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PubMed1994

The effects of LPS and probucol on interleukin 1 (IL-1) and platelet-derived growth factor (PDGF) gene expression in the human monocytic cell line U-937.

We have investigated the effects of lipopolysaccharide (LPS) and probucol (a lipid soluble antioxidant) on the gene expression of interleukin 1 alpha and beta (IL-1 alpha and IL-1 beta), and platelet-derived growth factor A chain and B chain (PDGF-A and PDGF-B) in the human monocytic cell line U-937. Steady-state mRNA levels were measured quantitatively by the reverse transcription-polymerase chain reaction (RT-PCR) using a non-radioactive label. Cells were incubated with LPS, in the presence or absence of probucol for 20 h. The cells were harvested and RNA was then prepared, reverse-transcribed in the presence of an internal standard and subsequently amplified and labelled with digoxigenin-11-dUTP by the PCR reaction. The PCR products were subjected to agarose gel electrophoresis, blotted onto nylon membranes and visualised by immunological detection of digoxigenin followed by a chemiluminescent reaction. We found that: (1) LPS treatment of U-937 cells caused an up-regulation of gene expression of IL-1 beta and PDGF-A chain by approximately 250% and 100% respectively, although it did not stimulate the expression of IL-1 alpha nor PDGF-B chain mRNA. (2) Probucol treatment in vitro had no effect on the basal or LPS-stimulated mRNA levels of IL-1 alpha, IL-1 beta, PDGF-A and PDGF-B despite its reported activity in vivo. (3) PDGF-A and PDGF-B were expressed at a similar level in unstimulated U-937 cells approximately 10-50 copies/ng total RNA, whereas the expression of IL-1 beta mRNA was approximately 2-4 times higher than IL-1 alpha mRNA. (4) Finally, in U-937 monocytic cells the expression of IL-1 alpha and IL-1 beta, and PDGF-A and PDGF-B appear to be independently regulated.

Base Sequence↗
PubMed2005

Combined effect of probucol and insulin on cataracts of diabetic rats fed a high cholesterol diet.

We investigated the effects of long-term treatment with probucol, a hypolipidemic agent with antioxidative action, insulin, or their combination on cataracts of streptozotocin-induced diabetic rats fed a high cholesterol diet. Each rat was checked for cataracts at 0, 1, 2, 4, 8, 12 and 15 weeks after streptozotocin injection. Cataracts were observed from 8 weeks in untreated hypercholesterolemic and diabetic rats and the incidence of catarats increased to 100% by 15 weeks. The incidence of cataracts in rats treated with probucol, insulin and their combination was first seen at 12, 12 and 15 weeks, respectively, and was 86%, 63% and 33%, respectively, at 15 weeks. The preventive effects of both agents alone and their combination on the cataracts were confirmed by histopathological evaluation of eyeballs. The combined treatment with both agents markedly improved hyperglycemia, hyperlipidemia and increased serum lipid peroxide levels. These results indicate that the combined treatment with probucol and insulin is useful in preventing the development and progression of diabetic cataracts.

Animals↗
PubMed1988

Effect of probucol on development of diabetes mellitus in BB rats.

Insulin-dependent diabetes mellitus (IDDM) results from an inflammatory process leading to destruction of the insulin-producing beta cells of the pancreas. Genetically mediated autoimmune processes are considered the most likely explanation for IDDM in humans, while viral infections, toxic agents, nutritional alterations and stress are also considered possibilities. The precise mechanisms by which autoimmunity, infections, toxins or other agents produce beta cell damage are not known. Toxin-induced diabetes in animals can be prevented by antioxidant therapy, while an agent that inhibits hydroxyl radical formation, desferrioxamine, extends the survival time of free allotypic islets in nonobese diabetic mice. The BB/W rat develops IDDM secondary to a pervasive autoimmune defect. This well-studied animal model develops IDDM with a highly predictable frequency and timing. This study describes the effects of the potent antioxidant, probucol, on the development of diabetes in BB rats by introducing it into standard rat chow at a 1% concentration at the time of weaning, and continuing this feeding schedule through 160 days of life. Control rats from split litters received standard chow only. Diabetes developed in 86.2% of the control rats at a mean age of 90.4 days. Probucol administration was associated with a reduction to 62% and a delay in diabetes diagnosis to 99.6 days. These very preliminary results suggest that probucol may be altering the inflammatory process, resulting in beta cell destruction in these genetically diabetes-prone rats.

Actuarial Analysis↗
PubMed1998

High prebeta1-HDL levels in hypercholesterolemia are maintained by probucol but reduced by a low-cholesterol diet.

Previous study has shown that prebeta1-HDL levels increase in hypercholesterolemia, or high cholesteryl ester transfer protein (CETP) activity. To determine how prebeta1-HDL levels change after treatment with probucol or by following a low-cholesterol diet, we randomly assigned 24 hypercholesterolemic patients to either the probucol (P), or low-cholesterol diet group (D), and measured prebeta1-HDL levels before and after treatments using native two-dimensional gel electrophoresis. We also examined 12 subjects with normolipidemia (N). At baseline, prebeta1-HDL levels were higher in P (P < 0.05) and D (P < 0.05) than in N (9.2 +/- 4.3, 10.4 +/- 5.5, and 5.9 +/- 2.3 mg/dl apo A-I). After a 4-week treatment, prebeta1-HDL levels were still high in P (10.5 +/- 4.2 mg/dl apo A-I, N.S.), but reduced in D (7.7 +/- 3.0 mg/dl apo A-I, P < 0.001). Delta prebeta1-HDL (Y) was positively correlated with deltaCETP mass (X) in P (y = 7.83x - 1.93; r = 0.584, P < 0.05). In summary, high prebeta1-HDL levels in hypercholesterolemia are maintained by probucol but reduced by a low-cholesterol diet. These findings suggest that prebeta1-HDL levels may be regulated by cholesterol and CETP levels.

Aged↗
PubMed2003

Effect of antioxidant probucol on cell-mediated LDL oxidation in vitro and in vivo.

We studied the effect of phenol antioxidant probucol on free radical oxidation of LDL isolated from blood plasma of healthy donors. Oxidation was induced by co-incubation of LDL with cultured peripheral blood monocyte-macrophages and human umbilical vein endothelial cells under conditions of ischemia-reperfusion. In addition, the effect of probucol therapy on oxidability of plasma LDL in CHD patients was examined. Probucol (0.1-10 microM) efficiently protected LDL from free radical oxidation in vitro and in vivo.

Anticholesteremic Agents↗
PubMed2002

Probucol preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level.

1. Oxide low-density lipoprotein (ox-LDL) is believed to play an important role in early events of atherogenesis, and asymmetric dimethylarginine (ADMA) is associated with the development of endothelial dysfunction. The present study examined the effect of a single injection of native low-density lipoprotein (LDL) on endothelium function and the serum level of ADMA and the effect of probucol on endothelium function and ADMA level in rats. 2. Endothelial injury was induced by intravenous injection of LDL at the dose of 2, 4, or 6 mg kg(-1) for 24, 48, or 72 h, and vasodilator responses to acetylcholine in the aortic rings and serum levels of ADMA, nitrite/nitrate (NO) and malondialdehyde (MDA) were determined. 3. Pretreatment with LDL markedly reduced endothelium-dependent relaxation in a concentration-dependent manner. Inhibition of vasodilator responses to acetylcholine by LDL was abolished in the presence of L-arginine (3 x 10(-4) M). Serum levels of ADMA and MDA were significantly elevated in the rats pretreated with LDL, while serum level of nitrite/nitrate was markedly decreased. 4. Pretreatment with probucol significantly improved endothelium-dependent relaxation, decreased concentrations of ADMA and MDA and increased nitrite/nitrate level in the rats treated with LDL. A similar effect was seen in the rats pretreated with an antioxidant vitamin E. 5. These results suggest that a single injection of native LDL causes endothelial dysfunction by elevation of ADMA levels and that the protective effect of probucol on endothelial cells is related to reduction of ADMA concentration.

Animals↗
PubMed1980

Eight-year toxicity study in monkeys and reproduction studies in rats and rabbits treated with probucol.

Probucol [4,4'-(isopropylidenedithio)bis(2,6-di-tert-butylphenol)], a hypocholesterolemic agent, was given orally to male and female rhesus monkeys at 0, 60, 125, 250, and 500 mg/kg . d for more than 8 yr without adverse effect. Of 40 monkeys on test, 14 were killed for interim studies (wk 81 and 102), 21 were maintained for more than 8 yr, and 5 were submitted for necropsy for conditions unrelated to treatment. Monitored parameters included growth rate, demeanor, hematology, clinical chemistries, urinalyses, ophthalmoscopy, organ weights, and gross, histopathologic, and electron microscopic evaluations. Bone marrow smears at the conclusion of the test revealed no differences between control and treated animals. Electron microscopy of liver specimens from monkeys treated for 8 yr revealed comparable hepatocellular ultrastructure in control and treated monkeys. Probucol was given orally at 0, 100, 500, and 1000 mg/kg to Sprague-Dawley rats during appropriate time intervals to evaluate effects on fertility and postnatal development. The same dose levels were given during organogenesis, or in some cases prior to breeding and throughout organogenesis, to Sprague-Dawley rats and New Zealand white rabbits. No adverse effects on fertility or postnatal development were observed in rats, and no evidence of teratogenicity was observed in either species. The results indicate that probucol does not affect reproduction of rats, lacks teratogenic potential in the species studied, and is nontoxic to subhuman primates treated for more than 8 yr.

Abnormalities, Drug-Induced↗
PubMed2003

Probucol in the treatment of nonalcoholic steatohepatitis: an open-labeled study.

GOALS: To evaluate the effects of probucol, an agent with strong antioxidant properties, in reversing biochemical changes in nonalcoholic steatohepatitis (NASH). BACKGROUND: There is currently no well-established medical treatment of NASH. It is believed that oxidative stress plays a major role in hepatic damage in these patients. STUDY: Cases of biopsy-proven NASH referring to a referral center in Tehran during a 12-month period were included in the study. Viral, autoimmune and other hepatic diseases were excluded. Alcohol ingestion was excluded by repeated questioning of the patient and at least two family members. Patients were given 500mg of probucol daily for 6 months. Serum levels of liver enzymes, the serum lipid profile, and weight was recorded monthly. RESULTS: A total of 17 patients completed the study. The mean age was 37.2 years, 13 patients were male and 4 female. The mean pretreatment value of ALT and AST was 93.5 and 80.4 U/L, and the mean posttreatment value was 41.8 and 35.9 U/L respectively ( = 0.001 and 0.006). CONCLUSION: Probucol, even in the low dose of 500 mg/d, appears to be significantly effective in decreasing the ALT and AST levels in patients with NASH.

Adult↗
PubMed1979

Adrenergaically mediated ventricular fibrillation in probucol-treated dogs: roles of alpha and beta adrenergic receptors.

A high incidence of sudden death due to ventricular fibrillation (VF) has been observed in dogs under chronic treatment with probucol, a new hypocholesterolemic agent. The present study describes the cardiac electrophysiologic properties of probucol-treated dogs and characterizes the electrophysiological response of these animals to manipulation of the autonomic nervous system. There was no significant difference in the spontaneous sinus cycle length, the QT interval, refractory period of the atrium, ventricle or A-V junction between normal and probucol-treated dogs. Epinephrine produced VF with few and sometimes no preceding premature ventricular extrasystoles. Electrical stimulation of the stellate ganglion induced VF in 16/19 dogs whereas stimulation of the right stellate ganglion induced VF in 1/19 dogs. Phenylephrine induced VF in 0/19 dogs, isoproterenol in 5/19 dogs, but phenylephrine + isoproterenol induced VF in 9/11 dogs in which isoproterenol did not produce VF. alpha (phentolamine) or beta (propranolol) blockade prevented initiation of VF by epinephrine, phenylephrine + is isoproterenol, and left stellate stimulation but alpha blockade did not prevent induction of VF by isoproterenol when isoproterenol alone produced VF. In this nonischemic model, we conclude that left stellate stimulation is a far more potent initiator of VF than right stellate stimulation and that induction of VF appears to require both alpha and beta adrenergic receptor stimulation.

Angiotensin II↗
PubMed1988

Treatment with probucol of children with familial hypercholesterolaemia.

Nine children with familial hypercholesterolaemia, age range 2 to 12 years, were treated with a low cholesterol diet and probucol (10 mg/kg/day). The year before, the children received, as only treatment, a low fat-cholesterol diet. During this period their mean plasma total cholesterol level fell from 8.2 +/- 1.45 mmol/l to 7.17 +/- 0.84 mmol/l (12.6%). This level was further reduced to 5.92 +/- 0.63 mmol/l (17.1%) after the addition of probucol. Plasma high density lipoprotein cholesterol levels were lowered in absolute terms but not in relation to total cholesterol. No apparent side effects were observed. However, the use of probucol should be restricted for the moment to severe cases of hypercholesterolaemia as the long-term excretion of the drug in children is not yet known.

Child↗
PubMed2006

Comparative effects of pitavastatin and probucol on oxidative stress, Cu/Zn superoxide dismutase, PPAR-gamma, and aortic stiffness in hypercholesterolemia.

Reactive oxygen species-scavenging enzyme Cu/Zn superoxide dismutase (SOD) regulated by peroxisome proliferator-activated receptors (PPARs) plays an important role in vascular responsiveness. However, it remains unknown whether statin restores vascular dysfunction through the activation of reactive oxygen species-scavenging enzymes in vivo. We hypothesized that pitavastatin restores vascular function by modulating oxidative stress through the activation of Cu/ZnSOD and PPAR-gamma in hypercholesterolemia. New Zealand White male rabbits were fed either normal chow or a 1% cholesterol (CHO) diet for 14 wk. After the first 7 wk, the CHO-fed rabbits were further divided into three groups: those fed with CHO feed only (HC), those additionally given pitavastatin, and those additionally given an antioxidant, probucol. The extent of atherosclerosis was assessed by examining aortic stiffness. When compared with the HC group, both the pitavastatin and probucol groups showed improved aortic stiffness by reducing aortic levels of reactive oxidative stress, nitrotyrosine, and collagen, without affecting serum cholesterol or blood pressure levels. Pitavastatin restored both Cu/ZnSOD activity (P < 0.005) and PPAR-gamma expression and activity (P < 0.01) and inhibited NAD(P)H oxidase activity (P < 0.0001) in the aorta, whereas probucol inhibited NAD(P)H oxidase activity more than did pitavastatin (P < 0.0005) without affecting Cu/ZnSOD activity or PPAR-gamma expression and activity. Importantly, Cu/ZnSOD activity was positively correlated with the PPAR-gamma activity in the aorta (P < 0.005), both of which were negatively correlated with aortic stiffness (P < 0.05). Vascular Cu/ZnSOD and PPAR-gamma may play a crucial role in the antiatherogenic effects of pitavastatin in hypercholesterolemia in vivo.

Animals↗
PubMed2003

Experimental and clinical studies show that the probucol derivative AGI-1067 prevents vascular growth.

AGI-1067 is a derivative of probucol that is a promising new development for the treatment of restenosis and possibly atherosclerosis. In monkeys fed a high-fat diet for 1 year, AGI-1067 prevented the development of atherosclerosis. In these monkeys, AGI-1067 lowered plasma levels of low-density lipoprotein (LDL)-cholesterol and, in contrast to probucol, was capable of increasing high-density lipoprotein (HDL)-cholesterol levels. Although AGI1067 did not have marked lipid-lowering effects in two transgenic mouse models (the LDL-receptor-deficient and apolipoprotein-E-deficient models) fed a high-fat chow, it decreased the atherosclerotic lesion area in the aorta. In a mouse model of acute inflammation, the mRNA for the pro-inflammatory vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 was upregulated and this was inhibited by AGI-1067. AGI-1067 inhibited the TNF-alpha induction of redox-sensitive inflammatory proteins, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1 and Eselectin, in cell culture. In addition, AGI-1067 is an antioxidant. In the Canadian Antioxidant Restenosis Trial (CART-1) of AGI-1067 in percutaneous coronary interventions, AGI-1067 had no effect on LDL-cholesterol but lowered HDL-cholesterol. At 6 months follow up, the lumen area of the percutaneous coronary interventions segments was greater in patients treated with AGI1067 than in untreated patients. Restenosis rates were 37.5% in the placebo group and 26% in the AGI-1067 group. The lumen area of reference segments was reduced in the placebo group but increased with the higher doses of AGI1067. Unlike probucol, AGI-1067 did not alter QTc interval.

Animals↗
PubMed1996

Effectiveness of probucol in preventing restenosis after percutaneous transluminal coronary angioplasty.

Lipid lowering therapies were employed to prevent restenosis following elective percutaneous transluminal coronary angioplasty (PTCA). The effect of probucol was compared to that of Pravastatin in 141 coronary atherosclerosis patients. Probucol (750 mg/day) was administered for at least 30 days prior to PTCA (34 patients, group P-1) or less than 14 days prior to PTCA (27 patients, group P-2). Pravastatin (10 mg/day) was administered for at least 30 days prior to PTCA (38 patients, group V-1) or less than 14 days prior to PTCA (42 patients, group V-2). In group P-1, the patient restenosis rate was 17.6% and lesion restenosis rate was 14%. These rates were significantly lower than those of group V-1, which were 44.7% and 40.4% respectively (p < 0.05). The respective values were 48.1% and 51.8% in group P-2 (p < 0.05, vs group P-1) and 35.7% and 34% (p < 0.05, vs group P-1) in group V-2. Probucol seems to work, not only by lowering cholesterol but also by its antioxidative properties when administered for a sufficient period prior to PTCA.

Angioplasty, Balloon, Coronary↗
PubMed1982

Colestipol and probucol: treatment of primary and familial hypercholesterolemia and amelioration of atherosclerosis.

Colestipol is a safe, effective, cholesterol-lowering, bile-acid sequestrant that lowers low-density-lipoprotein (LDL) and total plasma cholesterol levels without consistently affecting high-density-lipoprotein (HDL) cholesterol levels. Long-term colestipol therapy in conjunction with diet may reduce xanthoma size, arrest progression of coronary artery atherosclerosis, and may reduce mortality from coronary heart disease. Probucol, a bisphenol cholesterol-lowering drug, is an effective cholesterol-lowering agent that reduces levels of HDL cholesterol, HDL cholesterol, and apoprotein A-1, the major apolipoprotein of HDL. Because HDL cholesterol is independently and inversely associated with development of coronary heart disease, the ramifications of simultaneous lowering of LDL and HDL cholesterol levels by probucol treatment need further study. Long-term, placebo-controlled studies of repetitive coronary arteriography, coronary heart disease morbidity and mortality, or both are needed to ascertain the efficacy of long-term probucol use in relation to development of atherosclerosis.

Arteriosclerosis↗
PubMed1999

[Mechanisms of anti-atherogenic action of probucol].

Probucol has been recognized to have antioxidant properties as well as lipid-lowering effects, and contribute to prevention of atherosclerosis. Pharmacologically, this agent has shown several unique actions, and a lot of investigations have been reported regarding the mechanisms. Recently, it has been reported that probucol increases selective uptake of high density lipoprotein cholesterol esters by the medium of the class B, type I scavenger receptor (SR-BI), and that antioxidant potent may inhibit the restenosis of post coronary angioplasty. This review attempts to focus on the mechanism of antioxidant and HDL-lowering effects of probucol.

Anticholesteremic Agents↗
PubMedDate not supplied

Ceftriaxone induced lipid peroxidation and its inhibition with various antioxidants: Part II. Evaluation of glutathione and probucol as antioxidants.

Exploratory studies on drug induced lipid peroxidation in goat whole blood and its inhibition with antioxidants were carried out using sodium ceftriaxone (CTS) as the representative drug and glutathione and probucol as the representative antioxidants. The studies showed that CTS could induce lipid peroxidation to a significant extent. Lipid peroxidation is a toxicity mediating process, this finding may be correlated with the toxic potential of the drug. It was further found that glutathione and probucol caused significant suppression of CTS induced lipid peroxidation. The results suggest that glutathione and probucol merit further assessment to explore their potential to reduce drug induced lipid peroxidation and thus to increase therapeutic index of the drug by way of reducing toxicity that may be mediated through free radical mechanism.

Animals↗
PubMed2000

Probucol inhibits lipid peroxidation of macrophage and affects its secretory properties.

AIM: To investigate the mechanisms of anti-atherogenic actions of probucol. METHODS: Human peripheral blood monocytes were cultured, and treated by copper ion (10 mumol/L) and/or probucol (PBC). Lipid peroxidation was measured by assaying malondialdehyde (MDA). The cytokine interleukin-1 beta (IL-1 beta) and apolipoprotein E (apo E) secreted by monocyte were assayed by enzyme linked immunoassay (ELISA). RESULTS: PBC 10-80 mumol/L inhibited copper ion-induced cellular lipid peroxidation from 15.30 to 7.74 mumol MDA/g cell protein. PBC 40 mumol/L inhibited oxidized macrophage-mediated oxidation of LDL from 5.18 to 1.65 mumol MDA/g cell protein, and attenuated secretory properties of monocytes induced by copper ion. The release of apo E, which is involved in reverse cholesterol transport, increased by 65%. And the release of IL-1 beta, which was shown to enhance vascular smooth muscle cell proliferation, decreased by 45%. CONCLUSION: Probucol inhibits lipid peroxidation of macrophages and affects their secretory properties.

Anticholesteremic Agents↗
PubMedDate not supplied

Evaluation of probucol as suppressor of ceftizoxime induced lipid peroxidation.

Considering drug induced lipid peroxidation, a possible mediator of drug induced toxicity and exploiting free radical scavenging action of probucol, which is a synthetic antioxidant of therapeutic interest, in vitro effects of the antioxidant on drug induced lipid peroxidation have been studied to explore its possible potential in reducing drug induced toxicity. In the present study, ceftizoxime sodium, a third generation of cephalosporin, has been taken as the representative drug and goat whole blood has been used as the lipid source. The study revealed that probucol could suppress drug induced lipid peroxidation to a significant extent. This provides scope for further study on probucol to evaluate its potential for reducing drug induced toxicity and increasing therapeutic index of drug by possible cotherapy.

Animals↗