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PubMed1992

Chronopharmacology of probucol in mice.

Mice were maintained under conditions of light from 7 a.m. to 7 p.m. and dark from 7 p.m. to 7 a.m. Probucol was given orally to these animals once daily at 10 a.m. or 10 p.m. for 7 days. Blood samples for serum cholesterol were obtained at 24 hours after the final dosage. Blood samples for plasma probucol were obtained just before and at 3, 6, 12, 24, 48, 72, 96 and 120 hours after the final dosage. The cholesterol lowering effect of the agent at 10 p.m. was greater than that at 10 a.m. Plasma probucol concentrations of the two trials did not differ at any observation point. These data suggest that the effect of probucol varies with its time of administration. This might not be caused by a time-dependent change in plasma probucol concentration.

Administration, Oral↗
PubMed2002

Effects of probucol in hyperlipidemic rabbit liver: a preliminary ultrastructural study.

Probucol is a lipid-lowering agent with an antioxidant effect; however, its influence on the liver remains unclear. The effects of probucol on hyperlipidemic rabbit liver are investigated to add a structural data on its therapeutical profile. Local albino rabbits were divided into three groups. 1) Hyperlipidemic group: fed with 1% cholesterol (150 g/kg/day) enriched chow for 2 months. 2) Probucol treated group: group 1 + intraperitoneal probucol (10 mg/kg/day) administration for 15 days. 3) Control group fed with normal chow. The blood lipid profile was investigated biochemically. Liver samples were examined electronmicroscopically. Within the parenchymal cells of group 1, the amount of rough surfaced endoplasmic reticulum was increased, its cisterna was dilated displaying a moderately electron dense substance in it and showed close apposition with the condensed mitochondria. In group 2, smooth surfaced endoplasmic reticulum was in extensive amounts filling almost all of the cytoplasm, displayed a reticular, degenerated appearance and was in close relation with the condensed, degenerated mitochondria. Probucol may cause degenerative changes on the liver parenchyme at the subcellular level. It alters the structure of these cells mainly acting on the smooth surfaced endoplasmic reticulum and the mitochondria that are known to be involved in cellular detoxification.

Animals↗
PubMed2005

In vitro and in vivo effects of probucol on hydrolysis of asymmetric dimethyl L-arginine and vasospasm in primates.

OBJECT: Increased cerebrospinal fluid (CSF) levels of asymmetric dimethyl L-arginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), are associated with delayed vasospasm after subarachnoid hemorrhage (SAH); however, the source, cellular mechanisms, and pharmacological inhibition of ADMA production following SAH are unknown. METHODS: In an in vitro experiment involving human umbilical vein endothelial cells (HUVECs), the authors examined mechanisms potentially responsible for increased ADMA levels during vasospasm and investigated whether this increase can be inhibited pharmacologically. In a second study, an in vivo experiment, the authors used probucol, which effectively inhibited ADMA increase in HUVEC cultures in vitro, in a randomized double-blind placebo-controlled experiment in a primate model of delayed cerebral vasospasm after SAH. Oxidized low-density lipids (OxLDLs; positive control; p < 0.02) and bilirubin oxidation products (BOXes; p < 0.01), but not oxyhemoglobin (p = 0.74), increased ADMA levels in HUVECs. Probucol inhibited changes in ADMA levels evoked by either OxLDLs (p < 0.001) or BOXes (p < 0.01). Comparable changes were observed in cell lysates. In vivo probucol (100 mg/kg by mouth daily) did not alter serum ADMA levels on Days 7, 14, and 21 after SAH compared with levels before SAH, and these levels were not different from those observed in the placebo group (p = 0.3). Despite achieving therapeutic levels in plasma and measurable levels in CSF, probucol neither prevented increased CSF ADMA levels nor the development of vasospasm after SAH. Increased CSF ADMA and decreased nitrite levels in both groups were strongly associated with the degree of delayed vasospasm after SAH (correlation coefficient [CC] 0.5, 95% confidence interval [CI] 0.19-0.72, p < 0.002 and CC -0.43, 95% CI -0.7 to -0.05, p < 0.03, respectively). CONCLUSIONS: Bilirubin oxidation products, but not oxyhemoglobin, increased ADMA levels in the HUVEC. Despite its in vitro ability to lower ADMA levels, probucol failed to inhibit increased CSF ADMA and decreased nitrite levels, and it did not prevent delayed vasospasm in a primate SAH model.

Animals↗
PubMed2001

Angiotensin-converting enzyme inhibitors and probucol suppress the time-dependent increase in urinary Type IV collagen excretion of Type II diabetes mellitus patients with early diabetic nephropathy.

BACKGROUND: A multicenter prospective clinical trial was carried out in 9 National Hospitals in Japan to elucidate the time-dependent change in urinary Type IV collagen excretion rate of Type II diabetes mellitus (DM) patients, and to investigate whether an angiotensin-converting enzyme inhibitor (ACE-I) or probucol is effective in preventing progression of renal involvement of diabetics by evaluating urinary Type IV collagen excretion. METHODS: Normo- and microalbuminuric patients with Type II DM were recruited. Patients were assigned to either the control (n = 88), ACE-I (n = 43) or probucol (n = 37) group and treated for 24 months. Besides albumin excretion rate (AER), urinary Type IV collagen excretion rate was also measured. RESULTS: Although, AER, urinary N-acetyl-beta-D-glucosaminidase and beta2-microglobulin excretion rates in the control group did not vary over 24 months, urinary Type IV collagen excretion rate in the control group increased time-dependently (p < 0.01 vs baseline at 18 months and p < 0.005 vs baseline at 24 months). In the ACE-I and probucol groups, time-dependent increases in urinary Type IV collagen excretion rates were not observed. In the ACE-I group, the urinary Type IV collagen excretion rate was significantly lower than that in the control group at 24 months (p < 0.05). In the probucol group, the urinary Type IV collagen excretion rate was significantly lower than that in the control group at 6 months (p < 0.05). In the ACE-I group, AER decreased significantly compared with baseline at 18 months (p < 0.05) and at 24 months (p < 0.005). CONCLUSIONS: ACE-I has a beneficial effect and probucol may have a beneficial effect in preventing the progression of early diabetic nephropathy. Measurement of the urinary Type IV collagen excretion rate in combination with AER would be useful for the management of early renal involvement in Type II DM.

Acetylglucosaminidase↗
PubMedDate not supplied

Probucol and liver efficiency during chemically-induced hepatocarcinogenesis.

Probucol is a clinically used cholesterol-lowering drug, with pronounced antioxidant properties. The chemoprotective effect of probucol during the early steps of DENA and CCl4-induced hepatocarcinogenesis was studied. Treatment of animals with a single lethal dose of CCl4 (2ml/Kg, i.g.) after two weeks of DENA initiation, induced a significant increase in hepatic gamma-glutamyl transferase and liver content of glutathione and lipid peroxides five weeks later. On the other hand, a significant decrease in hepatic glutathione peroxidase activity was also observed after five weeks of CCl4 injection. Moreover, there was a significant decrease in hepatic blood flow manifested by decrease in indocyanine green elimination rate constant and increase in its half-life and area under the curve. The pharmacokinetic of antipyrine (a marker for hepatic metabolizing capacity) was altered due to decrease in the metabolizing capacity of damaged liver. In addition, haemorrhagic centrilobular necrosis and multifocal neoplastic lesions were microscopically detected. Treatment of animals with probucol (10 mg/Kg) three times/week for six weeks during DENA and CCl4-induced hepatocarcinogenesis counteracted significantly the alteration in hepatic blood flow and the hepatic metabolizing capacity. Moreover, probucol treatment restored the hepatic gamma-glutamyl transferase and liver content of glutathione and lipid peroxides. In addition, histopathological examination of liver specimens showed minimal centrilobular necrosis without any evidence of neoplastic lesions. The result of this study suggest that probucol may be useful as a chemopreventive agent, in addition to being a cholesterol-lowering drug with low toxicity.

Alanine Transaminase↗
PubMed2002

Antioxidant treatment of therapy-resistant idiopathic membranous nephropathy with probucol: a pilot study.

BACKGROUND: Proteinuria in Heymann's nephritis, an experimental rat model disease corresponding to membranous nephropathy, has been shown to be due to lipid peroxidation. Since the pathophysiology might be similar to idiopathic membranous nephropathy in humans, we performed a prospective multicenter trial to investigate the efficacy of the lipid peroxidation scavenger, probucol. METHODS: Fifteen patients with biopsy-proven idiopathic membranous nephropathy resistant to conventional immunosuppressive therapy (n = 7) and/or ACEI treatment (n = 12) were recruited. Probucol (1 g/d orally) was administered for three months, followed by a washout period of four weeks, whereon lovastatin (10-20 mg/d orally) was administered for additional three months. RESULTS: A significant reduction in proteinuria was seen during the probucol treatment (median (range): 6.4 (3.8-9.1) g/d vs. 4.7 (1.3-16) g/d; P < 0.05), with partial remission achieved in four patients. Three of these patients had previously been resistant to immunosuppressive therapy. Median protein excretion increased to pretreatment values during the washout period (6.2 (1.9-15) g/d; P < 0.05) and was not significantly different after the intake of lovastatin (4.9 (1.8-19) g/d; P = NS). None of the patients achieved partial remission during lovastatin therapy (P < 0.05 vs. probucol). CONCLUSION: The present study led us to conclude that proteinuria can be reduced by probucol in some patients with idiopathic membranous nephropathy. A randomized multicenter study to further elucidate the influence of lipid peroxidation scavengers on membranous nephropathy is warranted.

Adult↗
PubMed1992

[Probucol inhibits tobacco smoke-induced decrease in plasma anti-elastase activity and ferroxidase activity in rats].

Elastolytic enzymes and active oxygen species derived from leukocytes and alveolar macrophages during exposure to tobacco smoke, together with active oxygen species directly derived from tobacco smoke, are thought to play a crucial role in the pathogenesis of pulmonary emphysema by inactivating alpha 1 protease inhibitor (alpha 1 PI), a novel anti-elastase. We studied the inhibitory effect of probucol, an oral hypocholesterolemic agent, on tobacco smoke-induced decrease in plasma anti-elastase activity (EIA) and ferroxidase activity (FA) in conscious venous catheter instrumented rats. Rats exposed to the smoke of 5 cigarettes (nicotine 11 mg, tar 115 mg) in a plastic chamber showed a prompt increase in plasma COHb to 17.9 +/- 2.7%, and a prompt decrease in plasma EIA by -17.9% (p less than 0.05) and FA by -14.8% (p less than 0.01), which lasted for 6 hours after exposure. Rats administered probucol (1% probucol in food) for 3 days showed normal cholesterol plasma levels, and rats administered probucol for 4 weeks showed hypocholesterolemic plasma levels. EIA and FA were not depressed after smoking, and lipid peroxide product (TBA reactive substance) in lung tissue (p less than 0.05) and serum (p less than 0.1) showed a smaller increase in association with a smaller decrease in the ratio of lung tissue GSH/GSSG (p less than 0.01) compared with control rats. These results indicate that probucol, via its antioxidant action rather than its cholesterol lowering effect, has a protective effect on lung exposed to tobacco smoke in terms of protease-antiprotease balance and oxidant-antioxidant balance.

Animals↗
PubMedDate not supplied

Probucol, a hypocholesterolemic agent, prevents the development of uterine adenomyosis induced by pituitary grafting in mice.

This in vivo experimental study was designed to investigate the effects of probucol, a hypocholesterolemic agent, on uterine adenomyosis which is frequently induced by pituitary grafting in mice. SHN mice, which are known to develop uterine adenomyosis spontaneously, and much sooner after pituitary grafting, were used and histopathological study on the uteri in pituitary gland-implanted mice with or without probucol treatment was performed. Four out of 10 pituitary gland-implanted mice developed uterine adenomyosis with dilated blood vessels, but none of the probucol-treated mice. There were no differences between pituitary-grafted mice with or without probucol treatment in body weight and wet weights of uterus, ovaries, kidney and liver except spleen. Probucol markedly reduced the serum levels of total cholesterol, free cholesterol, free fatty acids, phospholipids and triglycerides and, thus, this agent inhibited the incidence of uterine adenomyosis induced by pituitary grafting in mice.

Animals↗
PubMed1992

Effects of probucol on low-density lipoprotein catabolism in guinea pigs.

We studied the effects of administering probucol on the catabolism of low density lipoprotein (LDL) in guinea pigs. Probucol administration significantly lowered the levels of total and LDL-cholesterol in animals given either normal chow or the high cholesterol (1% W/W) diet. High-density lipoprotein cholesterol was decreased significantly in the animals fed cholesterol, but not normal chow diet. Triglyceride levels were unaffected in both groups. No significant changes were observed in the LDL receptor-dependent and LDL receptor-independent catabolism of native LDL and LDL obtained from a probucol-treated patient. However, when the LDL isolated from a probucol-treated patient was injected, the fractional catabolic rate was significantly lower than that of injected native LDL. This study indicates that probucol lowered the plasma LDL cholesterol level neither by an increased catabolism of LDL via an LDL receptor nor an LDL receptor-independent pathway.

Animals↗
PubMed1991

Antiatherosclerotic effect of probucol in WHHL rabbits: are there plasma parameters to evaluate this effect?

Probucol has been used as a lipid-lowering agent for over 10 years. Lately it has been found that its antiatherogenic action is due mainly to its antioxidative capacity, in addition to its known lipid-lowering effect. To study the antioxidative capability of probucol and its influence on plaque development we used the animal model of the LDL-receptor-defective Watanabe heritable hyperlipidemic (WHHL) rabbit. In this study we measured all lipid values before and after probucol feeding and compared them with corresponding values in untreated controls. Probucol levels were determined, as were the physiological antioxidants alpha and gamma tocopherol (vitamin E). Thiobarbituric reactive substances were measured in plasma as a parameter for lipid peroxidation. In addition to the biochemical measurements the plaque area was analyzed macroscopically and microscopically to check the antiatherosclerotic effect and correlate it with the biochemical parameters. In four experiments we showed that probucol treatment in WHHL rabbits decreases the progression of atherosclerotic plaques by way of a combined lipid-lowering and antioxidative effect.

Animals↗
PubMed1991

New combined therapy of niceritrol and probucol on heterozygous familial hypercholesterolemia.

Seventeen patients with heterozygous familial hypercholesterolemia were sequentially treated with: a low cholesterol, fat restricted diet; diet and probucol (500 mg/day); and diet, probucol and niceritrol (1500 mg/day). Concentrations of plasma cholesterol decreased from 348 + 49 mg/dl on diet alone to 304 + 32 mg/dl, to 256 + 30 mg/dl on diet and probucol, and fell to 212 + 41 mg/dl on the combined regimen with niceritrol. Concentrations of LDL-cholesterol declined 13% on diet, and 26% on diet and probucol; the subsequent addition of niceritrol resulted in a 42% fall from the baseline. Plasma concentrations of apolipoprotein B fell 37% on the combined regimen with niceritrol. As a result, normal levels of cholesterol (less than 230 mg) were achieved in thirteen subjects treated with this new combination therapy. Moreover, atherogenic index improved with the addition of niceritrol. These results suggest even a small dose of niceritrol affords opportunity to maintain normal lipid profile in heterozygous familial hypercholesterolemia when given in combination with probucol.

Adult↗
PubMed1990

Factors predictive of marked decrease in HDL-C by probucol treatment.

Probucol markedly reduces the LDL-C level in hyperlipidemic patients. However, it also reduces HDL-C which is believed to result in an anti-atherosclerotic effect. Many hyperlipidemic patients treated with Probucol show a marked reduction in the HDL-C level, and administration of the agent to these patients requires proper caution. In this study, factors useful for predicting the reduction in HDL-C were examined in order to be able to predict the problem before actual administration. Probucol (250-750 mg/day) was administered to 30 patients with type II hypercholesterolemia. Among them, 23 patients showed a decrease greater than 20% in the HDL-C level after administration. To evaluate the factors which permit identification of this group, linear descriminant function analysis was performed using 12 pre-administration lipid levels. The analysis indicated that the Apo A-I/HDL-C ratio before Probucol has the greatest predictive value (F = 17.8, P less than 0.01) of all the parameters, and that the HDL-C level is reduced by 20% or more by Probucol administration when this ratio is 5.3 or less.

Aged↗
PubMed1977

Diet and probucol in lowering cholesterol concentrations. Additive effects on plasma cholesterol concentrations in patients with familial type ii hyperlipoproteinemia.

Probucol [4,4-(isopropylidendithio bis)(2,6-di-t-butylphenol)], as as an adjunct to diet, was evaluated for its effect on lowering the plasma cholesterol level in patients with familial hypercholesterolemia (type II). The trial had a double-blind, placebo-controlled, crossover design. About half of the 30 patients responded to a low-cholesterol modified-fat diet with a decrease in the plasma cholesterol level of approximately 13%. When probucol was added to the diet of the responders, their plasma cholesterol level was lowered a further 13%. Patients who did not respond to the diet did show reduced plasma cholesterol concentrations when receiving probucol plus the diet. Analysis of the cholesterol content of the various lipoprotein fractions showed that the low-density lipoproteins accounted for most of the total plasma cholesterol level decrease. There was, as expected, no effect on plasma triglyceride concentrations. Neither the 7-dehydrocholesterol nor the desmosterol level was increased in the plasma of patients treated with probucol for three months. Probucol is useful as an adjunct to diet in lowering plasma cholesterol levels in patients with familial hypercholesterolemia. The drug was well tolerated by all patients.

Adult↗
PubMed1983

The hypolipidemic action of probucol: a study of its effects on high and low density lipoproteins.

This study examines the effects of probucol (1 g/day) on the plasma concentration, composition, and metabolism of low and high density lipoproteins (LDL and HDL) in eleven hyperlipidemic subjects, (seven Type II and four Type IV). The drug lowered plasma cholesterol in the Type II patients by 11% (P < 0.02) without affecting triglyceride. Both LDL and HDL cholesterol levels fell by 6% and 26%, respectively. The small reduction in the former was not associated with a change in the composition of the lipoprotein nor with a measurable alteration in the level of circulating apoLDL. Kinetic studies revealed that probucol had no consistent effect on either the synthesis or catabolism of apoLDL. However, probucol did exert a potent influence on HDL, lowering the level of this lipoprotein in both the Type II and Type IV patients despite the fact that total plasma cholesterol in the latter group was unchanged by treatment. The fall in HDL mass largely affected the HDL(3) subfraction; HDL(2), which was initially low in our subjects, did not show a consistent response to therapy. Not all of the constituents in HDL were equally affected by the drug. Specifically, the fall in total plasma apoA levels (which derived from significant reductions in the rates of synthesis of apoproteins A-I and A-II) was less than that of HDL cholesterol. Direct measurement of the composition of the lipoprotein confirmed that during therapy it carried less cholesterol per unit protein. The significance of these observations in relation to the prophylaxis of ischemic heart disease is not yet clear, but it seems prudent at present to use probucol selectively in subjects who show a substantial hypocholesterolemic response that derives primarily from a reduction in circulating LDL.-Atmeh, R. F., J. M. Stewart, D. E. Boag, C. J. Packard, A. R. Lorimer, and J. Shepherd. The hypolipidemic action of probucol: a study of its effects on high and low density lipoproteins.

Adult↗
PubMed1981

The long-term effects of probucol on serum lipid levels.

Probucol, a serum cholesterol-lowering agent, was studied in a double-blind, placebo-controlled trial for one year in 118 hypercholesterolemic men. The mean decrease in the level of serum cholesterol in the probucol group (N = 88) from baseline for months 6 through 12 ranged from 16.2% to 20.9%. The mean decrease from baseline for the placebo-treated patients (N = 30) ranged from 5.2% to 12.7%. The difference between the groups was highly significant. At the end of this one-year trial, 61 of the probucol-treated patients continued receiving therapy in an open trial for up to seven years. After the second year of probucol treatment, the reduction in serum cholesterol levels ranged from 23.1% to 27.4% and was subsequently maintained. The present report shows that probucol is safe and effective for the long-term lowering of serum cholesterol levels in patients with primary hypercholesterolemia.

Cholesterol↗
PubMed1982

Treatment of homozygous familial hypercholesterolaemia with probucol.

Ten patients with homozygous familial hypercholesterolaemia were treated with the recently introduced drug probucol (Lurselle; Mer-National) for 15-21 months. Xanthomas regressed or disappeared in most patients, angina lessened in two-thirds of cases and the ECG improved in half of those with pretreatment abnormalities. The mean fall in serum total cholesterol levels after 18 months of therapy was 27%. High-density lipoprotein cholesterol levels fell transiently in the early months of therapy but then returned to the pretreatment range. Plasma probucol levels varied between 20 micrograms/ml and 90 micrograms/ml, indicating good compliance, but did not correlate with the clinical or hypocholesterolaemic responses. Probucol was well tolerated by child and adult patients. The effects of probucol in this therapeutically resistant disorder were better than expected. Considered in relation to efficacy, safety, tolerance and convenience probucol appears to be the most satisfactory treatment for homozygous familial hypercholesterolaemia currently available.

Adolescent↗
PubMed1980

[Probucol: chemical structure, physical properties and assay methods (author's transl)].

Probucol is isopropylene dithio-4-4' di (di-tert-butyl-2,6 phenol), a molecule containing two atoms of sulphur. Its chemical structure therefore is very different from that of other known hypolipaemic compounds. Probucol is a white, odourless crystalline powder, almost insoluble in water but soluble in most organic solvents. It is strongly lipophilic. The UV spectrum of probucol in methanol shows maximum absorption at a wave-length of 242 nanometers. The finished product is presented as tablets containing 250 mg of probucol. The active substance in the pharmaceutical preparation can be identified by thin layer chromatography and assayed by ultraviolet spectrometry. Serum levels of probucol can be measured by gas chromatography with electron capture detection or by mass spectrometry and high pressure liquid chromatography.

Chemical Phenomena↗
PubMed1980

[Plasma levels of probucol in man after single and repeated oral doses (author's transl)].

Following administration of a single oral dose of 3 g probucol to healthy volunteers, mean peak plasma concentrations of 3.9 microgram/ml were observed at 24 hours. Successive blood levels measurements showed diphasic elimination, with half-lives of about 1 and 23 days. Plasma levels after a single 250 mg dose in volunteers are also reported. In 51 patients who received probucol 1 g daily for periods of 1 to 12 months, a concentration plateau was obtained within 1 to 3 months of treatment; the mean plasma levels ranged from 18.2 to 39.2 microgram/ml depending on the duration of probucol therapy. In another study carried out on 8 patients who were given the same daily dose during 12 months, the mean probucol plasma level at the end of that period was 18.9 microgram/ml. Repeated administration of probucol to healthy volunteers showed good correlation between dosage and blood levels.

Administration, Oral↗