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PubMed2000

Failure of probucol to prolong survival in salt-loaded stroke-prone spontaneously hypertensive rats.

We examined the effect of probucol, a lipid-lowering agent with strong antioxidant properties, on neurological events and survival in stroke-prone spontaneously hypertensive rats (SHRSP). Rapid onset of stroke was induced by maintaining the animals on 1% NaCl solution in place of drinking water. Probucol (10 or 30 mg/kg/day), both of which doses are therapeutic in humans was given by gastric gavage once daily to salt-loaded SHRSP. Animals receiving vehicle were used as controls. Probucol did not influence the elevation of blood pressure. Although probucol did not improve the survival rate of salt-loaded SHRSP, 30 mg/ kg/day of probucol slightly but significantly delayed the development of neurological events (p=0.0235 by generalized Wilcoxon test). However, a high dose of probucol (100 mg/kg/day) did not change the survival or neurological events of salt-loaded SHRSP. These results suggest that probucol may be protective against the development of neurological events, but is not preventive for the progression of stroke in SHRSP.

Animals↗

PubMed2004

Long-term treatment with probucol improves endothelial function in patients with coronary artery disease.

Recent studies have shown that endothelial function is impaired in patients with coronary artery disease (CAD). Probucol has been recognized to have antioxidant properties as well as lipid-lowering effects, and may improve endothelial function. The aim of this study was to evaluate the effects of probucol on endothelial function in patients with CAD. We evaluated endothelial function, based on flow-mediated vasodilation during reactive hyperemia (FMD), and the intima-media thickness (IMT) of the common carotid artery using high resolution ultrasonography in patients either with (CAD group, n=26) or without CAD (Control group, n=12). We measured the serum cholesterol concentration, including the low-density lipoprotein cholesterol (LDL-cholesterol) concentration, and the plasma concentrations of homocyst(e)ine and asymmetric dimethylarginine (ADMA). Measurements of FMD and serum cholesterol were repeated after 3 months of probucol (500 mg/day, n=9) or placebo (n=9) treatment in patients with CAD. The IMT was significantly greater (p < 0.001) and FMD was significantly lower (p < 0.001) in the CAD group than in the Control group. While the serum cholesterol concentration and plasma ADMA were similar in the two groups, the plasma homocyst(e)ine concentrations were higher in the CAD group than in the Control group (p < 0.01). After probucol therapy, FMD was significantly improved in the CAD group (p < 0.05). The serum LDL-cholesterol concentration did not significantly decrease after probucol treatment. Placebo treatment did not alter FMD or the serum cholesterol concentration. Our findings suggest that long-term treatment with probucol improves endothelial function in patients with CAD, an outcome independent of the LDL-cholesterol-lowering effects of probucol, and that homocyst(e)ine may be a better predictor of atherosclerosis than ADMA.

Aged↗

PubMed1996

Inhibition of progression of chronic puromycin aminonucleoside nephrosis by probucol, an antioxidant.

Oxidants have been shown to be involved in the initiation of chronic puromycin aminonucleoside nephrosis in rats, but it is uncertain whether they have a role in the progression of this disease. Rats given a single internal jugular venous bolus of puromycin aminonucleoside (PA) develop early nephrotic syndrome that subsides after about 28 days followed by a 4-wk period of minimal proteinuria and then the development of focal glomerulosclerosis and increasing proteinuria. Fifty-two rats on a high-cholesterol diet were divided into four groups. Two groups of 16 animals each received a single internal jugular venous bolus of PA. One of these groups was started on the dietary antioxidant, probucol (1% wt/wt), 4 days after the PA injection and continued on it until termination. The remaining rats were given an internal jugular venous injection of an equivolume of normal saline. Five of these animals were also started on dietary probucol 4 days after the saline injection. At 11 days postinjection all animals given PA, whether on probucol or not, developed marked proteinuria with histologically minimal glomerular change and significant increases in intraglomerular monocyte and proliferating cell nuclear antigen counts. Forty-two days after PA injection all PA-injected rats had minimal urinary protein injection and no glomerular changes. At 98 days postinjection rats given PA without probucol developed focal glomerulosclerosis and significant proteinuria compared with PA-injected rats on probucol and those injected with saline (P < 0.05). The probucol-fed PA-injected rats showed no glomerular disease and their urinary protein excretion rates were very similar to those of the saline controls. The results indicate that probucol inhibits the progression of chronic puromycin aminonucleoside nephrosis and are consistent with the suggestion that oxidants are involved in the progression of this entity.

Animals↗

PubMed1989

Probucol. A reappraisal of its pharmacological properties and therapeutic use in hypercholesterolaemia.

Probucol is a lipid-regulating agent structurally dissimilar to other known agents, with a unique pharmacodynamic and clinical profile. It is effective in the treatment of primary Type IIa and IIb hyperlipoproteinaemias, including polygenic (non-familial) hypercholesterolaemia and both heterozygous and homozygous forms of familial hypercholesterolaemia, with reductions in plasma total cholesterol and low density lipoprotein (LDL)-cholesterol levels of about 10 to 20% being attained. Marked effects on cutaneous and tendinous xanthomas have been observed, with significant regression often apparent after 2 or 3 months' therapy. Preliminary trials also indicate efficacy in hyperlipoproteinaemia secondary to nephrotic syndrome and diabetes mellitus. The mechanism of the reduction in LDL-cholesterol levels is yet to be fully elucidated, but it is thought that the decrease results from enhanced catabolism, and there is preliminary evidence of an independent antioxidant effect. In contrast with all other known lipid-lowering agents, probucol also effects a consistent reduction in serum high density lipoprotein (HDL)-cholesterol levels, of around 20 to 30%; the clinical significance of this observation is unclear, although some preliminary investigations suggest a beneficial effect in enhancing reverse cholesterol transport. The influence of probucol treatment on cardiovascular morbidity and mortality remains to be fully investigated; a large trial quantifying the potential effect of probucol against the development of atherosclerotic lesions is currently in progress. Adverse effects of probucol are generally mild, seldom requiring treatment withdrawal, with gastrointestinal effects such as diarrhoea predominating. However, indications of an increased frequency of ventricular arrhythmias and sudden death in association with QT interval prolongation in some animals have prompted some concern. Although there is evidence of a degree of QT prolongation in a number of trials in humans, the nature and clinical significance of this effect requires clarification, as no increased incidence of cardiac arrhythmias is apparent. Thus, probucol appears to be of benefit in primary and secondary hyperlipoproteinaemia of Types IIa and IIb, and particularly in homozygous familial hypercholesterolaemia, with marked effects on xanthomas, and a generally favourable adverse effect profile. There is no evidence to date causally relating occasional QT interval prolongation in patients to any incidence of arrhythmias or sudden death. Pharmacodynamic investigations are likely to clarify further the place of probucol in therapy, particularly with respect to its distinctive lowering of plasma HDL-cholesterol levels.

Humans↗

PubMed1994

Differing effects of probucol and vitamin E on the oxidation of lipoproteins, ceroid accumulation and protein uptake by macrophages.

Studies using 125I-low density lipoprotein (125I-LDL) show that probucol (10 microM) and alpha-tocopherol (100 microM) inhibit protein degradation in LDL exposed to Cu (II) in vitro. The inhibitory effect of alpha-tocopherol on protein fragmentation exceeded that of probucol. On the other hand, probucol was more able to inhibit lipid peroxidation. The subsequent uptake of Cu (II)-oxidised 125I-LDL by murine peritoneal macrophages (MPM) was virtually unaffected by the presence of probucol during LDL oxidation. The same was not true for alpha-tocopherol which led to lower levels of 125I-LDL uptake by MPM. Thus, it appears that although the antioxidant activity of probucol exceeds that of alpha-tocopherol for lipid oxidation, the reverse is true for protein degradation and, perhaps more significantly, for subsequent macrophage uptake. Further studies used artificial lipoproteins composed of cholesteryl linoleate or cholesteryl arachidonate complexed with bovine serum albumin. Culture of these artificial lipoproteins with MPM resulted in protein uptake, protein degradation, cholesterol oxidation to cholest-5-en-3 beta,7 beta-diol and the intracellular accumulation of ceroid in MPM. The presence of alpha-tocopherol (0-100 microM) inhibited all of these processes. Probucol (0-10 microM) inhibited ceroid accumulation and cholesterol oxidation to the same degree as alpha-tocopherol (0-100 microM) but had no effect upon protein degradation and protein uptake. Control studies of lipoproteins incubated without cells showed that protein degradation by cell-independent processes was also inhibited by alpha-tocopherol, but not by probucol. These observations are discussed in the context of the role of lipoprotein oxidation in atherogenesis.

Animals↗

PubMedDate not supplied

Induction of estradiol synthesis by probucol in the adenocarcinoma cells of an ovarian clear cell tumor.

BACKGROUND: Clear cell tumor of Müllerian organs have characteristic intracellular structures with numerous small mitochondria, free ribosomes, lamellae of granular endoplasmic reticulum and intracytoplasmic glycogen granules, but synthesize no estrogens under ordinary conditions. MATERIALS AND METHODS: Cells from an ovarian clear cell tumor cultured with 10 micrograms/ml of the antioxidant probucol released more estradiol into the medium than cells cultured without probucol. Immunocytological analysis revealed the predominance of estradiol in the adenocarcinoma cells cultured with probucol. RESULTS: There was no difference in the distribution of low-density lipoprotein receptors in adenocarcinoma cells according to whether they had been cultured with or without probucol. Cytochemical analysis showed that hydroxylation of estrone was accelerated in the adenocarcinoma cells cultured with probucol as compared to the cells cultured without probucol. CONCLUSION: Probucol is thought to have an unknown function in the acceleration of hydroxylation of steroids in some types of cells with estrogen-producing potential.

Adenocarcinoma, Clear Cell↗

PubMed1991

Clinical and therapeutic use of probucol.

Previous studies showed that probucol significantly lowered both LDL cholesterol and HDL cholesterol. In addition, there is evidence that as an essential antioxidant probucol causes variations in cellular interactions and cardiovascular functions in patients. Therefore, 14 hypercholesterolemic men were investigated before and during probucol treatment in order to document both serological and cardiovascular changes with special regard to (1) serum apolipoproteins (A-I, A-II, B, C-II, C-III, E) (2) composition and distribution of HDL and LDL subfractions, (3) cardiovascular performance using a maximum exercise stress test, and (4) induced platelet aggregation. In contrast to reduced total, LDL-, and HDL-cholesterol values, highly significant changes in serum apolipoproteins were found in apoA-I only; apoA-II was unchanged both in serum and in HDL subfractions. Despite unchanged serum apoB levels, the results showed that probucol has a significant influence on the composition (TG/FC ratio) of LDL particles of d less than 1.019 g/ml. In addition to lipoprotein-related changes, significant decreases in heart rate data and cardiac work and in lactic acid accumulation during exercise were induced by probucol administration; furthermore, adrenaline-induced platelet aggregation was also decreased. The results found significantly demonstrate that probucol acts by way of more mechanisms than cholesterol lowering alone. This aspect may be of special interest in the clinical use of probucol, because a coronary-risk-reducing therapy should not affect the lipoprotein profile only.

Adult↗

PubMed1987

Mode of hypocholesterolemic action of probucol in animals and man.

Probucol is a widely used serum-cholesterol lowering drug. It is proposed that in humans probucol stimulates the plasma clearance of low density lipoproteins (LDL), which accounts for the drug-induced decrease in LDL cholesterol levels. In the liver the enhanced uptake of LDL cholesterol stimulates the conversion of cholesterol into bile acids, which in turn causes an increase in the output of bile acids with the feces. The increased flux through the bile acid biosynthesis pathway tends to deplete the liver pools of cholesterol. This causes stimulation of cholesterol synthesis, which is associated with a higher hepatic efflux of LDL. Thus in humans taking probucol cholesterol turnover is enhanced. In this way a new equilibrium is reached in which LDL production equals LDL catabolism, and in which cholesterol turnover is increased. The probucol-induced reduction in high density lipoprotein (HDL) cholesterol may be caused by inhibition of HDL synthesis. If we assume that the absolute rate of HDL clearance from the plasma is proportional to HDL concentration, then serum HDL will settle at a new, lower level where the clearance rate equals the rate of production. In contrast to humans, probucol may decrease the turnover of cholesterol in rats. The relatively large amounts of probucol generally fed inhibit cholesterol absorption, and this may account for the reduction in serum total cholesterol, which essentially represents HDL cholesterol. The decrease in absorption diminishes intestinal formation of HDL, which in turn leads to a diminished flux of serum cholesterol into the liver, and causes inhibition of bile acid synthesis because substrate availability is depressed. The effect of probucol on cholesterol synthesis is not clear, but the drug must lower the sum of cholesterol absorption and synthesis. In this way, serum cholesterol settles at a new, lower level, where cholesterol input equals its output.

Animals↗

PubMed1984

A novel mechanism by which probucol lowers low density lipoprotein levels demonstrated in the LDL receptor-deficient rabbit.

Treatment of low density lipoprotein (LDL) receptor-deficient rabbits (WHHL rabbits) with probucol (1% w/w in a chow diet) lowered their LDL-cholesterol levels by 36%, consonant with the reported effectiveness of the drug in patients deficient in the LDL receptor. Initial studies of LDL fractional catabolic rate (FCR) using 125I-labeled LDL prepared from the serum of untreated WHHL rabbits showed no difference between probucol-treated WHHL rabbits and untreated WHHL rabbits. When, however, 125I-labeled LDL was prepared from donor WHHL rabbits under treatment with probucol and injected back into them, the FCR was found to be increased by about 50% above that measured simultaneously using 131I-labeled LDL prepared from untreated WHHL donors. The labeled LDL from probucol-treated donors was also metabolized more rapidly than that from untreated donors when injected into untreated WHHL rabbits or into untreated wild-type New Zealand White rabbits. Finally, it was shown that rabbit skin fibroblasts in culture degraded labeled LDL prepared from probucol-treated WHHL rabbits more rapidly than that prepared from untreated WHHL donors. This was true both for normal rabbit fibroblasts and also for WHHL skin fibroblasts, although the absolute degradation rates in the latter were, of course, much lower for both forms of LDL. The data indicate that a major mechanism by which probucol lowers LDL levels relates not to changes in the cellular mechanisms for LDL uptake or to changes in LDL production but rather to intrinsic changes in the structure and metabolism of the plasma LDL of the probucol-treated animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

[Probucol and alpha-tocopherol stimulate the synthesis of bile acids in cultured rabbit hepatocytes].

Primary cultures of rabbit hepatocytes were used to examine the effect of probucol and alpha-tocopherol on cholesterol and bile acid metabolism. After 24-hour preincubation of cells with 100 microM probucol, the cholesterol and cholesteryl ester content increased--by 30% and 50%, respectively. This was accompanied by decreasing incorporation of [14C]acetate into cholesterol (down to 25-35%). At the same time, alpha-tocopherol had no effect on cholesterol accumulation in hepatocytes, while cholesterol synthesis was stimulated by 30-50%. Addition of 100 microM probucol or alpha-tocopherol to a culture medium containing 10% fetal calf serum and [14C]cholesterol caused a significant (30-40%) stimulation of bile acid synthesis. Stimulation by probucol was dependent on the presence of exogenous plasma or HDL2 cholesterol, while alpha-tocopherol enhanced this process in a cholesterol-free medium. Stimulation (40%) of bile acid secretion by probucol in the presence of physiological concentrations of apo E-free HDL2 was found. Study of receptor-mediated uptake of HDL2 revealed that: (i) probucol stimulated apo E secretion; (ii) HDL2 isolated from a medium of probucol-treated cells contained 2-3 times more apo E than the particles preincubated with cells without the drug; (iii) apo E-enriched HDL2 particles were incorporated into cultured human skin fibroblasts 1.5-3.0 times more effectively than apo E depleted HDL2; (iv) monoclonal antibody against the LDL-receptor binding domain of apo E effectively (by 40%) inhibited the apo E-enriched HDL2 uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Probucol treatment reverses antioxidant and functional deficit in diabetic cardiomyopathy.

Earlier we reported that probucol treatment subsequent to the induction of diabetes can prevent diabetes-associated changes in myocardial antioxidants as well as function at 8 weeks. In this study, we examined the efficacy of probucol in the reversal of diabetes induced myocardial changes. Rats were made diabetic with a single injection of streptozotocin (65 mg/kg, i.v.). After 4 weeks of induction of diabetes, a group of animals was treated on alternate days with probucol (10 mg/kg i.p.), a known lipid lowering agent with antioxidant properties. At 8 weeks, there was a significant drop in the left ventricle (LVSP) and aortic systolic pressures (ASP) in the diabetic group. Hearts from these animals showed an increase in the thiobarbituric acid reacting substances (TBARS), indicating increased lipid peroxidation. This was accompanied by a decrease in the myocardial antioxidant enzymes activities, superoxide dismutase (SOD) and glutathione peroxidase (GSHPx). Myocardial catalase activity in the diabetic group was higher. In the diabetic + probucol group both LVSP and ASP showed significant recovery. This was also accompanied by an improvement in SOD and GSHPx activities and there was further increase in the catalase activity. Levels of the TBARS was decreased in this group. These data provide evidence that diabetic cardiomyopathy is associated with an antioxidant deficit which can be reversed with probucol treatment. Improved cardiac function with probucol may be due to the recovery of antioxidants in the heart.

Animals↗

PubMed1993

Factors related to QT interval prolongation during probucol treatment.

To clarify factors related to the QT interval prolongation produced by probucol, multivariate analysis was applied to clinical and laboratory data retrospectively obtained from 89 patients with hypercholesterolaemia, who had taken probucol for more than 3 months. The corrected QT interval (QTc) increased from 0.410s before treatment to 0.431 s after the administration of probucol; the total cholesterol level decreased from 267 mg.dl-1 to 212 mg.dl-1. None of the patients demonstrated new arrhythmia. The QTc after probucol was independently correlated with sex, serum albumin level and baseline QTc. Changes in QTc after probucol were independently correlated with the presence of ischaemic heart disease, baseline QTc, and a change in the total cholesterol level. The results suggest that a prolonged QTc is likely to appear in female patients, and in patients with a long baseline QTc or with a low serum albumin. It is also suggested that marked lengthening of the QTc is likely to occur in patients with ischaemic heart disease or with a short baseline QTc. Probucol can be used safely in patients with hypercholesterolaemia, but ECG monitoring may be necessary, especially in female patients, as well as in those with hypoalbuminaemia or with ischaemic heart disease.

Electrocardiography↗

PubMed1983

Effects of clofibrate, bezafibrate, fenofibrate and probucol on plasma lipolytic enzymes in normolipaemic subjects.

Ten male, normolipaemic, non-obese subjects were given clofibrate 2 g daily, fenofibrate 300 mg daily, bezafibrate 600 mg daily and probucol 1 g daily for eight days, in a crossover study with a wash-out period of 4-8 weeks between each drug regimen. Clofibrate, fenofibrate and bezafibrate caused a significant decrease in serum triglycerides, total cholesterol and LDL-cholesterol concentrations. Probucol caused a significant increase in serum LDL-cholesterol concentration. Serum HDL-cholesterol concentration was significantly increased by bezafibrate and significantly decreased by probucol. All drugs but probucol led to a significant rise in the activity of the plasma lipoprotein lipase; there was not a significant increase in the activity of plasma hepatic lipase after any drug. The activity of plasma lecithin: cholesterol acyltransferase was significantly increased by fenofibrate and probucol. Analysis of the correlations between serum lipids and plasma lipolytic enzymes suggests that the mechanism of the hypolipidaemic action of clofibrate and bezafibrate might be related to increased catabolism of triglyceride-rich particles; that of fenofibrate and probucol was less clear and might be multifactorial in origin.

Adult↗

PubMed1994

Interactions of MDL 29,311 and probucol metabolites with cholesteryl esters.

The hypothesis that the efficacy of hydrophobic antioxidants in animal models of atherogenesis may, in part, be related to physical effects on cholesteryl esters in cells was probed with analogs and metabolites of probucol. The interactions of an effective bis-thiomethane analog (MDL 29,311) and selected metabolites of probucol with cholesteryl oleate were examined by differential scanning calorimetry and polarized light microscopy. Like probucol, MDL 29,311 and the bisphenol metabolite decrease the liquid-crystalline phase transition enthalpy of cholesteryl oleate with increasing concentrations. At 20 mol%, no transition is detectable. By contrast, the spiroquinone metabolite of probucol and the diphenoquinone metabolite common to both molecules have minimal effects on the liquid-crystalline transitions of cholesteryl oleate. At 20 mol%, neither compound has as great an effect as 1 mol% MDL 29,311. Consistent with their effects on dry cholesteryl oleate, MDL 29,311 and the bisphenol metabolite convert lipid inclusions in cells supplemented with cholesterol to an isotropic physical state similar to that observed with probucol. The number of anisotropic inclusions in the cells decreases with increasing concentration in the medium in the range of 50 to 250 micrograms/mL. In cells fed with the spiroquinone or diphenoquinone metabolites, the lipid inclusions are liquid-crystalline and resemble those observed with cholesterol-fed controls. These data are interpreted in terms of a model in which hydrophobic antioxidants closely related to probucol disrupt the packing of cellular cholesteryl esters.

Animals↗

PubMed1984

Low-dose colestipol plus probucol for hypercholesterolemia.

The hypocholesterolemic and adverse effects of colestipol, 20 g/day, and colestipol, 10 g/day combined with probucol, 1 g/day, were compared. A double-placebo, diet-controlled, crossover trial that lasted 19 months was undertaken on 22 hypercholesterolemic patients who had low-density lipoprotein (LDL) cholesterol levels greater than 180 mg/dl after 3 months of diet and placebo treatment. Uniformity of diet and physical activity were monitored throughout the study. Compared with baseline values after 3 months on diet-placebo treatment, "combined" therapy reduced LDL cholesterol by more than 20% in 15 patients, more than 25% in 9 patients and more than 45% in 2 patients. Treatment with "half-dose" colestipol and probucol resulted in the greatest mean LDL cholesterol reduction, from 239 mg/dl during diet-placebo period to 170 mg/dl; the difference was not statistically significantly different from the reduction to 180 mg/dl with 20 g of colestipol alone. Fifteen patients showed the greatest reduction in LDL cholesterol after combined therapy. Probucol produced statistically significant reductions in very low density lipoprotein and high-density lipoprotein cholesterol. The major gastrointestinal side effects of single therapy with colestipol (constipation) and probucol (diarrhea) were ameliorated or abolished by concomitant administration. Probucol-colestipol co-administration allowed a 50% reduction in the colestipol dosage, with similar efficacy and improved tolerability and reduced mean serum LDL cholesterol with a frequency and magnitude rarely seen with other hypocholesterolemic treatments. Hypercholesterolemic persons who cannot tolerate full doses of resins may receive equal benefit by half the dose if probucol is added to the regimen.

Adult↗

PubMed1986

Long-term use of probucol in the multifactorial primary prevention of vascular disease.

Over 1,200 middle-aged men with no apparent vascular disease participated in a 5-year multifactorial primary prevention trial, in which 612 received dietetic, hygienic and--when indicated--pharmacologic treatment for the following risk factors: hyperlipidemia, hypertension, smoking, obesity and abnormal glucose tolerance. Pharmacologic therapy included hypolipidemic agents (mainly probucol and clofibrate) and antihypertensive drugs (mainly diuretics and beta blockers). At the end of the 5 years, results in these men were compared with findings in 610 high risk and 593 low risk control subjects, none of whom had received treatment. Although intervention decreased the mean risk factor status of the treated men by 33%, their 5-year coronary incidence exceeded that of the high risk control subjects (3.1% vs 1.5%). Stroke incidence, however, was markedly reduced in the treated subjects (0% vs 1.3%). Multivariate analysis showed that the coronary events occurred in patients taking beta blockers or clofibrate, while few occurred in those receiving probucol or the diuretics. The decrease in mean serum cholesterol was 15% in men receiving only probucol, and ranged from 0% to 13% in those receiving different drug combinations, including clofibrate plus probucol (11%). Probucol also markedly decreased high density lipoprotein cholesterol levels, especially when combined with clofibrate. It is possible that adverse drug effects offset the probable benefit of an improved risk profile in the treated men, thereby explaining the greater than expected occurrence of cardiac events in this group. The probucol data, however, suggest that it may not be harmful to lower the high density lipoprotein cholesterol level when there is a significant decrease in total cholesterol as well.

Adrenergic beta-Antagonists↗

PubMed1989

Effects of simvastatin and probucol in hypercholesterolemia (Simvastatin Multicenter Study Group II).

This 12-week, randomized, double-blind, multicenter study compared the efficacy, tolerability and safety of simvastatin (a potent HMG-CoA reductase inhibitor) and probucol. Two doses of simvastatin, 20 or 40 mg once daily, were compared to probucol, 500 mg twice daily. Both simvastatin doses were significantly more effective than probucol in improving the plasma lipid profile. Mean reduction in low density lipoprotein (LDL) cholesterol was 34% with 20-mg simvastatin and 40% with the 40-mg dosage, compared to a mean reduction of 8% with probucol. Simvastatin significantly decreased total cholesterol, triglycerides and apolipo-protein B, and increased high density lipoprotein (HDL) cholesterol and apolipoprotein A-I. Probucol caused some reduction in LDL cholesterol but significantly decreased HDL cholesterol. Both simvastatin and probucol were well tolerated and no serious drug-related events occurred. Simvastatin appears to be a well-tolerated and effective new agent used once-a-day as an adjunct to diet in the management of patients with hypercholesterolemia.

Adult↗

PubMed1990

A multicenter comparison of lovastatin and probucol for treatment of severe primary hypercholesterolemia. The Lovastatin Study Group IV.

A multicenter study was undertaken to compare the effects of lovastatin (given in 4 different dosage regimens) and probucol in patients with severe primary hypercholesterolemia. The subjects were 290 patients taking lipid-lowering diets who were randomly assigned to 1 of the following treatment regimens for 14 weeks: lovastatin, 40 mg once a day with the morning meal (qam); lovastatin, 40 mg once a day with the evening meal (qpm); lovastatin 80 mg qpm; lovastatin, 40 mg twice daily, or probucol, 500 mg twice daily. One-third of the patients received probucol, and the other two-thirds were equally divided between the 4 lovastatin treatment groups. The mean reductions in total cholesterol in the 5 groups were, respectively, 20, 25, 30, 33 and 10%. The corresponding values for low-density lipoprotein cholesterol were 25, 32, 37, 40 and 8%. High-density lipoprotein cholesterol increased by 9 to 12% in all the lovastatin groups, but decreased by 23% in the probucol group. Triglycerides were reduced by 17 to 25% in all the lovastatin groups, but did not change significantly in the probucol group. Both drugs were well tolerated; no serious adverse events could be attributed to either agent. It is concluded that lovastatin is a considerably more effective lipid-lowering agent than probucol. In addition, lovastatin is almost as effective when given in a single daily dose as when given in a divided dose. When a once-a-day regimen is used, lovastatin is more effective if taken in the evening rather than the morning.

Adult↗