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At least 937 records · Page 52Linked to original sources
PubMed1998

Chain-breaking antioxidants and ferriheme-bound drugs are synergistic inhibitors of erythrocyte membrane peroxidation.

Induced erythrocyte membrane peroxidation (EMP) is considered as an accurate model of reperfusion injuries and as such was used to investigate protective effects of various drugs. EMP was induced by an azo initiator and monitored by oxygen uptake. Both hydrophilic (ascorbic acid) and lipophilic (alpha-tocopherol, probucol, nicanartine) chain-breaking antioxidants as well as ferriheme-bound drugs (deferoxamine, chloroquine) inhibited EMP. When antioxidants and ferriheme-bound drugs were combined, synergistic effects were observed. It is proposed that ferriheme compounds which catalyse peroxide induced lipid peroxidation were blocked by deferoxamine and/or chloroquine. So these drugs inhibited at least partly the membrane peroxidation process and added their effects to the ones of chain-breaking antioxidants.

Adult↗
PubMed2003

Ascorbic acid augments cytotoxicity induced by oxidized low-density lipoprotein.

Although ascorbic acid (ASA) is known as a water-soluble antioxidant, we found that it accelerated the cytotoxicity induced by oxidized low-density lipoprotein (OxLDL) in vitro. This suggests that ASA may enhance the oxidation of LDL to augment the atherogenic activities of OxLDL under certain conditions. Thus, this study was designed to investigate the underlying mechanism that ASA enhances OxLDL-induced cytotoxicity. ASA enhanced the cytotoxicity of macrophage cell line (J774) induced by OxLDL in a dose-dependent manner, whose effect was more apparent in high glucose concentration in the medium. The ASA-induced enhancement in cytotoxicity was inhibited by the presence of lipid-soluble antioxidants, such as alpha-tocopherol and probucol, suggesting that the pro-cytotoxic effect by ASA is likely due to its pro-oxidant property. We also investigated the effects of ASA at different time points on the Cu2+-mediated oxidation of LDL. ASA decreased the rate of conjugated dienes formation when added at the early phase of oxidation, whereas it increased when added at the late phase of oxidation. These data suggest that ASA may act as a pro-oxidant under the condition of extensive LDL oxidation. To prevent oxidation stress, ASA would be better used together with lipid-soluble antioxidants for antioxidant therapies.

Animals↗
PubMed2005

Danshen inhibits oxysterol-induced endothelial cell apoptosis in vivo.

Oxysterols induce apoptosis in vascular endothelial cells in vitro, but it is not clear whether they do so in vivo. We intravenously injected an oxysterol, cholestan-3beta, 5alpha, 6beta-triol, into rats and quantitatively analyzed endothelial cell apoptosis in the aorta. Oxysterol significantly promoted apoptosis in a time- and dose-dependent fashion. The apoptosis had increased 4.5-fold 6 hrs after injection, and returned to the background level at 48 hrs. An extract of the Chinese herb Danshen as well as probucol abolished triol-induced endothelial cell apoptosis in vitro and in vivo. Since apoptotic cells are quickly cleared, oxysterol-induced apoptosis could significantly affect endothelial integrity over a long period of time. Radical scavengers may be useful for the prevention of endothelial damage.

Animals↗
PubMed1999

[Effectiveness of synthetic antioxidants in treatment of patients with peptic ulcer (an open randomized controlled trial)].

Two randomized groups of ulcer patients were compared. 102 patients of group 1 were treated with synthetic antioxidants (dibunol, probucol, emoxipine), while 100 patients of group 2 received a conventional treatment. Treatment results in group 1 appeared better: shortening of ulcer scarring, higher percentage of ulcer healing for 2 and 4 weeks, fall in the number of relapses during the first year of the follow-up, improvement in lipid peroxidation and antioxidant activity.

Adult↗
PubMed2000

[Role of oxidative stress in permeability changes observed in the microcirculation of diabetic rats in vivo].

AIM: Since an increase in the generation of free radicals has been shown in diabetes, we were interested on its involvement in changes in microvascular permeability during diabetes. METHODS: Intravital microscopy was used to study changes in microvascular permeability during diabetes. The extravasation of a fluorescent macromolecular tracer (FITC-Albumin) was measured for one hour and, after computer-aided image analysis, was expressed as variations of normalized grey levels (arbitrary units). RESULTS: The extravasation of the tracer was increased in diabetic rats. An intravenous bolus of probucol (an other anti-oxidant) inhibits this increase (fig. 1). The increase of the extravasation of the macromolecular tracer can also be inhibited when both superoxide dismutase, (which dismutates superoxide to hydrogen peroxide) and catalase (which reacts with hydrogen peroxide to form water and molecular oxygen) are administered simultaneously (fig 2). When administered separately, these enzymes failed to inhibit the increase of the extravasation of the macromolecular tracer. Five-week treatment of diabetic rats by pentoxifyllin, a drug which inhibits leukocyte activation did not have any effect on the increase of albumin extravasation (fig. 3a). In addition, no difference was found in adherent leukocytes or in the leukocyte rolling flux between diabetic and normoglycemic rats (fig. 3b). CONCLUSION: Reactive oxygen species are responsible for an increase in microvascular permeability likely by leukocyte-independent mechanisms.

Animals↗
PubMedDate not supplied

Pathogenetic concepts of membranous glomerulopathy (MGN).

Membranous glomerulopathy (MGN) is a frequent cause for nephrotic syndrome in adults. In this overview, the basic pathogenic features of Heymann nephritis, a "classical" model of MGN in rats, are compared with those of human MGN. While the pathogenic antigen(s) of rat Heymann nephritis (the polyspecific receptor protein gp330/megalin), and that of human MGN (unknown) are obvioulsy different, the results indicate that the molecular mechanisms of proteinuria may be similar in both instances and involve the formation of lipid peroxidation adducts in the glomerular capillary filter. As a consequence, probucol - an efficient inhibitor of lipid peroxidation - drastically reduces proteinuria both in Heymann nephritis and in a large proportion of human patients with MGN.

Basement Membrane↗
PubMed2001

Restenosis drug discovery--a formidable task.

Restenosis is a complicated disease. Neointima formation and unfavorable remodeling seem to contribute to the development of restenosis after angioplasty. Remodeling, a relatively new hypothesis, might be more crucial than neointima formation, although the two could well be inter-related. Stenting prevents unfavorable remodeling to some extent and lowers restenosis rates as compared to conventional balloon angioplasty. However, restenosis still occurs at too high a rate with stent angioplasty. A great many drugs have been tested in humans for the prevention of restenosis and failed, as most addressed the neointima formation problem only. Future drug design for restenosis should address both remodeling and neointima formation and some antioxidants, such as probucol, have shown promising results in this respect.

Animals↗
PubMed2002

Immunomodulation with DiNAC-- a new approach to the treatment of atherosclerosis?

Not all antioxidants reduce atherosclerosis. This may be because atherosclerosis has an autoimmune, inflammatory pathogenesis. As probucol is both an antioxidant and an immunomodulatory drug, it may be the immunomodulatory effect that underlies its ability to reduce atherosclerosis. N,N-Diacetyl-L-cystine is not an antioxidant but is immunomodulatory. In the Watanabe-heritable hyperlipidaemic rabbit model of familial hypercholesterolaemia, N,N-diacetyl-L-cystine treatment does not lower lipid levels but it does reduce atherosclerosis. Immunomodulation may be a new approach to the treatment of atherosclerosis.

Adjuvants, Immunologic↗
PubMed1992

[The radioisotope labelling of thrombocytes using a monoclonal antibody against membrane glycoproteins IIb-IIIa and the measurement of thrombocyte adhesion/aggregation on the substrate surface].

A new method for platelet labeling based on binding of monoclonal antibody to human platelets has been suggested in this study. Monoclonal antibody VM16a against membrane glycoproteins IIb-IIIa was labeled by 125I and then incubated with platelets. About 70% of added antibody was bound when it was used at the concentrations corresponding to the linear part of the concentration curve (0.5 and 1.0 micrograms/ml). Due to high efficiency of binding 125I-VM16a-labeled platelets were used for the measurement of adhesion/aggregation to the substrate in platelet-rich plasma without washing of the free label. Experiments with washed platelets double labeled with 51Cr and 125I-VM 6a showed high correlation between the data obtained with both labels. The method of platelet labeling has been applied for the assessment of drug action on platelet adhesion/aggregation. Measurements were performed in platelet-rich plasma and adhesion/aggregation was stimulated by ADP and analogue of thromboxane A2, U46619. It was shown/that antianginal drug trapidil strongly inhibited and antiatherogenic drug probucol did not affect platelet adhesion/aggregation stimulated by both agonists.

Adenosine Diphosphate↗
PubMedDate not supplied

[Mechanism of action of hypolipemic drugs].

Hypolipemic drugs decrease the plasmatic concentrations of atherogenic lipoproteins, especially LDL. Two main drug families are used: fibrates and inhibitors of HMG CoA reductase. Fibrates act essentially as an activator of lipoprotein lipase and by increasing the catabolism of triglyceride rich lipoproteins. Further, they have a slight and non specific inhibitory effect on HMG CoA reductase activity, while, the new drug family of "statines" have a high, specific inhibitory effect on this essential enzyme of the cholesterol synthesis pathway. This enzymatic inhibition decreases the cholesterol synthesis and increases the activity of the hepatic LDL receptors, which are in charge of LDL elimination from the body. Resins entrap biliary salts and increase the cholesterol loss in feces and induce an over expression of the LDL receptors of the hepatocytes. Probucol inhibits atherogenesis by decreasing both LDL and HDL cholesterol and delaying LDL oxidative processing which is now believed to be one of the major factors of atherogenicity.

Cholesterol↗
PubMedDate not supplied

[Interaction between dinitrosyl iron complexes and intermediate products of oxidative stress].

The interaction between glutathione-containing dinitrosyl iron complexes and superoxide radicals has been studied under the conditions of superoxide radical generation in mitochondria and in a model system xanthine-xanthine oxidase. It has been shown that both superoxide radical and hydroxyl radical are involved in the destruction of dinitrosyl iron complexes. At the same time, iron contained in dinitrosyl iron complex, apparently, does not catalyze the decomposition of hydrogen peroxide with the formation of hydroxyl radical. It has been found that dinitrosyl iron complexes with different anion ligands inhibit effectively the formation of phenoxyl probucol radical in a hemin-H2O2 a system. In this process, different components of the dinitrosyl iron complexes take part in the antioxidant action of these complexes.

Animals↗
PubMed1991

[The role of apoprotein B in the diagnosis and follow up of hyperlipoproteinemias in childhood].

The levels of apoproteins AI, B, lipoproteins (Total-C, LDL-C HDL-C, VLDL-C) and B/AI, LDL-C/HDL-C ratios were analyzed in 41 patients with primary hypercholesterolemia. 25 patients (60%) had a positive family history of hyperlipemia. All the patients showed a "pathological" apo B values, but only 35 of them (85%) coexisted with high Total-C and LDL-C values. 28/41 patients (68%) were treated and followed for more than one year, after which two groups were obtained: Group 1, respondent (N = 15) in which we observed a significant decrease of Total-C and Apo B after diet treatment. Group 2, no respondent (N = 13) in which not change in any biochemical parameter was observed, and required the addition of drug treatment (Probucol). Apoprotein B level was the biochemical parameter, which showed the highest porcentual decrease after treatment, in comparison with other biochemical parameters, resulting in a lowering of 36.3 and 26.3 percent for group 1 and 2 respectively. These results prove the usefulness of Apo B level measurement in the diagnosis of hyperlipoproteinemia in the pediatric age, as well as that children with normal total-C and LDL-C may have pathological Apo B and Apo B level is the parameter with highest decrease with dietetic and/o farmacological treatment.

Apolipoproteins B↗
PubMed1990

Reducing high blood cholesterol level with drugs. Cost-effectiveness of pharmacologic management.

We performed a cost-effectiveness analysis of pharmacologic treatment of high blood cholesterol levels. Agents modeled were cholestyramine, colestipol, gemfibrozil, lovastatin, niacin, and probucol. Pharmacologic effectiveness was estimated from reported studies. Cost estimates reflect societal resource consumption. Annual costs for therapy ranged from $327 (niacin) to $1881 (lovastatin, 80 mg/d). Niacin was the most efficient agent for reducing low-density lipoprotein cholesterol levels, having an average cost over 5 years of $139 per percent reduction in low-density lipoprotein cholesterol level. Lovastatin (20 mg/d) was also efficient ($177 per percent reduction). Cholestyramine was least efficient at $347. For high-density lipoprotein cholesterol, niacin was most efficient, at $116 per percent increase in high-density lipoprotein cholesterol level, followed by gemfibrozil at $271. Analyses combining low-density lipoprotein cholesterol and high-density lipoprotein cholesterol effects suggest that niacin and lovastatin (20 mg/d) were most efficient for reducing cardiovascular risk.

Anticholesteremic Agents↗
PubMed1989

[Drug therapy of hypercholesterolemia. Treatment of hypercholesterolemia in adults--a Norwegian therapeutic program 1988].

There are indications that treatment of hypercholesterolemia by means of drugs reduce risk of atherosclerosis in patients with increased concentrations of atherogenic lipoproteins. Such therapy should be initiated only after satisfactory exclusion of secondary causes of hyperlipoproteinemia, and should be regarded as an adjunct to appropriate dietary therapy. Drug therapy should be strongly considered in patients with total cholesterol above 8-9 mmol/l on diet therapy only. Drug therapy should be considered at even lower concentrations of cholesterol when coronary heart disease is present and in familial forms of hyperlipidemia when increased risk of atherosclerosis has been documented. In patients with increased plasma concentrations of total cholesterol the drugs of choice are agents which enhance the rate of LDL catabolism (resins) or reduce the rate of LDL synthesis (nicotinic acid). Fibrates should be used when triglycerides and cholesterol are both increased. HMG CoA reductase inhibitors offer considerable promise in the therapy of patients with primary hypercholesterolemia. Probucol may be used in combination with other drugs, particularly when xanthomas are present in patients with familial hypercholesterolemia.

Humans↗
PubMed1986

Contemporary recommendations for evaluating and treating hyperlipidemia.

The biochemistry, etiology, and evaluation of hyperlipidemia and its management, including dietary and drug therapies, are discussed. Strong evidence supports the role of increased cholesterol concentrations as an independent risk factor for coronary artery disease (CAD); however, evidence that elevated triglyceride concentrations are also an independent risk factor remains questionable. The cornerstone of the laboratory diagnosis of hyperlipidemia involves repeated measurement of serum or plasma cholesterol and triglyceride concentrations. The goals of therapy should be to reduce cholesterol or triglyceride concentrations or both to below the 75th percentile, modify co-existing risk factors, individualize the treatment, and minimize any adverse effects. Specific interventions must be determined on the basis of patient age, gender, etiology of hyperlipidemia, presence of other risk factors, and degree of lipid abnormality. The majority of patients may be managed with dietary therapy alone. The three-phase diet developed by the American Heart Association emphasizes a gradual reduction in cholesterol and fats with the substitution of polyunsaturated for saturated fats. Patients at risk for CAD with sustained elevations in plasma cholesterol concentrations above the 95th percentile or a triglyceride concentration above 500 mg/dL after an adequate dietary trial should be considered for drug therapy. The effects of cholestyramine and colestipol hydrochloride, niacin, dextrothyroxine, clofibrate, neomycin sulfate, probucol, gemfibrozil, and mevinolin and compactin on lipids and lipoproteins are reviewed. Hyperlipidemia should be managed systematically using information about the association between increased lipid concentrations and CAD, patient risk factors, and limitations of both diet and drug therapy.

Clofibrate↗
PubMed1986

Tendon xanthomas associated with cholestanolosis and hyperapobetalipoproteinemia.

Large Achilles tendon xanthomas of the type found in severe familial hypercholesterolemia were the first manifestation of cholestanolosis (cerebrotendinous xanthomatosis) in our patient, an otherwise asymptomatic normolipidemic 21-year-old woman. Extensive laboratory investigation disclosed the presence of hyperapobetalipoproteinemia which did not resolve with the administration of probucol. Immunofluorescent studies revealed marked accumulation of apolipoprotein B in a xanthoma excised from the tricipital area. This was in contrast to the spotty and weak fluorescence observed in a tuberous xanthoma, from the same anatomical area and histologically otherwise identical, obtained from a patient with heterozygous familial hypercholesterolemia. Hyperapobetalipoproteinemia has been reported before in association with sitosterolemia but not with cholestanolosis. We suggest that cholestanol, like sitosterol, may interfere with the normal uptake and degradation of low-density lipoproteins by peripheral cells.

Adult↗
PubMed1983

Nutrient and drug effects on cholesterol metabolism in the laying hen.

The laying hen is a highly dynamic model for studies of cholesterol metabolism. Cholesterol biosynthesis takes place primarily in the liver where it is regulated by both diet and drugs. Ovarian cholesterol biosynthesis follows a pattern different from that in liver and is not influenced by dietary fat or cholesterol. The hen responds to high levels of dietary polyunsaturated fat by increasing cholesterol biosynthesis, egg cholesterol deposition, and fecal bile acid excretion. Dietary cholesterol curtails liver cholesterol biosynthesis and may or may not result in increased egg cholesterol deposition and/or increased fecal steroid excretion depending on the level of cholesterol intake. Dietary plant sterols and fiber may moderate egg cholesterol deposition but the conditions under which this takes place are not well defined. D-Thyroxin reduces blood cholesterol, increases blood sterol turnover, and increases egg cholesterol concentration. Triparanol and azasterols prevent desmosterol conversion to cholesterol with resultant appearance of both sterols in blood and eggs. Probucol moderates egg cholesterol deposition by reducing synthesis and/or transfer of the sterol to the egg. Implications for the use of the hen in cholesterol metabolism studies are discussed.

Animals↗
PubMed1983

Pharmacologic therapy for the hyperlipidemic patient.

Drug therapy should be instituted only after appropriate diet treatment has been started and adequate baseline lipid and lipoprotein values are established. Nicotinic acid is useful in treating most lipoprotein disorders and the cutaneous flushing that develops during the early part of treatment is usually alleviated by aspirin. Cholestyramine and colestipol are nonabsorbable resins whose use is limited to type II hyperlipoproteinemia. Clofibrate is primarily effective in lowering triglyceride levels, but its clinical use has considerably declined following the World Health Organization study results that reported increased morbidity and mortality rates among patients receiving this drug. Based on the finding of increased mortality among a subset of patients participating in the Coronary Drug Project, dextrothyroxine is only recommended for treating patients who do not have clinically evident atherosclerotic heart disease. Probucol lowers total and low-density lipoprotein cholesterol levels, but has the undesirable effect of simultaneously reducing high-density lipoprotein levels.

Bile Acids and Salts↗