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VITAMIN E (ALPHA TOCOPHEROL)




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Effectiveness of antioxidants (vitamin C and E) with and without sunscreens as topical photoprotectants.

Darr D Dunston S Faust H Pinnell S. Acta Derm Venereol (1996 Jul) 76(4):264-8

Considerable interest has been recently generated concerning the use of natural compounds, anti-oxidants in particular, in photoprotection. Two of the best known anti-oxidants are vitamins C and E, both of which have been shown to be somewhat effective in different models of photodamage. Very little has been reported, however, on the effectiveness of a combination of the two (known to be biologically the more relevant situation); nor have there been detailed studies on the ability of these antioxidants to augment commercial sunscreen protection against UV damage. We report that (in swine skin) vitamin C is capable of additive protection against acute UVB damage (sunburn cell formation) when combined with a UVB sunscreen. A combination of both vitamins E and C provided very good protection from a UVB insult, the bulk of the protection attributable to vitamin E. However, vitamin C is significantly better than vitamin E at protecting against a UVA-mediated phototoxic insult in this animal model, while the combination is only slightly more effective than vitamin C alone. When vitamin C or a combination of vitamin C and E is formulated with a commercial UVA sunscreen (oxybenzone), an apparently greater than additive protection is noted against the phototoxic damage. These results confirm the utility of anti-oxidants as photoprotectants but suggest the importance of combining the compounds with known sunscreens to maximize photoprotection. Melatonin Suppresses UV-Induced Erythema



Importance of the form of topical vitamin E for prevention of photocarcinogenesis.

Gensler HL Aickin M Peng YM Xu M, Nutr Cancer (1996) 26(2):183-91.

With increasing solar ultraviolet (UV)-B radiation reaching the Earth's surface and the incidence of skin cancer rising steadily, there is an ever-increasing need to determine agents that modulate photocarcinogenesis and to understand the mechanisms underlying this modulation. Our laboratory has demonstrated that topical application of the dl-alpha-tocopherol form of vitamin E to mice prevents skin cancer and the immunosuppression induced by UVB irradiation. However, dl-alpha-tocopherol has limited stability at room temperature. The current study was designed to ask whether the thermostable esters of vitamin E, alpha-tocopheryl acetate, or alpha-tocopheryl succinate prevent skin cancer and immunosuppression induced in mice by UV radiation. In the alpha-tocopheryl acetate study, skin cancers developed in 70% of UVB-irradiated control mice and in 90%, 73%, and 90% of mice receiving topical applications of 12.5, 25, and 50 mg of dl-alpha-tocopheryl acetate, respectively. In the alpha-tocopheryl succinate study, skin cancer developed in 59.3% of control UVB- irradiated mice and in 82%, 100%, and 81.5% of mice treated with 2.5, 12.5, and 25 mg d-alpha-tocopheryl succinate, respectively. Thus neither alpha-tocopheryl acetate nor alpha-tocopheryl succinate prevented photocarcinogenesis. At 12.5 and 25 mg/treatment, alpha- tocopheryl acetate and alpha-tocopheryl succinate, respectively, enhanced photocarcinogenesis (p = 0.0114 and 0.0262, respectively, log rank test). On the basis of high-performance liquid chromatography analysis at 16-17 weeks after the first vitamin E treatment, the esterified forms of vitamin E applied epicutaneously accumulated in the skin, but the levels of free alpha-tocopherol remained low. Neither alpha-tocopheryl acetate nor alpha-tocopheryl succinate prevented the induction by UV radiation of immunosusceptibility to implanted syngeneic antigenic UV-induced tumor cells. Thus alpha-tocopheryl acetate or alpha-tocopheryl succinate not only failed to prevent photocarcinogenesis, but may have enhanced to process. Considering that alpha-tocopherol esters are included in many skin lotions, cosmetics, and sunscreens, further studies are needed to determine the conditions under which topical alpha-tocopheryl acetate and alpha-tocopheryl succinate enhance photocarcinogenesis.



Topical vitamin E as a cause of erythema multiforme-like eruption.

Saperstein H Rapaport M Rietschel RL , Arch Dermatol (1984 Jul) 120(7):906-8

The topical use of vitamin E on scar tissue resulted in a generalized erythema multiforme reaction in two patients. Patch tests with vitamin E oil showed positive local reactions in both.

Sano M; Ernesto C; Thomas RG; Klauber MR; Schafer K; Grundman M; Woodbury P; Growdon J; Cotman CW; Pfeiffer E; Schneider LS; Thal LJ Department of Neurology, Columbia University College of Physicians and Surgeons, New York, USA. N Engl J Med (UNITED STATES) Apr 24 1997, 336 (17) p1216-22

Background: There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer's disease. Methods: We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimer's disease of moderate severity.

A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years.

The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3).

Results: Despite random assignment, the baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups, and this variable was highly predictive of the primary outcome (P&lt0.001). In the unadjusted analyses, there was no statistically significant difference in the outcomes among the four groups. In an analyses that included the base-line score on the Mini-Mental State Examination as a covariate, there were significant delays in the time to the primary outcome for the patients treated with selegiline (median time, 655 days; P=0.012), alpha-tocopherol (670 days, P=0.001) or combination therapy (585 days, P=0.049), as compared with the placebo group (440 days).

Conclusions: In patients with moderately severe impairment from Alzheimer's disease, treatment with selegiline or alpha-tocopherol slows the progression of disease.



Antioxidant defense systems: The role of carotenoids, tocopherols, and thiols

Di Mascio P.; Murphy M.E.; Sies H. Am. J. Clin. Nutr., 1991, 53/1 SUPPL. (194S-200S)

Reactive oxygen species occur in tissues and can damage DNA, proteins, carbohydrates and lipids. These potentially deleterious reactions are controlled by a system of enzymatic and nonenzymatic antioxidants which eliminate prooxidants and scavenge free radicals. The ability of the lipid-soluble carotenoids to quench singlet molecular oxygen may explain some anticancer properties of the carotenoids, independent of their provitamin A activity. Tocopherols are the most abundant and efficient scavengers of hydro peroxyl radicals in biological membranes. Water-soluble antioxidants include ascorbate and cellular thiols. Glutathione is an important substrate for enzymatic antioxidant functions and is capable of nonenzymatic radical scavenging. Thiols associated with membrane proteins may also be important to the antioxidant systems. Interactions between the thiols, tocopherols, and other compounds enhance the effectiveness of cellular antioxidant defense.



Protection by vitamin E selenium, trolox C, ascorbic acid palmitate, acetylcysteine, coenzyme Q, beta-carotene, canthaxanthin, and (+)-catechin against oxidative damage to liver slices measured by oxidized heme proteins.

Chen H; Tappel AL Free Radic Biol Med, Apr 1994, 16 (4) p437-44

Male SD rats were fed a vitamin E- and selenium-deficient diet, a diet supplemented with vitamin E and selenium, and diets supplemented with vitamin E, selenium, trolox C, ascorbic acid palmitate, acetylcysteine, beta-carotene, canthaxanthin, coenzyme Q0, coenzyme Q10, and (+)-catechin. Liver slices were incubated at 37 degrees C with and without CBrCl3, t-butyl-hydroperoxide, Fe+2, or Cu+2. The effect of antioxidant nutrients on the oxidative damage to rat liver was studied by measurement of the production of oxidized heme proteins (OHP) during the oxidative reactions. Diet supplemented with vitamin E and selenium showed a strong protection against heme protein oxidation compared to the antioxidant-deficient diet. Furthermore, increasing the diversity and quantity of antioxidants in the diets provided significantly more protection.



Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly

Losonczy KG; Harris TB; Havlik RJ Epidemiology, Demography and Biometry Program, National Institute on Aging, Bethesda, MD 20892-9205, USA. klosoncz@gibbs.oit.unc.edu Am J Clin Nutr (UNITED STATES) Aug 1996, 64 (2) p190-6

We examined vitamin E and vitamin C supplement use in relation to mortality risk and whether vitamin C enhanced the effects of vitamin E in 11,178 persons aged 67-105 y who participated in the Established Populations for Epidemiologic Studies of the Elderly in 1984-1993. Participants were asked to report all nonprescription drugs currently used, including vitamin supplements. Persons were defined as users of these supplements if they reported individual vitamin E and/or vitamin C use, not part of a multivitamin. During the follow-up period there were 3490 deaths. Use of vitamin E reduced the risk of all-cause mortality [relative risk (RR) = 0.66; 95% CI: 0.53, 0.83] and risk of coronary disease mortality (RR = 0.53; 95% CI: 0.34, 0.84). Use of vitamin E at two points in time was also associated with reduced risk of total mortality compared with that in persons who did not use any vitamin supplements. Effects were strongest for coronary heart disease mortality (RR = 0.37; 95% CI: 0.15, 0.90). The RR for cancer mortality was 0.41 (95% CI: 0.15, 1.08). Simultaneous use of vitamins E and C was associated with a lower risk of total mortality (RR = 0.58; 95% CI: 0.42, 0.79) and coronary mortality (RR = 0.47; 95% CI: 0.25, 0.87). Adjustment for alcohol use, smoking history, aspirin use, and medical conditions did not substantially alter these findings. These findings are consistent with those for younger persons and suggest protective effects of vitamin E supplements in the elderly.



Carotenoids, vitamins C and E, and mortality in an elderly population

Sahyoun NR; Jacques PF; Russell RM Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA. Am J Epidemiol (U.S.) Sep 1 1996, 144 (5) p501-11,

In 1981-1984, the nutritional status of 747 noninstitutionalized Massachusetts residents aged 60 years and over was assessed. Nine to 12 years later, the vital status of these subjects was determined. The data of a subset of 725 community-dwelling volunteers was used to examine associations between mortality and the nutrient antioxidants (carotenoids and vitamins C and E) in plasma, diet, and supplements. Results indicated that subjects with plasma vitamin C levels in the middle and high quintiles had a lower overall mortality (relative risk (RR) = 0.64, 95% confidence interval (CI) 0.44-0.94 and RR = 0.54, 95% CI 0.32-0.90, respectively) than those in the lowest quintile even after adjustment for potential confounders. These associations were largely due to reduced mortality from heart disease. Subjects in the highest quintile of total intake of vitamin C also had a significantly lower risk of overall mortality (RR = 0.55, 95% CI 0.32-0.93) and mortality from heart disease (RR = 0.38, 95% CI 0.19-0.75) than did those in the lowest quintile after potential confounders were controlled for. Intake of vegetables was inversely associated with overall mortality (p for trend = 0.003) and mortality from heart disease (p for trend = 0.04). No other significant associations were observed. In conclusion, the results indicate that high intakes and plasma levels of vitamin C and frequent consumption of vegetables may be protective against early mortality and mortality from heart disease.



Supplementation with vitamins C and E suppresses leukocyte oxygen free radical production in patients with myocardial infarction

Herbaczynska-Cedro K; K+osiewicz-Wasek B; Cedro K; Wasek W; Panczenko-Kresowska B; Wartanowicz M Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland Eur Heart J (ENGLAND) Aug 1995, 16 (8) p1044-9,

Clinical studies suggest that neutrophil activation during acute myocardial infarction (MI) aggravates tissue injury. Activated neutrophils are an important source of oxygen free radicals (OFR), the injurious effects of which are counteracted by endogenous antioxidants. We have previously shown in healthy subjects that supplementation with antioxidant vitamins C and E suppresses OFR production by isolated neutrophils assayed by chemiluminescence (CL). The present study, performed in patients with acute MI aimed (1) to investigate the effect of vitamin C and E supplementation upon neutrophil OFR production and serum lipid peroxides, (2) to evaluate serum levels of vitamins C and E in the course of MI. Forty-five patients with acute MI were randomized to receive either conventional treatment only (control, n=22). All measurements were performed on the 1st and 14th day. Neutrophil OFR production assayed by CL decreased significantly in VIT patients (Wilcoxon test for paired data P&lt0.01, Chi square test P&lt0.01). In the control group, changes in OFR production were not significant. Serum lipid peroxides (measured as TBARS) increased in controls (P&lt0.05), but remained stable in VIT patients. Mean (+/-SE) serum ascorbic acid and tocopherol on the 1st day were 0.43 +/- 0.18% and 3.25 +/- 1.32 microM.M(-1) cholesterol, respectively, in all patients. On the 14th day in non-supplemented patients mean tocopherol was unchanged, whereas ascorbic acid increased significantly (0.63 +/- 0.24 mg%, P&lt0.01) suggesting that a low basal level was associated at least in part with the acute phase of the disease. An expected increase in serum vitamin levels occurred in VIT patients. In conclusion, supplementation with vitamins C and E suppresses neutrophil OFR production and lowers the marker of lipid peroxidation in patients with MI.



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

Jialal I; Fuller CJ Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas 75235-9052, USA. Can J Cardiol (CANADA) Oct 1995, 11 Suppl G p97G-103G,

OBJECTIVE: The oxidative modification of low density lipoprotein (LDL) may be an 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. (97 Refs.)



Effect of intake of exogenous vitamins C, E and beta-carotene on the antioxidative status in kidneys of rats with streptozotocin-induced diabetes

Mekinova D; Chorvathova V; Volkovova K; Staruchova M; Grancicova E; Klvanova J; Ondreicka R Research Institute of Nutrition, Bratislava, Slovak Republic Nahrung (GERMANY) 1995, 39 (4) p257-61,

We studied the effect of supplementation with vitamins C, E and beta-carotene (PARABION, produced by Syndipharma) on antioxidative status in kidneys of male Wistar rats with diabetes induced by intravenous application of streptozotocin (45 mg.kg-1 of body weight). The animals received subtherapeutic doses of Insulin Interdep (6 U.kg-1 of body weight). A significant decrease of malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione and reduction of the activities of Se-glutathione peroxidase (Se-GSH-PX, EC. 1.11.1.9.) and glutathione S-transferase (GST, EC. 2.5.1.18.) were observed in kidneys of diabetic rats treated with these vitamins. On the contrary, the activity of CuZn-superoxide dismutase (CuZn-SOD, EC. 1.15.1.1) and the level of vitamin C (vit. C) increased significantly. No changes were observed for vitamin E (vit. E), beta-carotene and catalase (CAT, EC. 1.11.1.6). Supplementation with vitamins C, E and beta-carotene resulted in an improvement of antioxidative status of kidneys of rats with streptozotocin-induced diabetes.



Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis

Hodis HN; Mack WJ; LaBree L; Cashin-Hemphill L; Sevanian A; Johnson R; Azen SP Atherosclerosis Research Unit, University of Southern California School of Medicine, Los Angeles 90033, USA. JAMA (UNITED STATES) Jun 21 1995, 273 (23) p1849-54,

OBJECTIVE-To explore the association of supplementary and dietary vitamin E and C intake with the progression of coronary artery disease.

DESIGN-A subgroup analysis of the on-trial antioxidant vitamin intake database acquired in the Cholesterol Lowering Atherosclerosis Study, andomized, placebo-controlled, serial angiographic clinical trial evaluating the risk and benefit of colestipol-niacin on coronary artery disease progression.

SETTING-Community- and university-based cardiac catheterization laboratories.

SUBJECTS-A total of 156 men aged 40 to 59 years with previous coronary artery bypass graft surgery.

INTERVENTION-Supplementary and dietary vitamin E and C intake (nonrandomized) in association with cholesterol-lowering diet and either colestipol-niacin or placebo (randomized).

OUTCOME-Change per subject in the percentage of vessel diameter obstructed because of stenosis (%S) determined by quantitative coronary angiography after 2 years of randomized therapy on all lesions, mild/moderate lesions (< 50%S), and severe lesions (> or = 50%S).

RESULTS-Overall, subjects with supplementary vitamin E intake of 100 IU per day or greater demonstrated less coronary artery lesion progression than did subjects with supplementary vitamin E intake less than 100 IU per day for all lesions (P = .04) and for mild/moderate lesions (P = .01). Within the drug group, benefit of supplementary vitamin E intake was found for all lesions (P = .02) and mild/moderate lesions (P = .01). Within the placebo group, benefit of supplementary vitamin E intake was not found. No benefit was found for use of supplementary vitamin C exclusively or in conjunction with supplementary vitamin E, use of multivitamins, or increased dietary intake of vitamin E or vitamin C.

CONCLUSIONS-These results indicate an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression. Verification from carefully designed, randomized, serial arterial imaging end point trials is needed.



Gamma-Tocopherol traps mutagenic electrophiles such as NO(x) and complements alpha-tocopherol: Physiological implications

Christen S.; Woodall A.A.; Shigenaga M.K.; Southwell-Keely P.T.; Duncan M.W.; Ames B.N. Proceedings of the National Academy of Sciences of the United States of America (USA), 1997, 94/7 (3217-3222)

Peroxynitrite, a powerful mutagenic oxidant and nitrating species, is formed by the near diffusion-limited reaction of NO and O2 during activation of phagocytes. Chronic inflammation induced by phagocytes is a major contributor to cancer and other degenerative diseases.

We examined how gamma-tocopherol (gammaT), the principal form of vitamin E in the United States diet, and alpha-tocopherol (alphaT), the major form in supplements, protect against peroxynitrite-induced lipid oxidation. Lipid hydroperoxide formation in liposomes (but not isolated low-density lipoprotein) exposed to peroxynitrite or the NO and O2 generator SIN-1 (3-morpholinosydnonimine) was inhibited more effectively by gammaT than alphaT. More importantly, nitration of gammaT at the nucleophilic 5-position, which proceeded in both liposomes and human low density lipoprotein at yields of similar-50% and similar-75%, respectively, was not affected by the presence of alphaT.

These results suggest that despite alphaT's action as an antioxidant, gammaT is required to effectively remove the peroxynitrite-derived nitrating species. We postulate that gammaT acts in vivo as a trap for membrane-soluble electrophilic nitrogen oxides and other electrophilic mutagens, forming stable carbon-centered adducts through the nucleophilic 5-position, which is blocked in alphaT. Because large doses of dietary alphaT displace gammaT in plasma and other tissues, the current wisdom of vitamin E supplementation with primarily alphaT should be reconsidered.



T-2 toxin-induced DNA damage in mouse livers: The effect of pretreatment with coenzyme Q10 and alpha-tocopherol

Atroshi F.; Rizzo A.; Biese I.; Veijalainen P.; Antila E.; Westermarck T., Molecular Aspects of Medicine (United Kingdom), 1997, 18/SUPPL. (S255-S258)

Active oxygen species are reported to cause organ damage. This study was therefore designed to determine whether oxidative stress contributed to the initiation or progression of hepatic DNA damage produced by T-2 toxin. The aim of the study was also to investigate the behavior of the antioxidants coenzyme Q10 (CoQ10), and alpha-tocopherol (vitamin E) against DNA damage in the livers of mice fed T-2 toxin. Treatment of fasted mice with a single dose of T-2 toxin (1.8 or 2.8 mg/kg body weight) by oral gavage led to 76% hepatic DNA fragmentation. T-2 toxin also decreased hepatic glutathione (GSH) levels markedly. Pretreatment with CoQ10 (6 mg/kg) together with alpha-tocopherol (6 mg/kg) decreased DNA damage. The CoQ10 and vitamin E showed some protection against toxic cell death and glutathione depletion caused by T-2 toxin. Oxidative damage caused by T-2 toxin may be one of the underlying mechanisms for T-2 toxin-induced cell injury and DNA damage, which eventually lead to tumorigenesis.



Vitamin E and Immunity

Meydani SN, Meydani M, Blumberg JB, Leka LS, Siber G, Loszewski R, Thompson C, Pedrosa MC, Diamond RD, Stollar BD JAMA (1997 May 7) 277(17):1380-6

OBJECTIVE: To determine whether long-term supplementation with vitamin E enhances in vivo, clinically relevant measures of cell- mediated immunity in healthy elderly subjects. DESIGN: Randomized, double-blind, placebo-controlled intervention study. SETTING AND PARTICIPANTS: A total of 88 free-living, healthy subjects at least 65 years of age. INTERVENTION: Subjects were randomly assigned to a placebo group or to groups consuming 60, 200, or 800 mg/d of vitamin E for 235 days. MAIN OUTCOME MEASURES: Delayed-type hypersensitivity skin response (DTH); antibody response to hepatitis B, tetanus and diphtheria, and pneumococcal vaccines; and autoantibodies to DNA and thyroglobulin were assessed before and after supplementation. RESULTS: Supplementation with vitamin E for 4 months improved certain clinically relevant indexes of cell-mediated immunity in healthy elderly. Subjects consuming 200 mg/d of vitamin E had a 65% increase in DTH and a 6-fold increase in antibody titer to hepatitis B compared with placebo (17% and 3-fold, respectively), 60-mg/d (41% and 3-fold, respectively), and 800-mg/d (49% and 2.5-fold, respectively) groups. The 200-mg/d group also had a significant increase in antibody titer to tetanus vaccine. Subjects in the upper tertile of serum alpha-tocopherol (vitamin E) concentration (>48.4 micromol/L [2.08 mg/dL]) after supplementation had higher antibody response to hepatitis B and DTH. Vitamin E supplementation had no effect on antibody titer to diphtheria and did not affect immunoglobulin levels or levels of T and B cells. No significant effect of vitamin E supplementation on autoantibody levels was observed. CONCLUSIONS: Our results indicate that a level of vitamin E greater than currently recommended enhances certain clinically relevant in vivo indexes of T-cell-mediated function in healthy elderly persons. No adverse effects were observed with vitamin E supplementation.



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.



The Alzheimer's Disease Cooperative Study

Sano M; Ernesto C; Thomas RG; Klauber MR; Schafer K; Grundman M; Woodbury P; Growdon J; Cotman CW; Pfeiffer E; Schneider LS; Thal LJ
Department of Neurology, Columbia University College of Physicians and Surgeons, New York, USA. N Engl J Med (UNITED STATES) Apr 24 1997, 336 (17) p1216-22

Background: There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer's disease. Methods: We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimer's disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3). Results: Despite random assignment, the baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups, and this variable was highly predictive of the primary outcome (P&lt0.001). In the unadjusted analyses, there was no statistically significant difference in the outcomes among the four groups. In an analyses that included the base-line score on the Mini-Mental State Examination as a covariate, there were significant delays in the time to the primary outcome for the patients treated with selegiline (median time, 655 days; P=0.012), alpha-tocopherol (670 days, P=0.001) or combination therapy (585 days, P=0.049), as compared with the placebo group (440 days). Conclusions: In patients with moderately severe impairment from Alzheimer's disease, treatment with selegiline or alpha-tocopherol slows the progression of disease.



Vitamin E and Immunity

Meydani SN, Meydani M, Blumberg JB, Leka LS, Siber G, Loszewski R, Thompson C, Pedrosa MC, Diamond RD, Stollar BD JAMA (1997 May 7) 277(17):1380-6

OBJECTIVE: To determine whether long-term supplementation with vitamin E enhances in vivo, clinically relevant measures of cell- mediated immunity in healthy elderly subjects. DESIGN: Randomized, double-blind, placebo-controlled intervention study. SETTING AND PARTICIPANTS: A total of 88 free-living, healthy subjects at least 65 years of age. INTERVENTION: Subjects were randomly assigned to a placebo group or to groups consuming 60, 200, or 800 mg/d of vitamin E for 235 days. MAIN OUTCOME MEASURES: Delayed-type hypersensitivity skin response (DTH); antibody response to hepatitis B, tetanus and diphtheria, and pneumococcal vaccines; and autoantibodies to DNA and thyroglobulin were assessed before and after supplementation. RESULTS: Supplementation with vitamin E for 4 months improved certain clinically relevant indexes of cell-mediated immunity in healthy elderly. Subjects consuming 200 mg/d of vitamin E had a 65% increase in DTH and a 6-fold increase in antibody titer to hepatitis B compared with placebo (17% and 3-fold, respectively), 60-mg/d (41% and 3-fold, respectively), and 800-mg/d (49% and 2.5-fold, respectively) groups. The 200-mg/d group also had a significant increase in antibody titer to tetanus vaccine. Subjects in the upper tertile of serum alpha-tocopherol (vitamin E) concentration (>48.4 micromol/L [2.08 mg/dL]) after supplementation had higher antibody response to hepatitis B and DTH. Vitamin E supplementation had no effect on antibody titer to diphtheria and did not affect immunoglobulin levels or levels of T and B cells. No significant effect of vitamin E supplementation on autoantibody levels was observed. CONCLUSIONS: Our results indicate that a level of vitamin E greater than currently recommended enhances certain clinically relevant in vivo indexes of T-cell-mediated function in healthy elderly persons. No adverse effects were observed with vitamin E supplementation.



Effects of vitamin E on T cell lipid peroxidation, membrane fluidity and T cell functions in traumatized mice

Chinese Pharmacological Bulletin (China), 1996, 12/1 (47-49)

SUBFILES:Ranges of T cell malondialdehyde (MDA) contents, membrane fluidity, Tcell functions and therapeutic effects of vitamin E (V-E) were observed in traumatized mice. The results showed that T cell MDA contents were increased after trauma, membrane fluidity of T cell plasmalemma, mitochondria and microsome reduced and T lymphocytes transformation, interleukin 2 (IL-2) production, IL-2 receptor (IL-2R) expression and IL-2 mediated lymphocytes proliferation response were suppressed, which were related closely to MDA alteration. In vivo administration of V-E (50 or 100 mg/kg.d-1, im x 4 d) could reverse ahove parameters, indicating lipid peroxidation after trauma is an important cause resulting in reduced T cell membrane fluidity and were suppressed T cell functions, on which V-E shows significant therapeutic effects.



Vitamin E ameliorates adverse effects of endothelial injury in brain arterioles

American Journal of Physiology - Heart and Circulatory Physiology (USA), 1996, 271/2 40-2 (H637-H642)

Endothelium-dependent dilation, pros unaffected after 6 mo of a diet with zero vitamin E or 8 mo of a vitamin E-enriched diet. The enriched diet did not affect constriction produced by topically applied N(G)-monomethyl-L-arginine, an inhibitor of the synthesis of endothelium-derived relaxing factor (EDRF). EDRF mediates the response to ACh and is a basally released dilator and antiplatelet paracrine substance. Endothelial injury produced by a helium- neon laser and Evans blue technique eliminates the response to ACh, but in vitamin E-enriched mice the response to ACh was unaffected by the injury. More prolonged exposure of the laser induces platelet adhesion/aggregation at the injured site. A significantly longer exposure to the laser was required to initiate adhesion/aggregation in vitamin E-enriched mice. Because effects of endothelial damage in this model are mediated at least in part by singlet oxygen produced by injured tissue, we conclude that the antioxidant, radical-scavenging actions of vitamin E explain the protective action of the vitamin E-enriched diet. However, raising vitamin E levels did not protect against putative adverse effects of normally occurring oxidants.



Vitamin E, thiobarbituric acid reactive substance concentrations and superoxide dismutase activity in the blood of children with juvenile rheumatoid arthritis

Clinical and Experimental Rheumatology (Italy), 1996, 14/4 (433-439)

Objective: To study the role of amined the levels of thiobarbituric acid reactive substances (TBARS) and antioxidants of the first line antioxidative defence of the organism, i.e. vitamin E (VE) and superoxide dismutase (SOD) in the blood of 74 young patients with juvenile rheumatoid arthritis (JRA) and in 138 healthy children, all aged 3-15. Results: A statistically significant increase of TBARS was found in the blood plasma of the children with JRA compared with the control group. In the whole group of patients and in the patients over 6 years of age, the VE concentration was significantly lower in the blood plasma and significantly higher in the erythrocytes than in the control groups. SOD activity in the red blood cells (RBC) was significantly lower in children who had suffered from JRA for more than one year and in those with the systemic form of the disease. The type of treatment also affected the values for the plasma VE and SOD in the RBC. Conclusion: Our results seem to confirm the supposition of increased oxidative stress in children with JRA and low antioxidant levels in terms of SOD activity and vitamin E concentrations.



Acceleration of corneal wound healing in diabetic rats by the antioxidant trolox

Research Communications in Molecular Pathology and Pharmacology (USA), 1996, 93/1

Several corneal complications have been reported in patients with long standing diabetes, but their exact pathogenesis is not well understood. It has been observed that the rate of epithelial wound healing in diabetic rats is delayed compared to those in normal animals. Here we present the effect of the free radial scavenger, Trolox, a water soluble vitamin E analogue, on epithelial wound healing in diabetic rat cornea. Three groups of rats were included: 1) normal, 2) diabetic, 3) diabetic + Trolox. After 3 months, rats were sacrificed and corneas removed. Standard 3 mm diameter corneal epithelial defects were made and residual epithelial defects were measured after 18 hours at 37degreeC in a sterile cell culture incubator. Wound healing data measured in mm2 was used for statistical analysis. There were significantly larger (p < 0.05) epithelial defects in diabetic corneas as compared to control. Treatment with Trolox antioxidant in diabetic rats produced a significantly smaller (p < 0.05) epithelial defect than that of untreated diabetic rats. These studies suggest the involvement of free radicals in the delay of corneal epithelial wound healing in diabetes.



Effect of vitamin e on hydrogen peroxide production by human vascular endothelial cells after hypoxia/reoxygenation

Free Radical Biology and Medicine (USA), 1996, 20/1 (99-105)

Changes in oxidative stress status play an important role in tissue injury associated with ischemia-reperfusion events such as those that occur during stroke and myocardial infarction. Endothelial cells (EC) from human saphenous vein and aorta were incubated for 22 h and found to take up vitamin E from media containing 0-60 mM vitamin E in a dose-dependent manner. EC supplemented with 23 or 28 mM vitamin E in the media for 22 h were maintained at normoxia (20% O2, 5% CO2, and balance N2) or exposed to hypoxic conditions (3% 30 min. Saphenous EC supplemented with 23 mM vitamin E produced less (p < 0.05) H2O2 than unsupplemented controls, both at normoxic condition (supplemented: 4.9 plus or minus 0.05 vs. control:10.9 plus or minus 1.3 pmol/min/106 cells) and following hypoxia/reoxygenation (supplemented: 6.4 plus or minus 0.78 vs. control:17.0 plus or minus 2.7 nmol/min/106 cells). In contrast, aortic EC, which were found to have higher superoxide dismutase and catalase activity than EC from saphenous vein, did not produce any detectable levels of H2O2. Following hypoxia/reoxygenation, the concentration of vitamin E in supplemented saphenous EC was 62% lower than cells maintained at normoxia (0.19 plus or minus 0.03 vs. 0.5 plus or minus 0.12 nmoles/106 cells. p < 0.001); in aortic EC vitamin E content was reduced by 18% following reoxygenation (0.86 plus or minus 0.16 vs, 070 plus or minus 0.09 nmoles/106 cells, p < 0.05). Therefore, enrichment of vitamin E in EC decreases H2O2 production and thus may reduce the injury associated with ischemia-reperfusion events.



Amphiphilic alpha-tocopherol analogues as inhibitors of brain lipid peroxidation.

Eur J Pharmacol (NETHERLANDS) Feb 29 1996, 298 (1) p37-43

Neurological disorders, such as stroke, trauma, tardive dyskinesia, Alzheimer's and Parkinson's diseases, may be partially attributed to excessive exposition of the nervous tissue to oxygen-derived radicals. A novel water-soluble alpha-tocopherol analogue, 2,3-dihydro-2 ,2,4,6,7-pentam ethyl-3methylpiperazino) methyl-1-benzofuran-5-ol dihydrochloride (MDL), is a potent radical scavenger. Following subcutaneous administration to mice, MDL inhibited the lipid peroxidation induced in the 100-fold diluted brain homogenates, with an ID50 of 8 mg/kg. Rapid brain penetration, within 30-60 min postadministration, and even distribution into different brain areas were observed. MDL was also detected after oral administration. In brain homogenate undergoing lipid peroxidation, MDL prevented the consumption of an equal amount of alpha-tocopherol, while inhibiting the concomitant malondialdehyde formation. The radical scavenging capacity of MDL was superior to that of alpha-tocopherol, although the peak and half-peak potentials were not significantly different. However, MDL was much less lipophilic, the partition coefficient (log P) at the octanol/water interface being 1.91. Although it is yet unknown, whether the applied criteria sufficiently predict its usefulness, beneficial effects of MDL may be expected in the above mentioned disorders.



Amphiphilic alpha-tocopherol analogues as inhibitors of brain lipid peroxidation.

Eur J Pharmacol (NETHERLANDS) Feb 29 1996, 298 (1) p37-43

Neurological disorders, such as stroke, trauma, tardive dyskinesia, Alzheimer's and Parkinson's diseases, may be partially attributed to excessive exposition of the nervous tissue to oxygen-derived radicals. A novel water-soluble alpha-tocopherol analogue, 2,3-dihydro-2 ,2,4,6,7-pentam ethyl-3methylpiperazino) methyl-1-benzofuran-5-ol dihydrochloride (MDL), is a potent radical scavenger. Following subcutaneous administration to mice, MDL inhibited the lipid peroxidation induced in the 100-fold diluted brain homogenates, with an ID50 of 8 mg/kg. Rapid brain penetration, within 30-60 min postadministration, and even distribution into different brain areas were observed. MDL was also detected after oral administration. In brain homogenate undergoing lipid peroxidation, MDL prevented the consumption of an equal amount of alpha-tocopherol, while inhibiting the concomitant malondialdehyde formation. The radical scavenging capacity of MDL was superior to that of alpha-tocopherol, although the peak and half-peak potentials were not significantly different. However, MDL was much less lipophilic, the partition coefficient (log P) at the octanol/water interface being 1.91. Although it is yet unknown, whether the applied criteria sufficiently predict its usefulness, beneficial effects of MDL may be expected in the above mentioned disorders.



Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks

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

One hundred patients with transient ischemic attacks, minor strokes, or residual ischemic neurologic deficits were enrolled in a double-blind, randomized study comparing the effects of aspirin plus vitamin E (0.4 g (400 IU)/d; n = 52) with aspirin alone (325 mg; n = 48). The patients received study medication for 2 y or until they reached a termination point. Preliminary results show a significant reduction in the incidence of ischemic events in patients in the vitamin E plus aspirin group compared with patients taking only aspirin. There was no significant difference in the incidence of hemorrhagic stroke although both patients who developed it were taking vitamin E. Platelet adhesion was also measured in a randomized subgroup of both study populations by using collagen III as the adhesive surface. There was a highly significant reduction in platelet adhesiveness in patients who were taking vitamin E plus aspirin compared with those taking aspirin only. Measurement of alpha-tocopherol concentrations confirmed compliance of the patients with the medication schedule, showing a near doubling of serum concentrations of alpha-tocopherol. We concluded that the combination of vitamin E and a platelet antiaggregating agent (eg, aspirin) significantly enhances the efficacy of the preventive treatment regimen in patients with transient ischemic attacks and other ischemic cerebrovascular problems.



Effect of vitamin E on hydrogen peroxide production by human vascular endothelial cells after hypoxia/reoxygenation

Free Radical Biology and Medicine (USA), 1996, 20/1 (99-105)

Changes in oxidative stress status play an important role in tissue injury associated with ischemia-reperfusion events such as those that occur during stroke and myocardial infarction. Endothelial cells (EC) from human saphenous vein and aorta were incubated for 22 h and found to take up vitamin E from media containing 0-60 mM vitamin E in a dose-dependent manner. EC supplemented with 23 or 28 mM vitamin E in the media for 22 h were maintained at normoxia (20% O2, 5% CO2, and balance N2) or exposed to hypoxic conditions (3% O, 5% CO2, and balance N2) for 12 h, followed by reoxygenation (20% O2) for 30 min. Saphenous EC supplemented with 23 mM vitamin E produced less (p < 0.05) H2O2 than unsupplemented controls, both at normoxic condition (supplemented: 4.9 plus or minus 0.05 vs. control: 10.9 plus or minus 1.3 pmol/min/106 cells) and following hypoxia/reoxygenation (supplemented: 6.4 plus or minus 0.78 vs. control:17.0 plus or minus 2.7 nmol/min/106 cells). In contrast, aortic EC, which were found to have higher superoxide dismutase and catalase activity than EC from saphenous vein, did not produce any detectable levels of H2O2. Following hypoxia/reoxygenation, the concentration of vitamin E in supplemented saphenous EC was 62% lower than cells maintained at normoxia (0.19 plus or minus 0.03 vs. 0.5 plus or minus 0.12 nmoles/106 cells. p < 0.001); in aortic EC vitamin E content was reduced by 18% following reoxygenation (0.86 plus or minus 0.16 vs, 070 plus or minus 0.09 nmoles/106 cells, p < 0.05). Therefore, enrichment of vitamin E in EC decreases H2O2 production and thus may reduce the injury associated with ischemia-reperfusion events.



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.



Effect of a water-soluble vitamin E analog, Trolox C, on retinal vascular development in an animal model of retinopathy of prematurity

Free Radical Biology and Medicine (USA), 1997, 22/6 (977-984)

The debate over the efficacy of vitamin E as a therapy for retinopathy of prematurity (ROP) continues 45 years after it was first proposed. The discrepancies between one clinical study and another may be due to the difficulty of delivering a lipid-soluble molecule like vitamin E to the immature retina. Trolox C is a water-soluble analog of vitamin E with potent antioxidant activity. We have studied the effectiveness of intraperitoneal injection of Trolox C in an animal model of retinopathy remained for 1 4 d before sacrifice and assessment of retinal vasculature. Rats were administered 625 microg/kg Trolox C, or vehicle, by intraperitoneal injection on alternatedays for the duration of the exposure. Other rats were simultaneously raised in room air, injected, and assessed as controls. Percent avascular retinal area, vascular leakage, and retinal capillary density were measuredby computer-assisted image analysis. Trolox C-injected rats had significantly smaller avascular areas (14.6 plus or minus 4.8% vs. 25.4 plus or minus 6.3%), less leak area (0.04 plus or minus 0.07 mm2 vs. 0.16 plus or minus 0.14 mm2), and greater capillary density (24.3 plus or minus 2.6 pixel % vs. 18.9 plus or minus 3.1 pixel %) than vehicle-injected counterparts. These findings indicate that Trolox C facilitated the process of retinal vasculogenesis under hyperoxemic conditions. They also suggest that oxygen free radical- mediated damage plays a role in the pathologic effect of high oxygen rearing of newborn rats. Additional studies are warranted to determine precise site(s) and mechanism(s) of Trolox C activity in this and similar disease models in which peroxidation is believed to play a causal role.



Vitamin-E metabolism and its application

Nutrition Research (USA), 1996, 16/10 (1767-1809)

Vitamin E, the most active form is alpha-tocopherol, widely distributed in nature with different biological activities. It is a major lipid-soluble antioxidant responsible for protecting membranes against lipid peroxidation which could slow the aging process in humans or animals. Several roles of vitamin E have been reported such as antioxidant, intermediary in arachidonic acid and prostaglandin metabolism, nucleic acid, protein and lipid metabolism, mitochondrial function, sex hormones production, in maintaining the integrity of membranes, in protection against hemolytic anemia and impaired erythropoiesis, reducing the risks of heart disease, cancer, neurological diseases, cataract, retinopathy of premature infants and arthritis. Vitamin E deficiency results in neurological syndrome in people with chronic malabsorption. It is useful in the neurological diseases such as Parkinson's, Huntington's, epilepsy and tardiv dyskinesia. Several clinical applications of vitamin E are known in diseases such as abetalipoproteinemia, cystic fibrosis, cholestic liver disease, hemolytic anemias, respiratory distress, epilepsy, bums, aging, cancer, ischemic heart disease and cataract. The future study of vitamin E in humans or animal models should provide more definitive evidence of its absorption, transport, utilization and retention in various body organs and tissues as well as in protection and prevention of major neurological diseases.



Erythrocyte and plasma antioxidant ASMATIQUE DANS LE DIABETE DE TYPE I

Presse Medicale (France), 1996, 25/5 (188-192)

Objectives: Some biologic parameters involved in cell defence against oxygen radicals (plasmatic vitamins C and E, erythrocyte glutathione peroxidase, glutathione reductase and superoxide dismutase) were measured in single blood samples from 119 diabetic infants, adolescents and young adults. Methods: Data were studied in relation to residual insulin secretion determined by C peptide, level of metabolic control appreciated by glycosylated haemoglobin, lipid abnormalities and subclinical complications (retinopathy, neuropathy and nephropathy). Results: There was no change in antioxidant parameters with insulin secretion. Patients with poor glycaemic control and high plasma lipids had higher levels of plasma vitamin E. Patients with nephropathy had lower plasma vitamin C levels and those with neuropathy showed lower erythrocyte glutathione peroxidase activity. Plasma vitamin C concentrations and erythrocyte glutathione reductase activities were negatively correlated with the age of the patients and the duration of the disease. Conclusion: Higher transport capacity of vitamin E probably explains the elevated levels of vitamin E observed in patients with high lipid levels and long lasting illness. The lower levels of vitamin C in the presence of nephropathy may be due to an increased renal excretion of this vitamin. The reduction of glutathione peroxidase, glutathione reductase activities and vitamin C levels confirms the existence of an oxidative stress in type 1 diabetes.



The regional distribution of vitamins E and C in mature and premature human retinas

INVEST. OPHTHALMOL. VISUAL SCI. (USA), 1988, 29/1 (22-26)

Vitamin E is used to ameliorate retinopathy of prematurity, but little is known about baseline vitamin E levels in retinas of premature infants or the effect of vitamin E supplementation on these levels. Vitamin E and C levels were measured in mature retinas (1 month to 73 years) and in retinas of premature infants (22 to 33 weeks of gestation). The infants fell into two groups: (1) those who survived < 12 hr and received no vitamin E, and (2) those who survived > 4 days and received vitamin E supplementation. Premature infants are born with 5 to 12 percent the vitamin E levels found in mature retinas. Vitamin E levels in vascular and avascular retina of premature infants increased with gestation. Infants born > 27 weeks gestation and surviving at least 4 days with vitamin E supplementation demonstrated markedly elevated vitamin E levels in vascular and avascular retina when compared to supplemented infants < 27 weeks gestation. Premature infants possessed 35-50% higher levels of retinal vitamin C than those found in mature retinas. These data demonstrate that premature infants are born with relatively low levels of retinal vitamin E, particularly in the avascular region, but contain an abundance of retinal vitamin C. These data further suggest that vitamin E supplementation results in a rapid increase in retinal vitamin E levels, particularly in infants > 27 weeks gestational age.



Oral vitamin E supplements can prevent the retinopathy of abetalipoproteinaemia

BR. J. OPHTHALMOL. (UK), 1986, 70/3 (166-173)

Six patients with abetalipoproteinaemia are described who received large doses of oral vitamin E for between 12 and 18 years in addition to a low fat diet and supplements of the other fat soluble vitamins. The progressive retinopathy observed in untreated abetalipoproteinaemia was substantially modified and most probably prevented by this therapy. Angioid streaks were noted in one patient. Treatment with vitamin A alone did not prevent or arrest the progression of the retinal lesion.



Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer

J. NATL. CANCER INST. (USA), 1990, 82/11 (941-946)

We investigated the associations of serum retinol, the carotenoids beta-carotene and lycopene, and tocopherol (vitamin E) with the risk of prostate cancer in a nested case-control study. For the study, serum obtained in 1974 from 25,802 persons in Washington County, MD, was used. Serum levels of the nutrients in 103 men who developed prostate cancer during the subsequent 13 years were compared with levels in 103 control subjects matched for age and race. Although no significant associations were observed with beta-carotene, lycopene, or tocopherol, the data suggested an inverse relationship between serum retinol and risk of prostate cancer. We analyzed data on the distribution of serum retinol by quartiles, using the lowest quartile as the reference value. Odds ratios were 0.67, 0.39, and 0.40 for the second, third, and highest quartiles, respectively.



Application of molecular epidemiology to lung cancer chemoprevention.

Mooney LA; Perera FP
Columbia University School of Public Health, Division of Environmental Health Sciences, New York, New York 10032, USA.
J Cell Biochem Suppl (UNITED STATES) 1996, 25 p63-8

Molecular epidemiology has made great progress in detecting and documenting carcinogenic exposures and host susceptibility factors, in an effort to explain interindividual variation in disease. Interindividual differences in genetic and acquired factors including nutritional status. Eleva ted risk of lung cancer has been associated with polymorphisms of metabolic genes such as CYP1A1 and GSTM1. On the other hand, numerous studies have demonstrated that diets rich in fruits and vegetables are protective against cancer, and have correlated high levels of antioxidants in the blood with decreased risk. As a first step in identifying susceptible individuals, we have assessed the combined effect of genetic factors and nutritional status on DNA adducts in a population of healthy smokers. Plasma retinol, beta-carotene, alpha-tocopherol, and zeaxanthin were inversely correlated with DNA damage, especially in subjects lacking the "protective" GSTM1 gene. Research is ongoing using biomarkers to determine the effect of supplementation with antioxidants/vitamins on DNA damage, especially in population subsets with putative "at risk" genotypes. Information on mechanisms of interactions between exposure, micronutrients, and other susceptibility factors is important in the development of effective practical interventions. (33 Refs.)



Effects of dietary vitamin C and E supplementation on the copper mediated oxidation of HDL and on HDL mediated cholesterol efflux.

Rifici VA; Khachadurian AK
Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick 08903-0019, USA.
Atherosclerosis (IRELAND) Nov 15 1996, 127 (1) p19-26

Copper mediated oxidative modification of high density lipoprotein (HDL) diminishes its capacity to promote cholesterol efflux from cells in culture. In the present study, HDL was isolated from eight subjects before and after a 10 day administration of the antioxidant vitamins C and E. After incubation HDL (1.25 mg protein/ml) with 10 microM copper for 0-4 h or with 0-20 microM copper for 4 h, thiobarbituric acid reactive substances (TBARS) production was significantly decreased following vitamin administration suggesting that the vitamins decreased the susceptibility of HDL to oxidation. However, two other assays of lipoprotein oxidation, trinitrobenzene sulfonic acid reactivity and conjugated diene formation, did not show a consistent effect of vitamin administration. To study cholesterol efflux, J774 macrophages were labeled with 3H cholesterol (0.1 microCi/ml, 50 micrograms/ml) and incubated with HDL or oxidized HDL (100 micrograms protein/ml) for 24 h. HDL isolated before vitamins and oxidized in vitro was 39% less effective in mediating efflux compared to unmodified HDL, while HDL isolated after vitamins and oxidized was 22% less effective (before vs. after vitamins, P < 0.015). HDL oxidation determined by measuring TBARS production correlated with decreased cholesterol efflux (r = 0.37, P < 0.050). These data suggest that oxidation of HDL interferes with its role in reverse cholesterol transport and that antioxidant vitamins have a protective effect.



Comparative study of the effect of 21-aminosteroid and alpha-tocopherol on models of acute oxidative renal injury.

Salahudeen AK; Wang C; Kanji VK
Department of Medicine, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Free Radic Biol Med (UNITED STATES) 1996, 21 (5) p691-7

21-Aminosteroids have incited a great deal of interest owing to its ability to inhibit lipid peroxidation and prevent organ damage. The main mechanism by which 21-aminosteroids idation is similar to the naturally occurring chain-breaking antioxidant alpha-tocopherols. Therefore, to determine whether 21-aminosteroids offer any advantage over alpha-tocopherol, we compared their effects on an in vivo and in vitro models of renal injury. 21-Aminosteroid (U-74006 F) at 3 mg/kg or alpha-tocopherol succinate at 10 mg/kg was administered intravenously once before bilateral renal ischemia and again before reperfusion. Acute administration 21-aminosteroid but not alpha-tocopherol, was attended by suppression of ischemia reperfusion-induced renal lipid peroxidation and injury. However, 4 weeks of dietary enrichment of rats with alpha-tocopherol (1000 IU/kg) was effective in suppressing these ischemia reperfusion-induced changes. In cell culture system, concurrent presence of 21-aminosteroid but not alpha-tocopherol abrogated H2O2-induced renal epithelial lipid peroxidation and injury. However, alpha-tocopherol was completely effective when cells were incubated with it for 14 h. Further, only the cells incubated with vitamin E for 14 h-but not for 1 or 3 h-had a significant increase in vitamin E content, which suggests that a delay in prompt cellular up take of vitamin E may explain its lack of acute effects. Thus, unlike alpha-tocopherol, 21-aminosteroid appears readily and completely available for its chain-breaking antioxidant activity both in vitro and in vivo. 21-Aminosteroids may, therefore, offer a therapeutic advantage over alpha-tocopherols in acute injury settings.



Effectiveness of antioxidants (vitamin C and E) with and without sunscreens as topical photoprotectants.

Darr D; Dunston S; Faust H; Pinnell S
North Carolina Biotechnology Center, Raleigh, N.C., USA.
Acta Derm Venereol (NORWAY) Jul 1996, 76 (4) p264-8,

Considerable interest has been recently generated concerning the use of natural compounds, anti-oxidants in particular, in photoprotection. Two of the best known anti-oxidants are vitamins C and E, both of which have been shown to be somewhat effective in different models of photodamage. Very little has been reported, however, on the effectiveness of a combination of the two (known to be biologically the more relevant situation); nor have there been detailed studies on the ability of these antioxidants to augment commercial sunscreen protection against UV damage. We report that (in swine skin) vitamin C is capable of additive protection against acute UVB damage (sunburn cell formation) when combined with a UVB sunscreen. A combination of both vitamins E and C provided very good protection from a UVB insult, the bulk of the protection attributable to vitamin E. However, vitamin C is significantly better than vitamin E at protecting against a UVA-mediated phototoxic insult in this animal model, while the combination is only slightly more effective than vitamin C alone. When vitamin C or a combination of vitamin C and E is formulated with a commercial UVA sunscreen (oxybenzone), an apparently greater than additive protection is noted against the phototoxic damage. These results confirm the utility of anti-oxidants as photoprotectants but suggest the importance of combining the compounds with known sunscreens to maximize photoprotection.



Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infraction

Rapola JM; Virtamo J; Ripatti S; Huttunen JK; Albanes D; Taylor PR; Heinonen OP
National Public Health Institute, Helsinki, Finland.
Lancet (ENGLAND) Jun 14 1997, 349 (9067) p1715-20

BACKGROUND: Epidemiological data suggest that the intake of antioxidants such as alpha-tocopherol (vitamin E) and beta-carotene has an inverse correlation with the incidence of coronary heart disease. The results from clinical trials of antioxidant supplementation in people with known coronary heart disease are inconclusive. METHODS: We studied the frequency of major coronary events in 1862 men enrolled in the alpha-tocopherol beta-carotene Cancer Prevention Study (smokers aged between 50 and 69 years) who had a previous myocardial infarction. In this randomised, double-blind. placebo-controlled study, men had received dietary supplements of alpha-tocopherol (50 mg/day), beta-carotene (20 mg/day), both, or placebo. The median follow-up was 5.3 years. The endpoint of this substudy was the first major coronary event after randomisation. Analyses were by intention to treat. FINDINGS: 424 major coronary events (non-fatal myocardial infarction and fatal coronary heart disease) occurred during follow-up. There were no significant differences in the number of major coronary events between any supplementation group and the placebo group (alpha-tocopherol 94/466; beta-carotene 113/461; alpha-tocopherol and beta-carotene 123/497; placebo 94/438 [log-rank test, p = 0.25]). There were significantly more deaths from fatal coronary heart disease in the beta-carotene (74/461, multivariate-adjusted relative risk 1.75 [95% CI 1.16-2.64], p = 0.007) and combined alpha-tocopherol and beta-carotene groups (67/497, relative risk 1.58 [1.05-2.40], p = 0.038), but there w as no significant increase in the alpha-tocopherol supplementation group (54/466, relative risk 1.33 [0.86-2.05], p = 0.20). INTERPRETATION: The proportion of major coronary events in men with a previous myocardial infarction who smoke was not decreased with either alpha-tocopherol or beta-carotene supplements. In fact, the risk of fatal coronary heart disease increased in the groups that received either beta-carotene or the combination of alpha-tocopherol and beta-carotene; there was a non-significant trend of increased deaths in the alpha-tocopherol group. We do not recommend the use of alpha-tocopherol or beta-carotene supplements in this group of patients.



Validity of diagnoses of major coronary events in national registers of hospital diagnoses and deaths in Finland.

Rapola JM; Virtamo J; Korhonen P; Haapakoski J; Hartman AM; Edwards BK; Heinonen OP
National Public Health Institute, Helsinki, Finland.
Eur J Epidemiol (NETHERLANDS) Feb 1997, 13 (2) p133-8

We validated diagnoses of acute myocardial infarction (AMI) and death from coronary heart disease (CHD) found in the Finnish National Hospital Discharge Register and the Register of Causes of Death from a sample of the 29,133 men participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The cases were traced to hospitals and institutes performing medico-legal death cause examinations and all relevant information was collected. The cardiac events were re-evaluated according to the diagnostic criteria of the Finnish contribution to the WHO MONICA project, i.e. the FINMONICA criteria. Altogether 408 cases of non-fatal AMI (n = 217) and death from CHD (n = 191) were reviewed. In the re-evaluation 94% of them (95% confidence interval 92-96%) were diagnosed as either definite (57%) or possible (37%) AMI. Non-fatal cases were more often classified definite AMI in the review, whereas fatal cases were more often classified possible AMI. Age or trial supplementation group did not affect classification, and no secular trend was observed. In conclusion, the diagnoses of AMI and death from CHD in the registers were highly predictive of a true major coronary event defined by strict criteria, thus their use in endpoint assessment in epidemiological studies and clinical trials is justified.



Equine degenerative myeloencephalopathy.

Miller MM; Collatos C
New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, USA.
Vet Clin North Am Equine Pract (UNITED STATES) Apr 1997, 13 (1) p43-52

EDM is a neurologic disease of young horses characterized by the insidious development of symmetric ataxia. Decreased or absent cutaneous trunci reflex or slap test responses are considered clinical signs that increase the index of suspicion for this disease. In addition, concurrent predisposing factors, such as familial history, inadequate access to green pasture, and possible exposure to wood preservatives or insecticides, provide further supporting evidence for a clinical diagnosis. Vitamin E deficiency and a hereditary predisposition currently are considered the most significant factors in the pathogenesis of this disease. Histopathologically the lesions of EDM are those of neuraxonal dystrophy, characterized by prominent axonal and dendritic swelling, mild glial proliferation, and neuronal depletion and atrophy with lipofuscin-like pigment accumulation. Animals predisposed to EDM or with a clinical diagnosis of EDM should receive oral alpha-tocopherol acetate supplementation. Improvement in clinical signs may be seen following long-term treatment, but in general, the prognosis for complete recovery is poor. (31 Refs.)



[Vitamin E as a possible aid in the control of disease problems on pig farms: a field test]

Lamberts FJ
Dierenartsenpraklijk Bladel-Haperl.
Tijdschr Diergeneeskd (NETHERLANDS) Apr 1 1997, 122 (7) p190-2

In two sow-herds problems with weaning-diarrhoea and Streptococcus suis meningitis were successfully controlled by strategic use of antibiotics during the post-weaning period. In an attempt to reduce the intake of antibiotics by farm animals, the vitamin E level in the post-weaning diet was increased from 20 IE/kg to 80 IE/kg, because vitamin E is thought to increase resistance. The effect on both farms was stunning, so a small field trial was started. In this trial the higher level of vitamin E had a statistically significant beneficial effect on weaning-diarrhoea. The author concludes that in some cases an increased level of vitamin E can have a positive effect on disease management on pig-farms and can lead to reduced use of antibiotics.



Effects of dietary vitamin C and E supplementation on the copper mediated oxidation of HDL and on HDL mediated cholesterol efflux.

Rifici VA; Khachadurian AK
Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick 08903-0019, USA.
Atherosclerosis (IRELAND) Nov 15 1996, 127 (1) p19-26

Copper mediated oxidative modification of high density lipoprotein (HDL) diminishes its capacity to promote cholesterol efflux from cells in culture. In the present study, HDL was isolated from eight subjects before and after a 10 day administration of the antioxidant vitamins C and E. After incubation HDL (1.25 mg protein/ml) with 10 microM copper for 0-4 h or with 0-20 microM copper for 4 h, thiobarbituric acid reactive substances (TBARS) production was significantly decreased following vitamin administration suggesting that the vitamins decreased the susceptibility of HDL to oxidation. However, two other assays of lipoprotein oxidation, trinitrobenzene sulfonic acid reactivity and conjugated diene formation, did not show a consistent effect of vitamin administration. To study cholesterol efflux, J774 macrophages were labeled with 3H cholesterol (0.1 microCi/ml, 50 micrograms/ml) and incubated with HDL or oxilated before vitami ns and oxidized in vitro was 39% less effective in mediating efflux compared to unmodified HDL, while HDL isolated after vitamins and oxidized was 22% less effective (before vs. after vitamins, P < 0.015). HDL oxidation determined by measuring TBARS production correlated with decreased cholesterol efflux (r = 0.37, P < 0.050). These data suggest that oxidation of HDL interferes with its role in reverse cholesterol transport and that antioxidant vitamins have a protective effect.



Comparative study of the effect of 21-aminosteroid and alpha-tocopherol on models of acute oxidative renal injury.

Salahudeen AK; Wang C; Kanji VK
Department of Medicine, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Free Radic Biol Med (UNITED STATES) 1996, 21 (5) p691-7

21-Aminosteroids have incited a great deal of interest owing to its ability to inhibit lipid peroxidation and prevent organ damage. The main mechanism by which 21-aminosteroids inhibit lipid peroxidation is similar to the naturally occurring chain-breaking antioxidant alpha-tocopherols. Therefore, to determine whether 21-aminosteroids offer any advantage over alpha-tocopherol, we compared their effects on an in vivo and in vitro models of renal injury. 21-Aminosteroid (U-74006 F) at 3 mg/kg or alpha-tocopherol succinate at 10 mg/kg was administered intravenously once before bilateral renal ischemia and again before reperfusion. Acute administration 21-aminosteroid but not alpha-tocopherol, was attended by suppression of ischemia reperfusion-induced renal lipid peroxidation and injury. However, 4 weeks of dietary enrichment of rats with alpha-tocopherol (1000 IU/kg) was effective in suppressing these ischemia reperfusion-induced changes. In cell culture system, concurrent presence of 21-aminosteroid but not alpha-tocopherol abrogated H2O2-induced renal epithelial lipid peroxidation and injury. However, alpha-tocopherol was completely effective when cells were incubated with it for 14 h. Further, only the cells incubated with vitamin E for 14 h-but not for 1 or 3 h-had a significant increase in vitamin E content, which suggests that a delay in prompt cellular up take of vitamin E may explain its lack of acute effects. Thus, unlike alpha-tocopherol, 21-aminosteroid appears readily and completely available for its chain-breaking antioxidant activity both in vitro and in vivo. 21-Aminosteroids may, therefore, offer a therapeutic advantage over alpha-tocopherols in acute injury settings.



Rationale and design of a large study to evaluate the renal and cardiovascular effects of an ACE inhibitor and vitamin E in high-risk patients with diabetes. The MICRO-HOPE Study. Microalbuminuria, cardiovascular, and renal outcomes. Heart Outcomes Prevention Evaluation.

Gerstein HC; Bosch J; Pogue J; Taylor DW; Zinman B; Yusuf S McMaster University, Hamilton, Ontario, Canada. Diabetes Care (UNITED STATES) Nov 1996, 19 (11) p1225-8

OBJECTIVE: To describe the rationale and design of a large international study (microalbuminuria, cardiovascular, and renal outcomes [MICRO] in the HOPE [Heart Outcomes Prevention Evaluation] study) of an ACE inhibitor and vitamin E for the prevention of diabetic nephropathy (DN) and cardiovascular disease (CVD) in patients with diabetes and microalbuminuria (MA). RESEARCH DESIGN AND METHODS: A total of 3,657 diabetic subjects, including 1,129 with MA, are randomly allocated to receive the ACE inhibitor ramipril (or placebo) and vitamin E (or placebo) for 4 years in a two-by-two factorial design. Diabetic subjects are a subset of the 9,541 subjects enrolled in the HOPE study. RESULTS: The development of DN in microalbuminuric diabetic subjects and the development of MA in normoalbuminuric subjects, as well as cardiovascular death, myocardial infarction, and storke, are the main outcomes. The correlation of changes in albuminuria with changes in carotid atherosclerosis documented in a subset of subjects will also be analyzed. CONCLUSIONS: The effect of both an ACE inhibitor and vitamin E on the progression of renal and CVD in patients with diabetes is being assessed in the MICRO-HOPE study.