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PubMed1994

Vitamin E or probucol as donors for oxidation of human low-density lipoprotein by peroxidases/H2O2.

Horseradish peroxidase or myeloperoxidase and H2O2 oxidize human low-density lipoprotein (LDL) in the presence or absence of a xenobiotic donor without an essential lag phase as revealed by an increase in the absorption at 234 nm. In the latter case, natural antioxidants like vitamin E and congeners serve as donor; radical formation by the action of peroxidase has been described before. Otherwise trolox C or probucol have donor function in this system. After oxidation by peroxidase/H2O2 LDL showed the expected reduced antioxidant capacity against vitamin-E-consuming radicals.

Antioxidants↗
PubMed1995

Probucol protects against adriamycin cardiomyopathy without interfering with its antitumor effect.

BACKGROUND: The usefulness of adriamycin (ADR), a potent antitumor antibiotic, is limited by the development of life-threatening cardiomyopathy and congestive heart failure. Subcellular changes leading to heart failure are suggested to be mediated by a drug-induced increase in free radicals and lipid peroxidation. In an earlier study, concurrent treatment with probucol (PROB), a lipid-lowering drug with strong antioxidant properties, was shown to offer only partial protection against ADR cardiomyopathy. The present study had two aims: to determine whether this protective effect can be improved further by extended treatment with PROB, and to determine whether PROB affects the antitumor properties of ADR. METHODS AND RESULTS: ADR (cumulative dose, 15 mg/kg body wt) was administered in rats in six equal injections (IP) over a period of 2 weeks. Three weeks after the end treatment, cardiomyopathy and congestive heart failure were characterized by ascites, congested liver, depressed cardiac function, elevated left ventricular end-diastolic pressure, and myocardial cell damage. Myocardial glutathione peroxidase (GSHPx) activity was decreased and lipid peroxidation was increased. Administration of PROB (cumulative dose, 120 mg/kg body wt) in 12 equal injections (IP), before and concurrent with ADR, completely prevented these cardiomyopathic changes, normalized left ventricular function, lowered mortality, and eliminated ascites. Treatment with PROB was also accompanied by an increase in myocardial GSHPx and superoxide dismutase activities with a concomitant decrease in lipid peroxidation. Tumor regression in syngeneic DBA/2 mice inoculated with L5178Y-F9 lymphoma cells in the ADR+PROB group was significant and comparable to the ADR group. CONCLUSIONS: These data show for the first time that PROB can provide complete protection against ADR cardiomyopathy without interfering with antitumor properties of the drug. This protective effect of PROB may be related to the maintenance of the antioxidant status of the heart.

Animals↗
PubMed2002

The effect of probucol on atherosclerosis in streptozotocin-induced diabetic-hyperlipidemic APA hamsters in different stages of atherosclerosis.

We investigated the effect of probucol (PB) on atherosclerosis in streptozotocin (SZ)-induced diabetic-hyperlipidemic APA hamsters in three different stages, the early, middle and late stages of atherosclerosis. Male APA hamsters were injected intraperitoneally with SZ or vehicle alone (citrate buffer; CB) as a control at the age of 8 weeks. At 6 weeks after injection (WAI) of SZ or CB (the early stage), 14 WAI (the middle stage) and 26 WAI (the late stage), animals were assigned to PB treated- or non-treated groups (CBPB, SZPB, CB, SZ). After 8 weeks of PB administration with diet, the aorta was taken from each animal for assessment of atheromatous lesions and blood samples were subjected to serum biochemical analysis and the measurement of blood lipid peroxide (LPO). In the middle stage, PB treatment significantly decreased serum total cholesterol level, slightly decreased LPO, and also tended to reduce the lesion area, although no statistical difference was seen. There was no marked effect of PB treatment in the early and late stages. These findings suggest that single use of PB has little effect on atherosclerosis of a hyperglycemia-hyperlipidemia animal model.

Animals↗
PubMed2003

Protective effects of probucol treatment on pancreatic beta-cell function of SZ-induced diabetic APA hamsters.

To clarify whether oxidative stress is involved in the pathogenesis of islet lesions of diabetic animals, the effects of probucol (PB), an antioxidant and anti-hyperlipidemia agent, on the islets in streptozotocin (SZ)-induced diabetic APA hamsters in the acute and chronic phases of diabetes were examined. The control (CB group) and diabetic (SZ group) hamsters were treated with PB (1% in the diet) for 4 weeks from several days after SZ injection as the acute diabetic group, or 8 weeks from 6 weeks after SZ injection as the chronic diabetic group. Glucose tolerance test revealed that PB treatment decreased the high serum glucose level after glucose injection in the diabetic APA hamsters in the acute diabetic phase. Immunohistochemistry revealed that PB treatment significantly increased the percentage of the insulin positive area in the diabetic hamsters pancreata in both the acute and chronic phases. In addition, 4-hydroxy-2-nonenal (4HNE; an oxidative stress marker) positive cells were slightly reduced by PB treatment in the acute diabetic phase. Double-immunostaining for insulin and PCNA (proliferating cell nuclear antigen) revealed that elevation of the percentage of insulin and PCNA double-positive cells against insulin-positive cells was seen in the islets of PB-treated diabetic hamsters, but the difference was not significant compared with untreated diabetic hamsters (p = 0.07). In semi-quantitative RT-PCR, the expression of two genes, Reg (Regenerating gene) and INGAP (islet neogenesis associated protein), in the diabetic APA hamsters was significantly increased compared to the control groups in both diabetic phases. PB treatment significantly reduced Reg expression in the chronic diabetic phase. These data suggest that PB treatment in SZ-injected diabetic hamsters partially restored beta-cell function through acting as an antioxidant and induced higher expression of Reg and INGAP genes in the pancreas of hamsters.

Aldehydes↗
PubMed1998

Probucol inhibits oxidized-low density lipoprotein-induced adhesion of monocytes to endothelial cells by reducing P-selectin synthesis in vitro.

Probucol (PBC) is an unique antiatherogenic drug producing its effect by antioxidant action rather than hypolipidaemic effect. However, the exact mechanism of its antiatherogenic effect is unclear. Therefore we investigated the PBC effects on the adhesion of monocytes to endothelial cells, an early event in atherogenesis. Monocyte adhesion to cultured pig aortic endothelial cells (EC) was induced by oxidized low density lipoprotein (Ox-LDL). To elucidate the mechanisms of the inhibition on adhesion, PBC effects on the Ox-LDL-induced expression of P-selectin, on the synthesis of von Willebrand factor (vWF) and prostacyclin (PGI2) were examined. The results showed that Ox-LDL enhanced the adhesion of monocytes to EC in a concentration-dependent and time-related manner. PBC 25, 50 and 75 micromol/L inhibited the Ox-LDL-induced adhesion index from 37.3% to 19.7, 16.6 and 14.6% respectively (p all < 0.05), and inhibited the Ox-LDL-induced expression of P-selectin from 293.0 ng/ml to 180.0, 132.9 and 132.6 ng/ml respectively. Furthermore, PBC significantly attenuated the Ox-LDL-impaired synthesis of PGI2 and vWF. These results indicate that PBC may provide a new approach in the prevention of atherosclerosis (AS) by intervention of monocyte adhesion to EC. In conclusion, PBC inhibits the Ox-LDL-induced adhesion of monocytes to EC. This effect is associated with the inhibition of the Ox-LDL-induced expression of P-selectin and the protection on the synthesis of PGI2.

Animals↗
PubMedDate not supplied

[The reduction of dyslipidemia and oxidative stress in experimental diabetes mellitus treated with probucol].

There is considerable controversy regarding the role of oxidative stress in development of macro and microangiopathy in diabetes--a free radical associated disease. Increasing the oxidative glycosylation of plasma lipoproteins by reactive oxygen species (ROS) and reduction of scavenging system under conditions of hyperglycemia may accelerate diabetic vascular disease. We have investigated the effect of Probucol (P) a drug with strong lipophilic radical scavenger action, on plasma lipoproteins variations, malondialdehid (MDA) production, atherosclerotic index (total Cholesterol/HDL Cholesterol), glycemia and glucosuria in Wistar male alloxanic rats with/without enriched cholesterol diet. The inhibition of lipoproteins oxidation, resulting from diminishing MDA, in our study, would furthermore delay the absorption and penetration of lipids and lipoproteins into deeper vascular layers and thereby reduce the risk of atherosclerotic vascular lesion. Our result suggest that treatment with inhibitors of lipoproteins oxidation may reduce the risk of cardiovascular complications in diabetes.

Animals↗
PubMedDate not supplied

[Antioxidant effect of novel probucol analogs and their combinations with alpha-tocopherol].

The antioxidant and antiradical activities of sulfur containing phenols which are analogues of probucol in comparison with alpha-tocopherol and BHT were tested using initiated methyl oleate oxidation model. The antioxidant effect linearly increased with increasing concentration of phenols. The ability of investigated phenols to destroy and reduced accumulation of hydroperoxides is revealed. The combined inhibitory effects of composition most effective researched antioxidant--CO-3--with alpha-tocopherol for the first time are described.

Antioxidants↗
PubMedDate not supplied

Evaluation of alpha-tocopherol, probucol and ascorbic acid as suppressors of digoxin induced lipid peroxidation.

Protective effects of three free radical scavengers, tocopherol (TOC), probucol (PR) and ascorbic acid (AA), on cardiotonic glycoside digoxin (DIG) induced lipid peroxidation in goat liver homogenate, have been studied by measuring malondialdehyde and glutathione contents as indicator parameters. The level of reduced glutathione decreased vis-a-vis malondialdehyde content increased in the drug treated samples in comparison with the controls. This suggests that DIG may have significant lipid peroxidation induction capacity. Considering lipid peroxidation as a toxicity mediating process, this may be related to the toxic potential of the drug. When the liver homogenate samples were incubated with antioxidant (TOC/PR/AA) in conjunction with the drug (DIG), lipid peroxidation was suppressed as indicated by increased level of reduced glutathione and decreased level of malondialdehyde in comparison with those of drug treated samples. This indicates that TOC, PR and AA may have considerable suppressive action on DIG induced lipid peroxidation. Thus, these antioxidants merit further extensive study to explore their potential in reducing DIG induced toxicity that may be mediated by free radical mediated process.

Animals↗
PubMed2002

Probucol inhibits oxidized-low density lipoprotein-induced adhesion of monocytes to endothelial cells in vitro.

AIM: To investigate the mechanism by which probucol (PBC) affected adhesion of monocytes to human umbilical vein endothelial cells (HUVEC). METHODS: Effects of PBC on expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, a nd E-selectin in human umbilical vein endothelial cells were examined. Moreover, the inhibitory effect of PBC were compared with that of monoclonal antibodies (mAbs) to ICAM-1, VCAM-1, P-selectin, and E-select in on adhesion induced by oxidized-low density lipoprotein(Ox-LDL). RESULTS: PBC at 10 to 80 micromol/L inhibited Ox-LD L-induced adhesion index from 16.7 % to 7.0 % (P < 0.01) and Ox-LDL-induced expression of ICAM-1 (75 %) and P-selectin (72 %). mAbs to ICAM -1 or P-selectin, when used alone, could only slightly reduce the adhesion of monocyte to HUVEC. When both monoclonal antibodies were used in combination, the adhesion was markedly inhibited from 16.7 % to 11.3 % (P < 0.01), but the effect was still weaker than that of PBC (average 9.3 %). CONCLUSION: PBC exerts its inhibitory effect on the adhesion of monocyte to HUVEC by inhibiting the expression of ICAM-1 and P-selectin.

Anticholesteremic Agents↗
PubMed1991

[Effects of lovastatin and probucol on lipoprotein fractions in patients with hypercholesterolemia. A Brazilian multicenter study].

PURPOSE: The changes in lipoproteins induced by lovastatin (L) and probucol (P) were compared in patients with primary hypercholesterolemia. METHODS: After a six-week period of screening, during which patients were maintained on lipid-lowering diet, they were administered placebo for four weeks. Those patients, whose total cholesterol (TC) remained above 250 mg/dl were eligible for active treatment. Thirty-one patients were administered L and P for 12 weeks. The initial dosage of L was 20 mg daily and it was titrated up to 40 mg daily at the end of the fifth week of treatment, whenever total cholesterol levels remained above 200 mg/dl; P was administered at a dosage of 500 mg b.i.d. through 12 weeks. Lipid analyses (TC, triglycerides-Tg, high-density cholesterol (HDL-C) non HDL cholesterol, low-density cholesterol (LDL-C) very low-density cholesterol (VLDL-C) and the ratios CT/HDL-C and laboratory safety measurements were performed during placebo period and at the end of the 5th and 12th weeks of active treatment. Clinical and ophthalmological evaluations were performed and eventual adverse reactions were recorded on different occasions. RESULTS: 1) L induced decrease of TC, LDL-C/HDL-C of 27.9, 34.1, 32.2, 30.9 and 36.5% respectively. These reductions were significantly more pronounced than those induced by P (21.7, 23.8, 24.5, 11.3 and 13.4% respectively); 2) L induced an increase of HDL-C of 6.8%, while P induced a reduction of HDL-C of 6.9%; 3) 54.8% and 51.6% of the patients treated with L showed reductions of the ratios TC/HDL-C and LDL-C/HDL-C respectively. The patients who were administered P showed decrease in those indices of 15.7% and 13.1% respectively; 4) L was associated with 77.4% and 77.3% of excellent and good responses for TC and LDL-C. Regular and poor responses were more frequently observed during the treatment with P (39.4% each); 5) the incidence of adverse reactions was low and tolerability was considered good for both drugs. CONCLUSION: Lovastatin was more effective in the reduction of atherogenic lipoprotein fraction and in the increase of the protective one, with more pronounced reduction of the risk indices. They suggest that with the administration of L, that leads to an appropriate normalization of TC and LDL-C levels, greater benefits on morbidity and mortality of coronary disease can be achieved.

Analysis of Variance↗
PubMed1986

[Clinical research on the hypolipidemic action of a probucol preparation].

Probucol is a drug with hypolipidemic effect from the group of diphenols. The preparation has been administered to 33 patients with hyperlipoproteinemia--15 with type IIA, 17--with IIB and 1--with type III, in a dose of 750 mg for 28 days. The following serum indices were studied: total cholesterol (TCh), cholesterol in lipoproteins with high density (Ch-HDL), triglycerides (Tg), percentage of free cholesterol FCh) and ester cholesterol (ECh) in HDL and lipid-acid composition of ECh in HDL and lipoproteins with low density (LDL). The preparation has a good tolerance. By the end of the treatment, TCh was significantly reduced in the patients with type IIA--with 28.4% (p less than 0.001) and in IIB--with 23.3% (p less than 0.001). Ch-HDL was reduced with 19% on the average in type II ChLD (p less than 0.001). An essential reduction of serum Tg was established--with 32.2%. Significant reduction of lipid acids in the composition of ECh and HDL was established in type IIA ChLD.

Adult↗
PubMed1983

Combined effects of cholestyramine and probucol on regression of atherosclerosis in rhesus monkey aortas.

Adult male rhesus monkeys were fed a high fat, high cholesterol diet for 13 months. During the subsequent 12 months this diet was continued, but the animals were also treated with cholestyramine and/or probucol. The combined drug treatment caused lowering of blood cholesterol without a change in HDL-cholesterol. Regression of plaques was more marked than in animals treated with either drug alone. Animals remained in good health during the treatment period.

Animals↗
PubMed1982

Correlative design of electrophoretic and ultracentrifugal investigation of metabolic effects of probucol.

Probucol demonstrated a profound metabolic effect on the metabolism of plasma lipoproteins by lowering the levels of circulating low-density lipoproteins (LDL). This main metabolic phenomenon was usually accompanied with other substantial events in lipoprotein patterns. Their significance ought to be confirmed by more than one analytical method. Our primary analytic system used for the basic analysis of plasma lipoproteins consisted of analytical ultracentrifugation, highly standardized agarose-gel electrophoresis and molecular separation of lipoproteins according to their molecular sizes. This paper refers to an attempt to endorse electrophoresis as a supporting technique for ultracentrifugal studies. Correlation between corresponding ultracentrifugal classes and electrophoretic fractions, declared by their coefficients, were therefore studied in order to further examine the usefulness and applicability of agarose-gel electrophoresis in the research, as well as in determining and monitoring patient therapy. Close correlations were found between the group of chylomicrons (CHY), very-very-low-density lipoproteins (VVLDL), very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), their remnants and the entire pre-beta-electrophoretic complex of plasma lipoproteins (r=0.91). CHY, VVLDL and VLDL were also well related to the alpha 2- and pre-beta 2-electrophoretic fraction (r=0.95). However, if we consider concentration units for comparison of the relation between pre-beta 1- and beta-electrophoretic fractions versus all sub-classes of LDL, such correlation was found weaker (r=0.77); results were similar when such correlation was made with HDL2,3 classes versus alpha electrophoretic fractions (r=0.78). On the contrary, when the relative percentage in the spectra of the same classes and fractions were correlated, the correlation coefficients were different: CHY and all subclasses and remnants of VLDL, versus the entire pre-beta-electrophoretic complex demonstrated r=0.87, versus the alpha 2- and pre-beta 2-electrophoretic fraction r=0.73. The electrophoretic pre-beta 1-beta-complex correlated weakly (r=0.50) with low and medium density lipoproteins (MDL). Unexpectedly tight (r=0.89) was the correlation between relative percentages of the electrophoretic alpha 1-fraction and the high-density lipoproteins (HDL).

Blood Protein Electrophoresis↗
PubMed1980

[Effects of medium-term probucol treatment on plasma lipids and lipoproteins. 16 cases of type IIa and IIb hyperlipoproteinaemia (author's transl)].

Probucol was used to treat 16 patients with atherogenic hyperlipoproteinaemia. The duration of treatment varied between 30 days (16 patients) and 510 days (4 patients). The drug was found to be remarkably well tolerated, without any clinical or biological side-effects. There was an 8 to 13 p. cent reduction in plasma total cholesterol, a 4 to 17 p. cent reduction in LDL cholesterol and a very favorable increase (19 to 23 p. cent) in the HDL/LDL + VLDL cholesterol ratio. Little or no change was found in triglyceride and HDL cholesterol levels.

Cholesterol↗
PubMed1995

[The ameliorative effect of probucol on adriamycin (ADR) induced nephrotic rats].

This paper reports the ameliorative effect of Probucol (Pb) on ADR-induced nephrotic rats. Male Wistar rats underwent unilateral nephrectomy followed by one-week subsequent intravenous injection of 4.0 mg/kg of ADR. The rats were then divided into 3 groups: Pb-treated, non-treated and the control. The control group received 0.9% saline (vehicle) by injection. The 24-hr urinary protein excretion was measured for 24 weeks. When the animals were sacrificed at weeks 4, 12, and 24, respectively, blood samples were collected for biochemical study and the kidneys were extracted for measurement of malondialdehyde (MDA). In the morphological study, glomerular volume, glomerular sclerosis in dex (GSI), and tubulointerstitial index (TII) were calculated. Pb treatment lowered the serum lipid level and 24-hr urinary protein excretion. Total cholesterol was closely correlated with the urinary protein. However, there was no difference in terms of glomerular volume, kidney weight and GSI between the two groups. Pb treatment suppressed the kidney tissue MDA and TII significantly, the values of which were mutually correlated. The 24-hr protein excretion was significantly correlated with TII, but not with GSI. The decreased proteinuria was explained on the basis of suppression of enhancement of intraglomerular pressure induced by interstitial lesion. The findings suggest that renoprotection of Pb may derive from the amelioration of interstitial lesions.

Animals↗
PubMed1994

Effects of dietary fat levels on the absorption and tissue accumulation of probucol in the rat.

The effects of dietary fat level on the absorption and tissue accumulation of probucol (PB, CAS 23288-49-5) were studied in male Wistar rats. Addition of 1% PB (w/w) to the diets as compared to the diets without an addition (P) resulted in a decrease in the concentration of both serum and high-density lipoprotein (HDL) cholesterol as well as TBA-reactive substances (TBARS), without influencing food intake or growth. When rats were fed with the PB diet, the apparent intestinal absorption of PB was 7.9%, while the serum PB level was 5 micrograms/ml. The tissue distribution of PB, when expressed per g of tissue, was highest in the adrenal glands, followed by the liver, heart, epididymal adipose tissues, kidneys, lung, spleen, and testes. The addition of 10% olive oil (PBO) to the PB diet (w/w) appeared to double the PB diet-induced increase in apparent intestinal absorption and the serum concentration of PB. Furthermore, compared with the PB diet, the PBO diet caused 3- to 4-fold higher accumulation of PB in the liver and its subcellular fractions and 2-fold higher accumulation in the spleen. However, there was no further accumulation of the drug in the heart, kidneys, lungs, and testes. Incorporation of the drugs into adipose tissues was significantly lower with the PBO diet than with the PB diet. These results suggest that dietary manipulation leads to changes in the intestinal absorption and serum level of PB.

Animals↗