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At least 757 records · Page 42Linked to original sources
PubMed2003

Association of Chlamydia pneumoniae antibody with the cholesterol-lowering effect of statins.

To investigate the association between Chlamydia pneumoniae (C. pneumoniae) infection and atherosclerosis, we compared the effect of lipid-lowering drugs on carotid intima-media thickness (IMT) between patients who were positive and negative for C. pneumoniae antibodies. A total of 165 asymptomatic hypercholesterolemic patients were randomized to probucol (500 mg per day, n = 82) or pravastatin (10 mg per day, n = 83) and followed for 2 years. The 2-year change of IMT in the common carotid artery was the primary endpoint, while mean IMT change and major cardiovascular events were secondary endpoints. C. pneumoniae antibodies (IgA and IgG) were measured by enzyme-linked immunosorbent assay. The 50 patients without C. pneumoniae antibodies showed significant reduction of IMT progression (-19%), while no significant change of IMT was noted in the 115 antibody-positive patients (-6%). Significant inverse associations were found between the reduction of IMT progression and the C. pneumoniae IgA- and IgG-antibody index (P < 0.01 and 0.01, respectively). No significant differences in the reduction of serum total-cholesterol and LDL-cholesterol were found between antibody-positive and -negative patients. There was no significant difference of efficacy between probucol and pravastatin. These observations suggest that C. pneumoniae infection reduces the effect of lipid-lowering therapy on carotid atherosclerosis and that this organism may play a role in the progression of atherosclerosis.

Adult↗
PubMed2004

Solubilisation of poorly water-soluble drugs during in vitro lipolysis of medium- and long-chain triacylglycerols.

The partitioning of poorly soluble drugs into an aqueous micellar phase was exploited using an in vitro lipid digestion model, simulating the events taking place during digestion of acylglycerols in the duodenum. The aqueous micellar phase was isolated after ultracentrifugation of samples obtained at different degrees of triacylglycerol hydrolysis. Flupentixol, 1'-[4-[1-(4-fluorophenyl)-1-H-indol-3-yl]-1-butyl]spiro[iso-benzofuran-1(3H), 4' piperidine] (LU 28-179) and probucol were studied. The effect of the alkyl chain length of the triacylglycerol was studied using a medium-chain triacylglycerol (MCT) and a long-chain triacylglycerol (LCT), respectively. In general, an oil solution was used as the lipid source in the model. Samples were analysed in regard to micellar size, lipid composition and drug concentration. During lipolysis, the content of lipolytic products in the aqueous micellar phase increased. The micellar size (R(H) approximately 3 nm) only increased when long-chain lipolytic products were incorporated in the mixed micelles (R(H) approximately 7.8 nm). Flupentixol was quickly transferred to the mixed micelles due to high solubility in this phase (100% released). A tendency towards higher solubilisation of LU 28-179, when it was administered in the LCT (approximately 24% released) compared to when it was administered in the MCT (approximately 15% released) at 70% hydrolysis, and a lagphase was observed. There was no difference in the solubilisation of probucol using MCT or LCT ( approximately 20% released), respectively. Differences in the physicochemical properties of the drugs resulted in differences in their distribution between the phases arising during lipolysis.

Animals↗
PubMed2005

Apolipoprotein E, cholesterol transport and synthesis in sporadic Alzheimer's disease.

The discovery that the apolipoprotein E4 (apoE4) allele is genetically linked to both sporadic and familial late onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain of AD subjects. The presence of the E4 allele has been associated with lower levels of apoE in both serum and brain tissues of normal and AD subjects. In an attempt to reverse the apoE deficit in AD, we identified and characterized several apoE inducer agents using a low throughput-screening assay. The most promising of these compounds is called probucol. Administration of probucol, an old cholesterol lowering drug, in mild to moderate sporadic AD led to significant increases in CSF apoE levels and a decrease of CSF beta amyloid 1-42 without significant modifications of CSF tau concentration or CSF lipid peroxides levels. These results are consistent with recent reports suggesting that the long term use of cholesterol lowering drugs that block 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity in the fourth and fifth decade of life may help reduce the risk of developing AD at later age. These results indicate that, in addition to lipid transport mediated by apoE, cholesterol homeostasis in the brain is markedly altered in response to changes in the HMGR pathway; suggesting a possible explanation for the potentially beneficial effect of statins in common AD.

Alzheimer Disease↗
PubMed2000

Antioxidants attenuate myocyte apoptosis in the remote non-infarcted myocardium following large myocardial infarction.

OBJECTIVE: Increased oxidative stress and myocyte apoptosis co-exist in the remote non-infarcted myocardium (RM) following a large myocardial infarction. We proposed that these phenomena are causally related. METHODS AND RESULTS: On day 3 after induction of myocardial infarction, Sprague-Dawley rats were randomized to receive probucol and pyrrolidine dithiocarbamate (MI-T), or vehicle only (MI) for 7 weeks. Control rats (C) received vehicle. At 7 weeks, lipidperoxidation within the RM was assessed by measuring thiobarbituric acid reactive substances, which were significantly increased in MI vs. C, while MI-T was not different from C. There was a significant increase in cardiac myocytes positive for in situ TdT-UTP nick-end labeling within the RM in MI vs. C, which was inhibited in MI-T. Furthermore, internucleosomal DNA fragmentation was clearly demonstrated on agarose gels from RM in the MI group, while it was much less apparent on gels from RM in the C and MI-T groups. Western blot analysis showed a significant increase in p53, Bax and caspase-3 protein expression within the RM of MI vs. C, all of which were inhibited in the MI-T group. Furthermore, there was evidence for an increase in caspase-3 activity within the RM from MI vs. C, which was normalized in the MI-T group. CONCLUSIONS: Long-term treatment with the antioxidants probucol and pyrrolidine dithiocarbamate attenuates oxidative stress, myocyte apoptosis, caspase-3 like activity and the expression of p53, bax and caspase-3 within RM in rats after a large myocardial infarction.

Analysis of Variance↗
PubMed1997

Antioxidants prevent high-D-glucose-enhanced endothelial Ca2+/cGMP response by scavenging superoxide anions.

Very recently we proposed that hyperactivity of endothelial Ca2+/cGMP signaling under hyperglycemic conditions is due to superoxide anion (O2-) release. The present study was designed to investigate changes in endothelial glutathione (GSH) levels in response to high D-glucose and possible prevention of the high-D-glucose-initiated changes in Ca2+/cGMP signal by antioxidants. Under hyperglycemic conditions, GSH content increased by 29% within 4 h. Co-incubation with 10 mM GSH during high-D-glucose treatment normalized the Ca2+/cGMP response associated with an increase in GSH content by 222%. Vitamin C (250 microM) markedly diminished the high-D-glucose-mediated hyperreactivity of endothelial Ca2+ entry (by 40%) and Ca2+ release (by 52%). Similar to GSH, co-incubation with vitamin E (alpha-tocopherol; 50 micrograms/ml) and probucol (50 microM) completely prevented the high-D-glucose-initiated hyperreactivity of the endothelial Ca2+/cGMP response. Vitamin E, probucol, GSH and vitamin C diminished the high-D-glucose-mediated O2- release by 78, 65, 89 and 46%, respectively. These data suggest that antioxidants prevent high-D-glucose-initiated changes in endothelial Ca2+/cGMP response by scavenging the overshoot of O2-.

Animals↗
PubMed1999

d-Alpha-tocopherol prevents the hyperglycemia induced activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway in vascular smooth muscle cell by an increase of DAG kinase activity.

We have reported that d-alpha-tocopherol can prevent hyperglycemia-induced activation of DAG and PKC levels in vascular tissues as well as normalizing retinal blood flow and renal hyperfiltration. The mechanism of this effect, however, is not clear. Aside from alpha-tocopherol's principal role as an antioxidant agent, it has also been shown to act as a membrane stabilizer. Another possibility is that the effect of alpha-tocopherol is focused on the activation of DAG kinase, which is a key enzyme in the metabolism of DAG. Therefore, in this study, we examined the effect of alpha-tocopherol on the DAG kinase activity in vascular smooth muscle cell. We have also examined the effect of alpha-tocopherol, its analogues, and probucol on DAG kinase activities and expression. The present study showed that d-alpha-tocopherol's inhibitory effect on DAG-PKC pathway is by increasing DAG kinase activity in rat and human vascular smooth muscle cell (VSMC). Total DAG level was increased by 40 +/- 10% (mean +/- S.E.) (P < 0.05) in human VSMC, after exposure to 22 vs 5 mM glucose. This increase was normalized by d-alpha-tocopherol treatment in a concentration-dependent manner. In parallel, DAG kinase activation by d-alpha-tocopherol was also induced in a time- and dose-dependent manner. DAG kinase activity was increased by 57 +/- 19% (P < 0.05) in human VSMC and 112 +/- 35% (P < 0.05) in rat VSMC after 24 h of incubation with d-alpha-tocopherol (100 microg/ml). Another lipophilic antioxidant, probucol, also increased DAG kinase activity by 124 +/- 34%, but other vitamin E analogues with much less antioxidant potencies were ineffective. Western blots of various DAG kinase isoforms were not changed by d-alpha-tocopherol treatment. These results provide strong and detailed evidence that d-alpha-tocopherol can prevent hyperglycemia induced DAG-PKC activation by enhancing DAG kinase activity, probably through an antioxidant effect.

Animals↗
PubMed2001

A comparison of alternative polymer excipients and processing methods for making solid dispersions of a poorly water soluble drug.

Solid dispersions were prepared with the extremely poorly water soluble drug, probucol and the water soluble polymers, polyvinyl pyrrolidone (PVP), polyacrylic acid (PAA) or polyethylene oxide (PEO) and blends of these polymers. The solid dispersions were prepared either by the solvent evaporation method, or by compression moulding into films. The materials were characterised by a combination of thermal analysis and FT-Raman spectroscopy. The physical state of the drug was observed to be dependent on the carrier, thus the PVP solid dispersions contained amorphous probucol, whilst the PAA and PEO systems contained the crystalline polymorph II. The method of production was not found to greatly influence the state of the drug in the solid dispersion. The greatest extent of release into solution was observed for the binary blend of drug and PEO, and the blending of polymers was not found to have any advantageous effects in this study.

Anticholesteremic Agents↗
PubMed2000

Syntheses and biological evaluation of 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones as antioxidant and hypolipidemic agents.

A new series of compounds belonging to 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones (4-12a-e) have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven compounds, namely 5b, 5d, 6e, 8a, 8b, 10b and 11a, exhibit better antioxidant activity than probucol. Two compounds, 5d and 10b, have been evaluated in detail for antioxidant and hypolipidemic activities and show comparable activity profile to that of probucol and guggulipid. From the present study it may be postulated that the mechanism of action of these compounds could be through activation of lecithin cholesterol acyltransferase (LCAT), liver lipolytic activity, increased faecal bile acid secretion and inhibition of hepatic cholesterol biosynthesis.

Alkenes↗
PubMed1999

Induction of cellular cholesterol efflux to lipid-free apolipoprotein A-I by cAMP.

In the present study apolipoprotein-mediated free cholesterol (FC) efflux was studied in J774 macrophages having normal cholesterol levels using an experimental design in which efflux occurs in the absence of contributions from cholesteryl ester hydrolysis. The results show that cAMP induces both saturable apolipoprotein (apo) A-I-mediated FC efflux and saturable apo A-I cell-surface binding, suggesting a link between these processes. However, the EC50 for efflux was 5-7-fold lower than the Kd for binding in both control and cAMP-stimulated cells. This dissociation between apo A-I binding and FC efflux was also seen in cells treated for 1 h with probucol which completely blocked FC efflux without affecting apo A-I specific binding. Thus, cAMP-stimulated FC efflux involves probucol-sensitive processes distinct from apo A-I binding to its putative cell surface receptor. FC efflux was also dramatically stimulated in elicited mouse peritoneal macrophages, suggesting that cAMP-regulated apolipoprotein-mediated FC efflux may be important in cholesterol homeostasis in normal macrophages. The presence of a cAMP-inducible cell protein that interacts with lipid-free apo A-I was investigated by chemical cross-linking of 125I-apo A-I with J774 cell surface proteins which revealed a Mr 200 kDa component when the cells were treated with cAMP.

Animals↗
PubMed2000

Adriamycin-induced heart failure: mechanism and modulation.

Adriamycin (doxorubicin) is one of the most effective chemotherapeutic agents against a variety of cancers, but its usefulness is seriously curtailed by the risk of developing heart failure. Available laboratory evidence suggests that an increase in oxidative stress, brought about by increased free radical production and decreased myocardial endogenous antioxidants, plays an important role in the pathogenesis of heart failure. Adriamycin-induced apoptosis and hyperlipidemia may also be involved in the process. Probucol, a lipid-lowering drug and an antioxidant, completely prevents the occurrence of heart failure by reducing oxidative stress as well as by the modulation of apoptosis and high lipid concentrations. Thus, combined therapy with adriamycin and probucol has a high potential for optimizing the treatment of cancer patients.

Animals↗
PubMed1993

Gelatin-acacia microcapsules for trapping micro oil droplets containing lipophilic drugs and ready disintegration in the gastrointestinal tract.

Nonhardened gelatin-acacia microcapsules were studied for encapsulation of microdroplets of oil solution containing a lipophilic drug as core material and ready disintegration with release of micro oil droplets in the gastrointestinal tract. Probucol and S-312-d, a Ca-channel blocker, were employed as model lipophilic drugs. Glyceryl tricaprylate and tricaprate mixture solutions containing these drugs were encapsulated according to the complex coacervation method and were recovered as free-flowing powders without any hardening (cross-linking) step. The microcapsules obtained were disintegrated, and the emulsion was reproduced within 3 min at 37 degrees C in the first or second test solution defined in the Japanese Pharmacopeia XII. When the microcapsules were stored as a powder at room temperature in a closed bottle, no significant change in their appearance or disintegration time upon rehydration was observed even after 1 year. Oral bioavailabilities of model drugs from the microcapsules were tested in rats and dogs and compared with those from other conventional formulations. Gastrointestinal absorption of both probucol and S-312-d from the microcapsules was remarkably more efficient than that from other formulations such as powders, granules, or oil solution. The proposed method for microencapsulation could be useful for powdering drug-containing oil solutions or O/W emulsions while maintaining excellent bioavailability.

Acacia↗
PubMed2003

Interrelation between compensation of carbohydrate metabolism and severity of manifestations of oxidative stress in type II diabetes mellitus.

Glycosylation end-products formed during diabetes mellitus promoted atherogenic oxidative modification of low-density lipoproteins. We evaluated the effects of compensation of carbohydrate metabolism and therapy with antioxidant probucol on parameters of free radical oxidation in patients with type II diabetes mellitus. Compensation of carbohydrate metabolism reduced manifestations of oxidative stress, which was manifested in accelerated enzymatic utilization of reactive oxygen species and lipid peroxides and decreased content of free radical oxidation products in low-density lipoproteins. In patients with type II diabetes mellitus combination therapy with antioxidant probucol decreased the severity of oxidative stress and stabilized carbohydrate metabolism without increasing the dose of hypoglycemic preparations.

Aged↗
PubMed2005

Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans.

How genetic and environmental factors interact in Parkinson disease is poorly understood. We have now compared the patterns of vulnerability and rescue of Caenorhabditis elegans with genetic modifications of three different genetic factors implicated in Parkinson disease (PD). We observed that expressing alpha-synuclein, deleting parkin (K08E3.7), or knocking down DJ-1 (B0432.2) or parkin produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than nontransgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben, or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (Fe(II) or Cu(II)), or etoposide compared with the nontransgenic nematodes. Each of the PD-related lines was also partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-beta-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid. Complete protection in all lines was achieved by combining d-beta-hydroxybutyrate with tauroursodeoxycholic acid but not with probucol. These results show that diverse PD-related genetic modifications disrupt the mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.

3-Hydroxybutyric Acid↗
PubMed1998

Irradiation of Crotalus durissus terrificus crotoxin with 60Co gamma-rays induces its uptake by macrophages through scavenger receptors.

PURPOSE: To investigate the action of 2 kGy 60Co gamma-rays on crotoxin and its favoured uptake through scavenger receptor (ScvR) mouse peritoneal macrophages. MATERIALS AND METHODS: Native or irradiated crotoxin (iCTX) (50 microg/ml) dosed with 2 kGy 60Co gamma-rays (dose-rate 540 Gy/h) were offered to mouse peritoneal macrophages; their uptake was evaluated by immunohistochemistry and quantitative in situ ELISA. Receptors recognizing irradiated crotoxin were evaluated with specific ScvR blockers (Probucol and dextran sulphate) or with non-specific blocking using foetal calf serum (FCS). RESULTS: Immunohistochemical assays revealed more deeply staining intracytoplasmic vacuoles in macrophages incubated with iCTX. Using in situ ELISA with ScvR specific blockers, it was shown that the increased uptake of iCTX was blocked by Probucol or dextran sulphate, but not by FCS. On the other hand, the uptake of native crotoxin was decreased by FCS, but not affected by ScvR blockers. The morphology and viability of macrophages were preserved during the experiments. CONCLUSIONS: It is concluded that 60Co gamma-rays probably induced oxidative changes in crotoxin, driving this toxin towards ScvR mouse peritoneal macrophages. This suggests a different in vivo route of iCTX away from toxic neural sites by a preferential and rapid internalization and processing by macrophages, leading to the induction of a better immune response.

Animals↗
PubMed1994

Treatment of cholesterol-fed rabbits with dietary vitamins E and C inhibits lipoprotein oxidation but not development of atherosclerosis.

New Zealand White rabbits were made hypercholesterolemic by feeding a high cholesterol diet (10 g/kg diet) with or without added antioxidants. The antioxidants used were either probucol (10 g/kg) or vitamin E (10 g/kg) plus vitamin C (0.6 g/kg). Serum cholesterol concentrations were monitored as a function of time. At the end of 10 wk, serum and lipoprotein vitamin E concentrations, the extent of oxidation of lipoprotein fractions (thiobarbituric acid reacting substances), the susceptibility of lipoprotein to oxidation in vitro (conjugated diene formation) and the extent of atherosclerosis (aortic area stained by Sudan IV and plaque thickness) were measured. Rabbits fed diets supplemented with vitamins E and C had markedly higher serum vitamin E concentrations, marked vitamin E enrichment in all lipoprotein fractions, less oxidation in VLDL and LDL and enhanced resistance of LDL to further in vitro oxidation, but did not have significantly less aortic atherosclerosis. Rabbits given supplemental probucol likewise exhibited reduced oxidation of lipoproteins. However, aortic atherosclerosis in these animals was significantly lower, as were serum cholesterol concentrations. Inhibition of lipoprotein oxidation itself was not sufficient to reduce atherosclerosis in cholesterol-fed New Zealand White rabbits.

Animals↗
PubMed1997

Adriamycin cardiomyopathy: pathophysiology and prevention.

Current knowledge about adriamycin cardiomyopathy indicates that the major cause of this condition is increased oxidative stress although the drug's antitumor action in patients may involve other mechanisms. Controversies about the different antioxidants in preventing cardiomyopathy likely stem from the fact that antioxidants must be effective in both the lipid and water phases, and the dose must be optimal, in order to be protective. Probucol, an antioxidant and promoter of endogenous antioxidants, is one such agent. Conducting clinical trials with an optimal dose of probucol is the next step and should make this great anticancer drug safer and more efficient in the fight against the cancer.

Animals↗
PubMed1996

Antioxidants in the prevention of atherosclerosis.

Four antioxidant treatment modalities against atherosclerosis and coronary heart disease are scrutinized: probucol, beta-carotene, alpha-tocopherol and anti-iron treatment. A pattern seems to have emerged in which some treatments look promising, but others are disappointing. Most published studies of antioxidation in atherosclerosis have been ad-hoc in that the primary endpoint of the study has not been a diagnosis related to atherosclerosis; this may be misleading. The most promising antioxidant seems to be alpha-tocopherol, supported by the results of the Cambridge Heart Antioxidant Study. Probucol has the drawback of decreasing high density lipoprotein concentration and is therefore unlikely to influence atheroma in people. beta-Carotene has been repeatedly shown to be ineffective against coronary heart disease. Anti-iron treatment has not yet been tested in animal models or in man. More has to be learned of the role of antioxidation in atherosclerosis before the effectiveness of this treatment modality can be established.

Anticholesteremic Agents↗
PubMed2003

AGI-1067: a multifunctional phenolic antioxidant, lipid modulator, anti-inflammatory and antiatherosclerotic agent.

To explore the therapeutic efficacy and potential mechanisms of action of a new class of antiatherosclerotic drugs, AGI-1067 [mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl] ester] (butanedioc acid) was tested in several animal models of atherosclerosis. AGI-1067, a novel phenolic antioxidant, was well tolerated in a 1-year study in hypercholesterolemic cynomolgus monkeys. It lowered low-density lipoprotein cholesterol (LDLc) by 41 and 90% at oral doses of 50 and 150 mg/kg, respectively and increased high-density lipoprotein cholesterol (HDLc) by 107% at the higher dose. In contrast, another phenolic antioxidant, probucol, had a modest LDLc-lowering effect (15% at 250 mg/kg) while decreasing HDLc (37% at 150 mg/kg). Histopathology of the aortas and coronary arteries revealed no atherosclerosis in the AGI-1067 (150 mg/kg) group and minimal-to-moderate atherosclerosis in the vehicle and probucol (150 mg/kg) groups. AGI-1067 also inhibited atherosclerosis in LDL receptor-deficient (LDLr -/-) mice and apolipoprotein E-deficient (ApoE -/-) mice even in the absence of a lipid-lowering effect. In LDLr -/- mice, AGI-1067 reduced aortic atherosclerosis by 49%. In ApoE -/- mice, AGI-1067 reduced atherosclerosis by 25, 41, and 49% in the arch, thoracic, and abdominal regions of the aorta. AGI-1067 also reduced vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in lungs of lipopolysaccharide-stimulated mice. At the cellular level, AGI-1067 inhibited tumor necrosis factor-alpha-inducible expression of VCAM-1, MCP-1, and E-selectin in human aortic endothelial cells (IC50 values = 6, 10, and 25 microM, respectively). These data show that AGI-1067 can inhibit atherosclerosis not only via its lipid-lowering effects but also by having direct anti-inflammatory effects on the vessel wall and suggest that it may be a novel therapeutic agent for coronary artery disease.

Animals↗