vitamin E or Probucol increased migration. The content of cellular cholesterol and cholesteryl esters was not changed when acLDL-treated cells were exposed at the same time to vitamin E, but cholesteryl ester content was increased in the presence of Probucol. Overall, the findings indicate that the antioxidants vitamin E and Probucol have a potential anti-atherogenic action in stimulating migration of lipid-laden macrophages without major impairment of the ability of the cells to accumulate and metabolize modified LDL.

Animals↗
PubMed1998

[Antioxidant probucol: effects on free radical lipid peroxidation, blood rheology and course of angina pectoris].

AIM: Study of the effect of antioxidant probucol on free-radical lipid peroxidation, blood rheology, and course of angina pectoris in coronary patients. MATERIALS AND METHODS: The above parameters and clinical hemodynamic values were monitored over the course of probucol therapy in 48 men (mean age 54.8 +/- 1.3 years) with coronary disease and angina of effort of the II-III functional class. RESULTS: Long therapy with probucol effectively inhibited free-radical lipid peroxidation, normalized lipid spectrum of the blood, and had a favorable impact on the course of angina pectoris. CONCLUSION: Probucol stabilizes the structure and function of red cells and platelets in coronary patients.

Angina Pectoris↗
PubMed1990

Probucol: pharmacology and clinical application.

Increased levels of cholesterol, LDL-cholesterol, and VLDL-cholesterol are known risk factors for the development of atherosclerotic vascular disease. Probucol is an orally active agent that can reduce total cholesterol and LDL-cholesterol. The drug also reduces HDL-cholesterol. However, it may modify the lipoprotein in such a way that removal of cholesterol from peripheral tissues is still enhanced. Probucol also has antioxidant activity, which may inhibit the oxidative modification of LDL that contributes to lipid deposition in blood vessel walls. Probucol is a well tolerated agent. However, its ability to prolong life in human subjects still needs to be determined.

Animals↗
PubMed1995

High-density lipoprotein and apolipoprotein A-I deficiency induced by combination therapy with probucol and bezafibrate.

The effects of the administration of slow-release bezafibrate to hypercholesterolaemic patients who were already receiving long-term probucol treatment (mean 865 days, 500-1000 mg.day-1) were investigated. Bezafibrate was administered at either 200 mg.day-1 (13 males, 13 females, mean age 55.2 years) or 400 mg.day-1 (11 males, 14 females, mean age 57.2 years), and blood was taken at 0, 3, 6 and 12 months after the beginning of combination therapy. Overall, serum total cholesterol (TC), triglyceride (TG), very low density lipoprotein (VLDL)-TC, high-density lipoprotein (HDL)-TG, VLDL-TG, VLDL-phospholipid (PL), lipoprotein (a) [Lp(a)], apolipoprotein (apo) C-III, apo E levels and LCAT activity decreased significantly with this combination therapy, while HDL cholesterol (C), HDL3-C, HDL-PL, apo A-I and apo A-II levels significantly increased, as assessed by analysis of variance (ANOVA). Five patients (one receiving 200 mg.day-1, four receiving 400 mg.day-1 bezafibrate) showed drastic reductions in HDL-C (HDL-C levels were reduced by a mean of 46.2%, 59.3% and 61.6% at 3, 6 and 12 months, respectively) after beginning combination therapy. These HDL-C reductions were maintained for the 1 year of combination therapy, but then returned to pre-combination treatment levels 1 month after discontinuation of bezafibrate. Serum probucol concentrations and cholesteryl ester transfer protein (CETP) mass were assayed at 6 months, and the probucol concentration was higher in the HDL-deficient group (56.2 vs 26.5 micrograms/ml). In contrast, CETP mass was significantly lower in HDL-deficient patients than in non-HDL-deficient patients (2.08 vs 2.87 mg.1-1)(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Biliary lipid composition in heterozygous familial hypercholesterolemia and influence of treatment with probucol.

The lipid composition of fasting duodenal bile was determined in 11 healthy subjects with normolipidemia and 15 patients with heterozygous familial hypercholesterolemia (FH) (12 with type IIa, three with type IIb). The age distribution among the groups of subjects was similar. In the patients with heterozygous FH type IIa, the mean value for molar percentage of cholesterol and lithogenic index (LI) of bile were significantly higher than those of controls (8.4 +/- 1.0%, 1.47 +/- 0.18 calculated by Hegard, Dam, and Holzbach vs 4.3 +/- 0.4%, 0.81 +/- 0.07, respectively). The value of LI in the patients with FH type IIb was also found to be significantly higher than that of the controls. In the patients with heterozygous FH type IIa, we observed both a significant decrease in the molar percentages of glycochenodeoxycholic acid, glycoursodeoxycholic acid, and glycolithocholic acid, and a significant increase of taurochenodeoxycholic acid compared to the corresponding values in the controls. Bile analysis of six patients was reexamined during probucol treatment after 16 weeks. Probucol significantly lowered serum cholesterol levels. However, biliary lipid composition and individual bile acid proportions was not altered by the treatment. The results suggest that most of the patients with heterozygous FH have supersaturated bile and are predisposed to cholesterol gallstone formation. In addition, the mechanism by which probucol lowers serum cholesterol appears to be independent of any change in the metabolism of biliary lipid.

Adult↗
PubMed1993

Combined therapy with probucol and pravastatin in hypercholesterolaemia. One year follow-up study.

The effect of co-administration of low doses of pravastatin to hypercholesterolaemic patients already receiving long-term probucol treatment (mean 500-1,000 mg/day for 350 days) were investigated. Pravastatin 5 mg/day (Group 1; 12 m, 13 f; mean age 59.1 y) or 10 mg/day (Group 2; 8 m, 11 f; mean age 60.8 y) was administered, and blood was taken after 0, 3, 6, and 12 months. Both groups showed a significant reduction in serum total cholesterol (TC), phospholipid (PL), low density lipoprotein-cholesterol (LDL-C), LDL-triglyceride (TG), LDL-PL, apolipoprotein (apo) B, and apo E after the combined therapy. These levels were reduced more in Group 2 than in Group 1 subjects. In Group 2, significant falls in serum TG and apo CII were also observed. The changes in TC, PL, LDL-C, apo B, apo CII and apo E were dependent upon the dose of pravastatin, as assessed by two-way analysis of variance. Serum high density lipoprotein (HDL)3-C, apo AI and apo AII were slightly but significantly increased in both groups after 12 months of combined therapy, but the increase was not sufficient to reverse the probucol-induced lowering of the HDL level. We conclude that combined therapy resulted in a significant reduction in atherogenic lipoproteins and apolipoproteins, and an increasing dose of pravastatin (5 mg to 10 mg daily) made the lipid lowering effect more prominent. The reduction in serum HDL-C due to long-term probucol administration was not reversed by the addition of pravastatin.

Adult↗