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At least 883 records · Page 49Linked to original sources
PubMed1984

Influence of hypocholesterolemic drugs on aortic cholesterol esterase in rabbits.

We have studied the influence of three hypocholesterolemic drugs (Fenofibrate, Pirinixil and Probucol) on aortic cholesterol esterase (E.C.3.1.1.13) activity in cholesterol-fed rabbits. After three weeks, cholesterol-fed controls exhibited a 28% increase in cholesteryl ester synthetase activity (S) and a 13% decrease in cholesteryl ester hydrolase activity (H) giving a 47% increase in S/H ratio. None of the drugs influenced cholesterol-induced synthetase activity, but fenofibrate treatment increased hydrolase activity resulting in a fall in the S/H ratio to the level observed in rabbits fed corn oil but no cholesterol. The other two hypocholesterolemic agents did not affect the aortic S/H ratio.

Animals↗
PubMed2000

Emerging potentials for an antioxidant therapy as a new approach to the treatment of systemic sclerosis.

Oxidative stress, favoring disease progression by a rapid degeneration of endothelial cell function is deeply involved in Systemic Sclerosis (SSc) pathogenesis. Raynaud's phenomenon (RP), present in 90% of patients with SSc, provoking frequent daily episodes of hypoxia-reperfusion injury, produces several episodes of free radicals-mediated endothelial derangement. These events results in a positive feedback effect of luminal narrowing and ischemia and therefore to the birth of a vicious cycle of oxygen free radicals (OFR) generation, leading to endothelial damage, intimal thickening and fibrosis. Thus ischemia and reperfusion are two criticals events that may induce oxidative stress and inactivation of antioxidant enzymes. In RP and SSc, a reduced concentration of ascorbic acid, alpha-tocopherol and beta-carotene as well as low values of Selenium have been reported. This antioxidative potential deficiency increases the propensity to oxidative stress. favoring the development of injury mediated by OFR. We reviewed several antioxidant compounds, aiming at their capacity of reverting endothelial dysfunction and damage, scavenging lipid peroxidation and reducing multiple episodes of hypoxia-reperfusion injury. In order to interrupt SSc vicious cycle, we propose a main strategy for SSc treatment by a supplementation of antioxidants and different kind of drugs with antioxidant property, such as Lazaroids, Resveratrol, Melatonin and Probucol.

Antioxidants↗
PubMed1999

Noninvasive 3-D ultrasound of atherosclerotic plaques in the Watanabe rabbit.

We have investigated the ability to quantitate atherosclerosis in the aortic arch of the Watanabe rabbit using noninvasive 3-D ultrasound. Our methodology utilizes postprocessing of videotaped freehand 2-D interrogations to form a compound 3-D data block. Structures may then be segmented on the attributed grey-scale level and volumes measured. Analysis of 3-D reconstructions revealed a low echo structure in the aortic arch of atherosclerotic rabbits, absent in nonatherosclerotic rabbits, at recognized sites of plaque predilection. This structure volume correlated closely with fatty streak volume determined from histology (r = 0.890). During a 30-week study, this structure volume increased in untreated animals, but was blocked by treatment with the antiatherosclerotic agent probucol. Thus, a new 3-D ultrasound methodology has been used noninvasively to detect and quantitate a low echo structure corresponding to fatty streaks in the Watanabe rabbit aortic arch. This new methodology could potentially aid plaque burden quantification in human peripheral arteries.

Algorithms↗
PubMed2006

Antioxidants: the good, the bad and the ugly.

Inflammation has a fundamental role in mediating all stages of atherosclerotic disease. The key role of oxidation in linking lipids and inflammation to atherosclerosis is compelling and is supported by experimental evidence. However, the relevance of the antioxidant hypothesis for the treatment of patients with atherosclerosis has not been definitively proven. Results of randomized trials with 'antioxidant' vitamins have been disappointing, and there are potentially important problems associated with their use, including their potential pro-oxidant effects. Probucol has reduced postpercutaneous coronary intervention (PCI)-restenosis and progression of carotid atherosclerosis in clinical trials. The antioxidant vascular protectant AGI-1067 has also been effective at preventing atherosclerosis in all tested animal models. The nonintervened reference coronary segments of the PCI vessel demonstrated improvements with AGI-1067 in the Canadian Antioxidant Restenosis Trial-1 (CART-1), evidence supportive of a clinical effect on slowing atherosclerosis progression. Two trials test the antioxidant/anti-inflammatory hypothesis with AGI-1067; CART-2 assesses its value for the reduction of both atherosclerosis progression and post-PCI restenosis, and Aggressive Reduction of Inflammation Stops Events (ARISE), which is evaluating its effects on hard cardiovascular outcomes.

Angioplasty, Balloon, Coronary↗
PubMedDate not supplied

Effects of inhibition of glycation and oxidative stress on the development of diabetic nephropathy in rats.

We investigated whether aminoguanidine (AG), an inhibitor of advanced glycated end product formation, or probucol (PB), a free radical scavenger, could influence signs of glomerular and distal tubular function and morphological changes in kidneys of male Wistar rats after 6 months of streptozocin (STZ)-induced diabetes. Diabetic rats had a higher kidney weight/body weight ratio (P<.001), but neither AG nor PB influenced the increased ratio. Diabetes caused an increased urinary albumin excretion (P<.05), which was normalized by AG, but further exaggerated by PB (P<.001). Diabetes also caused an increase in the urinary excretion of Tamm-Horsfall protein (P<.001). Both AG and PB attenuated this increase (P<.05 for both). A few glomeruli displayed focal thickening of varying degrees. Silver staining disclosed the glomerulopathy to be intercapillary glomerulosclerosis. Rats on PB-enriched diet displayed less pronounced changes than untreated rats (P<.01), while AG had no effect. The results suggest that oxidative stress could be involved in the development of diabetic nephropathy.

Animals↗
PubMed1999

Effect of dietary lipid-lowering drugs upon plasma lipids and egg yolk cholesterol levels of laying hens.

To evaluate the effect of lipid-lowering agents upon egg quality, reproductive performance, plasma lipids, and egg yolk cholesterol levels, 30-week-old Shaver laying hens were fed a basal diet (commercial ration) supplemented with 0.1% probucol (PROB), 0.025% gemfibrozil (GEMF), or lovastatin at 0.0005% (LOV1), 0.001% (LOV2), or 0.0015% (LOV3) for a 12-week experimental period. It was observed that the supplementation of the drugs did not impair albumen and shell quality. Hen performance was not adversely affected. The depression in triglyceride concentrations approached statistical significance only in LOV2 (38.5%), and total cholesterol was significantly depressed in LOV2 (36.0%), LOV3 (36.8%), PROB (29.6%), and GEMF (30.4%) treatments. Egg cholesterol content, expressed per gram of yolk, was significant lowered in LOV1 (7.5%) and LOV3 (12. 7%).

Animals↗
PubMed2004

Discovery of novel phenolic antioxidants as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases.

Vascular cell adhesion molecule-1 (VCAM-1) mediates recruitment of leukocytes to endothelial cells and is implicated in many inflammatory conditions. Since part of the signal transduction pathway that regulates the activation of VCAM-1 expression is redox-sensitive, compounds with antioxidant properties may have inhibitory effects on VCAM-1 expression. Novel phenolic compounds have been designed and synthesized starting from probucol (1). Many of these compounds demonstrated potent inhibitory effects on cytokine-induced VCAM-1 expression and displayed potent antioxidant effects in vitro. Some of these derivatives (4o, 4p, 4w, and 4x) inhibited lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 from human peripheral blood mononuclear cells (hPBMCs) in a concentration-dependent manner in vitro and showed antiinflammatory effects in an animal model. Compounds 4ad and 4ae are currently in clinical trials for the treatment of rheumatoid arthritis (RA) and prevention of chronic organ transplant rejection, respectively.

Animals↗
PubMed2005

Design, synthesis, and evaluation of pharmacological properties of cinnamic derivatives as antiatherogenic agents.

A series of cinnamic and phosphonocinnamic derivatives have been synthesized and their ability to inhibit cell-mediated LDL oxidation and oxidized LDL-induced cytotoxicity was investigated. Electron-donating substituents surrounding the necessary 4-OH group of the aromatic ring showed the best results. Among the different series tested, amide 1, thioester 5c, phosphonoester 7c, and the fluorophosphonocinnamic analogue 12c exhibited a potent inhibitory effect against LDL oxidation (and subsequent toxicity) mediated by cultured human microvascular endothelial cells (HMEC-1), with an efficacy comparable to that observed with probucol. Beside this indirect protective effect, these compounds exhibited a direct protective effect against the toxicity of previously oxidized LDL in HMEC-1. These data suggest that the newly synthesized cinnamic compounds should protect against early events (cell-mediated LDL oxidation) occurring within the vascular wall in atherosclerosis.

Antioxidants↗
PubMed2000

Pharmacological and genetic modifications of somatic cholesterol do not substantially alter the course of CNS disease in Niemann-Pick C mice.

Niemann-Pick type C (NPC) is a neurodegenerative disorder with somatically altered cholesterol metabolism. The NPC1 gene has recently been cloned and shown to have sequences shared with known sterol-sensing proteins. We have used a mouse model with a disrupted Npc1 gene to study two cholesterol-lowering drugs (nifedipine and probucol) and the effects of introducing a null mutation in the low-density lipoprotein receptor (LDLR). Although these treatments significantly ameliorated liver cholesterol storage, little effect on the onset of neurological symptoms was found.

Animals↗
PubMed1990

The oxidative modification of low-density lipoproteins by macrophages.

1. Mouse resident peritoneal macrophages in culture modified human 125I-labelled low-density lipoprotein (LDL) to a form that other macrophages took up about 10 times as fast as unmodified LDL. The modified LDL was toxic to macrophages in the absence of serum. 2. There was a lag phase of about 4-6 h before the LDL was modified so that macrophages took it up faster. A similar time lag was observed when LDL was oxidized by 5 microM-CuSO4 in the absence of cells. 3. LDL modification was maximal when about 1.5 x 10(6) peritoneal cells were plated per 22.6 mm-diam. well. 4. Re-isolated macrophage-modified LDL was also taken up much faster by macrophages, indicating that the increased uptake was due to a change in the LDL particle itself. 5. Micromolar concentrations of iron were required for the modification of LDL by macrophages to take place. The nature of the other components in the culture medium was also important. Macrophages would modify LDL in Ham's F-10 medium but not in Dulbecco's modified Eagle's medium, even when iron was added to it. 6. The macrophage-modified LDL appeared to be taken up almost entirely via the acetyl-LDL receptor. 7. LDL modification by macrophages was inhibited partially by EDTA and desferrioxamine and completely by the general free radical scavengers butylated hydroxytoluene, vitamin E and nordihydroguaiaretic acid. It was also inhibited completely by low concentrations of foetal calf serum and by the anti-atherosclerotic drug probucol. It was not inhibited by the cyclo-oxygenase inhibitors acetylsalicylic acid and indomethacin. 8. Macrophages are a major cellular component of atherosclerotic lesions and the local oxidation of LDL by these cells may contribute to their conversion into cholesterol-laden foam cells in the arterial wall.

Animals↗
PubMed1999

Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity.

UNLABELLED: Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity. BACKGROUND: Cephaloridine (CER) has been used to elucidate the mechanisms of cephalosporin antibiotic-induced nephrotoxicity. Organic anion transporters have been thought to mediate CER uptake by the proximal tubule. The purpose of this study was to elucidate the possible involvement of organic anion transporter 1 (OAT1) in CER-induced nephrotoxicity. METHODS: A mouse terminal proximal straight tubule (S3) cell line stably expressing rat OAT1 (S3 rOAT1) was established and used in this study. The cellular uptake of [14C]-para-aminohippuric acid (PAH), a prototype organic anion, and that of [14C]-CER were measured. The effects of CER on the viability of the cells and the amount of lipid peroxidation were estimated. RESULTS: S3 rOAT1 expressed a functional organic anion transporter in the cytoplasmic membrane, and exhibited CER uptake activity. CER treatment resulted in a more significant decrease in the viability and a more significant increase in the amount of lipid peroxidation in S3 rOAT1 than in S3 cells transfected with an expression vector lacking the rOAT1 insert. Probenecid, an inhibitor of organic anion transport, and probucol, an antioxidant, significantly suppressed the decrease in viability and increase in the amount of lipid peroxidation in S3 rOAT1 treated with CER. The effects of various cephalosporin antibiotics on the uptake of [14C]PAH were correlated significantly with the effects of these drugs on cell viability. CONCLUSIONS: These results suggest that rOAT1 is, at least in part, responsible for the cellular uptake of CER and therefore CER-induced nephrotoxicity.

Animals↗
PubMed1999

Lipid-lowering therapy in membranous nephropathy.

Membranous nephropathy (MN) is a very common cause of nephrotic syndrome in adults, and lipid abnormalities are, therefore, frequently found in these subjects. Although efficient lipid-lowering therapy is available, almost nothing is known about the contribution of hyperlipidemia in the pathogenesis of progressive renal failure in MN. Studies in an experimental animal model of human MN, Heymann nephritis, have shown that lipids play an essential role in the pathogenesis of proteinuria. Local production of reactive oxygen species after subepithelial immune complex deposition leads to the formation of lipid peroxidation (LPO) adducts, which ultimately alter the composition of the glomerular basement membrane. As the magnitude of urinary protein excretion is associated with the long-term prognosis, a normalization of glomerular permselective properties has been used as a surrogate parameter for the beneficial effects of treatment. Probucol, a drug with LPO inhibitor potential, is able to reduce urinary protein excretion in rats with passive Heymann nephritis. In humans with MN, preliminary data also support this observation. It remains to be determined, however, if this intervention, which does not interfere with immune complex formation, will reduce the number of the patients reaching end-stage renal failure because of MN. In conclusion, lipids may contribute to glomerular injury in MN, as LPO might be an especially important factor, opening the possibility for new therapeutic interventions, thereby avoiding the side-effects of the currently used treatment regimen.

Glomerulonephritis, Membranous↗
PubMed2003

Resolution of typical lipoprotein glomerulopathy by intensive lipid-lowering therapy.

Lipoprotein glomerulopathy (LPG), characterized by glomerular lipoprotein thrombi, presumably composed of abnormal apolipoprotein E (apoE), leads to a progressive decline in renal function and eventually results in end-stage renal failure. A successful treatment for LPG has not yet been established. The authors treated a 36-year-old woman with LPG and exhibiting a nephrotic syndrome using an intensive lipid-lowering therapy consisting of fenofibrate (300 mg), niceritrol (750 mg), ethyl-icosapentate (1,800 mg), and probucol (500 mg). After the start of treatment, a remarkable decrease in urinary protein excretion and improvement in the hyperlipidemia were obtained; proteinuria was no longer detected 11 months after the initiation of treatment. A second biopsy performed 11 months after the initiation of treatment showed the complete disappearance of the lipoprotein thrombi that had been observed in a diffuse and global manner in the first renal biopsy. These findings suggest that typical LPG could be regressed if the abnormal lipoproteinemia is controlled sufficiently.

Adult↗
PubMed2001

Effect of nilvadipine in weak acidic medium by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay.

A new medium (pH 5.6 reached by addition of 0.1 mol/l acetate buffer, 37 degrees C, 60 min) was established for detecting anti-free radical compounds in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. DPPH bleaching activities of typical antioxidants appeared generally weaker at pH 8.0 (the measured ethanol solution pH by the classical DPPH assay method) than at pH 5.6. Nilvadipine (CAS 75530-68-6), a lipophilic calcium antagonist, enhanced the bleaching much more at pH 5.6 than at pH 8.0. Nifedipine (CAS 21829-25-4) and amiodipine (amiodipine besilate, CAS 88150-42-9) showed some effect, but the other five calcium antagonists failed to bleach DPPH at any pH tested (pH 4.4-8.0). Probucol and beta-carotene (standard antioxidant) showed nearly the same bleaching activity as nilvadipine. Captopril, glutathione and bilirubin were weaker anti-free radical compounds at pH 5.6. No intermediating participation of superoxide radicals and hydroxyl radicals were observed in the DPPH assay, both at pH 8.0 and 5.6. Thus, nilvadipine was shown to be an efficient free-radical scavenger only at around pH 5.6, a weak acidic condition which may occur as a result of inflammation and/or ischemia-reperfusion.

Amlodipine↗
PubMed1995

The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.

BACKGROUND: Patients with coronary artery disease and abnormalities of serum lipids often have endothelial vasodilator dysfunction, which may contribute to ischemic cardiac events. Whether cholesterol-lowering or antioxidant therapy can restore endothelium-dependent coronary vasodilation is unknown. METHODS: We randomly assigned 49 patients (mean serum cholesterol level, 209 +/- 33 mg per deciliter [5.40 +/- 0.85 mmol per liter]) to receive one of three treatments: an American Heart Association Step 1 diet (the diet group, 11 patients); lovastatin and cholestyramine (the low-density lipoprotein [LDL]-lowering group, 21 patients); or lovastatin and probucol (the LDL-lowering-antioxidant group, 17 patients). Endothelium-dependent coronary-artery vasomotion in response to an intracoronary infusion of acetylcholine (10(-8) to 10(-6) M) was assessed at base line and after one year of therapy. Vasoconstrictor responses to these doses of acetylcholine are considered to be abnormal. RESULTS: Treatment resulted in significant reductions in LDL cholesterol levels of 41 +/- 22 percent in the LDL-lowering-antioxidant group and 38 +/- 20 percent in the LDL-lowering group (P < 0.001 vs. the diet group). The maximal changes in coronary-artery diameter with acetylcholine at base line and at follow-up were -19 and -2 percent, respectively, in the LDL-lowering-antioxidant group, -15 and -6 percent in the LDL-lowering group, and -14 and -19 percent in the diet group (P < 0.01 for the LDL-lowering-antioxidant group vs. the diet group; P = 0.08 for the LDL-lowering group vs. the diet group). (The negative numbers indicate vasoconstriction). Thus, the greatest improvement in the vasoconstrictor response was seen in the LDL-lowering-antioxidant group. CONCLUSIONS: The improvement in endothelium-dependent vasomotion with cholesterol-lowering and antioxidant therapy may have important implications for the activity of myocardial ischemia and may explain in part the reduced incidence of adverse coronary events that is known to result from cholesterol-lowering therapy.

Acetylcholine↗
PubMed1994

Vitamin C prevents cigarette smoke-induced leukocyte aggregation and adhesion to endothelium in vivo.

A common feature of cigarette-smoke (CS)-associated diseases such as atherosclerosis and pulmonary emphysema is the activation, aggregation, and adhesion of leukocytes to micro- and macrovascular endothelium. A previous study, using a skinfold chamber model for intravital fluorescence microscopy in awake hamsters, has shown that exposure of hamsters to the smoke generated by one research cigarette elicits the adhesion of fluorescently labeled leukocytes to the endothelium of arterioles and small venules. By the combined use of intravital microscopy and scanning electron microscopy, we now demonstrate in the same animal model that (i) CS-induced leukocyte adhesion is not confined to the microcirculation, but that leukocytes also adhere singly and in clusters to the aortic endothelium; (ii) CS induces the formation in the bloodstream of aggregates between leukocytes and platelets; and (iii) CS-induced leukocyte adhesion to micro- and macrovascular endothelium and leukocyte-platelet aggregate formation are almost entirely prevented by dietary or intravenous pretreatment with the water-soluble antioxidant vitamin C (venules, 21.4 +/- 11.0 vs. 149.6 +/- 38.7 leukocytes per mm2, P < 0.01; arterioles, 8.5 +/- 4.2 vs. 54.3 +/- 21.6 leukocytes per mm2, P < 0.01; aortas, 0.8 +/- 0.4 vs. 12.4 +/- 5.6 leukocytes per mm2, P < 0.01; means +/- SD of n = 7 animals, 15 min after CS exposure). No inhibitory effect was observed by pretreatment of the animals with the lipid-soluble antioxidants vitamin E or probucol. The protective effects of vitamin C on CS-induced leukocyte adhesion and aggregation were seen at vitamin C plasma levels (55.6 +/- 22.2 microM, n = 7) that can easily be reached in humans by dietary means or supplementation, suggesting that vitamin C effectively contributes to protection from CS-associated cardiovascular and pulmonary diseases in humans.

Animals↗
PubMed2001

Retinal glial cell immunoreactivity and neuronal cell changes in rats with STZ-induced diabetes.

PURPOSE: To study whether diabetes could influence glial cells, retinal neurons, and pigment epithelial cells and if so, to evaluate whether any changes could be influenced by aminoguanidine (AG) or probucol (PB). METHODS: Streptozocin (STZ)-induced diabetic male Wistar rats and age-matched control rats were fed a normal diet, addition of AG in the drinking water (0.5 g/l for diabetic and 1.0 g/l for control rats) or PB in the pellets (1 % w/w) for one or six months. Paraffin embedded retinal sections were incubated in the primary antibodies GFAP, calbindin, RPE65, and Hu, for glial, horizontal, pigment epithelial, and ganglion cells, respectively, and in fluorescent secondary antibodies. RESULTS: One month after STZ injection, GFAP immunoreactivity was sparse, but after six months it was prominent in glial cells in 5/5 diabetic and 1/7 control retinas (p = 0.015). Neither AG, nor PB influenced this immunoreactivity. Numbers of retinal pigment epithelial cells and cells in the ganglion cell layer, were similar at one and six months of diabetes. By time, the number of horizontal cells decreased (p < 0.001) and branching and numbers of their terminals were reduced (p < 0.001). CONCLUSION: Diabetes for six months resulted in increased glial cell immunoreactivity, and by age, horizontal cell numbers and branching of their terminals decreased, morphological patterns that were unaffected by AG or PB. The numbers of retinal pigment epithelial cells and cells in the ganglion cell layer were unaffected both by age and diabetes.

Animals↗
PubMed2000

Antioxidative property of T-0970, a new ureidophenol derivative.

We investigated the antioxidative property of T-0970, a newly synthesized ureidophenol derivative. The inhibitory effect of T-0970 on spontaneous lipid peroxidation in rat brain was 10 times greater than those of well-known antioxidants such as butylhydroxytoluene (BHT), probucol and alpha-tocopherol. T-0970 also showed dose-dependent free radical scavenging activities in vitro for both superoxide anions and hydroxyl radicals. The radical-scavenging potencies of T-0970 were about 10-30 times stronger than those of BHT. We evaluated the in vivo antioxidative ability of T-0970 in the animal model of acute oxidative tissue injury in rats. Intraperitoneal injection of ferric nitrilotriacetate (Fe/NTA) caused an acute and remarkable increase in the level of thiobarbituric acid-reactive substances (TBARS) in both plasma and the liver, and also resulted in a considerable elevation of the plasma levels of GOT and GPT indicative of hepatic injury. Both oral and intravenous administration of T-0970 dose-dependently depressed these diagnostic parameters. These results indicate that T-0970 may have a therapeutic potential in various diseases associated with oxidative tissue injury.

Alanine Transaminase↗