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Antiatherosclerotic effects of antioxidants are lesion-specific when evaluated in hypercholesterolemic New Zealand white rabbits.

Oxidative modification of LDL may represent an initiating event in the formation of monocyte-macrophage foam cells, a major cell present in fatty streaks and atherosclerotic fibrous plaques. Therefore, we studied the effect of such antioxidants as probucol (500 mg/kg) and vitamins E and C (500 mg/kg each) on the regression of induced iliac-femoral lesions and progression of naturally occurring thoracic aortic fatty streak lesions in hypercholesterolemic New Zealand White rabbits. Following an initial 9-week lesion induction phase, both therapies were evaluated for 8 weeks. Probucol lowered plasma cholesterol 47% while vitamins E and C had no effect on plasma cholesterol. Probucol decreased the cholesteryl ester (CE) content of the thoracic aorta by 31% without changing the thoracic aortic lesion coverage. Vitamins E and C decreased thoracic aortic CE content by 40% and lesion coverage by 46%. Neither probucol nor vitamins E and C altered the CE content, lesion size, or macrophage/lesion ratio of the iliac-femoral artery. Thus, we conclude that the effects of antioxidants are specific to the stage of atherosclerotic lesion development. Antioxidant therapy alters the progression and cholesteryl ester enrichment of diet-induced thoracic aortic fatty streaks but has no effect on the progression and/or regression of more complicated injury-induced iliac-femoral lesions.

Animals↗

The resistance of low density lipoprotein to oxidation promoted by copper and its use as an index of antioxidant therapy.

The measurement ex vivo of the resistance of low density lipoprotein (LDL) to oxidation promoted by copper is now being used in surveys of human populations at risk of developing atherosclerosis. However, it is not known whether a relationship between LDL oxidisability measured in this way and the development of atherosclerotic lesions exists. Using Watanabe rabbits as a model of the disease, we have found that dietary supplementation with the antioxidants, probucol and alpha-tocopherol, increased the resistance of LDL isolated from small volumes of plasma to oxidation. The antioxidant effects of probucol incorporated into LDL through dietary supplementation were greater than when incorporated ex vivo. When dietary supplementation was extended to a period of three months, the well established anti-atherosclerotic effects of probucol were confirmed and a highly significant relationship between the probucol content of the LDL particle and the extent of the atherosclerotic lesion in the aorta emerged. These results suggest that the assessment of the resistance of LDL isolated from plasma to oxidation promoted by copper may reflect the response of the arterial atherosclerotic process to antioxidant therapy.

Administration, Oral↗

Reduction of oxidative stress and apoptosis in hyperlipidemic rabbits by ellagic acid.

Oxidative stress is one of the major risk factors for coronary artery disease. Ellagic acid is a phenolic compound present in fruits and nuts, and has been found to have antioxidative property. Twenty-four New Zealand white (NZW) rabbits were assigned randomly into four dietary groups. The normal group was fed regular rabbit chow, and the cholesterol group was fed a high fat and cholesterol diet. The ellagic acid (E) group and probucol group were fed the same diet as the cholesterol group plus the addition of 1% (w/w diet) ellagic acid and probucol, respectively. Oxidative stress [as measured by plasma lipids, oxygen free radicals and thiobarbituric acid reactive substances (TBARS)] increased in the cholesterol group compared with the normal group; however, it decreased in the probucol and E groups compared with the cholesterol group. Forty-five percent of the intimal surface of the thoracic aorta was covered with atherosclerotic lesions in the cholesterol group, but only 2-3% was covered in the E and probucol groups. The aortic level of 8-(OH)dG and the expression of caspase-8, caspase-9 and Fas ligand were also suppressed after ellagic acid supplement. These results indicated that ellagic acid could prevent atherosclerosis via suppression of oxidative stress and apoptosis in hyperlipidemic rabbits.

8-Hydroxy-2'-Deoxyguanosine↗

Antioxidative activity of green tea polyphenol in cholesterol-fed rats.

This study investigated the effects of green tea polyphenol on the serum antioxidative activity and cholesterol levels of cholesterol-fed rats and compared them with those of probucol, an antioxidant hypocholesterolemic agent. To evaluate the antioxidative activity, the susceptibility to oxidative modification of low-density lipoprotein (LDL) isolated from the serum of cholesterol-fed rats was measured, as was the serum antioxidative activity using the spontaneous autoxidation system of brain homogenate. Administration of green tea polyphenol effectively inhibited LDL oxidation and elevated serum antioxidative activity to the same degree as probucol. However, higher amounts of polyphenol than probucol needed to be administered to reduce the total, free, and LDL cholesterol levels. Furthermore, green tea polyphenol increased the levels of high-density lipoprotein (HDL) cholesterol, leading to dose-dependent improvement of the atherogenic index, an effect that was not seen with probucol. Thus, green tea polyphenol may exert an antiatherosclerotic action by virtue of its antioxidant properties and by increasing HDL cholesterol levels.

Animals↗

Antioxidant BO-653 and human macrophage-mediated LDL oxidation.

Oxidation of LDL is now widely accepted to be involved in atherogenesis. The aim of this study was to examine the effect of BO-653, a strong radical scavenger and antioxidant, on oxidation of LDL by human macrophages in vitro. Fifty microg/ml LDL protein was incubated with macrophages in Ham's F10 medium, supplemented with additional Fe2+, for up to 48 h. Then the medium was analysed by LDL agarose gel electrophoresis, the thiobarbituric acid assay and gas chromatography. In the absence of added exogenous antioxidants, after 24h LDL oxidation produced 30.48 nmoles MDA equivalents/mg LDL protein and a relative electrophoretic mobility of 4.74. Linoleic acid (18:2), arachidonic acid (20:4) and cholesterol were depleted and 7beta-hydroxycholesterol was generated. BO-653 completely inhibited this cell-mediated oxidation of LDL in concentrations as low as 5 microM, being more effective than either alpha-tocopherol or probucol, which completely inhibited oxidation at 200 and 80 microM and only partially at 80 and 8 microM, respectively. This inhibition of cell-mediated LDL oxidation was not due to toxicity, as alpha-tocopherol, probucol and BO-653 were not toxic for the macrophages at the concentrations tested. Eighty microM alpha-tocopherol, 8 microM probucol and 5 microM BO-653 significantly reduced the toxicity to the oxidising culture caused by LDL oxidation. The results show that in this system BO-653 is a more effective antioxidant than alpha-tocopherol or probucol.

Antioxidants↗

Dynamics of action of bisphenol as radical-scavenging antioxidant against lipid peroxidation in solution and liposomal membranes.

Probucol is used commercially as an antiatherogenic drug. Bisphenol is formed in vivo as a metabolite of probucol. The structure of bisphenol suggests the antioxidant function but its capacity has not been studied in detail. In the present study, dynamics of the antioxidant action of bisphenol were studied in several model systems and compared with those of probucol and alpha-tocopherol. The reactivity toward radicals and antioxidant activity of bisphenol per se were found to be much smaller than those of alpha-tocopherol or N,N'-diphenyl-p-phenylenediamine (DPPD) but stronger than probucol. However, bisphenol spared alpha-tocopherol in the oxidation of phosphatidylcholine liposomal membranes and it spared DPPD and acted as a synergist against the oxidant of methyl linoleate in solution. These results imply that bisphenol may act as a potent antioxidant in combination with other antioxidants.

Anticholesteremic Agents↗

Mechanisms of glomerular immune injury: effects of antioxidant treatment.

Significant glomerular vasoconstriction and production of reactive oxygen species has been known to occur with exposure to anti-glomerular basement membrane antibody (AGBM-Ab) in the rat model. Previously published studies have demonstrated that such effects can be reduced by therapy with phentolamine, an alpha-adrenergic antagonist. It was hypothesized that antioxidant pretreatment with water-soluble probucol would improve glomerular hemodynamics 60 to 90 min after the administration of AGBM-Ab. These relationships were examined with both in vivo renal micropuncture and in vitro studies in rats. Single-nephron GFR (SNGFR) decreased markedly in untreated rats after AGBM-Ab as a result of afferent and efferent arteriolar vasoconstriction with consequent reductions in nephron plasma flow (SNPF) and decreases in the glomerular ultrafiltration coefficient (LpA). Basal SNGFR was increased, and SNGFR was significantly higher after AGBM-Ab in probucol-treated versus untreated rats. This finding was due solely to higher values for SNPF and prevention of afferent arteriolar constriction. A reduction in LpA after AGBM-Ab was not prevented by probucol treatment. In vitro analyses of glomeruli revealed reduced myeloperoxidase activity in antioxidant-treated rats. Lipoxygenase activity and leukotriene products, however, were not changed by antioxidant therapy, yet vasoconstriction was prevented. H(2)O(2) generation before and after formyl-methionyl-leucyl-phenylalanine stimulation was significantly reduced before and after AGBM-Ab in glomeruli harvested from rats that were treated with the antioxidant. Antioxidant therapy in this model of AGBM-Ab injury did not prevent reductions in LpA, an index of glomerular membrane damage, but did prevent afferent arteriolar vasoconstriction. Reactive oxygen species generation was reduced by probucol. The specific mechanisms whereby antioxidant therapy ameliorates glomerular hemodynamic effects will be defined in additional studies and is likely to involve either enhanced vasodilator or diminished vasoconstrictor activity.

Animals↗

An experimental model of tumor dormancy therapy for advanced head and neck carcinoma.

An experimental model of tumor dormancy therapy for advanced head and neck carcinoma was developed. After transplantation of KB cells into nude mice, the mice were given tiracoxib, a selective cyclooxygenase (COX)-2 inhibitor, probucol, an antioxidant, and S-1, an oral pro-drug of 5-fluorouracil (5-FU), or combinations of two of them. The combined administration of tiracoxib with probucol significantly inhibited the tumor growth. The angiogenesis in this group was markedly reduced. Tiracoxib and probucol did not affect the intratumoral concentration of 5-FU when coadministered with S-1. The combined use of tiracoxib and probucol is thus a candidate for use in maintenance therapy after the primary therapy for patients with advanced head and neck carcinoma.

Animals↗

Zinc accumulation in adriamycin-induced cardiomyopathy in rats: effects of melatonin, a cardioprotective antioxidant.

We have recently reported that melatonin protects against adriamycin-induced cardiomyopathy whose pathogenesis may involve free radicals and lipid peroxidation. Melatonin has also been shown to affect zinc turnover. Since zinc may act as an antioxidant, we investigated the role of zinc in the pathogenesis of adriamycin-induced cardiomyopathy as well as in the treatment of melatonin against this disorder. Sprague-Dawley rats were given adriamycin (cumulative dose, 15 mg/kg); melatonin (cumulative dose, 84 mg/kg); adriamycin plus melatonin; adriamycin plus probucol, another antioxidant (cumulative dose, 90 mg/kg); or vehicle alone, according to previously-used regimens. Cardioprotective effects of both antioxidants (melatonin and probucol) were confirmed by the parameters of fractional shortening, heart weight, heart/body weight ratio, ascites volume, and mortality. Adriamycin increased both the myocardial and plasma levels of thiobarbituric acid reactive substances (TBARS) and myocardial zinc levels, and decreased plasma zinc levels. The significant negative correlation observed between the myocardial and plasma zinc levels (r = 0.73, P < 0.01) among the samples of adriamycin-treated and control rats suggested an internal redistribution of zinc. Melatonin and probucol were equally effective in inhibiting the increase in myocardial TBARS as well as zinc levels, suggesting that myocardial zinc accumulation might be a protective response against adriamycin-induced oxidative stress. Melatonin also inhibited the adriamycin-induced decrease in plasma zinc levels; probucol was not as effective in doing so. In addition to melatonin's antioxidative effect, it may have the effect of maintaining the plasma zinc levels.

Animals↗

Iatrogenic profound hypoalphalipoproteinaemia: an unrecognised cause of very low HDL cholesterol.

A significant reduction in plasma high density lipoprotein (HDL) cholesterol is a recognised consequence of treatment with probucol. By contrast, fibrate therapy in general has the opposite effect. We report two cases where the combination of probucol and a fibrate led to profoundly reduced plasma levels of HDL cholesterol associated with very low levels of apolipoprotein A-I (apoA-I). In the first, bezafibrate was added to probucol, and in the second, probucol added to a combination of simvastatin and fenofibrate. In both cases, plasma levels of HDL and apoA-I returned towards normal after discontinuation of one or both drugs, indicating that the reduction was reversible.

Adult↗

Reduction of oxidative stress and atherosclerosis in hyperlipidemic rabbits by Dioscorea rhizome.

Hyperlipidemia may induce oxidative stress, which is important in the pathogenesis of atherosclerosis. Dioscorea rhizome (DR) is the powdered form of yams, and possesses antioxidant and hypolipidemic function. We therefore investigated the antioxidative and antiatherogenic effects of DR on hyperlipidemic rabbits. The control group was fed chow containing 0.5% cholesterol and 10% corn oil. The probucol and DR groups were fed the same diet as the control group but with the addition of 100 mg probucol/kg chow and 200 mg DR/kg chow, respectively. Total cholesterol and triacylglycerol plasma levels, RBC hemolysis T50, lucigenin chemiluminescence, and luminol chemiluminescence increased in the control group compared with the normal group, and decreased in the probucol and DR groups compared with the control group. The activity of antioxidant enzymes superoxide dismutase and catalase was significantly higher in the probucol and DR group than in the control group. The level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in liver DNA was lower in the probucol and DR group than in the control group. Eighty percent of the intimal surface of the thoracic aorta was covered with atherosclerotic lesions in the control group but only 40% of the surface was covered in the DR group. These results suggest that supplementation with DR reduces oxidative stress and attenuates atherosclerosis in hyperlipidemic rabbits.

Animals↗

Contribution of the endothelium to intimal thickening in normocholesterolemic and hypercholesterolemic rabbits.

Endothelial cell injury is considered to be a primary event in the pathogenesis of atherosclerosis. In this study, we investigated the aortic intimal lesion after balloon catheterization in hypercholesterolemic and normocholesterolemic rabbits with or without probucol, an antioxidant. After deendothelialization, the rabbits were divided into four groups: 1) a control group fed a standard diet; 2) a probucol-treated group; 3) a cholesterol-fed group; and 4) a group fed a mixed cholesterol and probucol diet. Four animals from each group were killed at 2, 4, and 8 weeks after deendothelialization. The aortic segments of nonendothelialized areas, borderline areas, and uninjured areas were histologically and immunohistochemically examined. Deendothelialized areas showed various degrees of intimal thickening, which was mainly composed of smooth muscle cells in rabbits from groups 1 and 2. The intimal thickness of group 3 was significantly larger than that of other groups in any area examined. The intimal thickness of group 4 was less than that of group 3 despite the hypercholesterolemic state in the former group. The intima of borderline areas was generally thicker than that of nonendothelialized areas. Although the borderline lesions of groups 3 and 4 contained numerous macrophages, the number of macrophages was lower in the nonendothelialized compared with the reendothelized lesion. These data indicate that endothelial cell injuries can cause intimal thickening. The regenerated endothelial covering is favorable for monocyte migration and attachment. This process, together with the proliferation of smooth muscle cells, greatly contributes to the progression of atherosclerosis, which appears to involve lipid oxidation. Probucol prevented intimal thickening to a certain degree in this experiment in the normocholesterolemic as well as the hypercholesterolemic state.

Animals↗

Ischemic acute renal failure and antioxidant therapy in the rat. The relation between glomerular and tubular dysfunction.

The effects of antioxidant therapy with probucol were evaluated in rats subjected to 1 h renal ischemia and to 24 h reperfusion. Probucol exerted significant antioxidant effects in renal cortical tubules in vitro when exposed to a catalase-resistant oxidant. At 24 h probucol treatment (IP) improved single nephron glomerular filtration rate (SNGFR) (28.1 +/- 3.3 nl/min) in comparison to untreated ischemic (I) rats (15.2 +/- 3.0), primarily as a result of improving SNGFR in a population of low SNGFR, low flow and/or obstructed nephrons. However, absolute proximal reabsorption remained abnormally low in IP rats at 24 h (5.9 +/- 0.8 nl/min), and cell necrosis was greater than in I rats. Kidney GFR remained low in IP rats due to extensive tubular backleak of inulin measured by microinjection studies. Evaluations after 2 h of reperfusion revealed a higher SNGFR in IP (36 +/- 3.1 nl/min) than I rats (20.8 +/- 2.7 nl/min). Absolute proximal reabsorption was essentially normal (11.6 +/- 1.3 nl/min) in IP rats, which was higher than IP rats at 24 h and the concurrent I rats. Administration of the lipophilic antioxidant, probucol, increased SNGFR and proximal tubular reabsorption within 2 h after ischemic renal failure. Although SNGFR remained higher than I rats at 24 h, absolute reabsorption fell below normal levels and tubular necrosis was more extensive in IP rats. Early improvement in nephron filtration with antioxidants may increase load dependent metabolic demand upon tubules and increase the extent of damage and transport dysfunction.

Acute Kidney Injury↗

Protection against acute adriamycin-induced cardiotoxicity by garlic: role of endogenous antioxidants and inhibition of TNF-alpha expression.

BACKGROUND: Oxidative stress is the major etiopathological factor in adriamycin-induced cardiotoxicity. Relatively low amounts of endogenous antioxidant makes the heart vulnerable to oxidative stress-induced damage. Chronic oral administration of garlic has been reported to enhance the endogenous antioxidants of heart. We hypothesized that garlic-induced enhanced cardiac antioxidants may offer protection against acute adriamycin-induced cardiotoxicity. RESULTS: Rats were either administered freshly prepared garlic homogenate (250 and 500 mg/kg daily, orally, for 30 days) or probucol (cumulative dose, 120 mg/kg body weight divided in 12, i.p. over a period of 30 days) or double distilled water (vehicle), followed by a single dose of adriamycin (30 mg/kg i.p.). In the adriamycin group, increased oxidative stress was evidenced by a significant increase in myocardial TBARS (thiobarbituric acid reactive substances) and decrease in myocardial SOD (superoxide dismutase), catalase and GPx (glutathione peroxidase) activity. Histopathological studies showed focal as well as subendocardial myocytolysis with infiltration of macrophages, lymphocytes and edema. Immunocytochemistry showed marked expression of TNF-alpha (tumor necrosis factor-alpha) in the myocardium. Increase in myocardial TBARS and decrease in endogenous antioxidants by adriamycin was prevented significantly in the garlic treated rat hearts, which was comparable to the probucol-treated group. Histopathological evidence of protection was also evident in both garlic-treated and probucol-treated groups. Probucol, 250 mg/kg and 500 mg/kg of garlic reduced adriamycin induced TNF-alpha expression in the myocardium and was associated with reduced myocyte injury. CONCLUSIONS: It is concluded that chronic garlic administration prevents acute adriamycin-induced cardiotoxicity and decreases myocardial TNF-alpha expression.

Animals↗

Decreased serum cholesteryl-ester transfer activity in a patient with familial hyperalphalipoproteinemia.

Lipoprotein patterns and cholesteryl-ester transfer activity (CETA) were examined in a patient with familial hyperalphalipoproteinemia (FHALP). The proband was a 41-year-old Japanese male. He was found to have hypercholesterolemia, with a serum total cholesterol level of 382 mg/dl and a HDL-cholesterol level of 177 mg/dl. HDL showed a high cholesterol/Apo AI ratio. His father, all of his siblings and one of his children showed high HDL-cholesterol levels (91, 100, 70, 108, 75 and 98 mg/dl, respectively). These data suggest that all members of his family were heterozygotes. He had neither cutaneous or tendinous xanthomas nor any clinical signs of atherosclerosis. The proband appears to have only one-tenth of the normal level of CETA. However, the level of lipid-transfer protein I (LTP-I) activity was near normal. Thus, this patient is most likely to have an exaggerated level of LTP-I inhibitor(s). Effects of probucol on serum lipoprotein and apolipoprotein levels were studied in our patient. Treatment with 250 mg of probucol twice daily reduced total serum cholesterol, low density lipoprotein (LDL) and HDL-cholesterol levels by 33.32 and 33%, respectively. Apo AI, B and E levels decreased by 22, 16 and 35% respectively. HDL-cholesterol/Apo AI ratio decreased from 0.9 to 0.76. CETA showed no significant changes. However, cholesterol ester mass transfer increased from 10.8 to 14.9% after treatment with probucol. These results suggest that probucol appears to be a useful drug for FHALP.

Adolescent↗

N,N'-diacetyl-L-cystine (DiNAC), the disulphide dimer of N-acetylcysteine, inhibits atherosclerosis in WHHL rabbits: evidence for immunomodulatory agents as a new approach to prevent atherosclerosis.

Oxidation of lipoprotein-derived lipids is generally accepted to be important in atherogenesis, and lipophilic antioxidants have been suggested as potential antiatherosclerotic agents. The antiatherogenic effects observed by certain antioxidants, especially probucol, in different animal models support this suggestion. There are however also cases where other lipophilic antioxidants have not been able to support this hypothesis. This has raised the question whether the effects of probucol and similar compounds are mainly due to some other property, unrelated to their antioxidant efficacy. For example, probucol is shown to possess immunomodulatory properties. Immune reactions are known to occur during atherogenesis. We therefore tested the dimer of N-acetylcysteine, DiNAC, which is a disulfide with immunomodulating properties and enhances oxazolone-induced contact sensitivity (CS) reactions in mice, for effects on atherosclerosis. When given to male heritable hyperlipidemic rabbit (WHHL) rabbits from 10 to 22 weeks of age, this compound reduced by 50% thoracic aorta atherosclerosis (p < 0.05), without affecting plasma lipid levels. Here we also show that probucol and a close chemical analog, both known to prevent atherosclerosis in WHHL rabbits, enhance the CS reaction in mice, while two other related antioxidants did not affect the CS reaction. At least one of these is also without effect on atherosclerosis in WHHL rabbits. The results show that DiNAC might represent a new treatment modality for atherosclerosis-related disease, and suggest that some antioxidants may have antiatherosclerotic properties more related to "immunomodulatory" properties than to antioxidant properties in general.

Acetylcysteine↗

The role of oxidized lipoproteins in the pathogenesis of atherosclerosis.

1. Oxidized low density lipoprotein (LDL) has been suggested to play an important role in atherogenesis by facilitating the accumulation of lipids in macrophages. In vitro studies from this laboratory have shown that oxidized LDL is recognized not only by the specific receptor for it, but also by the receptor which is common for oxidized LDL and acetyl LDL. Probucol, originally developed as an antioxidant, prevents the oxidative modification of LDL in vitro. Recent studies by the authors show that probucol prevents the progression of atherosclerosis in homozygous Watanabe heritable hyperlipidaemic rabbits in vivo without any changes in plasma LDL cholesterol levels. 2. These results strongly suggest that oxidative modification of LDL could occur in vivo and probucol could slow the progression of atherosclerosis, without changes in plasma cholesterol levels. 3. In addition, recently the authors demonstrated that high density lipoprotein (HDL) particles are also oxidized. Once HDL particles were oxidized, they showed a lessened effect on the decrease of cholesteryl ester in foam cells, suggesting oxidative modification of HDL may stimulate development of atherosclerosis by limiting efflux of cholesterol from foam cells. Moreover, HDL particles from probucol-treated patients are hardly oxidized; subsequently, these HDL particles caused a marked efflux of cholesterol from foam cells.

Animals↗

Liquid chromatographic method for the simultaneous determination of different lipid-soluble antioxidants in human plasma and low-density lipoproteins.

We describe a reverse phase HPLC method, employing a simple methanol:water gradient as mobile phase, for the determination of several lipophilic antioxidants, such as retinol, gamma-tocopherol, alpha-tocopherol, lycopene, alpha-carotene and beta-carotene among others, using UV detection. Additionally, this method allows the simultaneous separation of probucol, an hypocholesterolemic drug with antioxidant properties. Retinol acetate and alpha-tocopherol acetate were added to samples as internal standards. A NovaPack ODS C18, 150 x 3.9 mm, 0.4 microm column was used and the flow rate was set constant at 1m/min, which allowed the separation of all the desired antioxidants in a total run time of 35 min. A photodiode array detector was used because of its advantages to study the purity of the peaks, however, any programmable multiwavelength UV/VIS detector could be employed given the good resolution of the peaks. The analytical recoveries of the studied compounds were > 96% and the detection limits were: retinol 0.050 microg/ml, gamma-tocopherol 0.137 microg/ml, alpha-tocopherol 0.906 microg/ml, lycopene 0.022 microg/ml, alpha-carotene 0.008 microg/ml, beta-carotene 0.015 microg/ml and probucol 1.503 microg/ml. The intra- and inter-assay coefficients of variation were calculated by using two human plasma samples with different levels of lipophilic antioxidants. The simplicity, rapidity and economy, make this method suitable for the routine measurement of plasma and low-density lipoproteins antioxidants, and may also be used in large scale epidemiological studies. The method has been used to measure antioxidants in samples from patients undergoing treatment with probucol, showing there is a good correlation between the probucol content in LDL and that in total plasma.

Antioxidants↗