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PubMed1999

Effect of dietary fish oil, vitamin E, and probucol on renal injury in the rat.

Dietary fish oil, vitamin E, and probucol have been considered in a variety of human and experimental models of kidney disease. Using subtotal nephrectomized cholesterol-fed rats as a model for progressive kidney disease, we examined the effect of 5% dietary fish oil, or a combination of 5% dietary fish oil with 500 IU vitamin E/kg diet or 1% probucol on renal injury. Three-month-old Sprague Dawley rats were fed a control diet (C group) or a cholesterol supplemented (2%) diet (Ch group) containing either fish oil (FO group) or fish oil plus vitamin E (FO+E group) or fish oil plus probucol (FO+P group). After 4 weeks of dietary treatment, the right kidney was electrocoagulated and the left kidney nephrectomized. After 8 weeks, 24-hour urine was collected before sacrifice. No effect of the dietary treatments was noted on serum creatinine, blood urea nitrogen, or proteinuria, except that proteinuria was highest in FO+P group. Rats receiving the cholesterol diets had higher serum low density lipoprotein (LDL) + very low density lipoprotein (VLDL) cholesterol (P < 0.05). In contrast, rats in the FO+P group had the lowest serum total cholesterol and LDL+VLDL cholesterol among all groups. The FO group had 26% lower kidney alpha-tocopherol concentrations than the C group. However, inclusion of vitamin E in the diet (FO+E group) increased the kidney alpha-tocopherol status to a level comparable to that in the C group, whereas inclusion of probucol in fish oil diet (FO+P group) did not improve the kidney alpha-tocopherol status. Rats fed the cholesterol diet had a 2.5-fold higher glomerular segmental sclerosis (GSS) score and 1.5-fold higher glomerular macrophage (GM) subpopulation than the C group. These effects of the cholesterol diet were ameliorated by a fish oil diet (FO group: GSS by 30%, GM by 24%). The inclusion of vitamin E in the fish oil diet (FO+E group) did not further improve the GSS score or GM subpopulation. However, inclusion of probucol in fish oil diet (FO+P group) lowered the GSS score by 73% and reduced GM subpopulation by 83% compared with the Ch group. These remarkable changes can be attributed to the powerful hypocholesterolemic activity of probucol. Our findings indicate that progression of glomerular sclerosis in the rat remnant kidney model of progressive kidney disease can be significantly modulated with fish oil treatment.

Journal Article↗
PubMed2002

Effect of antioxidant probucol for preventing stent restenosis.

Probucol is a lipid-lowering drug that has an antioxidant effect. The authors sought to investigate the effect of probucol on stent restenosis after the usual 3-day pretreatment protocol. From March 1999 to August 2000, 78 patients (mean age, 56 +/- 8; 49 male) with coronary artery disease who underwent coronary stenting were enrolled. After a diagnostic angiography was done, each eligible patient was randomized to either the probucol or the control group. Following the procedure, ticlopidine was administered for 1 month; aspirin and probucol continuously. Angiographic follow-up was done in 81% (57/70) and angiographic restenosis was not different between the two groups (21% vs. 24%; P = 0.81). In conclusion, antioxidant probucol did not show a beneficial effect on stent restenosis with 3 days of premedication protocol.

Aged↗
PubMed1981

Synergistic effects of probucol and cholestyramine to lower serum cholesterol.

Ten men with hypercholesterolemia were treated sequentially with a fat-modified diet, a diet plus probucol (1 Gm/day), and a diet plus probucol plus cholestyramine (16 Gm/day). Each treatment period was 12 weeks. Diet alone reduced mean serum cholesterol by 1.0 per cent. Diet plus probucol caused a mean 7.7 per cent reduction in serum cholesterol below the baseline values (P = 0.001 compared to diet). Adding cholestyramine to probucol and diet resulted in a mean 18.2 per cent reduction in serum cholesterol below baseline values (P = 0.001 compared to probucol and diet). The treatment was well tolerated.

Adult↗
PubMed1995

Antioxidant, probucol, can inhibit the generation of hydrogen peroxide in islet cells induced by macrophages and prevent islet cell destruction in NOD mice.

The preventive effect of antioxidant on the islet cell destruction in NOD mice was studied. Oral administration of probucol prevented the development of cyclophosphamide induced diabetes in NOD mice (incidence of diabetes; probucol: 0/10 vs. control: 9/15) As in vitro studies, the effects of probucol on the generation of H2O2 in the content of H2O2 in islet cells co-cultured with M phi were measured. Intracellular oxidation of 2'7'-dichlorofluorescin by H2O2 was analyzed by flow cytometry. The probucol-treated M phi induced less marked increase of H2O2 in islet cells in comparison with control M phi. The generation of H2O2 by M phi in islet cells from treated mice was less marked than that in controls. These results suggest that the preventive effect of probucol may be mediated by protection of islet cells from oxidative stress induced by M phi.

Animals↗
PubMed1999

Protective effects of vitamin e and probucol against gentamicin-induced nephrotoxicity in rats.

Gentamicin (GM) is widely used as a bactericidal agent for the treatment of severe gram negative infections, however, its clinical use is partially limited due to its nephrotoxicity. Recent evidence suggests a role of reactive oxygen metabolites in GM nephrotoxicity. The present study was designed to investigate a possible potential protective role of vitamin E and/or probucol against GM nephrotoxicity. GM was administered to rats in a single dose of (150 mg kg(-1)i.p.), while vitamin E (250 mg kg(-1)i.m.) and/or probucol (60 mg kg(-1)i.m.) were given once daily for 3 consecutive days prior to GM administration. GM-induced nephrotoxicity was evidenced by marked elevations in serum urea and creatinine levels, urinary activity of N-acetyl-beta- d -glucosaminidase (NAG) and gamma-glutamyl-transferase (gamma-GT). Also, GM caused significant increases in kidney content of malondialdehyde (MDA), and significant decreases in kidney content of reduced non-protein sulphydryls (NPSH) and superoxide dismutase (SOD) activity. Vitamin E pretreatment significantly lowered the elevated serum urea and creatinine levels, and urinary activity of NAG and gamma-GT. In addition, vitamin E ameliorated the rise in renal content of MDA and enhanced the renal NPSH content as well as SOD activity. Similarly, probucol significantly inhibited the elevations in urea and creatinine levels and enhanced renal NPSH content and SOD activity. Simultaneous use of vitamin E and probucol was more effective in mitigating disturbances in the assessed parameters. The present work indicates that, due to their antioxidant activity, vitamin E and probucol have potential protective effects against GM nephrotoxicity.

Acetylglucosaminidase↗
PubMed2005

Low daily dose of antioxidant probucol decreases incidence and severity of restenosis after transluminal coronary balloon angioplasty.

Antioxidant probucol in both high (1000 mg) and low (250 mg) daily doses effectively reduced manifestations of oxidative stress in patients with atherosclerosis (assessed by in vivo accumulation of lipoperoxides in atherogenic LDL). When probucol was administered in a dose of 250 mg/day for 7-10 days before transluminal balloon coronary angioplasty and then for 6 months after surgery, the incidence of restenosis decreased to 25% compared to 45% in the control (without probucol therapy). In the group of operated patients receiving probucol (250 mg/day for 6 months) the minimal artery lumen was significantly higher, and the degree of artery occlusion significantly lower than in the control group not treated with probucol.

Angioplasty, Balloon, Coronary↗
PubMed1986

Controlled studies of the efficacy and safety of combined probucol-colestipol therapy.

A comprehensive clinical evaluation of the effects of combined probucol-colestipol therapy was undertaken in 71 hypercholesterolemic patients. In the first 18-month double-blind, double-placebo, crossover study, the effects of 1 g/day of probucol and 20 g/day of colestipol were compared with the drugs used singly in 47 patients. The combination decreased low density lipoprotein (LDL) cholesterol from a diet-placebo baseline of 242 +/- 51 mg/dl to 171 +/- 41 mg/dl. LDL cholesterol levels were decreased by more than 30% in 49% of patients, and by more than 40% in 17% of patients. Combined drug use eliminated the gastrointestinal side effects of single-drug administration or diminished their severity. Twenty-two patients who complained of resin-induced constipation entered a 19-month continuation trial that called for a half-dose of colestipol during combination treatment. This therapy decreased the LDL baseline level of 239 +/- 46 mg/dl by more than 25% in 41% of patients, and by more than 45% in 9% of patients. All patients were able to tolerate the modified probucol-colestipol therapy. Finally, a comparison was made between the hypocholesterolemic effects of combined probucol-colestipol therapy obtained after 1 and 3 years in 24 patients. These were sustained in all but 5 patients. Combined probucol-colestipol therapy increases the hypocholesterolemic effects and decreases the gastrointestinal side effects of either drug used alone. In patients who cannot tolerate full doses of resin, a half-dose may render the drug more acceptable without diminishing its lipid-lowering effect.

Cholesterol, HDL↗
PubMed1991

The effects of probucol on lipoprotein metabolism in the rat.

The effects of probucol on liver and intestinal apolipoprotein, LDL-receptor and hepatic lipase gene expression, as well as plasma lipid and apolipoprotein levels and liver lipase activity were evaluated in male rats. Administration of probucol decreased plasma triacylglycerols, without affecting plasma cholesterol. Plasma apo E and apo B concentrations increased after probucol. Since liver and intestinal apo B and apo E mRNA levels remained unchanged, this increase could be attributed to a delayed clearance by the LDL-receptor, whose mRNA levels dropped by 50% in the liver. For the HDL-apolipoproteins, only liver apo A-IV mRNA levels decreased after probucol, which was reflected by a fall of plasma apo A-IV. Neither hepatic lipase activity nor mRNA levels were significantly influenced by probucol.

Animals↗
PubMed1993

Inhibition of low density lipoprotein oxidation by thyronines and probucol.

Oxidation of low density lipoproteins (LDL) results in increased macrophage uptake of LDL which may contribute to the formation of macrophage-derived foam cells in the early atherosclerotic lesion. In this study we show that thyroxine (T4), its optical antipodes, certain desiodo analogs and probucol inhibited cupric sulfate-catalyzed oxidation of human LDL in a concentration-dependent manner as assessed by measuring the electrophoretic mobility, thiobarbituric acid reactive substances (TBARS) and LDL degradation in mouse macrophages. In Cu(2+)-catalyzed LDL oxidation at 24 hr, the TBARS level was 80 nmol/mg LDL protein/24-hr incubation. The concentrations (microM) of each agent producing 50% inhibition in the formation of oxidized LDL (IC50) for TBARS, electrophoretic mobility and macrophage degradation, respectively, were 1.13, 1.27 and 1.30 for reversed triiodothyronine; 1.33, 1.80 and 1.27 for triiodothyronine; 1.33, 1.37 and 1.37 for racemic thyroxine, DL-T4; 1.10, 1.40 and 1.50 for L-T4; 1.13, 1.33 and 1.23 for D-T4; and 1.47, 1.63 and 1.37 for probucol. No differences in inhibitory potency were observed when rT3, T3, the optical antipodes of T4 and the hydrophobic antioxidant drug probucol were compared. In air-induced LDL oxidation, TBARS was 16.1 nmol/mg LDL protein/6-hr incubation. The IC50 concentrations (microM) for TBARS and diene conjugation, respectively, were 0.187 and 0.336 for D-T4; 0.205 and 0.243 for L-T4 and 1.30 and 3.02 for probucol. With air-induced LDL oxidation conditions, the L-T4 concentrations included the physiological range, and thyroid-binding globulin did not modify the inhibitory effect of the endogenous enantiomer, L-T4. Putative uptake of this stereoisomer into LDL inhibited oxidation of these lipoproteins. Since concentrations of these thyronines which blocked air-induced LDL oxidation were in the physiological range, we conclude that thyronines, like the pharmacological agent probucol, limit the oxidative modification of LDL and thus may serve as natural inhibitors of atherogenesis.

Air↗
PubMed1992

Probucol, incorporated into LDL particles in vivo, inhibits generation of lipid peroxides more effectively than endogenous antioxidants alone.

One of the first steps in lipid autoxidation leads to the generation of lipid peroxides (LPO). The time course of LPO generation during Cu++ catalyzed oxidation of LDL before and after treatment with probucol was determined in this study. Before analysis the samples had been stored for about 3 years at -20 degrees C. The results show that in LDL samples without probucol the total antioxidative potential had been depleted during the long-term storage. In contrast, LDL containing probucol showed almost no signs of lipid autoxidation. In addition, the ratio of vitamin E to cholesterol was significantly higher in serum samples containing probucol. We conclude that, in vivo, probucol is incorporated into LDL particles in concentrations high enough to inhibit even early steps of lipid autoxidation.

Antioxidants↗
PubMed1980

Effect of probucol on cholesterol metabolism in the rat.

The effects of probucol treatment on cholesterol metabolism were examined in rats. Male Sprague-Dawley rats were divided into 3 groups: one group was given 0.25% probucol containing chow diet, one group was given 0.25% clofibrate containing chow diet, and the third group was fed chow diet alone. All groups of rats were maintained on these regimens for 4 weeks before killing. Probucol treatment resulted in a decrease in plasma cholesterol and cholesterol 7 alpha-hydroxylase activity. Clofibrate treatment resulted in a reduction of plasma cholesterol, hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities. The fecal excretion of neutral and acidic sterols were decreased significantly in the probucol or clofibrate-treated rats. In the bile there was a decrease in the concentration of total bile acids. These results suggest the mechanism for hypocholesterolemic action of probucol to be different from that of clofibrate.

Animals↗
PubMedDate not supplied

Effect of probucol on cholesterol synthesis, plasma lipoproteins and the activities of lipoprotein and hepatic lipase in the rat.

The postheparin plasma lipoprotein lipase (LPL) activity and plasma HDL and LDL cholesterol concentrations, decreases significantly during probucol treatment of the rat. The reduction of the LPL activity obviously took place in adipose tissue. The activity of hepatic lipase and the in vitro synthesis of cholesterol in the liver or isolated jejunal villous cells were unaffected by the probucol treatment. Plasma triglyceride and VLDL cholesterol concentrations remained similar in the control and probucol groups despite the difference in the LPL activity, whereas the esterified VLDL cholesterol level was significantly reduced in the probucol group. The results suggest that the HDL lowering action of probucol is contributed by the reduced LPL activity probably via impaired VLDL metabolism.

Animals↗
PubMed1984

Effects of probucol on the in vivo plasma clearance of human low density lipoproteins in rabbits and on the expression of lipoprotein receptors in vitro.

The purpose of this study was to investigate the effects of probucol on the plasma levels of low density lipoproteins in rabbits and whether the resulting decrease of low density lipoproteins was related to the effects of probucol on the expression of lipoprotein receptors. Probucol administration effectively lowered plasma cholesterol in normal rabbits. Both low density and high density lipoprotein cholesterol decreased, as well as apo B in the former fraction. Probucol had no effect on the fractional catabolic rate of low density lipoprotein while the flux of this lipoprotein decreased to about 50%. Moreover both the binding of lipoproteins to liver membranes and the in vitro uptake of low density lipoprotein by human skin fibroblasts were not affected by the drug. These findings are consistent with an effect of probucol on low density lipoprotein synthesis.

Animals↗
PubMed1985

The hypolipidemic action of probucol. Drug transport and lipoprotein composition in type IIa hyperlipoproteinemia.

In this study Probucol transport and the effect of the drug on lipoprotein composition in 9 cases of type IIa hypercholesterolemia were investigated. Probucol lowered plasma cholesterol by 20%, without affecting triglycerides. HDL cholesterol was decreased and a slight reduction in LDL cholesterol was noted. This was due to a reduction in the number of circulating lipoprotein particles, without modification in the lipid/protein ratio, mainly cholesterol/protein ratio. Probucol was almost entirely removed by lipoproteins; 75% of the drug was found in LDL, the remainder being equally distributed in VLDL and HDL. There was no correlation between the serum Probucol level, or the amount of Probucol bound to lipoproteins, and the decrease in serum or lipoprotein cholesterol. However, there was a significant increase of the EC/TC (esterified cholesterol/total cholesterol) ratio in VLDL and LDL, but not in HDL.

Adult↗
PubMed1988

Comparison of lovastatin and probucol in treatment of familial and non-familial hypercholesterolemia: different effects on lipoprotein profiles.

In order to compare the effects of lovastatin and probucol on lipoprotein profiles, we treated 32 familial hypercholesterolemia (FH) heterozygotes and 26 patients with non-familial hypercholesterolemia for 14 weeks with either probucol (1 g/d) or lovastatin (40-80 mg/d) in a randomized double-blind study. Lovastatin at 80 mg/d reduced low density lipoprotein (LDL)-cholesterol and apo B by more than 40% in both familial and non-familial hypercholesterolemia (non-FH). Probucol reduced LDL-cholesterol by 10-17% while LDL-apo B levels were not influenced at all (FH) or fell by 13% (non-FH). Analysis of LDL composition demonstrated that the LDL-cholesterol lowering effect of probucol in FH was entirely due to reduction in the proportion of cholesterol in LDL with no reduction in LDL mass. Serum high density lipoprotein2 (HDL2)-cholesterol levels fell by 27-33% during probucol, whereas HDL2-cholesterol increased by 10-18% with lovastatin 80 mg/d. These changes in HDL2 were not mediated by lipoprotein lipase or hepatic lipase, both of which are known to participate in regulation of this lipoprotein.

Apolipoproteins↗
PubMed1990

Probucol does not alter acetylated low density lipoprotein uptake by murine peritoneal macrophages.

It has been suggested that the anti-atherogenic effect of probucol (MDL 11,309) in familial hypercholesterolemic rabbits may be due in part to the inhibition of the uptake of modified low density lipoproteins by macrophages in the arterial wall. To test this hypothesis, mice were treated with dietary probucol (0.25%) for fourteen days, peritoneal macrophages were isolated and the uptake of acetylated low density lipoprotein (ALDL) was studied. In addition, peritoneal macrophages from control animals were treated with probucol (200 micrograms/ml) for 24 h in vitro prior to the ALDL uptake assay. The assay involved a fluorescent ALDL probe (dioctadecyltetramethylindocarbocyanine perchlorate-labeled ALDL), and measurement of uptake with a flow cytometer. No differences in ALDL uptake were detected between the control macrophages and macrophages treated with probucol in vitro or macrophages taken from probucol-treated mice.

Acylation↗
PubMed1990

Probucol treatment in hypercholesterolemic patients: effects on lipoprotein composition, HDL particle size, and cholesteryl ester transfer.

Despite probucol's capacity to induce regression of tendinous xanthomata and reduce whole plasma and LDL cholesterol (LDL-C) in patients with hypercholesterolemia, its therapeutic use in the United States has been limited because of concern about its HDL-lowering effects. To assess the possibility that probucol might facilitate mobilization of tissue cholesterol in the presence of low HDL levels as a consequence of favorable changes in lipoprotein composition and function, we have analyzed lipoproteins and studied cholesteryl ester transfer (CET) in hypercholesterolemic patients before and after treatment. Prior to treatment, the free cholesterol (FC)/lecithin (L) ratio in plasma, a new index of cardiovascular risk, and the mass of cholesteryl ester transferred from HDL to the apo B-containing lipoproteins (CET) both were significantly increased (P less than 0.001). As previously shown, plasma cholesterol, LDL-C, HDL-C, HDL2, and apolipoproteins A-I, A-II, and B all fell significantly following probucol treatment. The FC/L ratio in plasma (P less than 0.01) and HDL2 (P less than 0.01) both fell significantly also, as did the sphingomyelin/lecithin ratio in VLDL + LDL (P less than 0.001) which is typically increased in untreated patients with hypercholesterolemia. Nondenaturing gradient gel electrophoresis in 6 patients revealed that the quantitative changes in HDL were associated with a redistribution of particles characterized by a decrease in the prevalence of the largest (HDL2b) and a relative increase in the number of the smallest (HDL3b) particles. Moreover, CET following probucol therapy returned to levels which were indistinguishable from those of normolipidemic controls. These results indicate that untreated patients with hypercholesterolemia have abnormalities in (1) lipoprotein composition which have been shown to retard the movement of cholesterol from tissues to HDL, and in (2) CET which is accelerated and can potentially lead to the formation in plasma of atherogenic CE-enriched apo B-containing lipoproteins. Probucol's capacity to reverse these specific alterations suggests that it may have beneficial effects on cholesterol transport in patients with hypercholesterolemia.

Adult↗
PubMed1993

Probucol inhibits mononuclear cell adhesion to vascular endothelium in the cholesterol-fed rabbit.

Mononuclear cells, isolated from the blood of hyperlipidaemic patients, are hyper-reactive and possess an increased propensity to adhere to vascular endothelial cells. Hyperlipidaemia is also associated with a dysfunctional endothelium, to which mononuclear cells stick with greater avidity. In order to assess the importance of lipid peroxidation and free-radical generation in these processes, we have investigated the effects of probucol on mononuclear cell adhesion to vascular endothelial cells in vivo and in vitro in the cholesterol-fed rabbit. New Zealand White rabbits were fed either: (i) control chow (n = 15), (ii) 2% cholesterol (n = 11), or (iii) 2% cholesterol with 1% probucol (n = 11). Mononuclear cell adherence to endothelium in the common carotid artery was assessed 5 weeks after the start of the experimental diet using the Hoechst 33342 staining technique. The 2% cholesterol diet caused a more than 6-fold increase in mean mononuclear cell adherence (P < 0.001). Concurrent probucol therapy abrogated the effects of cholesterol feeding, and in animals in this group, in vivo mononuclear cell adherence did not differ significantly from control animals. In vivo mononuclear cell adherence was directly related to serum cholesterol levels (r = 0.68, P < 0.0001) and inversely related to serum probucol concentrations (r = -0.63, P < 0.002). Concurrent probucol therapy also reduced the in vitro binding of mononuclear cells, isolated from hypercholesterolaemic animals, to endothelial cell monolayers (P < 0.01). These data suggest that the increased binding of mononuclear cells to vascular endothelium of cholesterol-fed rabbits may be a free radical mediated process that is inhibited by antioxidants.

Animals↗