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Survival in patients with amyotrophic lateral sclerosis, treated with an array of antioxidants.

J Neurol Sci (NETHERLANDS) Aug 1996, 139 Suppl p99-103

Between 1983 and 1988 we treated 36 patients with sporadic amyotrophic lateral sclerosis (ALS) by an array of antioxidants and added other drugs to the regimen whenever a patient reported deterioration. Our customary prescription sequence was N-acetylcysteine (NAC); vitamins C and E; N-acetylmethionine (NAM); and dithiothreitol (DTT) or its isomer dithioerythritol (DTE). Patients with a history of heavy exposure to metal were also given meso 2,3-dimercaptosuccinic acid (DMSA). NAC, NAM, DTT, and DTE were administered by subcutaneous injection or by mouth or by both routes, the other vitamins and DMSA by mouth alone. The hospital pharmacy supplied NAC and NAM injections fluid as 100 ml bottles of 5.0 and 5.85% solutions, respectively. DTT was delivered in special double-walled capsules of 200 mg. DTT/DTE injection fluid was added to the NAC and NAM bottles, the final DTT/DTE concentrations never exceeding 0.5%. DMSA was provided in 250 mg capsules. All of the 36 patients used NAC and DTT/DTE; 29 also used vitamins C and E; 21 also used NAM; and 7 also used DMSA, DMSA, NAM, vitamins C and E were tolerated well. In many patients, DTT, DTE, NAC and NAM induced pain, redness and swelling at the injection sites in that order of decreasing frequency. DTT and DTE did often and NAC did sometimes cause gastric pain, nausea and other abdominal discomfort. Comparison of survival in the treated group and in a cohort of untreated historical controls, disclosed a median survival of 3.4 years (95% confidence interval: 3.0-4.2) in the treated and of 2.8 (95% confidence interval 2.2-3.1) years in the control patients. This difference may be explained by self-selection of our highly motivated treated group and by its initial survival of diagnosis for an average of 8.5 months before onset of treatment. We conclude that antioxidants neither seem to harm ALS patients, nor do they seem to prolong survival.

Use and safety of elevated dosages of vitamin E in infants and children.

Int J Vitam Nutr Res Suppl (CANADA) 1989, 30 p69-80

The use of elevated dosages of vitamin E in humans has led to the discovery of vitamin E deficiency syndromes in neurological areas. This evidence comes from careful clinical studies in which elevated vitamin E dosages were applied. In long-term studies it has now been established that retinal and neurological abnormalities are due to vitamin E deficiency and can be ameliorated by therapy with a large amount of the vitamin enterally or parenterally, which can possibly completely prevent the development of clinical manifestations if adequate treatment is given from an early age. It has also become clear that similar neurological and ocular lesions occur in other chronic fat malabsorptive states such as cholestatic liver diseases, cystic fibrosis, and extensive resection of the gut, with respect to an elevated dosage of vitamin E therapy. More recently, several patients with spinocerebellar degeneration from vitamin E deficiency without other evidence of malabsorption have been reported on in whom the progression of the diseases is cessated by the vitamin E therapy. Whether or not the use of elevated dosages of vitamin E should be recommended for certain diseases in premature infants is controversial. Previously, it has been thought that newborn infants, especially premature infants, suffer from vitamin E deficiency, because of their low plasma vitamin E concentrations and high susceptibility of erythrocytes to hydrogen peroxide hemolysis test. Furthermore, tocopherol deficiency has been implicated in four neonatal conditions: anemia of prematurity, retrolental fibroplasia (RLF), bronchopulmonary dysplasia (BPD), and intraventricular hemorrhage (IVH). A hemolytic anemia, associated with thrombocytosis and edema, which is responsive to vitamin E therapy, is not well recognized and occurs in a minority of preterm infants, who were given high amounts of polyunsaturated fatty acids in their formula. However, prophylactic use of an elevated dosage of vitamin E to prevent anemia in the majority of premature infants is controversial. There is no evidence for beneficial effects in BPD. In addition, the prophylactic use of pharmacological dosages of vitamin E for prevention of RLF and IVH has also had conflicting results. In the course of therapy with elevated dosages of vitamin E, administered either orally, intramuscularly, or intravenously, many problems arose in the infants, such as unexpected death, increased frequency of necrotizing enterocolitis (NEC) and sepsis, and the development of unusual symptoms including hepatic injuries.

Vitamin E and the nervous system.

Crit Rev Neurobiol (UNITED STATES) 1987, 3 (1)

There is increasing evidence that vitamin E is essential for normal neurological function. In abetalipoproteinemia, which is the most severe deficiency state known in man, development of the associated spinocerebellar syndrome can be prevented by early vitamin E therapy. A neurological disorder similar to that seen in abetalipoproteinemia, comprising progressive ataxia, hyporeflexia, and proprioceptive loss, has been described in children and adults with chronic fat malabsorption and vitamin E deficiency. The neuropathological changes in such patients resemble those seen in vitamin E-deficient monkeys. Recent reports suggest that spinocerebellar degeneration may be caused by a selective defect of vitamin E absorption without other evidence of gastrointestinal disease.

Clinical uses of vitamin E.

Acta Vitaminol Enzymol (ITALY) 1985, 7 Suppl p33-43

Early administration of vitamin E to low birth weight (less than 1500 g) infants results in alleviation of the symptoms of retinopathy of prematurity and a lowered incidence of intraventricular hemorrhage. If vitamin E is given to children with cholestatic liver disease (orally or parenterally) before 3 years of age, neurological symptoms such as areflexia, ataxia, and sensory neuropathy are prevented or reversed. Restitution of neurological function is more limited in children ages 5-17 years even after prolonged therapy. Vitamin E is also useful in prevention of neuropathy and retinopathy associated with abetalipoproteinemia and cystic fibrosis. Blood levels of tocopherol are often low in subjects with hemolytic anemias. Administration of vitamin E to G-6-P-D-deficient subjects increased hemoglobin levels, and decreased the number of irreversibly sickled cells in sickle-cell anemia subjects. Most trials have indicated that administration of vitamin E for 6 months or more to subjects with intermittent claudication results in longer walking distance and improved blood flow. Vitamin E reduces platelet aggregation, platelet adhesion to collagen, and platelet thromboxane production. Prostacyclin production is generally enhanced. The significance of these effects to thrombotic diseases. Epidemiological studies have indicated that subjects with higher blood levels of vitamin E have lower risk of death from ischemic heart disease and cancer, a lower risk of breast cancer, and a lower incidence of infections.

Neurologic complications of vitamin E deficiency: case report and review of the literature.

Bull Clin Neurosci (UNITED STATES) 1985, 50 p53-60

A well-defined degenerative neurological condition has been associated with cholestatic liver disease in children. This syndrome, heralded by gait and limb ataxia, areflexia, and proprioceptive and vibratory sensory loss, has also been observed in abetalipoproteinemia (Bassen-Kornzweig syndrome), cystic fibrosis, and intestinal malabsorption states. A significant body of evidence suggests that vitamin E (alpha-tocopherol) deficiency is in large part responsible for this condition. In this article, a patient manifesting this syndrome is reported, and the current status of the vitamin E deficiency state is reviewed.

A progressive neurological syndrome associated with an isolated vitamin E deficiency.

Can J Neurol Sci (CANADA) Nov 1984, 11 (4 Suppl) p561-4

Several authors have recently reported a neurological disorder associated with chronic vitamin E deficiency in man. Except in one patient, this deficiency has always been secondary to an underlying disease resulting in lipid malabsorption. We report a second case of such a neurological syndrome in a patient in whom vitamin E deficiency was an isolated finding. The clinical picture in our patient was characterized by a diffuse muscle weakness most prominent distally and in the lower limbs, generalized areflexia, a decrease in proprioception and vibration sense and slight limb and gait ataxia. His condition improved on alpha tocopherol therapy so that it is very likely that vitamin E deficiency is responsible for his neurological deficit. Since in our patient as well as in several other reported cases this condition has been treatable, it is important that this syndrome be recognized in children presenting a suggestive clinical picture even if they do not have lipid malabsorption.

Vitamin E and Alzheimer's disease in subjects with Down's syndrome.

Journal of Mental Deficiency Research, 1988 Dec Vol 32(6) 479-484

Tested the hypothesis that a low level of serum Vitamin E would be associated with a likelihood of dementia in 24 Ss (aged 30+ yrs) with Down's syndrome. Blood samples were drawn, and evidence of deterioration in self-care skills was assessed. Nine Ss showed evidence of Alzheimer's disease (AD), and 9 did not. Plasma Vitamin E levels measured in Ss with AD were lower than in Ss without AD. It is suggested that there may be an interaction between risk of AD and the protective action of Vitamin E.

Nutritional status and cognitive functioning in a normally aging sample: a 6-y reassessment.

Am J Clin Nutr (UNITED STATES) Jan 1997, 65 (1) p20-9

Associations between nutritional status and cognitive performance were examined in 137 elderly (aged 66-90 y) community residents. Participants were well-educated, adequately nourished, and free of significant cognitive impairment. Performance on cognitive tests in 1986 was related to both past (1980) and concurrent (1986) nutritional status. Several significant associations (P < 0.05) were observed between cognition and concurrent vitamin status, including better abstraction performance with higher biochemical status and dietary intake of thiamine, riboflavin, niacin, and folate (rs = 0.19-0.29) and better visuospatial performance with higher plasma ascorbate (r = 0.22). Concurrent dietary protein in 1986 correlated significantly (rs = 0.25-0.26) with memory scores, and serum albumin or transferrin with memory, visuospatial, or abstraction scores (rs = 0.18-0.22). Higher past intake of vitamins E, A, B-6, and B-12 was related to better performance on visuospatial recall and/or abstraction tests (rs = 0.19-0.28). Use of self-selected vitamin supplements was associated with better performance on a difficult visuospatial test and an abstraction test. Although associations were relatively weak in this well-nourished and cognitively intact sample, the pattern of outcomes suggests some direction for further research on cognition-nutrition associations in aging.

Vitamin E inhibits low-density lipoprotein-induced adhesion of monocytes to human aortic endothelial cells in vitro

Arteriosclerosis, Thrombosis, and Vascular Biology (USA), 1997, 17/3 (429-436)

Monocyte adhesion to human aortic endothelial cells (ECs) is one of the early events in the development of atherogenesis. ECs were used to investigate the role of vitamin E in human monocyte adhesion to ECs in vitro. ECs incubated with 40 to 193 mg/dL of low-density lipoprotein cholesterol (LDL) for 22 hours exhibited increasing dose-dependent adherence for untreated, isolated human monocytes (P&lt.05). ECs exposed to the highest dose of LDL (193 mg/dL) but pretreated with 19 micromol/L alpha-ocopherol for 24 hours showed a trend to lower adherence for monocytes compared with nontreated ECs (4.4 plus or minus 1.2% versus 7.6 plus or minus 1.9%; P = .09). This effect of vitamin E became more significant (P&lt.05) when ECs were exposed to a lower level of LDL (40 mg/dL) or were pretreated with a higher level of alpha- tocopherol (42 micromol/L) and then exposed to 80 mg/dL LDL. Presupplementation of Ecs with 15, 19, and 37 micromol/L alpha-tocopherol significantly (P&lt.05) reduced monocyte adhesion by 6plus or minus1%, 37plus or minus6%, and 69plus or minus17%, respectively. Levels of soluble intercellular adhesion molecule-1 (sICAMn molecules for monocytes, increased after incubation of ECs with LDL 80 mg/dL (4.7plus or minus0.7 versus 6.4plus or minus1.2 ng/mL, respectively; P&lt.05). Treatment of Ecs with alpha-tocopherol (42 micromol/L) significantly reduced induction of sICAM-1 by LDL to 2.2plus or minus2.3 ng/mL. After exposure to LDL, prostaglandin I2 production by ECs was diminished, whereas presupplementation of ECs with alpha- tocopherol partially reversed the LDL effect. Production of interleukin-1beta was not detectable when ECs were treated with alpha-tocopherol, LDL, or alpha- tocopherol followed by LDL. Our findings indicate that vitamin E has an inhibitory effect on LDL-induced production of adhesion molecules and adhesion of monocytes to ECs via its antioxidant function and/or its direct regulatory effect on sICAM-1 expression.

The mechanism of apolipoprotein B-100 thiol depletion during oxidative modification of low-density lipoprotein

The mechanism of apolipoprotein B-100 thiol depletion during oxidative modification of low-density lipoprotein

Oxidation of low-density lipoprotein (LDL) is recognized to be a key step in atherogenesis. Previous studies show that LDL contains low-molecular- weight antioxidants such as vitamin E, beta-carotene, and ubiquinol, which can retard oxidative modification. In this report, we have evaluated the antioxidant potential of apolipoprotein B-100 (apo-B) thiols during LDL oxidation. Bath apo-B thiols and vitamin E were depleted concomitantly during the lag phase of Cu2+ -mediated LDL oxidation. The rate of thiol depletion was significantly inhibited by the lipophilic spin trap N-tert-butyl-alpha- phenylnitrone (PBN) but not by the water-soluble spin trap alpha-(4-pyridyl-1- oxide)-N-tert-butylnitrone (POBN). Blocking apo-Bthiols with sulfhydryl modifying agents increased the oxidizability of LDL. As with Cu2+, peroxynitrite also caused depletion of apoB thiols, and again thiol depletion was inhibited by PBN but not by POBN. A PBN/lipid-derived radical adduct was observed by the electron spin resonance technique during oxidation of LDL with peroxynitrite. We conclude that apo-B thiol depletion is mediated by lipid peroxidation, prior to the onset of the propagation phase of LDL oxidation. The implications of apoB thiols as intrinsic antioxidants of LDL are discussed.

Ascorbate and urate are the strongest determinants of plasma antioxidative capacity and serum lipid resistance to oxidation in Finnish men

Atherosclerosis (Ireland), 1997, 130/1 (223-233)

Copper-induced plasma lipoprotein oxidation resistance has usually been determined innsity lipoprotein (LDL) fractions, that do not contain water-soluble antioxidants present in blood plasma. The aim of this study was to find the main determinants of the measurements of copper-induced lipid oxidation istance (lag time) in whole serum and plasma total peroxyl radical trapping capacity (TRAP) in a population sample of smoking (n = 25) or non-smoking (n = 26) middle aged men at high risk of cardiovascular diseases. Smokers had significantly lower plasma ascorbic acid values, but only slightly lower alpha-tocopherol, beta-carotene and serum urate values than non-smokers. Plasma ascorbic acid concentration explained 23.5% of the lag time variation (standardized regression coefficient beta = 0.48; P = 0.004) in smokers and 5.6% in non-smokers. Serum urate concentration was the strongest determinant of lag time in non-smokers (beta = 0.64, P < 0.001). In addition, serum albumin, lipid standardized alpha-tocopherol and serum high density lipoprotein (HDL) cholesterol entered the multivariate regression model for lag time. For plasma TRAP, only urate and ascorbic acid entered the multivariate regression model. Lag times in serum and in isolated very low density lipoprotein (VLDL) and LDL fraction did not correlate, but the maximal rate of these reactions correlated significantly. These results confirm that lipid peroxidation resistance in serum or plasma are associated with ascorbic acid, urate, alpha-tocopherol, albumin and HDL concentrations. The measurement of lipid oxidation resistance in whole serum might be more physiological than in isolated lipoprotein fraction, as the effects of water-soluble antioxidants are not artificially removed.

Antioxidant status of hypercholesterolemic patients treated with LDL apheresis

Cardiovascular Drugs and Therapy (USA), 1996, 10/5 (567-571)

Oxidation of low density lipoprotein is involved in the pathogenesis of atherosclerosis. Epidemiological studies suggest a negative correlation between the occurrence of cardiovascular diseases and blood concentrations of lipophilic antioxidants such as vitamins A and E and beta-carotene. Trace elements, such zymes glutathione peroxidase and superoxide dismutase. The aim of this study was to determine the antioxidant and trace element status of patients with severe hypercholesterolemia who had been treated with dextran-sulphate low-density lipoprotein apheresis in comparison with two control populations, normocholesterolemic subjects and untreated hypercholesterolemic patients. Our results showed that, patients treated with LDL apheresis, compared with normocholesteromic subjects, were not deficient in vitamin E, beta-carotene, and copper, but had low plasma levels of selenium, zinc, and vitamin A. The low selenium and vitamin A levels were due to the LDL apheresis treatment, and the hypercholesterolemia might have provoked the low plasma levels of zinc.This study pointed out the potential benefits of supplemental selenium, zinc, and vitamin A in patients being treated with LDL apheresis.

Lack of correlation between the alpha-tocopherol content of plasma and LDL, but high correlations for gamma-tocopherol and carotenoids

Journal of Lipid Research (USA), 1996, 37/9 (1936-1946)

In 59 healthy human subjects (37 male and 22 female) the concentrations of the lipid-soluble antioxidants alpha and gamma-tocopherol, alpha- and beta-carotene, lycopene, cryptoxanthin, canthaxanthin, and lutein + zeaxanthin were determined in plasma (micromol/L) and in isolated low density lipoproteins (LDL) (micromol/mmol cholesterol). Plasma alpha-tocopherol concentrations were significantly correlated with plasma total cholesterol concentrations (r2 = 0.51, P < 0.0001) yet not with the LDL alpha-tocopherol content (r2 = 0.05, ns). Plasma gamma-tocopherol concentrations were weakly correlated with plasma total cholesterol (r2 = 0.12, P < 0.003) and both absolute and cholesterol standardized plasma gamma-tocopherol concentrations correlated strongly with the LDL gamma-tocopherol content (r2 = (0.58 and r2 = 0.72, respectively). In contrast, carotenoid concentrations did not correlate with cholesterol concentrations, but their LDL content correlated significantly with the respective plasma concentrations (r2 = 0.67 to 0.92, all P < 0.0001). In a subgroup of study subjects (n = 13) the distribution of vitamin E and carotenoids among LDL was calculated. The proportion of plasma alpha- and gamma- tocopherol found in LDL was 48 plus or minus 7 (range, 36-61%) and 41 plus or minus 7%, respectively, suggesting that LDL was in most of these subjects not the main carrier for these antioxidants. The lipophilic carotenoids, however, were predominantly carried by LDL (e.g., beta-carotene: 87 plus or minus 10%), whereas the proportion of the more polar ones carried by LDL was much smaller (e.g., lutein + zeaxanthin: 36 plus or minus 6%). The results of this study show that plasma alpha-tocopherol concentrations are not predictive for the alpha-tocopherol content of LDL in nonsupplemented individuals. This finding could have implications in interpreting the cause of the inverse relationship between plasma alpha- tocopherol and risk of atherosclerosis.

Oxidized low density lipoproteins in atherogenesis: Role of dietary modification

Annual Review of Nutrition (USA), 1996, 16/- (51-71)

The development of atherosclerosis is a complex and multistep process. There are many determinants in the pathogenesis of this condition, with different factors presumably playing key roles at different times in the evolution of the atherosclerotic plaque. It has been suggested that oxidation of low density lipoproteins (LDL) by cells in the artery wall leads to a proatherogenic particle that may help initiate early lesion formation. For this reason, understanding the determinants of LDL susceptibility to oxidation is essential for developing therapeutic strategies to inhibit this process. Oxidation of LDL begins with the abstraction of hydrogen from polyunsaturated fatty acids; thus, LDL fatty acid composition undoubtedly contributes to the process of LDL oxidation. Since dietary fatty acids influence the fatty acid composition of LDL and cell membranes, the amount and type of fat in the diet may effect susceptibility of LDL and cells to oxidative damage. Additionally, since cell membrane fatty acid composition also influences cellular formation of reactive oxygen species, dietary fatty acids may help determine the prooxidant activity of artery wall cells. Both cells and lipoproteins contain a variety of antioxidants that provide protection against oxidative stress. A major source of these antioxidants is the diet. Enrichment of the diet with foods high in such antioxidants as vitamin E, beta-carotene, or vitamin C, or supplementation of the diet with antioxidant vitamins, may inhibit oxidation and the process of atherosclerosis

Increased oxidation resistance of atherogenic plasma lipoproteins at high vitamin E levels in non-vitamin E supplemented men

Atherosclerosis (Ireland), 1996, 124/1 (83-94)

The oxidative modification of human low density lipoprotein (LDL) has been widely investigated. However, there are no tein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein fraction, although all of them are atherogenic and contain antioxidants such as alpha-tocopherol. We investigated the oxidation susceptibility and oxidation resistance of VLDL + LDL (including IDL) fraction by induction with CuCl2 and its relation to plasma alpha-tocopherol concentration and lipid standardised alpha-tocopherol concentration in 406 non-vitamin E-supplemented men from eastern Finland. Even though we did not give oral vitamin E or any other antioxidant supplementation to our study participants, we observed a significant, consistent relationship between measurements of oxidation resistance and plasma content of vitamin E. In the multivariate regression model, a high plasma content of vitamin E or lipid standardised vitamin E concentration were the most important determinants of lag time to maximal oxidation rate (standardised regression coefficient = 0.244, P < 0.0001 for vitamin E and 0.211, P < 0.0001 for lipid standardised vitamin E). After statistical adjustment for age, use of cigarettes, hypolipidemic medication (yes vs. no), month of the measurements, plasma concentrations of total ascorbic acid (ascorbic acid +dehydroascorbic acid), beta-carotene and phospholipids, serum concentrations of LDL cholesterol and triglycerides and dietary intake of linoleic acid, the lag time to maximal oxidation rate was 10% (95% C.I. 6.0-13.5%) longer in men in the highest fifth than in the lowest fifth of plasma vitamin E content (P < 0.0001 for trend). When the fifths of lipid standardised vitamin E were compared, the lag time to maximal oxidation rate was 6% (95% C.I. 1.8-10.1%) longer in men in the highest than in the lowest fifth (P < 0.0001 for trend). Our data suggest that alpha-tocopherol is an important antioxidant preventing the in vitro oxidation of VLDL + LDL fraction even in non-supplemented subjects.

Acetylsalicylic acid and vitamin E in prevention of arterial thrombosis.

Can J Cardiol (CANADA) May 1997, 13 (5) p533-5

Both acetylsalicylic acid and vitamin E have been shown to be beneficial in the prevention of stroke and heart attacks. It is implied that their combination in the treatment of thrombotic complications of atherosclerosis may have added benefits. It is suggested that vitamin E may work as a platelet lysosome stabilizing agent.

Vitamin E consumption and the risk of coronary disease in women

NEW ENGL. J. MED. (USA), 1993, 328/20 (1444-1449)

Background. Interest in thdocumented 552 cases of major coronary disease (437 nonfatal myocardial infarctions and 115 deaths due to coronary disease). Results. As compared with women in the lowest fifth of the cohort with respect to vitamin E intake, those in the top fifth had a relative risk of major coronary disease of 0.66 (95 percent confidence interval, 0.50 to 0.87) after adjustment for age and smoking. Further adjustment for a variety of other coronary risk factors and nutrients, including other antioxidants, had little effect on the results. Most of the variability in intake and reduction in risk was attributable to vitamin E consumed as supplements. Women who took vitamin E supplements for short periods had little apparent benefit, but those who took them for more than two years had a relative risk of major coronary disease of 0.59 (95 percent confidence interval, 0.38 to 0.91) after adjustment for age, smoking status, risk factors for coronary disease, and use of other antioxidant nutrients (including multivitamins). Conclusions. Although these prospective data do not prove a cause-and-effect relation, they suggest that among middle-aged women the use of vitamin E supplements is associated with a reduced risk of coronary heart disease. Randomized trials of vitamin E in the primary and secondary prevention of coronary disease are being conducted; public policy recommendations about the widespread use of vitamin E should await the results of these trials.

The role of free radicals in disease

Australian and New Zealand Journal of Ophthalmology (Australia), 1995, 23/1

Evidence is accumulating that most of the degenerative diseases that afflict humanity have their origin in deleterious free radical reactions. These diseases include atherosclerosis, cancer, inflammatory joint disease, asthma, diabetes, senile dementia and degenerative eye disease. The process of biological ageing might also have a free radical basis. Most free radical damage to cells involves oxygen free radicals or, more generally, activated oxygen species (AOS) which include non-radical species such as singlet oxygen and hydrogen peroxide as well as free radicals. The AOS can damage genetic material, cause lipid peroxidation in cell membranes, and inactivate membrane-bound enzymes. Humans are well endowed with antioxidant defences against AOS; these antioxidants, or free radical scavengers, include ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), beta-carotene, coenzyme Q10, enzymes such as catalase and superoxide dismutase, and trace elements including selenium and zinc. The eye is an organ with intense AOS activity, and it requires high levels of antioxidants to protect its unsaturated fatty acids. The human species is not genetically adapted to survive past middle age, and it appears that antioxidant supplementation of our diet is needed to ensure a more healthy elderly population.

Randomized, controlled trial of antioxidant vitamins and cardioprotective diet on hyperlipidemia, oxidative stress, and development of experimental atherosclerosis: The diet and antioxidant trial on atherosclerosis (DATA)

Cardiovascular Drugs and Therapy (USA), 1995, 9/6

The effects of administration of guava and papaya fruit (100 g/day), vegetables, and mustard oil (5 g/day) (group A); antioxidant vitamins C (50 mg/day) and E (30 mg/day) plus betacarotene (10 mg/day) (group B); a high-fat (5-10 g/day) (group C); or a low-fat (4-5 g/day) diet (group D) were compared over 24 diet weeks in a randomized fashion, while all groups of rabbits (five in each of four groups) received a hydrogenated fat diet (5-10 g/day) for a period of 36 weeks. After 12 weeks on the high fat diet, each group of rabbits had an increase in blood lipoproteins. The fruit and vegetable-enriched prudent diet (group A) caused a significant decline in blood lipids at 24 and 36 weeks, whereas the lipid levels increased significantly in groups C and D. Group A also had a significant rise in vitamin E (2.1 Umol/l), C (10.5 Umol/l), A (0.66 Umol/l), and carotene (0.08 Umol/l) and a decrease in lipid peroxides (0.34 nmol/ml at 36 weeks, whereas the levels were unchanged in groups C and D. Group B rabbits had a significant and greater increase than group A in plasma vitamins E, C, A, and carotene; a rise in HDL cholesterol; and a greater decrease in lipid peroxides after 24 and 36 weeks of treatment. After stimulation of lipid peroxidation in all rabbits, 3 of 5 group C and 2 of 5 group D rabbits died due to coronary thrombosis, whereas in groups A and B there were no deaths, indicating that antioxidant therapy can provide protection against lipid peroxidation and free radical generation. Aortic lipids and sudanophilia, indicating atherosclerosis, were significantly higher in groups C and D than in groups A and B. Fatty streaks and atheromatous and fibrous plaques were noted in all the rabbits in groups C and D. Intimal fibrosis and medial degeneration were also present in the group C rabbits. While group A (36.4 plus or minus 4.4 microm) and group B (37.1 plus or minus 4.2 microm) rabbits had minimal coronary artery plaque sizes, group C (75.4 plus or minus 10.6 microm) and group D rabbits (69.5 plus or minus 6.2 microm) had significantly greater plaque sizes. Aortic plaque sizes were also greater in groups C and D than in groups A and B. It is possible that combined therapy with antioxidant vitamins C, E, and carotene, and a diet rich in antioxidants, could independently inhibit free radical generation and the development of atherosclerosis.

Serum levels of vitamin E in relation to cardiovascular diseases

Journal of Clinical Pharmacy and Therapeutics (United Kingdom), 1995, 20/6

Serum vitamin E levels in healthy people (n = 71) and patients with cardiovascular diseases (n = 62) were determined. The cases of cardiovascular disease comprised patients with acute myocardial infarction (AMI) (n = 31), atherosclerosis (AT) (n = 23) and myocardial ischaemia (MI) (n = 8). The mean (plus or minus SD) serum vitamin E levels of the control group and the group with cardiovascular disease were 1.12 plus or minus 0.27 mg% and 0.98 plus or minus 41 mg%, respectively. Patients with AMI, AT and MI had corresponding levels of 0.97 plus or minus 48 mg%, 1.00 plus or minus 0.39 mg% and 1.01 plus or minus 0.44 mg%, respectively. Overall serum vitamin E levels were lower in the group with cardiovascular disease than in the control group. Patients and the control group are also discussed with respect to a number of potentially confounding parameters such as age, sex, smoking status, quetelet index (kg/m2), alcohol consumption, dietary intake and serum lipids.

Oxidative susceptibility of low density lipoprotein from rabbits fed atherogenic diets containing coconut, palm, or soybean oils

Lipids (USA), 1995, 30/12 (1145-1150)

The oxidative susceptibilities of low density lipoproteins (LDL) isolated from rabbits fed high-fat atherogenic diets containing coconut, palm, or soybean oils were investigated. New Zealand white rabbits were fed atherogenic semisynthetic diets containing 0.5% cholesterol and either (i) 13% coconut oil and 2% corn oil (CNO), (ii) 15% refined, bleached, and deodorized palm olein (RBDPO), (iii) 15% crude palm olein (CPO), (iv) 15% soybean oil (SO), or (v) 15% refined, bleached, and deodorized palm olein without cholesterol supplementation (RBDPO(wc)), for a period of twelve weeks. Total fatty acid compositions of the plasma and LDL were found to be modulated (but not too drastically) by the nature of the dietary fats. Cholesterol supplementation significantly increased the plasma level of vitamin E and effectively altered the plasma composition of long-chain fatty acids in favor of increasing oleic acid. Oxidative susceptibilities of LDL samples were determined by Cu2+-catalyzed oxidation which provide the lag times and lag-phase slopes. The plasma LDL from all palm oil diets (RBDPO, CPO, and RBDPO(wc)) were shown to be equally resistant to the oxidation, and the LDL from SO-fed rabbits were most susceptible, followed by the LDL from the CNO-fed rabbits. These results reflect a relationship between the oxidative susceptibility of LDL due to a combination of the levels of polyunsaturated fatty acids and vitamin E.

Coantioxidants make alpha-tocopherol an efficient antioxidant for low- density lipoprotein

American Journal of Clinical Nutrition (USA), 1995, 62/6 SUPPL.

The oxidation of low-density lipoproteins (LDLs) is now commonly implicated as an important early event in atherogenesis. The resulting interest in LDL antioxidation has focused on alpha-tocopherol, the biologically and chemically most active form of vitamin E and quantitatively the major lipid-soluble antioxidant in extracts prepared from human LDL. We review advances made in our understanding of the molecular action of alpha-tocopherol in radical-mediated oxidation of isolated human LDL and how the vitamin's antioxidant activity is enhanced or even dependent on the presence of suitable reducing species, which are referred to as coantioxidants.

Effect of vitamin E, vitamin C and beta-carotene on LDL oxidation and atherosclerosis

Canadian Journal of Cardiology (Canada), 1995, 11/SUPPL. G (97G-103G)

OBJECTIVE: The oxidative modification of low density lipoprotein (LDL) may be early step in atherogenesis. Furthermore, evidence of oxidized LDL has been found in vivo. The most persuasive evidence shows that supplementation of some animal models with antioxidants slows atherosclerosis. The purpose of this review is to examine the roles that vitamin E, vitamin C and beta-carotene may play in reducing LDL oxidation. DATA SOURCES: English language articles published since 1980, particularly from groups active in this field of research. STUDY SELECTION: In vitro, animal, and human studies on antioxidants, LDL oxidation, and atherosclerosis were selected. DATA SYNTHESIS: Vitamin E has shown the most consistent effects with regard to LDL oxidation. Beta-carotene appears to have only a mild or no effect on oxidizability. Ascorbate, although it is not lipophilic, can also reduce LDL oxidative susceptibility. CONCLUSIONS: LDL oxidizability can be reduced by antioxidant nutrients. However, more research is needed to establish their utility in the prevention of coronary artery disease.

Effects on health of dietary supplementation with 100 mg d-alpha-tocopheryl acetate, daily for 6 years

Journal of International Medical Research (United Kingdom), 1995, 23/5

To evaluate the clinical antioxidant effects of vitamin E, 161 healthy volunteers aged 39 to 56 years, were given 100 or 3 mg of d-alpha-tocopheryl acetate orally daily for 6 years using a randomized, double-blind design, among the 147 volunteers who qualified for the analysis, seven of the 73 volunteers receiving 3 mg d-alpha-tocopheryl acetate daily and none of the 74 volunteers receiving 100 mg had coronary disorders including myocardial damage (P < 0.02). ST or T wave abnormalities on electrocardiograms were considered to indicate coronary disorders (four volunteers). The mean serum total tocopherol (TOC) concentration in the 100-mg group was significantly higher than that in the 3-mg group 6 months after the start of the study, and this raised value was maintained throughout the study; the level in the 3-mg group did not change significantly from the baseline value, The low-density lipoprotein cholesterol/total TOC ratio, a parameter of the inhibition of peroxidation of low-density lipoprotein cholesterol, was the only serum lipid parameter that was significantly different, at baseline, in the volunteers with coronary disorders compared with the others. These findings indicate that long-term supplementation with 100 mg tocopheryl acetate daily may prevent the early stages of coronary atherosclerosis by decreasing peroxidation of low-density lipoprotein cholesterol.

Mechanisms of the cardioprotective effect of a diet enriched with omega-3 polyunsaturated fatty acids

Pathophysiology (Netherlands), 1995, 2/3 (131-140)

The review presents current views of metabolic conversions of class omega-3 polyunsaturated fatty acids (omega-3 PUFA) and their effects on the heart function. The role of these compounds in regulation of the membrane lipid composition is discussed. Within the organism, omega-3 PUFA incorporate more effectively into membrane phospholipids of the myocardium in comparison with other organs. In animals kept on a omega-3 PUFA-enriched diet, the intramembrane concentration of omega-6 PUFA, in the first place, of rachidonic acid, decreases. Substitution of omega-3 PUFA for arachidonic acid in the metabolic system of eicosanoid synthesis initiates the synthesis of prostaglandins and thromboxanes possessing lowered biological activity, thus minimizing the risk of clot formation in the cardiovascular system. As omega-3 PUFA are direct substrates for lipid peroxidation, any rise in omega-3 PUFA concentration sharply activates free-radical oxidation in the membranes of internal organs particularly in the liver. Original data are presented that in rats kept on omega-3 PUFA-enriched diets, the kinetic parameters of the Ca2+ transport system do not change. However, the resistance of the system to free radical oxidation increases considerably. This may increase myocardial resistance to free-radical-dependent injuries. A rise in the intramembrane omega-3 PUFA content which brings about structural rearrangements within lipids and changes the activity of membrane-bound enzymes in vitro, has no effect in vivo. This finding points to the existence of a mechanism compensating for changes in the fatty acid composition of foods. Data from literature analysis suggest that one of the most active participants in the compensatory system is alpha-tocopherol, a lipid peroxidation inhibitor and a structural stabilizer of biomembranes. With a rise in omega-3 PUFA concentration, alpha-tocopherol is released from the liver and blood flow and accumulated in the body (predominantly in myocardial membranes). Whereas potent chemical antioxidants display an ability to inhibit physiologically important free-radical reactions occurring in the organism, vitamin E is without side effects even when used at high concentrations. In case of long-term application of omega-3 PUFA-enriched diets, alpha-tocopherol must be added to the diet.

Vitamin E: Metabolism and role in atherosclerosis

ANN. BIOL. CLIN. (France), 1994, 52/7-8

Vitamin E is the term used for eight naturally occurring fat-soluble nutrients. Alpha-tocopherol predominates in many species and has the highest biological activity. Vitamin E is absorbed via the lymphatic pathway and transported in association with CM. Vitamin E is carried in plasma by lipoproteins. It is secreted by the liver in nascent VLDL with a preferential incorporation of alpha-tocopherol. Most of the plasma vitamin E is in LDL and in HDL. Vitamin E is exchanged readily between lipoproteins: tocopherol in HDL readily transfers to apolipoprotein B-containing lipoproteins (VLDL, LDL), with little return of tocopherol from the apolipoprotein B-containing lipoproteins to HDL. The mechanisms of tissue uptake of vitamin E from the lipoproteins is poorly understood. This uptake may occur during catabolism of triacylglycerol-rich lipoproteins by the activity of lipoprotein lipase, via the LDL receptor or by nonreceptor-mediated uptake. Vitamin E may act to prevent the initiation/progression of spontaneous atherosclerosis. This concept is based on in-vitro data: vitamin E influences the responses of cells (vascular endothelial cells, leukocytes, vascular smooth muscle cells) and the modification of lipoproteins (especially LDL) which, at least in principle, could contribute to the initiation/progression of spontaneous atherosclerosis. In vivo studies are clearly required to establish the extent and mode of vitamin E's antiatherosclerotic impact and, hence, its therapeutic potential.

Human atherosclerotic plaque contains both oxidized lipids and relatively large amounts of alpha-tocopherol and ascorbate.

Arterioscler Thromb Vasc Biol (UNITED STATES) Oct 1995, 15 (10) p1616-24

We assessed the antioxidant status and contents of unoxidized and oxidized lipids in freshly obtained, homogenized samples of both normal human iliac arteries and carotid and femoral atherosclerotic plaque. Optimal sample preparation involved homogenization of human atherosclerotic plaque for 5 minutes, which resulted in recovery of most of the unoxidized and oxidized lipids without substantial destruction of endogenous vitamins C and E and 87% and 43% recoveries of added standards of alpha- tocotrienol and isoascorbate, respectively. The total protein, lipid, and antioxidant levels obtained from human plaque varied among donors, although the reproducibility of replicates from a single sample was within 3%, except for ubiquinone-10 and ascorbate, which varied by 20% and 25%, respectively. Plaque samples contained significantly more ascorbate and urate than control arteries, with no discernible difference in the vitamin C redox status between plaque and control materials. The concentrations of alpha-tocopherol and ubiquinone-10 were comparable in plaque samples and control arteries. However, approximately 9 mol percent of plaque alpha-tocopherol was present as alpha-tocopherylquinone, whereas this oxidation product of vitamin E was not detectable in control arteries. Coenzyme Q10 in plaque and control arteries was only detected in the oxidized form ubiquinone-10, although coenzyme Q10 oxidation may have occurred during processing. The most abundant of all studied lipids in plaque samples was free cholesterol, followed by cholesteryl oleate and cholesteryl linoleate (Ch18:2). Approximately 30% of plaque Ch18:2 was oxidized, with 17%, 12%, and 1% present as fatty acyl hydroxides, ketones, and hydroperoxides, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin E protects nerve cells from amyloid beta protein toxicity.

Behl C; Davis J; Cole GM; Schubert D
Salk Institute for Biological Studies, San Diego, CA 92186-5800.
Biochem Biophys Res Commun (UNITED STATES) Jul 31 1992, 186 (2) p944-50

The amyloid beta protein (ABP) is a 40 to 42 amino acid peptide which accumulates in Alzheimer's disease plaques. It has been demonstrated that this peptide and a fragment derived from it are cytotoxic for cultured cortical nerve cells. It is shown here that ABP and an internal fragment encompassing residues 25 to 35 (beta 25-35) are cytotoxic to a clone of PC12 cells at concentrations above 1 x 10(-9)M and to several other cell lines at higher concentrations. Between 10(-9) and 10(-11) M beta 25-35 protects PC12 cells from glutamate toxicity. The antioxidant and free radical scavenger vitamin E inhibits ABP induced cell death. These results have implications regarding the prevention and treatment of Alzheimer's disease.

Pharmacotherapy in Alzheimer's dementia: Treatment of cognitive symptoms Results of new studies

Fortschritte der Neurologie Psychiatrie (Germany), 1997, 65/3 (108-121)

Recent investigations have given new insights into pathogenetical determinants of Alzheimer's disease. Amyloid deposition and neurofibrillary tangles are no longer considered to be primary pathological changes. Neurobiological research tries to work out the etiopathogenital cascade that finally causes Alzheimer's disease. So far, several relevant pathogenetical factors have been detected, e.g. pertubated control of glucose breakdown, impairment of oxidative metabolism, impaired neuroprotection due to increased oxidative stress and non-enzymatic protein glycation as well as immunological disturbances. Thus, new strategies for the development of cognition-enhancing drugs are emerging. The authors review reports on agents, that are under investigation for the treatment of cognitive symptomatology in Alzheimer's disease. Some of these agents have already been used for treatment of other medical conditions, e.g. nimodipine, memantine as well as selegiline. Many of them are still experimental. Promising strategies include antioxidative agents (e.g. vitamin E, vitamin C, beta-carotin), acetylcholinesterase-inhibitors with central selectivity (e.g. ENA 713), M1- and M4-muscarinic receptor agonists (milameline) as well as sabeluzole, a benzothazide derivative that shows neurotrophic activities and anti-inflammatory substances like indomethacin.

New agents for cancer chemoprevention

Nation996, 63/SUPPL. 26 (1-28)

Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned. The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids (e.g., retinol, retinyl palmitate, all-trans-retinoic acid, and 13-cis-retinoic acid), calcium, betacarotene, vitamin E, tamoxifen, and finasteride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase III chemoprevention trials. Prominent in this group are all-trans-N-(4-hydroxy phenyl)retinamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylomithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA). A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-l-cysteine, curcumin, DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3- carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., alpha-carotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs.Other agents of high interest are aromatase inhibitors (e.g., (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean trypsin inhibitor). Combinations are also being considered, such as vitamin E with l-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are ras isoprenylation and epidermal growth factor receptor inhibitors.

Effects of interaction of RRR-alpha-tocopheryl acetate and fish oil on low-density-lipoprotein oxidation in postmenopausal women with and without hormone-replacement therapy

American Journal of Clinical Nutrition (USA), 1996, 63/2 (184-193)

We evaluated the effects of RRR-alpha-tocopheryl acetate (alpha-tocopheryl acetate) and hormone-replacement therapy (HRT) on the oxidative susceptibility of low-density lipoprotein (LDL) in postmenopausal women consuming a fish oil supplement. The independent effect of fish oil was also assessed. Forty-eight women, equally divideed in a double-blind cross over trial. Each of the four periods lasted 5 wk and was followed by a 4-wk washout interval. During each period all subjects were given a 15-g supplement of fish oil and either 0 (placebo), 100, 200, or 400 mg alpha-tocopheryl acetate daily. LDL resistance to oxidative modification was assessed by calculating lag time, propagation rate, and maximum production of conjugated dienes. Supplementation with fish oil and placebo shortened lag time and slowed propagation rate in women both using and not using HRT. After subjects consumed fish oil, supplementation with alpha-tocopheryl acetate in creased plasma and LDL alpha-tocopherol contents significantly and lengthened lag time (at even the lowest concentration) but had no significant effect on propagation rate or maximum production compared with values measured after consumption of fish oil alone. Women not using HRT had faster propagation rates and higher maximum production than women using HRT; after supplementation with fish oil and alpha-tocopheryl acetate these differences prevailed. Supplements as low as 100 mg alpha-tocopheryl acetate/d increase the resistance of LDL to oxidation when fish oil supplements are used. HRT and fish oil supplements may independently affect LDL oxidative susceptibility.

On the mechanism of the anticlotting action of vitamin E quinone

Proceedings of the National Academy of Sciences of the United States of America (USA), 1995, 92/18 (8171-8175)

Vitamin E in the reduced, alpha-tocopherol form shows very modest anticlotting activity. By contrast, vitamin E quinone is a potent anticoagulant. This observation may have significance for field trials in which vitamin E is observed to exhibit beneficial effects on ischemic heart disease and stroke. Vitamin E quinone is a potent inhibitor of the vitamin K- dependent carboxylase that controls blood clotting. A newly discovered mechanism for the inhibition requires attachment of the active site thiolgroups of the carboxylase to one or more methyl groups on vitamin E quinone. The results from a series of model reactions support this interpretation of the anticlotting activity associated with vitamin E.

alpha-Tocopherol quinone level is remarkably low in the cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis.

Neurosci Lett (IRELAND) Mar 22 1996, 207 (1) p5-8

In order to investigate the role of free radicals in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS), the concentrations of alpha-tocopherol (alpha-TOH) and its oxidized form alpha-tocopherol quinone (alpha-TQ) in the cerebrospinal fluid (CSF) of SALS patients were determined. The alpha-TOH level was 31% lower (P < 0.05) and the alpha-TQ level was 75% lower (P < 0.001) in SALS patients than in normal subjects. The results of the present study do not support the hypothesis that activated lipid peroxidation accelerates oxidation of alpha-TOH into alpha-TQ in SALS patients.

Clinical study of vitamin influence in diabetes mellitus

Journal of the Medical Society of Toho University (Japan), 1996, 42/6 (577-581)

Vitamin deficiency is a result of an inadequale diet. Education on the importance of trace nutrients in diabetic patients with poor blood sugar control is examined. Those who prepare meals must consider the loss of vitamins in the process of cooking. Our study also suggested that marginal vitamin deficiency plays an indirect but important role in the development of diabetic complications. Vitamin C as altering total cholesterol (T-ch) and vitamin E as altering triglyceride (TG) could modify diabetic angiopathy. Pharmacologically, niacin might be responsible for the decrease in Lipoprotein (a) and vitamin C would inhibit the influence of rapid blood glucose control on diabetic retinopathy.

Antioxidants, Helicobacter pylori and stomach cancer in Venezuela.

de Sanjose S; Munoz N; Sobala G; Vivas J; Peraza S; Cano E; Castro D; Sanchez V; Andrade O; Tompkins D; Schorah CJ; Axon AT; Benz M; Oliver W
Servei d'Epidemiologia i Registre del Cancer, Institut Catala d'Oncologia Hospital Duran i Reynals, Barcelona, Spain.
Eur J Cancer Prev (ENGLAND) Feb 1996, 5 (1) p57-62

A randomized chemoprevention trial on precancerous lesions of the stomach is being conducted in Tachira State, Venezuela. The aims of the study are to evaluate the efficacy of vitamin supplementation in preventing the progression rate of precancerous lesions. Here we report on the pilot phase of the study in which two antioxidant preparations were evaluated on their ability to raise antioxidant levels in plasma and in gastric juice. The study aimed also to determine the antibiotic sensitivity profiles of Helicobacter pylori isolates prevalent in the area. Forty-three subjects with precancerous lesions (chronic gastritis, chronic atrophic gastritis, intestinal metaplasia and dysplasia) of the stomach were randomized to one of atments. Treatment 1 (250 mg of standard vitamin C, 200 mg of vitamin E and 6 mg of beta-carotene three times a day) or treatment 2 (150 mg of standard vitamin C, 500 mg of slow release vitamin C, 75 mg of vitamin E and 15 mg of beta-carotene once a day) for 7 days. Blood levels of total vitamin C, beta-carotene and alpha-tocopherol and gastric juice levels of ascorbic acid and total vitamin C were measured before and after treatment on day 8. Both treatments increased the plasma levels of total vitamin C, beta-carotene and alpha-tocopherol/cholesterol but not those of ascorbic acid or total vitamin C in gastric juice. Treatment 1 was the best choice and resulted in a greater increase in the plasma levels of beta-carotene and alpha-tocopherol. H. pylori was cultured from 90% of the gastric biopsies; 35 isolates were identified which were highly resistant to metronidazole, a front-line antibiotic recommended against H. pylori in other settings.

Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group.

Cancer Res. 1994 Apr 1. 54(7 Suppl). P 2029s-2031s

In Linxian China, the esophageal/gastric cardia cancer mortality rates are among the highest in the world. There is suspicion that the population's chronic deficiencies of multiple micronutrients are etiologically involved. We conducted two randomized, placebo-controlled nutrition intervention trials to test the effects of vitamin and mineral supplements in lowering the rates of esophageal/gastric cancer. In the first trial, the dysplasia trial, 3318 adults with a cytological diagnosis of esophageal dysplasia received daily supplementation with 26 vitamins and minerals in doses typically 2-3 times the United States Recommended Daily Allowances, or placebos, for 6 years. The second trial, the general population trial, involved 29,584 adults and used a one-half replicate of a 2(4) factorial experimental design which tested the effects of four combinations of nutrients: A, retinol and zinc; B, riboflavin and niacin; C, vitamin C and molybdenum; and D, beta-carotene, vitamin E, and selenium. Doses for these daily supplements ranged from 1 to 2 times the United States Recommended Daily Allowances, and the different vitamin/mineral combinations or placebos were taken for a period of 5.25 years. As part of the general population trial, and end-of-intervention endoscopy survey was carried out in a small (1.3%) sample of subjects to see if supplementation affected the prevalence of dysplasia and early cancer. Herein we review the methods of these trials and the results of the endoscopic survey. Fifteen esophageal and 16 gastric cancers were identified in endoscopic biopsies from the 391 subjects evaluated from two villages, and nearly all were asymptomatic. No significant reductions in the prevalence of esophageal or gastric dysplasia or cancer were seen with any of the four supplement groups. However, the prevalence of gastric cancer among participants receiving retinol and zinc was 62% lower than those not receiving those supplements (P = 0.09), while participants receiving beta-carotene, vitamin E, and selenium had a 42% reduction in esophageal cancer prevalence (0.34). We have reported separately that cancer mortality over the entire 5.25-year period was significantly reduced among those receiving beta-carotene, vitamin E, and selenium. The findings from the overall trial and the endoscopic sample offer a hopeful sign and should encourage additional studies with these agents in larger numbers of subjects.

Association of esophageal cytological abnormalities with vitamin and lipotrope deficiencies in populations at risk for esophageal cancer

ANTICANCER RES. (Greece), 1988, 8/4 (711-716)

Esophageal brush cytological screening was undertaken and blood concentrations of micronutrients (vitamins A, E, B12, folic acid and methionine) determined from adults at risk for esophageal carcinoma (EC) in Transkei and Ciskei, Southern Africa. Age-standardised EC rates per 100,000 per annum for both sexes in high, intermediate and low risk districts in Transkei were 74, 51 and 34, respectively. Corresponding rates in high and low EC risk districts in Ciskei were 129 and 9, respectively. Esophageal cytological changes including esophagitis, signs of folic acid deficiency, cellular atypia, dysplasia and cancer, were more prevalent in patients from high than from low EC risk areas. Dietary questionnaires revealed that corn was the main dietary staple in all populations, but that lower intakes of green vegetables, fruits and animal protein occurred in the high risk areas. Significantly lower concentrations of vitamins A, E, B12 and folic acid were present in the blood of patients presenting with cellular dysplasia or malignancy than in cytologically normal patients and in patients from the low risk areas. Concentrations of red cell and plasma folate were significantly lower in patients presenting with cytological signs of folic acid deficiency or cellular atypia. The association of vitamin A, vitamin E and folic acid deficiencies with specific esophageal cytological abnormalities in populations at risk for EC is reported for the first time.

Possible immunologic involvement of antioxidants in cancer prevention.

Am J Clin Nutr. 1995 Dec. 62(6 Suppl). P 1477S-1482S

The people of Linxian County, China have one of the world's highest rates of esophageal cancer. Two intervention trials were conducted to determine whether supplementation with specific vitamins and minerals could lower mortality from or incidence of cancer in this population and whether supplementation with multiple vitamins and minerals would reduce esophageal and gastric cardia cancer in persons with esophageal dysplasia. About 30,000 general population (GP) subjects in the GP trial were randomly assigned to one of eight intervention groups according to a one-half replicate of a 2(4) factorial experimental design and were supplemented for 5.25 y with four combinations of micronutrients at doses from one to two times the US recommended dietary allowance (RDA). About 3000 subjects in whom dysplasia was diagnosed in the dysplasia trial were randomly assigned to groups receiving daily supplementation with 14 vitamins and 12 minerals at two to three times the US RDA or placebo for 6 y. Results of the dysplasia trial indicate that in individuals with esophageal dysplasia, micronutrient supplementation had little effect on T lymphocyte responses. In contrast, male participants in the GP trial who were supplemented with beta-carotene, vitamin E, and selenium showed significantly (P < 0.05) higher mitogenic responsiveness of T lymphocytes in vitro than those not receiving these micronutrients.

Protein/platelet interaction with an artificial surface: effect of vitamins and platelet inhibitors.

Thromb Res (UNITED STATES) Jan 1 1986, 41 (1) p9-22

Protein adsorption and platelet adhesion are two important biological processes arising at the blood-prosthetic interface. The effect of Vitamins and antiplatelet drugs to modulate the surface induced platelet adhesion to polycarbonate was investigated using washed calf platelets in presence and absence of fibrinogen. This study also demonstrated the effects of Vitamins and antiplatelet drugs towards protein adsorption to an artificial surface. It seems Vitamin B6, Vitamin E, combinations of Aspirin-Persantine, Aspirin-Vitamin C, a synthetic Polyelectrolyte and Galactosamine reduced the fibrinogen (fg) surface concentration from a mixture of proteins. These antiplatelet agents also enhanced the albumin surface concentration. This itself may be one of the parameters to reduce the platelet adhesion towards an artificial surface. A combination of Aspirin-Vitamin C-Vitamin B6-Vitamin E inhibited the fibrinogen surface binding, which might be beneficial to improve the blood compatibility of an artificial surface.

Selected micronutrient intake and thyroid carcinoma risk

Cancer (USA) , 1997, 79/11 (2186-2192)

BACKGROUND. Protection from thyroid carcinoma due to certain dietary factors was suggested by several studies, but the findings were relatively inconsistent. The role of micronutrients has not yet been systematically analyzed. To investigate the relationship between micronutrient intake and thyroid carcinoma risk, the authors used data from a case-control study conducted in northern Italy between 1986 and 1992. METHODS. The study included 399 incident, histologically confirmed thyroid carcinoma cases and 617 controls admitted to the hospital for acute, nonneoplastic, nonhormone- related diseases. RESULTS. Retinol intake showed a direct association with thyroid carcinoma risk, with odds ratios (ORs) of 1.39 (95% confidence interval (CI), 0.9-2.0) in the third quartile of consumption and 1.52 (95% CI, 1.0-2.3) in the highest quartile, whereas beta-carotene had an inverse relationship, with ORs of 0.63 (95% CI, 0.4-0.9) in the third quartile of consumption and 0.58 (95% CI, 0.4- 0.9) in the highest quartile compared with the lowest quartile. Some protection was observed for measures of vitamin C intake (with an OR of 0.72) and vitamin E (with an OR of 0.67) for the highest quartile of consumption, although the estimates were not statistically significant, and were reduced after adjustment for beta- cern in risk appeared for vitamin D, folate, calcium, thiamin, or riboflavin. The inverse relationship between beta- carotene and thyroid carcinoma was observed in both papillary and follicular carcinomas. CONCLUSIONS. In this study, a significant inverse association between beta-carotene and thyroid carcinoma was observed, and some protection against thyroid carcinoma from vitamins C and E was also suggested.

Dietary fiber and the chemopreventive modelatio carcinogenesis

Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis (Netherlands) , 1996, 350/1 (185-197)

Comparative international epidemiological data indicate that the difference between the highest and lowest colon cancer incidence is approximately 10-fold. This suggests that the dominant causes of colon cancer are environmental rather than genetic in origin, with the dominant environmental cause being the typical diet of Western industrialized countries. Many epidemiological and experimental studies have suggested an important role for dietary fiber in the prevention of colon cancer. Using the Fischer-344 rat as the experimental model, data clearly demonstrate a strong protective effect of a diet that is low in fat, high in fiber and high in calcium (low-risk diet). Such a diet prevents the development of both preneoplastic aberrant crypt foci (ACF) and colon tumors. Recent experiments have also demonstrated a direct relationship between a ras point mutation in ACF at different stages of rat colon carcinogenesis, and a ras point mutation that is subsequently present in colon tumors. Using wheat bran as the model dietary fiber source, its effects were compared to the effects of psyllium, phytic acid, vitamin E, beta-carotene, folic acid, alone or in combination, for their ability to prevent colon cancer in rats on high-risk Western-style diets. Our studies clearly demonstrated the ability of wheat bran to reduce ACF and colon tumors in rats that consumed high-fat, Western-style diets. Although phytic acid, which is a constituent of wheat bran, alone demonstrated strong cancer-preventive potential, our experiments provided evidence for the cancer-preventive effect of the crude fiber fraction that is independent of the effect of phytic acid. The synergistic combination of wheat bran with the soluble fiber psyllium led to enhanced protection; while the combination of wheat bran with beta-carotene showed only an additive effect. beta-Carotene appeared to show higher protection than wheat bran at an intake level that is nutritionally relevant to humans, suggesting the possibility of using beta-carotene to enhance the effects of dietary fiber in high-risk Western populations. Using ACF as an intermediate endpoint, it was also shown that vitamin E and beta-carotene appear to inhibit progression of ACF to colon cancer, while wheat bran and folic acid appeared to have weak cancer-preventive potential at this late stage of carcinogenesis. In conclusion, wheat bran alone, or in combination with psyllium, appears to have greater potential to inhibit earlier phases of carcinogenesis, while beta-carotene and vitamin E may also inhibit later stages of carcinogenesis. Despite considerable epidemiological and experimental evidence that increasing the fiber and lowering the fat content o could substantially reduce the risk of cancer and heart disease, the real challenge is to find effective ways to educate and motivate people to overcome their intrinsic cultural resistance to such changes in their eating habits.

On the mechanism of the anticlotting action of vitamin E quinone

Proceedings of the National Academy of Sciences of the United States of America (USA), 1995, 92/18 (8171-8175)

Vitamin E in the reduced, alpha-tocopherol form shows very modest anticlotting activity. By contrast, vitamin E quinone is a potent anticoagulant. This observation may have significance for field trials in which vitamin E is observed to exhibit beneficial effects on ischemic heart disease and stroke. Vitamin E quinone is a potent inhibitor of the vitamin K- dependent carboxylase that controls blood clotting. A newly discovered mechanism for the inhibition requires attachment of the active site thiolgroups of the carboxylase to one or more methyl groups on vitamin E quinone. The results from a series of model reactions support this interpretation of the anticlotting activity associated with vitamin E.

alpha-Tocopherol quinone level is remarkably low in the cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis.

Neurosci Lett (IRELAND) Mar 22 1996, 207 (1) p5-8

In order to investigate the role of free radicals in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS), the concentrations of alpha-tocopherol (alpha-TOH) and its oxidized form alpha-tocopherol quinone (alpha-TQ) in the cerebrospinal fluid (CSF) of SALS patients were determined. The alpha-TOH level was 31% lower (P < 0.05) and the alpha-TQ level was 75% lower (P < 0.001) in SALS patients than in normal subjects. The results of the present study do not support the hypothesis that activated lipid peroxidation accelerates oxidation of alpha-TOH into alpha-TQ in SALS patients.