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PubMed1986

Effects of combined probucol-colestipol treatment for familial hypercholesterolemia and coronary artery disease.

To evaluate the effect of hypercholesterolemic treatment on coronary artery disease in patients known to be susceptible to disease progression, 44 patients with familial hypercholesterolemia and coronary artery disease were started on a lipid-lowering diet and either probucol (1 g/day) or colestipol (30 g/day). After 5 months of monotherapy, all patients went on a regimen of diet and 2-drug therapy. To date, combination therapy has continued for 3.4 to 4.1 years, and has resulted in the following changes from baseline in mean serum lipid levels: -48.5% in total cholesterol, -53.3% in low density lipoprotein cholesterol, -30.0% in high density lipoprotein cholesterol and +14.5% in triglycerides. The reduction in low density lipoprotein cholesterol apparently improved the clinical status of these patients despite the associated drop in high density lipoprotein cholesterol. In the 19 patients who underwent coronary arteriography before admission to the study, follow-up arteriograms showed that combined treatment stabilized the progression of established lesions and prevented the formation of new ones. Side effects occurred mainly with monotherapy and during the early phase of combination therapy. Reactions included diarrhea, constipation, other vague abdominal symptoms, headache and joint stiffness. In all instances, the side effects gradually subsided after the institution of combination therapy. The combination of probucol and colestipol plus diet appears to be effective in treating most patients with familial hypercholesterolemia.

Adult↗
PubMed1995

3,5-Di-t-butyl-4-hydroxytoluene (BHT) and probucol stimulate selectively the reaction of mammalian 15-lipoxygenase with biomembranes.

The lipophilic antioxidant 3,5-di-t-butyl-4-hydroxytoluene (BHT) and the structurally-related antiatherogenic drug probucol stimulate the oxygenation of mitochondrial membranes and erythrocyte ghosts by the rabbit 15-lipoxygenase as indicated by an increase in oxygen consumption as well as by an enhanced loss of polyenoic fatty acids and by the formation of specific lipoxygenase products in the membrane phospholipids. The oxygenation of linoleic acid, phospholipids and human low-density lipoproteins was not stimulated. With mitochondrial membranes, BHT causes a quenching of the 1-anilino-8-naphthalene sulfonate fluorescence. Thus, it is suggested that the stimulation of membrane oxygenation may be due to structural changes in the membranes leading to a better susceptibility of the polyenoic fatty acid residues towards lipoxygenase attack. Owing to this unexpected effect of the antioxidants, which is not related to their radical-scavenger capacity, care should be taken in interpreting experimental data on effects of BHT and probucol.

Animals↗
PubMed1994

The influence of magnesium-pyridoxal-5'-phosphate-glutamate in comparison with probucol, alpha-tocopherol and trolox on copper-induced oxidation of human low density lipoprotein in vitro.

Low density lipoprotein (LDL) in the presence of magnesium-pyridoxal-5'-phosphate-glutamate (MPPG), pyridoxal-5'-phosphate (PP), alpha-tocopherol, probucol or trolox is more resistant against copper-induced oxidation as control-LDL in vitro. The efficiency of the drugs is: probucol > MPPG > trolox > alpha-tocopherol > PP. LDL oxidation is determined by its increasing negative surface charge, fragmentation of apolipoprotein B-100 and changes of the fatty acid content of LDL. The protection of the drugs depends on their concentration and incubation time. Different experiments point to the fact that copper-induced oxidation of LDL in vitro starts with the binding of copper at the apolipoprotein B-100, resulting in an increasing negative surface charge and fragmentation of the apolipoprotein B-100. Afterwards a decrease of LDL-bound linoleic acid (18:2) is measurable.

Arteriosclerosis↗
PubMed1986

Effects of probucol on the composition and in vitro catabolism of LDL in type IIa hypercholesterolemia.

A possible mechanism of action of probucol on low density lipoprotein uptake was examined in 7 type IIa hypercholesterolemic subjects. Probucol administration effectively lowered plasma cholesterol. Both apo B-associated cholesterol and HDL cholesterol were decreased but a great inter-patient variability was noted. Plasma triglycerides were unchanged and phospholipids decreased. The composition of the isolated LDL was unaffected. The LDL displaceable activity of reference [125I]LDL measured by competition assays in control fibroblasts, was increased in 3 subjects, decreased in 1 subject and unchanged in the other 3. No correlation was found between the change in apo B-associated cholesterol and the change in the in vitro catabolism of LDL of treated patients. The results did not allow a simple mechanism of action to be ascribed to the drug, but questioned the origin of the hypercholesterolemia.

Adult↗
PubMed1986

Effect of probucol treatment on lipoprotein cholesterol and drug levels in blood and lipoproteins in familial hypercholesterolemia.

Twelve patients with mild and 3 with severe hypercholesterolemia were stabilized with an isocaloric diet containing less than 300 mg cholesterol daily with a P/S ratio of 1.8, and placebo period of 4 weeks. They were administered 1000 mg probucol daily for 12 weeks, followed by placebo for 6 weeks. In patients with mild disease, a significant cholesterol reduction was achieved in serum, LDL, and HDL (maximum decrease, 17%, 13%, and 31%, respectively). While HDL3 cholesterol was reduced significantly throughout the period (P less than 0.001), HDL2 cholesterol showed a significant decrease only at the 4th week of treatment (P less than 0.001), and returned to basal levels at the 8th and 12th treatment weeks. Serum apo B levels decreased only slightly, but the HDL-apo A-I fall was significant with a reduction in the HDL-CH/HDL-apo A-I ratio throughout the treatment period. In 3 patients with severe disease, cholesterol decrease in serum and in VLDL, LDL and HDL fractions varied, but on the whole was lower than in patients with mild disease. A decrease in VLDL-CH and HDL-CH was present in all 3, but LDL-CH levels were only slightly lowered in 2 patients, and unchanged in the third. Serum probucol levels fell 66% from the 4th to the 12th treatment week, and in parallel, the percentage of lipoprotein-bound drug increased about 2-fold. It is suggested that these changes in pharmacokinetics as well as the cholesterol-lowering effect of the drug may be due to a change in lipoprotein composition or structure.

Adult↗
PubMed1988

Influence of probucol administration on lipoprotein cholesterol and apolipoproteins in normolipemic males.

In order to interpret the known lipoprotein changes in probucol-treated patients, serum concentrations of apolipoproteins (A-I, A-II, B, C-II, C-III, E) were measured before, during and after probucol administration (2 X 500 mg p.d.), in 16 healthy males (30.3 +/- 5.6 years old). Cholesterol concentrations were determined in LDL and VLDL fractions as well as in HDL subfractions which were isolated by preparative ultracentrifugation. In addition, apolipoprotein A-I and A-II concentrations were measured in the HDL subfractions. Compared with the baseline values, significant apolipoprotein changes were found in the serum apolipoprotein A-I (151 +/- 18 to 115 +/- 31 mg/dl; P less than 0.001) and C-II levels during administration. The HDL subfraction analysis showed that the decrease of HDL-cholesterol and apolipoprotein A-I (59.9 +/- 23.5 to 34.4 +/- 16.4 mg/dl, P less than 0.001, and 65.7 +/- 49.0 to 37.5 +/- 23.5 mg/dl, P less than 0.05, respectively) was predominantly related to the HDL2b subfraction (d = 1.063-1.100 g/ml).

Adult↗
PubMed1996

Long-term probucol treatment results in regression of xanthomas, but in progression of coronary atherosclerosis in a heterozygous patient with familial hypercholesterolemia.

A 66-year-old male heterozygous familial hypercholesterolemia (FH) patient with significant coronary atherosclerosis has been treated by us with probucol (1000 mg daily) for eight years. This treatment has produced significant reductions in the cholesterol levels of his serum, low density lipoprotein (LDL), and high density lipoprotein (HDL) from 237 +/- 20 mg/dl (mean +/- S.D.) to 156 +/- 15, from 175 +/- 8 to 111 +/- 16 mg/dl, and from 23 +/- 4 to 19 +/- 2 mg/dl, respectively. These reductions have been maintained for eight years. Serum triglyceride levels also decreased, from 220 +/- 54 to 146 +/- 36 md/dl. During this period, marked regression of xanthomas on the eyelids and finger extensor tendons was observed, while thickness of the Achilles tendons was reduced from 21.0 mm to 13.0 mm. On other hand, effort-induced anginal symptoms requiring additional antianginal medication have been noticed, and angiographically-demonstrated coronary atherosclerosis has progressed significantly during these eight years. These observations lead us to suggest that maintaining low levels of HDL cholesterol with probucol, even though resulting in satisfactory reduction of LDL cholesterol and marked regression of xanthomas, appears to be associated with the progression of atherosclerosis in the coronary arteries.

Aged↗
PubMed1995

Combination therapy with probucol prevents adriamycin-induced cardiomyopathy.

Adriamycin (doxorubicin) is a broad spectrum anti-tumor antibiotic used to treat cancer patients. However, the potential usefulness of this drug is currently limited by the development of a dose-dependent cardiomyopathic process terminating in severe heart failure. Although several mechanisms have been suggested to explain the pathogenesis of adriamycin-induced cardiomyopathy, free-radical induced oxidative stress appears to play an important role. A concise description of adriamycin-induced cardiomyopathy is provided. Various combination therapies which have been attempted in the past to modulate the adriamycin-induced cardiomyopathy are also discussed. Recently, it has been discovered that probucol, a lipid lowering agent and potent antioxidant, provides complete protection against adriamycin-induced cardiomyopathy in rats without interfering with the anti-tumor properties of this antibiotic. Clinical trials employing adriamycin therapy in combination with probucol are needed to determine the applied value of these laboratory findings.

Animals↗
PubMed1991

Stenosis following laser thermal angioplasty--a blinded controlled randomized study between aspirin against Probucol.

Long-term patency of vascular angioplasties is limited by stenosis from neointimal hyperplasia or progressive arteriosclerosis. This study evaluated the hypothesis that ASA (an antiprostaglandin) or Probucol (an antioxidant) may be useful in preventing stenosis following laser thermal angioplasty. Aortoiliac arteriosclerosis was induced in 17 female New Zealand white rabbits with a combination of endothelial denudation (4 Fr. Fogarty balloon catheters) and 2% cholesterol-supplemented diet for 6 weeks. All rabbits then underwent arteriography and were immediately randomized to one of three groups: Group I (n = 6), control, laser but no adjunctive therapy; Group II (n = 5), laser and ASA 10 mg/kg/day; Group III (n = 6), laser and 1% Probucol diet. Retrograde laser thermal angioplasty was performed with a 1-mm coronary Laserprobe. Six watts of argon laser energy was delivered for a single 5-sec pulse using a continuous motion from the right common iliac artery to the aorta. Pre- and postlaser arteriography was performed in all groups. Rabbits were sacrificed 1 month following laser angioplasty, and aortoiliac sections were taken after in situ perfusion fixation with paraformaldehyde and 0.05% glutaraldehyde. Serial 5-mm segments, proximal to the aortic bifurcation and distally from the same, were taken, stained, and evaluated by quantitative morphometry. From each segment, lesion area and lesion area/internal elastic laminae area were evaluated and compared. Serum cholesterol increased from 60.8 +/- 19.5 to 1494.7 +/- 12.7 mg% following institution of the cholesterol diet (P less than 0.05). Arteriosclerotic lesions were observed in all rabbits and maximally located around the common iliac artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Laser↗
PubMed1982

Platelet function in familial hypercholesterolaemia in South Africa and the effects of probucol.

Patients with Familial Hyperlipoproteinaemia Type II showed evidence of increased platelet aggregability when compared to normal controls. This abnormality was not influenced by oral therapy with probucol whether or not the serum cholesterol levels were lowered during the study period. Probucol assays indicated adequate compliance during the study period but did not demonstrate any uptake of the drug by platelets. In vitro studies also failed to demonstrate any inhibition of platelet function at therapeutic drug levels although higher levels were inhibitory.

Adolescent↗
PubMed1983

In vivo cytogenetic study in rats maintained for eight days on diets containing probucol.

Probucol (4,4'-(isopropylidenedithio)bis(2,6-di-t-butylphenol], a cholesterol-lowering drug, was evaluated for cytogenetic toxicity in the bone-marrow cells of Sprague-Dawley rats. Male and female rats were fed diets containing 0, 200, 400, or 800 mg/kg body weight/day for 8 consecutive days. Animals treated with trimethylphosphate served as positive controls. Femoral bone-marrow specimens were aspirated from all animals for cytogenetic evaluation. Analysis of the data generated by this study indicated that the incidence of cytogenetic aberrations in the bone marrow of rats was not affected by administration of probucol within the present treatment regimen.

Administration, Oral↗
PubMed1988

The effects of probucol on QT/QS2 relation and systolic time intervals.

The QT, QTc, QS2 intervals, pre-ejection period-left ventricular ejection time ratios and serum lipoprotein levels were measured in 8 patients with primary hypercholesterolemia before and after a 3-month therapy with probucol, 1 g/day. Both QT and QTc intervals increased significantly, whereas no significant changes were observed between the pre- and post-treatment QT/QS2 and pre-ejection period-left ventricular ejection time ratios. These results help to explain why treatment with probucol, while effecting a prolongation of the QTc interval, does not result in serious arrhythmias in man.

Adult↗
PubMed1995

Protective effects of probucol against glutamate-induced cytotoxicity in neuronal cell line PC12.

The sympathetic nerve cell line PC12 is reportedly destroyed by glutamate in a concentration-dependent manner. In this study, cytotoxicity induced by 10 mM glutamate was blocked in a dose-dependent manner by incubating or pre-incubating cells with the antioxidant probucol (1-50 microM). Probucol also inhibited the increase in cellular thiobarbituric acid-reacting substances induced by glutamate exposure. These results suggest that the propagation of cellular lipid peroxidation may be related to glutamate-induced toxicity in PC12 cells.

Animals↗
PubMed1988

Probucol enhances cholesterol transport in cultured rat hepatocytes.

Probucol has been investigated extensively in vivo and ex vivo. However, little information is available on direct treatment of cultured cells. Treatment of cultured hepatocytes by 1 to 10 microM probucol for 16 to 20 hours had no apparent deleterious effect on the cell, and in fact decreased lactic dehydrogenase leakage. Also, total cellular cholesterol was increased, cholesterol synthesis was decreased, and cholesterol esterification was increased. The increase in cellular cholesterol was not the result of increased lipoprotein uptake but appeared to be the result of an interaction between cell and lipoprotein in which the cell became enriched and the lipoprotein depleted in cholesterol. This type of change in lipoprotein composition after treatment is also observed clinically.

Animals↗
PubMed2004

Biodistribution characteristics of galactosylated emulsions and incorporated probucol for hepatocyte-selective targeting of lipophilic drugs in mice.

PURPOSE: Galactosylated emulsions containing cholesten-5-yloxy-N-(4-((1-imino-2-D-thiogalactosylethyl)amino)butyl)formamide (Gal-C4-Chol) as a "homing device" were developed for hepatocyte-selective drug targeting. The targeting efficiency of galactosylated emulsions was evaluated by a distribution study in mice. METHODS: Soybean oil/EggPC/cholesterol (Chol) (weight ratio, 70:25: 5) (bare) emulsions and soybean oil/EggPC/Gal-C4-Chol (weight ratio, 70:25:5) (Gal) emulsions were prepared and labeled with [3H]cholesteryl hexadecyl ether (CHE). [14C]probucol as a model lipophilic drug was incorporated in the emulsions or EggPC/Chol/Gal-C4-Chol (Gal) liposomes. Their tissue and intrahepatic distribution were evaluated following intravenous injection in mice. RESULTS: After intravenous injection, Gal-emulsions were rapidly eliminated from the blood and accumulated in the liver, in contrast to the bare-emulsions. The liver uptake clearance of Gal-emulsions was 3.2- and 1.2-times greater than that of bare-emulsions and Gal-liposomes, respectively. The uptake ratio in liver parenchymal cells (PC) and nonparenchymal cells (NPC) of Gal-emulsions was higher than that of Gal-liposomes, being 7.4 and 3.0, suggesting that Gal-emulsions are an effective PC-selective carrier. The hepatic uptake of Gal-emulsions, but not that of bare-emulsions, was significantly inhibited by the pre-dosing of not only lactoferrin but also Gal-liposomes, suggesting asialoglycoprotein receptor-mediated endocytosis. Furthermore, [14C]probucol incorporated in Gal-emulsions was efficiently delivered to the liver compared with Gal-liposomes. CONCLUSION: Gal-emulsions have been proven to be an alternative carrier for hepatocyte-selective drug targeting.

Animals↗
PubMed2001

Apoptosis in adriamycin cardiomyopathy and its modulation by probucol.

The dose-dependent cardiomyopathy and heart failure due to adriamycin have been shown to be due to increased oxidative stress and loss of myocytes. We examined the incidence of myocardial apoptosis as well as changes in the expression of apoptotic regulatory gene products in an established animal model of adriamycin cardiomyopathy. Rats were treated with adriamycin (cumulative dose, 15 mg/kg), and the hearts were examined for apoptosis as well as expression of Bax, caspase 3, and Bcl-2 at 0, 4, 10, 16, and 21 days after the treatment. A significant increase in the incidence of apoptosis was seen at 4 days, followed by a decline at 10 and 16 days of posttreatment. At 21 days, the number of apoptotic cells increased again and included cells of the conducting system. Expression of Bax corresponded to these biphasic changes, whereas the converse was true for the expression of Bcl-2. The latter peaked at 10 days followed by a decline at 16 and 21 days. The Bax/Bcl-2 ratio also correlated with the incidence of apoptosis. Expression of caspase 3 correlated with increased apoptosis, but only at early time points. Probucol (cumulative dose, 120 mg/kg), a known antioxidant as well as promoter of endogenous antioxidants, significantly reduced the incidence of apoptosis as well as expression of Bax. Adriamycin-induced hemodynamic changes were also prevented by probucol. These data suggest that adriamycin-induced apoptosis is mediated by oxidative stress and may play a role in the development of heart failure.

Animals↗
PubMed1987

Treatment of familial and non-familial hypercholesterolaemia: a review of HMG-CoA reductase inhibitors and probucol.

Hypocholesterolaemic agents are powerful modifiers of the plasma lipoprotein pattern. In addition to lowering plasma low density lipoprotein (LDL) cholesterol, such drugs may elevate, decrease or have no effect on high density lipoprotein (HDL) cholesterol. Bile acid binding resins and 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors cause a reduction in hepatic cholesterol content resulting in stimulation of LDL receptor activity. This decreases the plasma LDL level, while HDL cholesterol levels remain unchanged or increase. Probucol, on the other hand, lowers both LDL and HDL cholesterol. It does not act by stimulating LDL receptor activity and is effective in some patients with homozygous familial hypercholesterolaemia who virtually lack LDL receptors. Despite their different lipoprotein-modifying effects, both HMG-CoA reductase inhibitors and probucol are regarded useful in the prevention and retardation of atherosclerosis.

Arteriosclerosis↗
PubMed1980

Effects of clofibrate, cholestyramine, zanchol, probucol, and AOMA feeding on hepatic and intestinal cholesterol metabolism and on biliary lipid secretion in the rat.

Utilizing newer techniques for measuring rates of cholesterol synthesis, the effects of clofibrate, cholestyramine, zanchol, probucol, and AOMA (a copolymer of maleic acid and an alpha-olefin chain of 18 carbons) on hepatic and intestinal cholesterol metabolism and on biliary lipid secretion in the rat were examined. Uncer conditions of isocaloric feeding, female rats were administered a fixed amount of these drugs each day for 14 days. In one set of experiments the rats were killed and rates of hepatic and intestinal cholesterol synthesis and tissue cholesterol levels were measured. In a second set of studies the rats were subjected to total biliary diversion for 2 hr and rates of biliary lipid secretion were determined. Plasma cholesterol concentrations were measured in all animals. Neither AOMA nor cholestyramine had any effect on plasma cholesterol levels or biliary lipid secretion, but both markedly enhanced intestinal cholesterol synthesis. Cholestyramine also increased hepatic cholesterol synthesis. Clofibrate significantly decreased plasma cholesterol levels, whereas zanchol had the opposite effect. Both clofibrate and zanchol increased liver size and bile secretion rates but lowered biliary lipid concentrations; however, total biliary lipid output was unchanged. Total hepatic cholesterol synthesis in clofibrate-fed animals was similar to that in the controls, but in zanchol-fed animals it was approximately doubled. Neither clofibrate nor zanchol had any effect on intestinal cholesterol synthesis. Probucol dramatically lowered plasma cholesterol levels but had no effect on the other parameters measured. None of the drugs was effective in altering the molar percentage of cholesterol in bile despite the diversity of metabolic changes which occurred. These studies point up the many diverse metabolic effects of these drugs, some of which are clinically useful in lowering plasma cholesterol levels, and delineate the marked dissociations that occur between rates of cholesterol synthesis, tissue cholesterol levels, and plasma cholesterol concentrations.

Animals↗