Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Probucol”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 397 records · Page 22Linked to original sources
PubMedDate not supplied

Probucol reduces lysophosphatidylcholines in low-density lipoprotein.

OBJECTIVES: Lysophosphatidylcholine (LPC) in low-density lipoprotein (LDL) comes into notice as an important atherogenic substance. METHODS: Since the effect of probucol, an antioxidative lipid-lowering drug, on LPC molecular species has not been elucidated, two LPC molecular species, stearoyl LPC (SLPC) and palmitoyl LPC (PLPC), were measured in LDL using high-pressure liquid chromatography. LDL was obtained from 11 hyperlipidemic patients, including 9 diabetic patients, in comparison with 11 age- and gender-matched controls. RESULTS AND CONCLUSION: Hyperlipidemic patients showed nearly twofold higher levels of SLPC and PLPC per gram of LDL protein than those of controls. All hyperlipidemic patients were treated with oral administration of 500 mg/day of probucol for 3 months. Both LPCs in LDL were significantly reduced to control levels and were increased again up to the pretreatment levels 4 weeks after cessation of the treatment. Therefore, probucol has a potent effect in reducing LPC and may contribute to decreasing the atherogenicity of LDL.

Adult↗
PubMed1978

Effect of probucol in hyperlipidemic patients during two years of administration.

Probucol, a new cholesterol-lowering agent, was administered to ambulatory outpatients representing several classes of hyperlipoproteinemia (HL) for two years without dietary restriction. In 32 patients with Type II HL and 12 with Type IIB HL, statistically significant reduction in mean serum cholesterol levels occurred within two weeks and persisted throughout two years of therapy at constant dosage (500 mg. twice daily). In smaller numbers of patients with Type IV HL (five patients) and Type V HL, (one patient) similar trends in mean serum cholesterol were observed but failed to achieve statistical significance. Mean triglyceride levels were generally lower during probucol therapy but varied widely between individuals. The drug was well tolerated, with no toxicity and few side effects (mild diarrhea, gas, bloating, and anal pruritus). Probucol should be a valuable addition to the therapeutic armamentarium for hypercholesterolemia.

Adult↗
PubMed1986

Lipoprotein fractions and receptors: a role for probucol?

Cholesterol transport in the plasma involves several lipoprotein families. The process is remarkably ordered and is driven vectorily by apolipoproteins, which activate appropriate enzymes or serve as recognition sites for lipoprotein receptors. Of the lipoproteins in plasma, low density lipoprotein (LDL) contains most of the cholesterol and has the greatest atherogenic potential. Its plasma concentration is determined by LDL receptor activity, which serves to regulate intracellular cholesterol concentrations. LDL receptor activity in the body is not fixed, but can be stimulated by drugs that affect hepatic cholesterol content, such as inhibitors of HMG-CoA reductase or bile acid sequestrants. By stimulating LDL receptor activity, these drugs increase the fractional catabolic rate of apoLDL. HMG-CoA reductase inhibitors also appear to reduce the apoLDL synthetic rate. As a consequence, LDL cholesterol levels are reduced while high density lipoprotein (HDL) cholesterol levels remain stable or increase. Probucol is a drug that lowers both LDL and HDL cholesterol levels. It appears to lower LDL cholesterol levels by affecting LDL structure rather than by stimulating LDL receptor activity. It has no consistent effect on LDL synthetic rates. Probucol lowers plasma HDL cholesterol levels by decreasing the synthetic rates of the major HDL apolipoproteins. The biologic significance of these probucol-induced changes in HDL metabolism is unknown.

Anticholesteremic Agents↗
PubMed1986

Medical management of hyperlipidemia and the role of probucol.

Recent experimental and epidemiologic evidence has dispelled all doubts about the need to treat patients with hyperlipidemia. Therapy should focus on 3 areas: control of concomitant risk factors for atherosclerosis, reduction of lipid levels through diet and, if response to diet proves inadequate, administration of lipid-lowering agents. There are 4 categories of first-line drugs: resins, fibrates, nicotinic acid and probucol. Probucol has a sustained effect, additive to that of a lipid-lowering diet; it can reduce total serum cholesterol and cause xanthoma regression even in patients with receptor-defective homozygous familial hypercholesterolemia. It is effective when used alone and has an additive effect when combined with resins or nicotinic acid. Compared with many other lipid-lowering medications, it is well tolerated. Although the combination of probucol and clofibrate may cause a significant decrease in high density lipoproteins, there is no evidence that this decrease carries any adverse consequences for the underlying disease process.

Adult↗
PubMed1990

In vitro activity of probucol on cholesteryl ester transport.

Probucol treatment in hypercholesterolemic patients promotes the transfer of cholesteryl esters from high-density-lipoproteins (HDL) to lower-density lipoproteins. In vitro studies, on hypercholesterolemic plasma incubated with or without probucol, show that drug binding to lipoprotein particles does not affect either cholesteryl ester transfer, or the lipoprotein modifications occurring in the process. Probucol stimulates reverse cholesteryl ester transfer in vivo apparently by mechanisms independent of lipoprotein binding.

Biological Transport↗
PubMed1994

Effects of ebselen and probucol on oxidative modifications of lipid and protein of low density lipoprotein induced by free radicals.

The oxidative modification of low density lipoprotein (LDL) is accepted to be an important early event of atherosclerosis, but it has not yet been well understood. The preventive effects of two antioxidants with different functions, ebselen and probucol, against the oxidative modification of LDL induced by copper or a water-soluble radical initiator, 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) were studied in order to elucidate the mechanism of modification of apolipoprotein B-100 (apoB). Ebselen inhibited the copper-induced oxidation completely by reducing the hydroperoxides in LDL, since the initiation of copper-dependent oxidation requires the presence of a trace amount of hydroperoxides in LDL. On the other hand, ebselen did not suppress the oxidations of LDL induced by AAPH which generated free radicals by its thermal decomposition. The AAPH-induced oxidation of LDL in the absence of ebselen gave phosphatidylcholine hydroperoxide and cholesteryl ester hydroperoxide as major products, while in its presence, the hydroperoxides were reduced to corresponding alcohols. Interestingly, ebselen had little effect on the increase of relative electrophoretic mobility and fragmentation of intact apoB in the AAPH-induced oxidation. Probucol inhibited the oxidation of lipids in LDL effectively induced by either copper or AAPH, but the protein modifications were observed even in the presence of probucol. It was suggested that (1) lipid hydroperoxides do not play an important role in the modification of apoB such as increase in negative charge and fragmentation, (2) the direct attack of free radicals upon apoB and its modification by lipid oxidation products derived from hydroperoxides increase the negative charge of apoB, and (3) its fragmentation is caused primarily by an attack of free radicals.

Amidines↗
PubMed1995

The inhibitory effects of boldine, glaucine, and probucol on TPA-induced down regulation of gap junction function. Relationships to intracellular peroxides, protein kinase C translocation, and connexin 43 phosphorylation.

The naturally occurring antioxidant boldine and its di-methoxy analogue glucine, as well as the drug antioxidant probucol, all inhibit TPA-induced downregulation of gap junctional intercellular communication in WB-F344 rat liver epithelial cells in dose-dependent manners. The compounds were essentially 100% inhibitory to the effect of TPA (10 nM) at 50 microM each. Analysis of the mechanism of the antitumor promotive action of these agents in vitro revealed that boldine and probucol (both at 10 microM) totally inhibited the TPA-induced accumulation of intracellular oxidants. Additionally, boldine, glaucine, and probucol, each at 50 microM, inhibited TPA-induced translocation of protein kinase C (PKC) to the particulate fraction of the cells, with concomitant inhibition of TPA-induced hyperphosphorylation of gap junctional connexin 43 (cx43) and TPA-induced internalisation of cx43 protein from the plasma membrane of the cells. None of the compounds inhibited the binding of (3H)-PDBu to TPA-specific binding sites in the cells. The results indicate that antioxidant molecules, irrespective of structure, possess common antitumor promotive potential in this model of gap junctional intercellular communication. The data also indicate that the compounds may interfere with the promotive function of TPA, at least in part, by the destruction of oxidants within the cells. Xanthine oxidase was excluded as a major source of such intracellular oxidants because allopurinol (50 microM) did not significantly affect either the accumulation of oxidants in the cells or the downregulation of gap junctional communication in response to TPA. Taken together, these data also suggest that TPA-induced oxidants play a role in the translocation of PKC to cellular membranes and it is at this level where the antioxidants may interfere in TPA-induced downregulation of gap junctional function.

Allopurinol↗
PubMed1990

Effect of probucol on the lipid composition of blood plasma, erythrocyte ghosts and liver membranes in mice.

1. Probucol treatment of mice (0.6 g/kg) induced a decrease of cholesterol (CH) and total phospholipids (PLs) in blood plasma, erythrocyte ghosts, liver plasma and microsomal membranes. 2. The incorporation of [14C]acetate in the microsomal lipids of probucol-treated mice was lowered by 23% compared to controls. 3. Probucol administration induced a reduced specific activity of PLs, CH and CH esters, whereas in triacylglycerols it was augmented. 4. Phospholipase A2 and neutral sphingomyelinase activities were not enhanced, indicating that the catabolism of the membrane PL was not elevated.

Acetates↗
PubMed1980

Effect of probucol on plasma lipids and lipoproteins in type IIb hyperlipoproteinemia.

Probucol was administered for 4 months in 20 adult males with Type IIb HLP in a total daily dose of 1.0 g per day. All patients had achieved a stable weight and diet response prior to entering the study. Plasma lipid and lipoprotein determinations were done at monthly intervals. Probucol produced mean reductions to TPC of -38.8 mg/dl (P < 0.0001), in LDL of -26.7 mg/dl (P < 0.001) and HDL of -8.1 mg/dl (P < 0.0001) for the entire treatment period. The mean LDL/HDL ratio increased from 5.43 to 6.08 (P < 0.02). There was no significant change in TG levels. During the study a progressive decrease in mean HDL levels from 38.9 to 29.2 mg/dl was noted. A progressive increase in the LDL/HDL ratio from 5.43 to 6.35 was also observed. These findings suggest that probucol should be used cautiously in patients with Type IIb HLP, because an inverse relationship between HDL levels and IHD incidence has been demonstrated in epidemiologic studies.

Adult↗
PubMedDate not supplied

Effects of probucol on low density lipoprotein removal and high density lipoprotein synthesis.

The possible mechanisms of action of probucol on the metabolism of low density lipoprotein and of high density lipoprotein were studied in 5 hyperlipidaemic subjects. The kinetics of LDL-B protein and of HDL-AI protein were determined by 2-pool analysis of specific radioactivity-time curves after reinjection of 131I-labelled LDL and 125I-labelled HDL at the end of placebo and treatment periods. Probucol increased the fractional removal rate of LDL in 4, an action probably linked to increased bile acid excretion which occurred in all 5 subjects. Nevertheless, the plasma cholesterol concentration fell significantly in only 3. The synthesis of HDL-AI protein fell substantially and was probably responsible for the consistent reduction in plasma apo-AI levels. Thus, probucol appears to enhance LDL-B protein removal and bile acid excretion but inhibits AI protein formation; all these effects may be determined in the small intestine.

Adult↗
PubMed1982

The effects of probucol on plasma lipoproteins in polygenic and familial hypercholesterolaemia.

During treatment with probucol at the dose of 1 g per day, the mean reduction in low density lipoprotein (LDL) cholesterol concentration was 11.2% in polygenic hypercholesterolaemia (n = 9) and 9.4% in heterozygous familial hypercholesterolaemia (n = 6). However, there was marked heterogeneity of response: in seven of the patients with polygenic hypercholesterolaemia who had in common moderate elevation of LDL cholesterol (5.3-6.4 mmol/1), the reduction ranged from 13 to 40% (mean, 23%). In two of this group the change in LDL concentration was associated with a decrease in LDL apolipoprotein B synthetic rate. Of the patients with familial hypercholesterolaemia one showed a 33% reduction in LDL cholesterol, and one a 13% reduction. Total high density lipoprotein (HDL) cholesterol concentration tended to decrease during treatment. This reflected a reduction of the cholesterol concentration in the HDL3 subclass; HDL2 cholesterol remaining unchanged. Plasma triglyceride and very low density lipoprotein cholesterol were unaffected by probucol. The drug was well tolerated with only one patient complaining of severe diarrhoea, and two of mild and transient diarrhoea. No clinically significant changes occurred in serial resting electrocardiograms. Thus, probucol appears to be a useful drug for the treatment of most patients with polygenic hypercholesterolaemia, and of some patients with heterozygous familial hypercholesterolaemia.

Adolescent↗
PubMed1983

Effect of probucol on the composition of lipoproteins and on VLDL apoprotein B turnover.

We studied the effect of probucol on lipoprotein composition and VLDL apo B turnover. In 7 hypercholesterolemic subjects, probucol therapy lowered mean total cholesterol, HDL cholesterol and HDL triglycerides, raised LDL triglycerides and did not change LDL cholesterol. LDL cholesterol:LDL triglycerides mass ratios fell. In all 6 subjects studied by rate-zonal ultracentrifugation, the flotation rate of LDL decreased. The isolated LDL were depleted of cholesteryl esters relative to protein. Thus, there were changes in the physical and chemical properties of LDL. All 6 subjects had reductions in HDL2, with variable changes in HDL3 on zonal ultracentrifugation. Probucol did not cause significant alterations in VLDL apo B turnover in 4 patients. The results suggest that the alterations in HDL probably are not related to changes in the flux of VLDL plasma, but rather may be due to direct effects of the drug on HDL production or catabolism.

Adult↗
PubMed1983

Effects of probucol on homozygous cases of familial hypercholesterolemia.

A marked reduction of serum cholesterol was obtained by treatment with probucol in heterozygous as well as in homozygous cases of familial hypercholesterolemia. A strict dietary regimen (low-fat, low-calories) intensified the hypocholesterolemic effect of the drug. The drug was also useful in diminishing the rebound of serum cholesterol after plasma exchange. Probucol reduced serum triglycerides in heterozygous cases of familial hypercholesterolemia, but there was a slight increase in triglycerides in homozygous cases. Treatment with probucol resulted in the regression of cutaneous and tendon xanthomas. Although it caused a decrease in HDL, it seems to be very effective in the treatment of familial hypercholesterolemia.

Adolescent↗
PubMed1991

Probucol, a superoxide free radical scavenger in vitro.

Free radical (FR) mediated oxidation of low density lipoproteins (LDL) has been implicated in atherogenesis. Probucol is a lipid lowering agent with antioxidant properties which may protect the LDL from FR mediated damage. The specific mechanism by which probucol acts as an antioxidant has not previously been reported. We therefore studied the FR scavenging properties of probucol in vitro and results show that this drug is a powerful superoxide scavenger. This property may be relevant in its use as a lipid lowering drug in the retardation of the atherosclerotic process.

Antioxidants↗
PubMed1993

Probucol and other antioxidants prevent the inhibition of endothelium-dependent relaxation by low density lipoproteins.

Hypercholesterolaemia and atherosclerosis impair responses to endothelium-derived nitric oxide (EDRF) in human and animal coronary arteries, a dysfunction that correlates with elevated low density lipoproteins (LDL). Previous studies show that native LDL immediately and reversibly inhibit acetylcholine-evoked EDRF responses in rabbit aortic ring precontracted with noradrenaline or serotonin whereas Cu(2+)-oxidised LDL (oxLDL) inhibit relaxations after 30 min with a potency that varies with the donor. We now show that antioxidants, probucol (10 microM) and ascorbic acid (100 microM) in vitro, prevent the inhibition by native LDL, indicating that this effect involves free radicals. As expected, the antioxidants had no influence on the inhibition by oxLDL. Superoxide dismutase appeared to have no effect on the inhibition by native or oxLDL. The oral administration of probucol to selected volunteers also prevented the inhibition of relaxation by their native LDL. These preparations showed a diminished susceptibility to oxidation and their oxLDL caused a markedly reduced and always reversible inhibition of relaxation compared to the potent and sometimes irreversible inhibition prior to administration of the drug. We conclude that antioxidants such as probucol reduce the formation of free radicals and the oxidative modification of LDL that lead to the impairment of EDRF responses and may prevent this same dysfunction in hypercholesterolaemia and atherosclerosis.

Acetylcholine↗
PubMed1987

Apolipoprotein E polymorphism and plasma cholesterol response to probucol.

Probucol has been shown to be an effective and well-tolerated cholesterol-lowering drug. However, response in terms of cholesterol reduction has been shown to vary significantly among individuals. The purpose of this study was to assess the role of apolipoprotein E polymorphism in determining this variation. A retrospective study of 89 hypercholesterolemic type II patients who had been treated with probucol (1 g/d) and for whom the apolipoprotein E phenotype was known was carried out. The patients were first grouped into those with heterozygous familial hypercholesterolemia (FH) and those considered to have other forms of hypercholesterolemia (non-FH). Further subclassification of the individuals in both groups as IIa or IIb, allowed the definition of four diagnostic classes, FH IIa or IIb and non-FH IIa or IIb. Among these classes there was no significant heterogeneity for the relationship between response and age or sex. After correction for between-class heterogeneity in duration of probucol treatment, comparison of individuals with the apo E3/3 phenotype with those carrying the epsilon 4 allele showed significant differences in cholesterol reduction both absolute change and percent change. Further contrasts between diagnostic and apo E genotype stratifications of these data showed that the FH patients carrying the epsilon 4 allele had the greatest reduction in cholesterol level.

Adult↗
PubMed1993

Mechanisms of high-density lipoprotein reduction after probucol treatment: changes in plasma cholesterol esterification/transfer and lipase activities.

Probucol treatment results in a significant reduction of plasma high-density lipoprotein (HDL) levels. Since the remodeling of HDL within the plasma compartment is a crucial determinant of HDL levels, the activities of several factors participating in the process, ie, lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and lipoprotein and hepatic lipases (LPL, HL), were evaluated in 15 hypercholesterolemic patients treated with probucol (1 g/d) for 8 weeks. Drug treatment was associated with significant reductions of HDL cholesterol ([HDL-C] -32%), HDL2-C (-65%), HDL3-C (-22%), apolipoprotein (apo)A-I (-27%), and apo A-II (-11%) levels and with the accumulation of small HDL in plasma. CETP activity increased by 48%, with minor changes in LCAT (-7%), LPL (+4%), and HL (-7%) activities. By linear regression analysis, CETP activity correlated inversely with HDL-C, HDL2-C, and apo A-I levels (r = -.63, -.52, and -.73, respectively) and with HDL particle size. In multivariate analysis, CETP activity was the strongest predictor of HDL-C levels, apo A-I levels, and HDL particle size. The hypothetical mechanism of probucol is a stimulation of CETP activity, resulting in the formation of triglyceride (TG)-enriched HDL. These are acted on by HL, leading to the accumulation of small HDL in plasma.

Apolipoprotein A-I↗
PubMed1994

MDL 29311, an analog of probucol, decreases triglycerides in rats by increasing hepatic clearance of very-low-density lipoprotein.

MDL 29311 is an analog of probucol that shares probucol's antioxidant and antiatherogenic properties. When fed to rats as a 1% dietary admixture, MDL 29311 decreased triglyceride levels by 65% without affecting total or high-density lipoprotein (HDL) cholesterol levels. Under the same conditions, probucol decreased triglyceride levels by 23% and total cholesterol levels by 29% (with a corresponding decrease in HDL cholesterol level). MDL 29311 treatment did not affect the rate of triglyceride entry into the plasma. However, MDL 29311-treated rats cleared in vivo-labeled very-low-density lipoprotein (VLDL)-associated [3H]-triglyceride ([3H]-VLDL) over threefold faster than control rats. This increase in clearance led to increased levels of [3H]-lipid in liver and decreased [3H]-lipid in fat, muscle, diaphragm, and kidney of MDL 29311-treated rats 1.5 to 2.0 minutes after injection of [3H]-VLDL. MDL 29311 treatment had no effect on lipoprotein lipase (LPL) or hepatic triglyceride lipase (H-TGL) activities, or on plasma apolipoprotein (apo) C-II-dependent LPL activation. Intravenously injected [3H]-VLDL was allowed to circulate in MDL 29311-treated or control rats for 1 minute, and the undiluted plasma was then perfused through rat livers in a recirculating system. The [3H] in MDL 29311 plasma was cleared threefold faster (t1/2, 1.3 v 3.8 minutes) than the [3H] in control plasma by control livers. Conversely, the [3H] in control plasma was cleared slowly (t1/2 = 3.5 minutes) by the livers of MDL 29311-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗