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PubMed1995

Probucol treatment decreases serum concentrations of diet-derived antioxidants.

The effect of probucol, which is both a cholesterol-lowering drug and an antioxidant, on the serum concentrations of diet-derived antioxidants vitamin E, beta-carotene, lycopene, and vitamin A was studied in 303 hypercholesterolemic subjects. In a 3-year, double-blind, randomized trial we investigated to determine whether combined treatment with diet, cholestyramine, and probucol could reduce the progression of femoral atherosclerosis. Serum and lipoprotein antioxidant levels were measured by reverse-phase high-performance liquid chromatography. Cholestyramine significantly lowered serum concentrations of vitamin E by 7%, beta-carotene by 40%, and lycopene by 30% (all P < .001) due to impairment of gastrointestinal absorption and to serum cholesterol lowering. Probucol reduced serum vitamin E by 14% (P < .001) secondary to cholesterol and triglyceride lowering. The carotenoids were reduced by probucol by 30% to 40% (P < .001) most probably due to reductions in lipoprotein particle size and to competition with these substances for incorporation into VLDL during its assembly in the liver. This study shows that the use of a lipid-soluble antioxidant and cholesterol-lowering drug may have unfavorable effects on blood levels of diet-derived antioxidants.

Antioxidants↗
PubMedDate not supplied

Mechanisms of HDL reduction after probucol. Changes in HDL subfractions and increased reverse cholesteryl ester transfer.

Treatment with probucol, a widely used lipid-lowering agent, is associated with a significant reduction of high density lipoprotein (HDL) cholesterol levels, but with an apparently improved removal of cholesteryl esters from tissues (e.g., from tendon xanthomas). The effects of probucol (500 mg twice daily) on HDL subfraction distribution and cholesteryl ester transfer activity were tested in 12 patients with stable type II hyperlipidemia [low density lipoprotein (LDL) cholesterol greater than 180 mg/dl] after a placebo-controlled cross-over trial. Probucol significantly lowered total cholesterol (-13.8%), LDL cholesterol (-9.1%), and HDL cholesterol (-30%). By rate zonal ultracentrifugation, a marked reduction of HDL2 cholesterol (-68%) was shown, whereas changes in HDL3 were less significant (-21%). These findings were confirmed by polyacrylamide gradient gel electrophoresis, typically showing a reduction or disappearance of HDL2b particles and the prevalence of particles in the HDL3a range. Cholesteryl ester transfer from HDL to lower density lipoproteins was significantly increased (30%) in all patients. These findings suggest that, in addition to the well-documented in vitro changes (prevention of LDL peroxidation and macrophage uptake), probucol characteristically modifies HDL particle distribution in vivo, and is associated with a significant increase of cholesteryl ester transfer activity.

Apolipoproteins↗
PubMed2002

Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation.

BACKGROUND: Oxidative stress and inflammation are potentially involved in the pathogenesis of heart failure (HF). We examined whether antioxidant and antiinflammatory treatment with probucol decreases myocardial oxidative stress and inflammation and attenuates the progression of left ventricular (LV) dysfunction and remodeling (dilatation) in tachycardia-induced HF. METHODS AND RESULTS: We studied 3 groups of dogs: a sham-operated control group and 2 other groups that underwent ventricular pacing at 240 bpm with and without probucol treatment (100 mg/kg IP per week) for 4 weeks. Dogs that underwent ventricular pacing for 4 weeks developed signs of HF, such as a reduction in the LV ejection fraction and increases in the LV end-diastolic dimension and LV end-diastolic pressure. Myocardial oxidative stress, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6,-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO), was significantly increased. There was an increase in myocardial monocyte infiltration, monocyte chemoattractant protein-1 expression, and renin-angiotensin system and matrix metalloproteinase activity. Probucol treatment prevented increases in oxidative stress, inflammation, and matrix metalloproteinase activity and attenuated LV dysfunction and remodeling. CONCLUSIONS: Probucol attenuated LV dysfunction and remodeling, possibly through its antioxidant and/or antiinflammatory effects in ventricular pacing-induced HF. These data suggest that inflammatory disorders, which cause an abnormal interaction between failing myocardium and activated monocytes, have an important role in the progression of HF.

Animals↗
PubMed1986

Probucol inhibits oxidative modification of low density lipoprotein.

Previous studies have established that low density lipoprotein (LDL) incubated with endothelial cells (EC) undergoes extensive oxidative modification in structure and that the modified LDL is specifically recognized by the acetyl LDL receptor of the macrophage. Thus, in principle, EC-modified LDL could contribute to foam cell formation during atherogenesis. Oxidatively modified LDL is also potentially toxic to EC. The present studies show that addition of probucol during the incubation of LDL with EC prevents the increase in the electrophoretic mobility, the increase in peroxides, and the increase in subsequent susceptibility to macrophage degradation. It has also been shown that oxidation of LDL catalyzed by cupric ion induces many of the same changes occurring during EC modification. Addition of probucol (5 microM) also prevented this copper-catalyzed modification of LDL. Most importantly, samples of LDL isolated from plasma of hypercholesterolemic patients under treatment with conventional dosages of probucol were shown to be highly resistant to oxidative modification either by incubation with endothelial cells or by cupric ion in the absence of cells. The findings suggest the hypothetical but intriguing possibility that probucol, in addition to its recognized effects on plasma LDL levels, may inhibit atherogenesis by limiting oxidative LDL modification and thus foam cell formation and/or EC injury. Other compounds with antioxidant properties might behave similarly.

Animals↗
PubMed2002

Effect of probucol on cytochrome P450 activities in human liver microsomes.

The effects of probucol, a cholesterol-lowering agent, on several cytochrome P450 (CYP) isoform-specific reactions in human liver microsomes were investigated to predict drug interactions with probucol in vivo from in vitro data. The following eight CYP catalytic reactions were used in this study: CYP1A1/2-mediated 7-ethoxyresorufin O-deethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated 7-benzyloxyresorufin O-debenzylation, CYP2C8/9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated bufuralol 1'-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6beta-hydroxylation. Probucol had neither stimulatory nor inhibitory effects on CYP1Al/2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, and 3A4 activities at concentrations up to 300 microM, indicating that probucol, at the expected therapeutic concentrations, would not be predicted to cause clinically significant interactions with other CYP-metabolized drugs.

Cytochrome P-450 Enzyme System↗
PubMed1995

Combined effects of pravastatin and probucol on high-density lipoprotein apolipoprotein A-I kinetics in cholesterol-fed rabbits.

The combined effects of pravastatin and probucol on high- density lipoprotein (HDL) apolipoprotein (apo) A-I kinetics in cholesterol (Ch)-fed rabbits were investigated. Japanese White rabbits were treated with 0.15% pravastatin and 0.5% Ch (group 1) or 0.15% pravastatin plus 1% probucol and 0.5% Ch (group 2) for 2 months. After treatment, the serum total cholesterol levels in groups 1 and 2 had significantly (p < 0.01) increased (37.4 +/- 6.7 mg/dl vs 117.1 +/- 46.4 mg/dl, and 31.4 +/- 4.9 mg/dl vs 143.0 +/- 84.5 mg /dl, respectively). The serum HDL-cholesterol levels in both groups decreased (18.2 +/- 2.8 mg/dl, vs 16.2 +/- 3.7 mg/dl p < 0.01 for group 1; 18.2 +/- 1.9 mg/dl vs 15.5 +/- 4.5 mg/dl, ns for group 2). Apo A-I kinetics were assessed by injecting (125)I-labeled HDL intravenously into both groups of rabbits, and taking blood samples periodically for 6 days. Kinetic parameters calculated from apo A-I specific radioactivity decay curves showed that the apo A-I fractional catabolic rates in rabbits fed pravastatin and Ch (group 1) were significantly less than those in rabbits fed pravastatin plus probucol and Ch (group 2) (0.546 +/- 0.017 /day vs 0.730 +/- 0.126 /day, p < 0.05), while the synthetic rate of apo A-I was lower in group 2 than in group 1 (14.76 +/- 1.71 mg/kg per day vs 11.21 +/- 2.38 mg/kg per day, respectively, p < 0.01). These data indicate that pravastatin and probucol have different effects on HDL-apo A-I kinetics in a diet which includes cholesterol.

Animals↗
PubMedDate not supplied

Probucol-induced QT prolongation and torsades de pointes.

Probucol administration of 4 weeks produced torsades de pointes associated with exacerbated QT interval prolongation in a 36-year-old woman with Romano-Ward syndrome. With discontinuance of probucol, the QT interval corrected for rate shortened from 620 msec to 500 msec and ventricular ectopic beats disappeared completely. Although probucol is known to prolong the QT interval, associated ventricular tachyarrhythmia has not been reported in humans as yet. This case suggests that one should be very careful in the administration of probucol to patients with long baseline QT intervals.

Adult↗
PubMed1995

Probucol normalizes cholesteryl ester transfer in IDDM.

OBJECTIVE: Cholesteryl ester transfer (CET) is pathologically increased in insulin-dependent diabetes mellitus (IDDM), and the resulting enrichment of the apolipoprotein B-containing lipoproteins with cholesteryl ester (CE) is believed to increase their atherogenicity. Because we have shown previously that treatment with the lipid-modifying antioxidant probucol normalizes CET in nondiabetic patients with hypercholesterolemia, we sought to determine whether the same beneficial effects could be achieved in IDDM. RESEARCH DESIGN AND METHODS: CET was measured by both mass and isotopic assay in eight normolipidemic (triglyceride, 102; cholesterol, 192; high-density lipoprotein [HDL] cholesterol, 45 mg/dl) IDDM patients (fructosamine 495 +/- 146 mumol/l; normal 174-286) before and after 2 months of treatment with probucol (1.0 g/day). RESULTS: Before treatment, CET was accelerated abnormally (P < 0.001). As expected, probucol decreased plasma (-13%; P < 0.025) and HDL2 cholesterol levels (-52%; P < 0.025) and the concentration of lipoprotein A-I particles (P < 0.025). In conjunction with these changes, CET fell dramatically in all subjects (mass assay: -94%; isotopic assay: -22%, P < 0.001) with no change in the mass of cholesteryl ester transfer protein (CETP) (pretreatment 2.91 +/- 0.97 vs. posttreatment 3.21 +/- 1.03 micrograms/ml). Glycemic control, however, improved significantly (fructosamine 409 +/- 85 mumol/l, P < 0.025). CONCLUSIONS: Because it is believed that accelerated CET promotes the formation of apolipoprotein B-containing lipoproteins enriched with atherogenic CE, the capacity of probucol to reverse this functional abnormality without adversely affecting glycemic control suggests that it has a place in the therapy of IDDM.

Adult↗
PubMed1991

[Separation of high density lipoprotein (HDL) using anti-apo A-I, apo A-II immuno-affinity chromatography to evaluate the effects of probucol].

An assessment has been made regarding the changes of the particles of lipoprotein A-I without A-II (Lp A-I) and lipoprotein A-I with A-II (LpA-I/A-II) which correspond to HDL subfraction isolated by the use of anti-apo A-I and A-II antibody affinity columns in order to quantitatively and qualitatively investigate the change of HDL caused by administration of probucol and pravastatin which are therapeutic drugs for hypercholesterolemia. Probucol caused significant decreases of HDL-cholesterol, plasma apo A-I/apo A-II ratio and particles larger in diameter than 10.4 nm. Comparing Lp A-I and A-I/A-II ratios with those in normolipidemic controls and the ratios before and after administration of probucol, the decrease of LpA-I ratio was found to be remarkable after prolonged administration of probucol, and it was presumed that the decrease of HDL cholesterol by prolonged administration reflects the decrease of LpA-I particles more than the decrease of LpA-I/A-II. On the other hand, no significant change was seen in HDL cholesterol, plasma apo A-I/apo A-II ratio or HDL particle size in the pravastatin group. It is considered essential to observe HDL from the aspect of apoprotein, which plays an important role in the metabolism of lipoprotein, in the assessment of the anti-atherogenic activity of HDL cholesterol in future. In other words, it is necessary to analyze the change of HDL from the aspect of Lp A-I and Lp A-I/AII and investigate their respective metabolisms and roles.

Adult↗
PubMed1986

Influence of probucol ((4,4'-isopropylidine dithio)-bis(2,6-di-t-butyl-phenol)) on egg yolk cholesterol content and performance of laying hens.

Addition of the hypocholesteremic agent Probucol ((4,4'-isopropylidine dithio)-bis(2,6-di-t-butyl-phenol)) to the diet of laying hens at up to 1% significantly reduced egg yolk cholesterol content (mg/g yolk) without impairment of rate of egg production, egg weight, shell strength, albumen quality, or other production related parameters. Dietary concentration of .1% Probucol significantly reduced yolk cholesterol within 2 weeks after feeding. Higher concentrations did not further reduce yolk cholesterol. Probucol at .025% reduced egg yolk cholesterol within 4 weeks after feeding, but after 8 weeks of feeding, eggs from hens fed .025% Probucol did not differ significantly in yolk cholesterol from those fed the basal unsupplemented diet. This suggests possible adaptation in cholesterol synthesis by the laying hen.

Animals↗
PubMedDate not supplied

Probucol decreases total body fat loss in VX2-carcinoma-induced cachectic rabbits.

We previously reported the continuous decrease of total body fat in VX2-carcinoma-bearing rabbits after tumor implantation, as well as changes in the serum lipid profile. Probucol, an antioxidant drug, has a cholesterol lowering effect against hyperlipidemic subjects. VX2-carcinoma-bearing rabbits fed with a diet containing 1% probucol did not show any difference in serum lipid compositions as compared with rabbits fed with a control diet. Similarly serum lipolytic activity showed no differences, whether probucol was administered or not, while the decrease in total body fat was significantly less when probucol was administered.

Adipose Tissue↗
PubMed1984

Probucol with colestipol in the treatment of hypercholesterolemia.

The effects of therapy with 1 g of probucol and 20 g of colestipol were compared with those of the drugs used singly on 47 patients with hypercholesterolemia in a double-blind, double-placebo, diet-controlled, crossover trial that lasted 18 months. The probucol and colestipol combination, but neither drug alone, reduced mean serum low-density-lipoprotein (LDL)-cholesterol levels from 242 +/- 51 (SE) mg/dL during the diet and placebo phase to 171 +/- 41 mg/dL. Probucol significantly lowered high-density-lipoprotein (HDL)-cholesterol levels and increased LDL:HDL-cholesterol ratios. Combination therapy did not change LDL:HDL cholesterol ratios. Probucol alone or in combination reduced very-low-density-lipoprotein cholesterol levels, despite concomitant elevations of serum triglyceride levels caused by colestipol in the combination protocol. Gastrointestinal side effects of single drugs were abolished when drugs were used in combination. Compared with the values in the diet-placebo phase, LDL-cholesterol levels were reduced by more than 20% in 81% of patients, by more than 30% in 49%, and by more than 40% in 17%. This drug combination proved to be safer and have greater hypocholesterolemic effects in more patients than other marketed drug treatments.

Adult↗
PubMed2001

[Effect of probucol on the concentration of cyclosporin A in patients with nephrotic syndrome].

The first choice of therapy for nephrotic syndrome is steroid, and cyclosporin A(CyA) or other immunosuppressants are selected for steroid resistant or recurrent cases. Nephrotic syndrome accompanies hyperlipidemia for which HMG-CoA reductase inhibitors are mainly used. On the other hand, probucol is used in cases showing inadequate effects or some adverse reactions under treatment with HMG-CoA reductase inhibitors. Recently, we experienced several cases whose blood levels of CyA were decreased to about half that before the combined use of probucol, and concomitant administrations were discontinued. Based on these cases, we considered that the use of probucol should be prescribed in patients with nephrotic syndrome accompanying hyperlipidemia giving preference to CyA treatment. In cases of unavoidable usage of probucol, CyA dose adjustments are required on the basis of frequent CyA blood level monitoring.

Adult↗
PubMed1992

Protective effect of probucol on ischemia-reperfusion arrhythmias in the rat heart.

OBJECTIVE: To evaluate the efficacy of probucol on ischemia-reperfusion injury in the isolated working rat heart. DESIGN: Twelve male Sprague-Dawley rats were divided into two groups: one was fed normal chow (group C) and the other was fed chow containing 1% probucol for four weeks (group P). Samples of heart organ and blood were then taken under anesthesia. Isolated hearts were perfused in a working heart model. After 5 mins of perfusion in aerobic conditions, global ischemia was induced for 15 mins, the hearts were then reperfused. Aortic and coronary flow, cardiac function and electrocardiogram were monitored throughout the experiment, including a 20 min period of reperfusion. Serum lipids and lipid peroxide were also measured in each rat. RESULTS: Rats in group P (probucol-treated) had significantly lower levels of serum cholesterol, triglyceride and phospholipid than those in group C (controls). Serum lipid peroxide was also significantly lower in group P than in group C rats (P < 0.05). The incidence of ventricular arrhythmias in the ischemia and reperfusion stages was lower in group P than in group C (P < 0.001) and the increase in coronary flow during the reperfusion stage was greater in isolated hearts of group P rats than in those of group C (P < 0.05). CONCLUSIONS: Probucol may have a protective effect on myocardium with respect to ischemia-reperfusion arrhythmia in the isolated rat heart, presumably due to an antioxidative effect.

Animals↗
PubMed1992

Post-marketing surveillance of probucol (Sinlestal) in Japan.

We surveyed the efficacy and safety of probucol (Sinlestal) in 6,002 patients with hyperlipidemia during the past six years between Oct., 1984 and Sep., 1990. Probucol was usually administered for more than 8 weeks at a dose of 500 mg per day and effects on serum lipids and adverse drug events (ADEs) were investigated. Total cholesterol (TC), triglycerides (TG) and HDL cholesterol (HDL) significantly decreased by 16-20%, 6-9% and 15-20% respectively. Further, LDL cholesterol (LDL) decreased by 15-19%. ADEs were reported in 2.7% (161/6,002 subjects), but severity was mild or moderate. In addition to survey in 6,002 patients, the effect on regression of xanthomas and safety in long-term administration of over one year was investigated in 44 and 142 patients, respectively. Regression of xanthoma was observed in 63.6% (28/44 subjects). Probucol was well tolerated in long-term administration. These PMS results showed probucol to possess good therapeutic efficacy and safety.

Adult↗
PubMed2006

Effect of probucol on elderly hypercholesterolemic patients in the FAST study.

The present study involved a detailed post hoc comparison of the efficacy and safety of lipid-lowering therapy in elderly hypercholesterolemic patients from the Fukuoka Atherosclerosis Trial (FAST). The FAST cohort of 246 hypercholesterolemic patients included 76 patients who were (75 years old. Patients were randomized to receive probucol (500 mg/day) or pravastatin (10 mg/day) therapy, or to a control group (diet alone), and then were followed for 2 years. In patients > or = 75 years old, either probucol or pravastatin achieved a significant reduction of carotid intima-media thickness (IMT). In patients <75 years old, lipid-lowering therapy also achieved a significant reduction of IMT. In patients > or = 75 years old receiving probucol, the relative risk (95% confidence interval) of all-cause mortality was 0.15 (0.02 to 1.28) and that for major coronary events was 0.12 (0.02 to 1.04). In conclusion, probucol reduced the incidence of cardiovascular disease in elderly hypercholesterolemic patients as well as younger patients.

Adult↗
PubMed2006

[Effect of probucol and losartan on growth factors after balloon angioplasty in rabbits].

OBJECTIVE: To investigate the effect of probucol and losartan on the prevention of restenosis after balloon angioplasty in hypercholesterolaemic rabbits, and to examine the expression of growth factors. METHODS: Forty male New Zealand white rabbits were randomly divided into high cholesterol diet group, probucol group, losartan group and combined drugs group. After one week of diet, all rabbits were injured on iliac arteries with balloon. Four weeks after the injury, the morphology of the iliac arteries of the rabbits were observed, and the insulin-like growth factor-I receptor (IGF-IR) and vascular endothelial growth factor (VEGF) were examined by immunohistochemical methods. RESULTS: Compared with the high cholesterol diet group, the lumen areas of the probucol group, losartan group and combined drugs group were larger (P < 0.01), the intimal areas were smaller (P < 0.05), and the expression of IGF-IR and VEGF significantly decreased (P < 0.05). There was no statistically significant difference among the three groups. CONCLUSION: Probucol and losartan can prevent the restenosis of rabbits' iliac artery from balloon injury, and inhibit the expression of IGF-IR and VEGF. There is no statistical difference between combined drugs and single drug administration.

Angioplasty, Balloon↗
PubMed2006

[Beneficial effects of probucol on endothelial function in patients with acute coronary syndrome].

OBJECTIVE: The study investigate the antioxidant probucol on endothelial function in patients with acute coronary syndrome (ACS). METHODS: A total of 49 ACS patients randomly received standard therapy plus probucol (P, n = 24) or standard therapy (C, n = 25). Plasma oxidized low-density lipoprotein (ox-LDL), nitric oxide (NO) and circulating endothelial cells (CEC) were measured. The brachial arterial hyperemia-induced flow mediated dilation (FMD) and sublingual nitroglycerin (NTG) mediated vasodilatations were measured by high resolution ultrasound. These variables were analyzed before and after 3 months therapy. RESULTS: Plasma NO and FMD was significantly increased after 3 months therapy than before therapy [(80.46 +/- 10.24) micromol/Lvs (48.46 +/- 12.24) micromol/L, P < 0.01; (13.46 +/- 1.20)% vs (7.45 +/- 1.02)%, P < 0.05, respectively], while the number of CEC and ox-LDL were significantly decreased (P < 0.01) in P group. These values were similar before and after 3 months in C group. The linear correlation analysis showed that plasma ox-LDL negatively correlated with NO (r = -0.574, P < 0.01) and FMD (r = -0.517, P < 0.01) and positively correlated with CEC (r = 0.385, P < 0.01) in patients received 3 months probucol therapy. CONCLUSIONS: Chronic antioxidant probucol therapy could improve endothelial function in patients with ACS.

Adult↗