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PubMed1993

[A trial of the clinical use of the Russian hypocholesterolemic preparation fenbutol--an analog of probucol].

Phenbutol, a Russian analogue of probucol, was studied by the single blind method by using placebo in 30 patients aged 36 to 65 years whose total serum cholesterol levels were more than 250 mg/dl after a month placebo therapy. The patients were divided into two groups: (1) 15 patients on placebo and (2) 15 patients on phenbutol, 500 mg twice a day for 5 months. Blood lipid parameters were monthly determined. The findings are in agreement with the data on the effects of probucol on lipids and its adverse effects. During the follow-up, phenbutol showed 17%, 14% and 10% decreases in total cholesterol and low density lipoprotein cholesterol and high density lipoprotein cholesterol, respectively, as compared with the baselines. These changes were greater than those in patients on placebo. In the first week of therapy with phenbutol, vomiting, appetite decrease, digestive disturbances were observed in 73% of patients. These adverse reactions did not require its withdrawal. Resting ECG Q-T interval became prolonged in 7 out of 15 patients receiving phenbutol (maximum 500 msec).

Adult↗
PubMed1990

An evaluation of the antioxidant and potential pro-oxidant properties of food additives and of trolox C, vitamin E and probucol.

The food additives propyl gallate and vanillin inhibited iron ion-dependent lipid peroxidation in rat-liver microsomes, but stimulated formation of a deoxyribose degrading species, probably hydroxyl radical, from ferric-EDTA and hydrogen peroxide. Propyl gallate accelerated DNA damage by the anti-tumour antibiotic bleomycin, although vanillin did not. The water-soluble vitamin E analogue Trolox C also stimulated bleomycin-dependent DNA damage, but not hydroxyl radical generation from ferric-EDTA and H2O2. Indeed, Trolox C was found to be a powerful scavenger of hydroxyl radical (rate constant greater than 10(10) M-1s-1). Probucol did not stimulate oxidative damage in any of the systems tested, and is a powerful inhibitor of lipid peroxidation in rat liver microsomes. The ESR spectrum of the radical produced by one electron-oxidation of probucol in ethanol is described.

Animals↗
PubMed1993

Repeated measurements over time: statistical analysis of the angiographic outcomes in the Probucol Quantitative Regression Swedish Trial (PQRST).

An increasing use of non-invasive techniques and arteriographies of the coronary, carotid or femoral arteries has taken place during recent years. This has prompted researchers to perform long-term randomized trials aiming at reducing atherosclerosis progression or achieving regression by cholesterol lowering in high risk populations. These trials are designed to use outcomes such as various indices of atherosclerosis which are assessed repeatedly over time. There are major decisions to be made contingent on the data structures in these trials, such as sphericity, interaction, development over time, missing data, non-normality etc. So, the statistical analysis of such data needs to be planned and specified a priori in a unified manner. This is demonstrated for the Probucol Quantitative Regression Swedish Trial (PQRST) which is designed to answer the question whether the drug probucol, given in combination with diet and cholestyramine, can delay development of atherosclerosis in hypercholesterolemic patients up to 70 years old. Change in atheroma volume is assessed by a newly developed quantitative angiographic technique based on digitized angiograms.

Analysis of Variance↗
PubMed1986

Severe hypoalphalipoproteinemia induced by a combination of probucol and clofibrate.

Observation of a markedly depressed HDL-cholesterol (5 mg/dL) in a patient with familial hypercholesterolemia (FH) receiving probucol (1 g/day) and clofibrate (2 g/day) prompted a review of all cases treated by this combination at our lipid clinic. Hypoalphalipoproteinemia (HDL-C less than 15 mg/dL) developed in 19 of 28 (70%) hyperlipidemic subjects who received this combination for an average of 1.5 years. This effect was sustained and reversible; it did not occur on either drug alone and was manifested on average 17 weeks after the combination was started. Plasma triglycerides increased significantly in most of those patients susceptible to this reduction in HDL-C. Plasma apolipoprotein A-I was decreased 82%, in proportion to the HDL-C fall, whereas apo A-II was lowered 65%. Since apo C-III concentrations tended to be high, the apo A-I/C-III ratio was markedly depressed. Apo E levels were unchanged and apo B levels reflected the high LDL concentrations of the underlying disease. An intermediate response was observed in subjects whose HDL-C remained well above 15 mg/dL on the combination. No deleterious side-effects could be attributed directly to the administration of the combined drugs in this high-risk group. One patient actually showed complete regression of xanthelasma and extensor tendon xanthomas of the finger on the combination. A parallel is drawn with Fish-Eye disease and the presence of the apolipoprotein A-I Milano variant, where similar HDL-C levels are observed in the absence of an increased atherogenic risk. It is mandatory to monitor plasma HDL-C in hypercholesterolemic patients treated with this combination, otherwise the pronounced HDL-deficiency could go unnoticed.

Apolipoproteins↗
PubMed1998

Survival and cardiovascular pathology of heterozygous Watanabe heritable hyperlipidaemic rabbits treated with pravastatin and probucol on a low-cholesterol (0.03%)-enriched diet.

This study was aimed at determining the effects of a combined pravastatin and probucol regimen on survival and vascular pathology of heterozygous Watanabe heritable hyperlipidaemic (WHHL) rabbits fed a low-cholesterol (0.03%)-enriched diet. Pravastatin monotherapy preceded the combined treatment. In animals receiving pravastatin and the enriched diet (verum group; n = 6), mean total serum cholesterol levels were consistently lowered at a dosage of 5 mg/kg pravastatin and with the combined treatment. Survival was increased (median 45 vs 25 months), while coronary atherosclerosis was less obstructive and altered to a more fibrous type than in controls (n = 8). The extent of aortic lesions, as determined by the relative plaque volume, was not related to survival in either group. However, aortic plaque types in verum group animals revealed less severe stages with a different composition and architecture, with a lower relative content of macrophage-derived foam cells and necrosis and a higher relative content of extracellular matrix. There was also a thicker fibrous cap than in control animals of similar age. Our data reveal a beneficial effect on survival of heterozygous WHHL rabbits when lipid-lowering and antioxidative treatment are combined. This appears to be due both to reduced coronary atherosclerosis and to a different, more stable type of atherosclerotic disease in this animal model.

Animals↗
PubMed1990

Phenothiazines inhibit copper and endothelial cell-induced peroxidation of low density lipoprotein. A comparative study with probucol, butylated hydroxytoluene and vitamin E.

The effect of two phenothiazines, chlorpromazine (CPZ) and trifluoperazine (TFP) on the copper and endothelial cell-induced peroxidation of low density lipoprotein (LDL) has been studied and compared to that of drugs previously shown to protect LDL against peroxidation: probucol (PBC) and butylated hydroxytoluene (BHT). Incubation with CPZ or TFP inhibited in a dose-dependent manner LDL peroxidation induced either by copper ions or by cultured endothelial cells. Both the electrophoretic mobility and the thiobarbituric reactive substance content of LDL returned to almost normal values in the presence of 50 microM CPZ or TFP. The two studied phenothiazines also strongly inhibited the hydrolysis of LDL phosphatidylcholine which accompanies copper or endothelial cell-induced peroxidation of the particle. CPZ and TFP were as effective as PBC and BHT in inhibiting the LDL peroxidation. Whereas copper or endothelial cell-oxidized LDL were recognized and rapidly catabolized by mouse peritoneal macrophages, CPZ- or TFP-, as well as PBC- or BHT-treated LDL were not. Moreover, it was found that, in contrast to vitamin E, neither CPZ nor PBC reacted with model peroxy radicals formed by gamma irradiation of aerated ethanol. The possible mechanisms underlying this protective effect of phenothiazines against LDL oxidative modification are discussed.

Animals↗
PubMed1992

Increased oxidizability of plasma lipoproteins in diabetic patients can be decreased by probucol therapy and is not due to glycation.

Atherosclerosis is considered to be the major complication of diabetes mellitus. Since diabetic patients have increased blood levels of lipid peroxidation products we investigated whether the susceptibility of blood components to oxidation is altered in this disease. We analysed the parameters characterizing the extent of oxidative change and the antioxidant status of low density lipoprotein (LDL) and high density lipoprotein (HDL) in a group of diabetic patients and in a control population. LDL oxidizability was significantly higher for patients (P = 0.001) than for individuals in the control group. There were no significant differences in the alpha-tocopherol content or levels of performed peroxides in LDL samples isolated from diabetic patients and control individuals which could account for this effect. Similarly, LDL glycation, common in diabetes mellitus, was not responsible, since LDL glycated in vitro was more rather than less resistant to oxidation. Even the presence of unbound glucose at normal or elevated physiological concentrations had a delaying effect on the oxidation of LDL. The increased oxidizability of LDL isolated from diabetic patients could be reduced to control levels by a 6-week standard treatment with Probucol, originally applied to reduce their blood cholesterol.

Adult↗
PubMed1981

Effect of probucol on the activity of postheparin plasma lipoprotein lipase and hepatic lipase.

The effect of discontinuation of long term (34-56 months) probucol treatment on serum lipids, lipoproteins and on the activity of postheparin plasma lipoprotein and hepatic lipase ahs been studied in 10 healthy males participating in a primary prevention programme of coronary heart disease. A significant increase was observed in the activity of postheparin plasma lipoprotein lipase, in the total serum cholesterol concentration and in the serum concentrations of high density lipoprotein (HDL) cholesterol, HDL phospholipids and apoprotein AI after withdrawal of the drug No changes were seen in the serum triglyceride levels or in the activity of postheparin plasma hepatic lipase. The activity of postheparin plasma hepatic lipase tended to correlate with the serum concentration of HDL. No correlations were present between the individual changes in the serum levels of HDL and in the activity of postheparin plasma triglyceride lipases.

Apolipoprotein A-I↗
PubMed1991

A family of familial hypercholesterolemia with cerebral infarction and without coronary heart disease. An unusual case with corneal opacity, polyneuropathy and carpal tunnel syndrome in the family: therapy with probucol and tocopherol nicotinate.

A study is presented of a 48-year-old female patient and her three siblings with familial hypercholesterolemia. The family members had episodes of cerebral infarction and apparently had atherosclerosis of the internal carotid artery, but no coronary heart disease due to their almost normal level of cholesterol. The laboratory studies of the family members revealed the elevations of serum lipid peroxides, serum lipoprotein(a), leukotriene C4 in blood, the thromboxane B2/6-keto-prostaglandin F1 alpha ratio in plasma and serum hydroxyl radical. Therefore, it is suspected that these factors accelerating atherosclerotic process caused the cerebral infarction. The patient demonstrated corneal opacities, palpebral xanthomas, thickened Achilles tendons, polyneuropathy and the carpal tunnel syndrome. Laboratory studies revealed an elevation in the OKT4/8 ratio, monocyte dysfunction with respect to phagocytosis and chemotaxis, and the presence of the 46XX/45XO mosaic chromosome. Lipid deposits were observed in the Achilles tendon, the transverse carpal ligament, the Schwann's cells and axons of the sural nerve, and in the keratocytes and stroma of the cornea. Following the administration of tocopherol nicotinate and probucol, the patient's serum lipid peroxide normalized and there was improvement in her palpebral xanthomas, thickening of the Achilles tendons and polyneuropathy. We conclude that the lipid deposits in this patient were due to the abnormal oxidative metabolism of low-density lipoprotein and a disturbance of the scavenger pathway due to the monocyte dysfunction.

Arteriosclerosis↗
PubMed1994

Ameliorative effect of dietary probucol on polychlorinated biphenyls-induced hypercholesterolemia and lipid peroxidation in the rat.

The hypocholesterolemic and antioxidant activities of probucol (PB) were examined in rats which were fed for 10 days with diets supplemented with or without 0.02% polychlorinated biphenyls (PCB). Dietary intake of PCB caused multiple effects on lipid metabolism, such as increased levels of both serum and HDL cholesterol, and increased TBA-reactive substances (TBARS), in hepatic subcellular fractions. PB 1% in comparison with either control or alpha-tocopherol (Toc) 0.1%, reduced the serum cholesterol levels in normolipemic as well as in PCB-induced hypercholesterolemic rats. In addition, this drug ameliorated the elevated TBARS induced by PCB in the hepatic subcellular fractions, although less antioxidant activity was noted in rats fed PB than in those fed Toc. The microsomes isolated from various groups were incubated for 2h at 37 degrees C in the presence or the absence of ferrous iron in vitro; microsomes from the PB-fed rats were as much resistant against lipid peroxidation in ferrous-free incubation medium as were those from Toc-fed rats, while in the presence of ferrous iron there was a higher antioxidant effect on lipid peroxidation in the latter fraction than in the former. HPLC analyses showed that less PB than Toc was incorporated into the hepatic subcellular fractions, suggesting that the concentration of antioxidants in hepatic subcellular fractions determine the extent of lipid peroxidation in situ. These results suggest that the administration of PB is an effective approach for the treatment of both hypercholesterolemia and elevated lipid peroxidation while Toc ameliorates only an elevated lipid peroxidation.

Animals↗
PubMed2003

Probucol restores the defective leukocyte-endothelial interaction in experimental diabetes.

Defective leukocyte-endothelial interactions have been observed in experimental type 1 diabetes. One of the mechanisms involved in the late complications of diabetes mellitus is the formation of free radicals species. Antioxidant treatment has been demonstrated to have beneficial effects on the complications observed in this pathology. Using intravital microscopy to visualize venules of the internal spermatic fascia, we demonstrated that the defective leukocyte-endothelial interactions in alloxan-induced diabetic rats could be corrected by probucol treatment. The defects were quantitated by the number of leukocytes rolling along the venular endothelium, sticking to the venular wall after topical application of zymosan-activated plasma (10%-0.1 ml) or leukotriene B4 (1 microM/0.1 ml) and migrated after the application of a local irritant stimulus (carrageenan, 100 microg/0.1 ml). Leukocyte counts, erythrocyte velocity and venular shear rate, unaltered in diabetic rats, were not modified by this treatment. Reactive oxygen species formation by endothelial cells increased in diabetic preparations, and the reduced expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and P-selectin in cross-sections of the whole testis of the animals, were both restored by the antioxidant agent. Therefore, antioxidant treatment improves leukocyte-endothelial interaction in diabetic rats at least in part by restoring the expression of adhesion molecules in venules of diabetic rats.

Animals↗
PubMed1988

Lipoprotein oxidation and cytotoxicity: effect of probucol on streptozotocin-treated rats.

For a number of years, the cell-damaging effects of oxidized low-density lipoproteins (LDL) have been studied. Oxidized LDL-induced tissue damage may be important in vivo; there is mounting evidence for the occurrence of oxidized lipoproteins in various pathologic conditions such as in atherosclerotic lesions and in the plasma of diabetic humans and experimental animals. These developments led to the current study of lipoprotein oxidation in streptozotocin-induced diabetes in the rat. This presentation will first review investigations of the toxicity of LDL to cells grown in tissue culture that occurs when LDL becomes oxidized. Then the results are presented indicating that lipoprotein oxidation occurs in vivo in experimental diabetes and renders diabetic lipoproteins cytotoxic in vitro. Both the oxidation and the cytotoxicity of diabetic lipoproteins are inhibitable by treating the diabetic rats with lipophilic antioxidants such as probucol.

Animals↗
PubMed1988

Probucol Quantitative Regression Swedish Trial: new angiographic technique to measure atheroma volume of the femoral artery.

The Probucol Quantitative Regression Swedish Trial is studying the development of atherosclerosis in hyperlipidemic patients through the use of digitized femoral arteriographic examinations. In a 20-cm segment of the femoral artery, cross-sectional areas are calculated using an algorithm that was introduced by Hilal and Crawford. Changes in atheroma volume are measured in repeat arteriographic examinations. This report describes the radiologic technique, the scanning procedure and the image analysis.

Arteriosclerosis↗
PubMed1983

Assessment of the antihypercholesterolemic drug, Probucol, in benign prostatic hyperplasia.

Seventy patients were administered either Probucol, an anti-cholesterol agent or a placebo in a double blind manner for a period of 1 year in an effort to assess the effectiveness of this agent in treating benign prostatic hyperplasia. Sensation of incomplete voiding and peak and mean voiding flow rates showed a trend which indicated a therapeutic effect, however, this effect was comparable for both placebo and the drug group. This is interpreted as indicating the effectiveness of standard urologic therapy, and double blind trials are therefore needed in assessing different agents for the medical management of benign prostatic hyperplasia.

Cholesterol↗
PubMed2002

Intensification of free radical oxidation of low-density lipoproteins in the plasma of patients with ischemic heart disease receiving beta-hydroxy-beta-methylglutaryl-coenzyme A reductase inhibitor cerivastatin and inhibition of low-density lipoprotein peroxidation with antioxidant probucol.

Inhibitors of the key enzyme of cholesterol biosynthesis beta-hydroxy-beta-methylglutaryl-coenzyme A reductase (statins) decrease cholesterol content in atherogenic low-density lipoproteins in patients with coronary heart disease and hypercholesterolemia, but inhibited biosynthesis of ubiquinone Q10 protecting low-density lipoproteins from free radical oxidation. Cerivastatin in a daily dose of 0.4 mg markedly increased the content of lipid peroxides in low-density lipoproteins. However, complex therapy with cerivastatin and antioxidant probucol (250 mg/day) was accompanied by a sharp decrease in the content of lipid peroxides in low-density lipoproteins in patients with coronary heart disease in vivo. These data indicate that antioxidant agents should be used in combination with inhibitors of beta-hydroxy-beta-methylglutaryl-coenzyme A reductase (hypolipidemic preparations) for the therapy of patients with coronary heart disease.

Antioxidants↗
PubMed2004

Role of antioxidant enzymes and antioxidant compound probucol in antiradical protection of pancreatic beta-cells during alloxan-induced diabetes.

The severity of disturbances in carbohydrate metabolism in rats with alloxan-induced diabetes depended on activity of antioxidant enzymes in the target organ (pancreas). Damage to the pancreas is related to intensive generation of reactive oxygen species, free radicals, and lipid peroxides. Alloxan-induced diabetes in rats is a free radical disease, which in vivo serves as a useful model for the search for pharmacological preparations with antiradical and antioxidant properties. The antioxidant compound probucol indirectly increased activity of antioxidant enzymes in the pancreas and prevented the development of alloxan-induced diabetes in rats. Our results indicate that different sensitivity of laboratory animals of various species (rats and guinea pigs) to the influence of alloxan is associated with abnormal variations in activity of enzymes utilizing reactive oxygen species and lipid peroxides in mammalian pancreatic cells.

Animals↗
PubMed1984

The effect of different oils on the absorption of probucol in the rat.

The effect of oily vehicles on the gastrointestinal absorption of the hypocholesterolaemic agent probucol has been investigated in the rat. The plasma concentration was determined following its administration in arachis oil (peanut oil), Miglyol 812 (fractionated coconut oil) and liquid paraffin. The total absorption of the drug, calculated as the area under the plasma concentration time curve, was significantly greater for the arachis oil formulation than with the other vehicles. The drug was selectively absorbed via the lymphatic system, lymph drug concentrations being highest following co-administration of arachis oil.

Animals↗