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PubMed2005

Effect of anti-oxidant (carvedilol and probucol) loaded stents in a porcine coronary restenosis model.

BACKGROUND: The long-term clinical efficacy of intracoronary stenting is limited by restenosis and delivery by the stent of agents inhibiting cell cycle progression should prevent in-stent neointimal hyperplasia. Carvedilol is an antioxidant that inhibits smooth muscle cell proliferation and migration, whereas probucol is a vascular protectant and reduces stent restenosis by improving the lumen dimension at the stent placement site. METHODS AND RESULTS: BiodivYsio phosphorylcholine-coated stents were dip-coated with carvedilol (5 mg/ml) or probucol (50 mg/ml) by immersion in respective methanol solutions. Twenty-four stents (carvedilol=8, probucol=8, control=8) were placed in 12 pigs and histopathologic analysis was done 4 weeks later. Histomorphometry of the carvedilol-coated stent group compared with the control groups showed that the neointimal area decreased by 42% (1.12+/-0.55 mm2 in the carvedilol group vs 1.92+/-0.52 mm2 in the control, p=0.004) and the lumen area increased by 20% (5.15+/-0.90 mm2 vs 4.17+/-0.87 mm2, p=0.008), resulting in a 43% reduction of the percent area stenosis (18.22+/-9.6% vs 31.9+/-9.2%, p=0.002). In the probucol-coated stent group, the lumen area, neointimal area, and %area stenosis did not different significantly from the control group. There were 7.7+/-2.97% proliferating nuclear cell antigen-positive cells in the carvedilol-coated stent group compared with 17.8+/-1.45% in the control group (p=0.0001) and 15.9+/-1.91% in the probucol group (vs control, p=NS). CONCLUSIONS: The carvedilol-coated stent, but not the probucol-coated one, inhibited neointimal hyperplasia in a porcine stent restenosis model.

Animals↗
PubMed1986

Effect of probucol, pantethine and their combinations on serum lipoprotein metabolism and on the incidence of atheromatous lesions in the rabbit.

Effect of probucol, pantethine and their combinations on serum lipoprotein metabolism and on the incidence of atheromatous lesions in aorta and coronary artery was studied in cholesterol-fed rabbits. Probucol treatment (0.5% in diet) resulted in reducing HDL cholesterol and serum apo A-I levels significantly, while pantethine treatment (0.25%-0.75% in diet) tended to increase HDL cholesterol and serum apo A-I levels. Combined treatment with these two drugs showed a significant prevention in the reduction of HDL cholesterol and serum apo A-I levels by probucol alone. Probucol or pantethine treatment reduced effectively (V) LDL cholesterol and serum apo B levels, and these effects were accelerated additively when the two drugs were given concurrently. Atheromatous lesions in aorta and coronary artery in cholesterol-fed rabbits were prevented by the treatment with probucol (0.5% in diet) or pantethine (0.75% in diet) for 24 weeks. The combined treatment with these two drugs showed more marked prevention than either drug alone. From these findings, it is concluded that the combined treatment of probucol with pantethine is effective for improvement of serum lipoprotein disorders and for prevention of the incidence of atheromatous lesions in aorta and coronary artery in cholesterol-fed rabbits.

Animals↗
PubMed2004

Effect of probucol on neointimal thickening in a stent porcine restenosis model.

Restenosis after stent deployment remains a major clinical problem. Antioxidants have been proposed as a promising strategy against restenosis. We tested the antioxidant probucol for its efficacy against neointimal hyperplasia in porcine coronary arteries after stent implantation. Probucol was then tested in vivo in 8 coronary arteries of 4 pigs (1000 mg/day orally beginning 7 days before stenting) and was compared to placebo (10 coronary arteries, 5 pigs) 28 days after stenting. Quantitative intravascular ultrasound (IVUS) revealed 38.8 +/- 4.0 versus 40.1 +/- 3.0% area stenosis in the probucol versus control group. Histopathologic assessment showed that probucol had no beneficial effect on inhibiting the neointimal proliferative response in stent lesions compared to placebo (2.35 +/- 0.26 versus 2.88 +/- 0.25 mm(2)), despite similar injury scores (1.20 +/- 0.12 versus 1.28 +/- 0.14). An edge segment (axially 2-mm proximal to the stent margins) was assessed by IVUS. Remodeling index, which is a good marker of constrictive remodeling, was defined by the ratio of the vessel area in the lesion site (stent edge) to the vessel area in the proximal reference site (6-mm proximal to the stent margins). The remodeling index was significantly larger in the probucol group that in the placebo group (1.18 +/- 0.10 versus 0.90 +/- 0.06, P = 0.0012). In conclusion, probucol reduced constrictive remodeling at the edge of the implant but did not inhibit the tissue response within the stent.

Animals↗
PubMed2004

Effects of probucol versus aspirin and versus brachytherapy on restenosis after femoropopliteal angioplasty: the PAB randomized multicenter trial.

PURPOSE: To evaluate the effect of probucol and/or of endovascular brachytherapy (EVBT) on restenosis after percutaneous transluminal angioplasty (PTA) of femoropopliteal arteries. METHODS: A total of 335 patients (206 men; mean age 72+/-9 years) with intermittent claudication were randomized according to a 2x2 factorial design to 1 of the 4 groups: probucol, placebo, EVBT, and EVBT+probucol. Probucol (1 g/d) or placebo were given in double-blinded fashion 1 month before and for 6 months after PTA. Gamma irradiation (192Iridium, 14 Gy, 5-mm reference depth) was randomly applied in an unblinded manner from a noncentered endoluminal catheter. All patients received aspirin (100 mg/d). Primary endpoint was restenosis (>50% diameter reduction) detected by duplex ultrasound 6 months after PTA. Secondary endpoints included clinical and hemodynamic assessment. RESULTS: Restenosis in patients undergoing EVBT was 17% (23/133) versus 35% (50/142) in patients without EVBT (p<0.001); in patients treated with probucol versus placebo, the rates were 23% (31/135) and 30% (43/140, p<0.001). Three quarters (77%, 102/133) of patients were free of claudication after EVBT therapy versus 61% (87/142) without EVBT (p<0.05). Need for target vessel revascularization was 6% (8/133) with EVBT versus 14% (20/142) without EVBT (p<0.01). Late thrombotic occlusions occurred in 4% (6/133), exclusively in patients treated with EVBT after stent implantation. CONCLUSIONS: Endovascular brachytherapy significantly reduces restenosis, improves symptoms, and reduces reinterventions after PTA of femoropopliteal arteries. Probucol reduces restenosis but has no additive effect when combined with brachytherapy.

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PubMed1999

Mechanisms of beneficial effects of probucol in adriamycin cardiomyopathy.

Probucol, a lipid-lowering drug, has been shown to offer protection against adriamycin-induced cardiomyopathy. In order to define the mechanism of this protection, we examined changes in antioxidants and lipid peroxidation in hearts as well as lipids in hearts and plasma from rats treated with either adriamycin or adriamycin and probucol with appropriate controls. Any potential free radical quenching as well as growth inhibitory effects of probucol were also examined using Chinese hamster ovary (CHO) cells in culture. In animal model, adriamycin caused a significant depression in glutathione peroxidase and increased plasma and cardiac lipids as well as lipid peroxidation. Probucol treatment modulated adriamycin-induced cardiomyopathic changes and increased glutathione peroxidase and superoxide dismutase activities. In the presence of adriamycin under hypoxic conditions, formation of adriamycin semiquinone radical was detected by ESR. The cell growth in these cultures was also inhibited by adriamycin in a dose-dependent manner. Probucol had no effect on adriamycin-induced growth inhibition as well as formation of semiquinone radicals. It is proposed that probucol protection against adriamycin cardiomyopathy is mediated by increased antioxidants and lipid-lowering without any effect on free radical production.

Animals↗
PubMed2000

[Effect of probucol on cardiac electrophysiology in anginal patients with hyperlipidemia and diabetes mellitus type II].

AIM: To investigate effects of a hypolipidemic drug with antioxidant action probucol on electrophysiological parameters of the heart in patients with ischemic heart disease (IHD), stable angina (SA), hyperlipoproteinemia (HLP) and diabetes mellitus (DM) type II. MATERIAL AND METHODS: The trial entered 48 IHD patients (11 males and 37 females) aged 47-73 years with SA functional class II and III (39.4 and 60.6%, respectively), secondary HLP (mean group total cholesterol 6.5 +/- 0.17 mmol/l), DM type II (mean fast glucose 7.7 +/- 1.8 mmol/l) and obesity (mean body mass index 29.7 +/- 2.2 kg/m2). Transesophageal pacing of the left ventricle was conducted in all the patients before probucol treatment and 18 hours, 1 month and 3 months after it. RESULTS: Probucol (a single dose 500 mg) significantly reduced the time of recovery of sinus node function. Three months of probucol administration in a dose 1000 mg/day enhanced pacemaker activity of the sinus node. CONCLUSION: In addition to a beneficial effect on lipid metabolism (a decrease of total cholesterol by 13.4%, LDLP cholesterol by 15.2%, triglycerides by 15.8%), probucol enhanced pacemaker activity of the sinus node. This makes it perspective in patients with sinus node dysfunction. Caution is necessary in prescribing probucol to patients with supraventricular tachycardia caused by re-entry mechanism.

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PubMed2002

[Effect of probucol on the blood concentration of cyclosporin A in patients with nephrotic syndrome: a case study with a microemulsion formulation (Neoral)].

Cyclosporin A(CyA) is used frequently in the treatment of steroid-resistant or recurrent cases with nephrotic syndrome. Recently, a new microemulsion formulation of CyA(Neoral) has been developed and used preferably because of a more stable bioavailability than an oily formulation(Sandimmun). Nephrotic syndrome accompanies hyperlipidemia, and probucol is used in cases showing inadequate effects or some adverse reactions under therapy with HMG-CoA reductase inhibitors. We reported previously that combined use of probucol caused a decrease in blood concentrations of CyA to about half of those without probucol. In the present study, we evaluated the influence of probucol on the blood concentrations of CyA in patients with nephrotic syndrome following Neoral. Coadministration of Neoral and probucol decreased the blood concentrations of CyA to approximately 75% of the levels before combined use. The change of blood CyA concentrations appeared to be smaller compared to those in cases with Sandimmun. Based on the present findings, we suggest that Neoral should be used preferentially instead of Sandimmun when the concomitant use of probucol is required, and that optimal dose adjustment of CyA is needed by frequent monitoring of CyA blood concentrations.

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PubMedDate not supplied

A controlled trial of pravastatin vs probucol in the treatment of primary hypercholesterolemia.

We compared the safety, tolerability and efficacy of the HMGCoA reductase inhibitor pravastatin and probucol in the treatment of patients with primary hypercholesterolemia using an active, drug controlled, double blind, randomized, double placebo design. Patients were included if LDL-C levels after a minimum of six weeks on an AHA phase I diet were greater than 150 mg/dL and triglycerides were less than 350 mg/dL. Included patients were randomly assigned to either pravastatin 40 mg pm or probucol 500 mg bi. They also received matching placebos for each drug. The active drug period lasted 16 weeks, during which the patients were seen at 4, 8, 12 and 16 weeks after baseline. There were no significant differences in baseline values between both treatment groups. Significantly lower values of total cholesterol and LDL-C were observed with pravastatin as compared to probucol. While a non significant increase of HDL-C was observed with pravastatin, a remarkable and statistically significant decrease was observed with probucol. A large dispersion of triglycerides levels was observed with both drugs and no statistically significant changes were demonstrated. Both pravastatin and probucol were well tolerated: only minimal clinical and laboratory changes, not considered to have been drug-related, were observed. No changes, considered drug-related, were observed in the cristalline lens. This study shows an overall superiority of pravastatin over probucol with significant larger decreases of total cholesterol and LDL-C and a better effect on HDL-C.

Double-Blind Method↗
PubMed1991

Effect of probucol on blood cholesterol and basal and lovastatin-induced 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in mice.

The drug probucol is known to reduce levels of blood cholesterol and to have antioxidant effects on lipoproteins that may alter their metabolism. While studying probucol feeding in mice, we observed that the drug lowered total hepatic, but not gut, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase activities during the diurnal cycle. Hepatic fatty acyl:cholesterol acyl transferase activity and cholesterol content were not measurably affected by probucol. Probucol also abolished the induction of HMG CoA reductase activity that resulted from feeding of lovastatin, when activity was measured in microsomes washed free of drugs. These effects are consistent with previous reports that probucol increases fractional clearance of lipoprotein cholesterol by the liver. The findings raise the possibility that some patients with hypercholesterolemia may benefit from combined therapy with lovastatin plus probucol.

Animals↗
PubMed1991

Probucol prevents oxidative injury to endothelial cells.

We evaluated the effect of the antioxidant, probucol, on the cytotoxic effects of oxidized low density lipoprotein (OX-LDL) or of cumene hydroperoxide (CumOOH) on cultured bovine endothelial cells (EC). The addition of CumOOH to EC caused the release of lactate dehydrogenase and the accumulation of thiobarbituric acid-reacting substances (TBARS), effects that were protected against by preincubation with either probucol or tocopherol. Similarly, preincubation of EC with those antioxidants protected against OX-LDL toxicity and the accumulation of TBARS. The content of probucol in EC measured by high performance liquid chromatography was directly correlated with the extent of protection against OX-LDL toxicity. We also found that treatment of EC with serum from patients receiving treatment with probucol resulted in the detection of probucol in the cells. We conclude that probucol is transported and incorporated into EC membranes to act as a radical-trapping antioxidant, protecting the EC against oxidative stress. Our results also indicate that lipid peroxidation in cellular membranes involves cell injury inflicted by OX-LDL.

Animals↗
PubMed1984

Influence of probucol on cholesterol and lipoprotein metabolism in man.

The mechanisms for the hypocholesterolemic action of probucol were examined in 17 patients with various levels of plasma cholesterol and triglycerides (TG). All the patients were studied on a metabolic ward. The first period of 6 weeks was for control. Thereafter, probucol was started, and after 2-6 months of drug treatment, the patients were readmitted for another 6-week period for a repeat study. During treatment with probucol, the cholesterol decreased in total plasma by an average of 12%, in low density lipoproteins (LDL) by 11%, and in high density lipoproteins (HDL) by 9%. The TG in total plasma and in very low density lipoproteins (VLDL) remained unchanged during probucol treatment. Turnover of low density lipoprotein apoprotein (apoLDL) was estimated following injection of 125I-labeled apoLDL. Probucol increased the fractional catabolic rate (FCR) for apoLDL by an average of 23%, but did not change apoLDL synthesis. The drug produced no consistent changes in fecal excretion of cholesterol (neutral steroids) and bile acids, in cholesterol absorption, in lipid composition of gallbladder bile, in biliary secretion of cholesterol and bile acids, or in the activities of lipoprotein lipase and hepatic lipase. These data show that probucol lowers LDL by increasing its catabolism. This effect appears to be independent of any changes in metabolism of cholesterol or bile acids.

Adult↗
PubMed1994

[Probucol treatment of hyperlipidemia].

Probucol lowers total and LDL cholesterol levels, and also lowers HDL cholesterol levels. Probucol is able to lower cholesterol levels in homozygous patients with familial hypercholesterolemia as well as in heterozygous patients. In heterozygous familial hypercholesterolemia, probucol lowered total cholesterol levels by 22%, LDL-cholesterol levels by 17%, and HDL-cholesterol levels by 40%, respectively. The lowering HDL cholesterol levels by probucol may reflect increased reverse cholesterol transport. Probucol increases cholesteryl ester transfer protein concentration, and diminishes HDL particle size. Probucol has been reported to retard and even regress atherosclerosis in animal models and to diminish tendinous xanthomas in man. Its lowering LDL-cholesterol levels, activation of reverse cholesterol transport process, and antioxidant effects may cause an antiatherogenic action.

Carrier Proteins↗
PubMed1994

[The effect of probucol and its new analog on cholesterol and lipoprotein metabolism in rabbit cultured hepatocytes].

The effects of the well-known hypolipidemic drug probucol and its new analog K5 on cholesterol and bile acid metabolism in cultured rabbit hepatocytes have been studied. Probucol (100 microM) inhibited by 24-28% the [2-14C]acetate incorporation into cholesterol. In contrast, the probucol analog K5 used at the same concentration did not affect the cholesterol synthesis but reduced by 44-55% the VLDL-apolipoprotein B (apo-B) secretion into the culture medium. Neither of the drugs influenced the [14C]leucine incorporation into cellular proteins. In addition, probucol (100 microM) stimulated by 29-64% the specific uptake of 125I-labelled LDL into the cells and increased the glycocholic and taurocholic acid synthesis by 29-93% and 45-77%, respectively, the total bile acid synthesis from [4-14C]cholesterol synthesis being increased by 25-36%. K5 had no appreciable effect on this process. The data obtained suggest that the enhanced specific uptake of LDL into hepatocytes as well as the slight inhibition of cholesterol synthesis and stimulation of cholesterol conversion into bile acids can, at least partly, account for the hypolipodemic effect of probucol. The observed reduction in the secretion of the hepatocyte apo-B containing lipoprotein by the probucol analog K5 suggests it to be a potentially hypolipodemic compound.

Animals↗
PubMed1993

Adipose tissue cholesteryl ester transfer protein mRNA in response to probucol treatment: cholesterol and species dependence.

Probucol treatment results in an increase in plasma concentrations of cholesteryl ester transfer protein (CETP) which may account, in part, for the effects of this agent on plasma concentrations of HDL cholesterol. We have examined the mechanism by which probucol increases plasma CETP and have determined the associated changes in the plasma distribution of high density lipoprotein (HDL) particles. Studies were carried out in nine hypercholesterolemic subjects and five normal volunteers. Probucol treatment resulted in a 31% increase in plasma concentrations of CETP and a 23% decrease in HDL cholesterol (P < 0.01). The plasma concentration of LpA-I decreased by 40% (P < 0.01) whereas no change occurred in the LpA-I/A-II subclass of HDL. Plasma CETP increased significantly by 1 week of therapy and remained stable over 10 to 14 weeks of therapy. In spite of the significant increase in plasma concentrations of CETP, the abundance of CETP mRNA in peripheral adipose tissue decreased markedly (P < 0.001). These results suggested that probucol may alter CETP synthesis in another tissue such as liver or, alternatively, may have other effects on CETP secretion into or catabolism out of the plasma pool. Further studies were carried out in hamsters because, in this species, adipose tissue is a major site and liver is a negligible site for CETP synthesis. Hamsters were fed probucol with or without dietary cholesterol because this species was previously shown to respond to dietary cholesterol with an increase in adipose tissue mRNA levels and in plasma CETP concentrations, thus providing the opportunity to determine whether probucol would alter these parameters independently of the dietary cholesterol effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1993

Long-term administration of probucol and QTc interval prolongation.

Electrocardiographic QTc intervals were measured in twenty-one hypercholesterolemic patients before and after long-term probucol (500-1,000 mg/day for 30 months) treatment. Probucol reduced serum total cholesterol (TC), triglyceride (TG), and high density lipoprotein-cholesterol (HDL-C). Mean QTc interval prolongation after probucol was 17 msec. A positive correlation was found between the change in QTc interval after probucol (delta QTc) and the total amount of probucol administered. delta QTc was negatively correlated to the pre-treatment QTc interval. No correlation was observed between serum probucol concentrations and delta QTc. Neither clinical evidence of cardiotoxicity nor critical arrhythmias were noted during the treatment period.

Aged↗
PubMed1996

Effect of probucol on the cytological and biochemical changes induced by adriamycin in Swiss albino mice.

Probucol [(4,4'-(-(isopropylidenedithio) bis (2,6-di-t-butylphenol)], a hypolipidemic drug, was evaluated for its effects on the clastogenic activity of ADM in Swiss albino mice. Male mice were treated i.p. with different doses (25, 50 and 100 mg/kg, body weight/day) of probucol for 7 days. Some of the mice in each dose group of probucol and those in the positive control group were injected i.p. with Adriamycin (ADM, 8 mg/kg, body weight) and killed after 24 hr. Femoral cells of mice were collected and studied for the frequency of micronuclei and the ratio of polychromatic erythrocytes to Normochromatic erythrocytes. Furthermore, proteins, DNA, RNA, Malondialdehyde (MDA) and non-protein sulfhydryl (NP-SH) levels were determined in the hepatic cells. Probucol treatment failed to induce any significant clastogenic, cytotoxic and biochemical changes. However, pre-treatment with probucol was found to reduce the ADM-induced micronuclei without any alteration in its cytotoxicity. The DNA, RNA, proteins and NP-SH levels in the hepatic cells of these animals were increased and the MDA concentrations were reduced. The inhibition of ADM-induced clastogenicity by probucol may be attributed to its lipids lowering, iron chelating, free radical scavenging and topoisomerase-II-depleting action.

Animals↗
PubMed1997

Effect of lipid peroxidation products and antioxidants on the formation of probucol radical in low density lipoproteins.

Effects of antioxidants and products of lipid peroxidation on hemin-induced formation of probucol radical in low density lipoproteins (LDL) from human plasma were studied by EPR-spectroscopy. Suppression of lipid peroxidation in LDL by probucol and other antioxidants (ascorbate, 6-O-palmitoylascorbate, and ubiquinol-10) prevents the formation of probucol radical. However, ubiquinol-10 stimulates the formation of probucol radical during advanced stages of LDL oxidation. Because the concentration of probucol radical depends on lipid hydroperoxide contents in LDL, the interaction of lipid hydroperoxides with hemin can result in the formation of probucol-oxidizing radical intermediates and ubiquinol-10 is a mediator of this process.

Anticholesteremic Agents↗
PubMed1997

[Influence of low high-density lipoprotein cholesterolemia induced by probucol on the progression of coronary atherosclerosis].

The influence of probucol-induced low high-density lipoprotein (HDL) cholesterolemia on the progression of coronary atherosclerosis was studied in 320 patients with angina pectoris or myocardial infarction, 32 patients with probucol 500 mg/day, 288 patients without probucol, who underwent follow-up angiography at intervals of at least 2 years. The 288 patients were divided into two groups depending on the serum HDL-cholesterol (HDL-C) level at the follow-up angiography: the low HDL-C group had a serum HDL-C level below 40 mg/dl (152 patients) and the control group had 40 mg/dl or above (136 patients). Coronary sclerosis index was defined as the total products of coronary scores (0-6) by segments according to the American Heart Association reporting system in the branches without angioplasty and was compared between the three groups. In the probucol group, serum HDL-C level was significantly reduced from 43.9 +/- 10.6 (at baseline) to 31.1 +/- 7.6 mg/dl (at follow-up, p < 0.01) and was lower than that in the other two groups (low HDL-C group 33.1 +/- 5.0 mg/dl, p < 0.07; control group 52.6 +/- 9.8 mg/dl, p < 0.01). Coronary sclerosis index was most increased in the low HDL-C group (8.3 +/- 5.4-->11.9 +/- 6.1, p < 0.01), whereas there was no significant change in the probucol group (7.2 +/- 5.9-->9.1 +/- 6.8, p = 0.24). Our results showed that treatment with probucol inhibits the progression of coronary atherosclerosis despite the decrease in HDL-C level. One possible reason may be remarkable improvement in the other lipid factors, especially the low-density lipoprotein cholesterol level (165.7 +/- 33.9-->123.7 +/- 29.0 mg/dl, p < 0.01).

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