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RESEARCH STUDY NUMBER 1: "Vitamin CE," A novel Prodrug form of vitamin E. Rosenau T, Habicher WD. Dresden University of Technology, Institute of Organic Chemistry, Germany. Abstract Reaction of 5a-bromo-alpha-tocopherol with ascorbic acid produces 5a-tocopheryl ascorbate which is designated "vitamin CE." This novel tocopherol derivative represents an interesting prodrug form of alphatocopherol (vitamin E) that is stable under acidic conditions, but regenerates finely dispersed vitamin E in basic media. The reaction mechanism of the base-induced decomposition of vitamin CE involves elimination of ascorbate and production of an ortho-quinone methide intermediate that oxidizes ascorbate, and is reduced to vitamin E. Kinetic experiments showed reaction to proceed in the pH range of 8 to 11 under physiological conditions. Tissue culture measurements demonstrated that vitamin E generated from the novel derivative is absorbed at much higher rates than conventional preparations and can even be absorbed under simulated conditions of malabsorption where there is no uptake of conventional vitamin E medications. SOURCE: PMID: 9214711 [PubMed - indexed for MEDLINE] Copyright: National Center for Biotechnology Information, U.S. National Library of Medicine 8600 Rockville Pike, Bethesda MD, 20894 USA **************************************************************************************************************************

RESEARCH STUDY NUMBER 2: Interaction between vitamins C and E affects their tissue concentrations, growth, lipid oxidation, and deficiency symptoms in yellow perch (Perca flavescens). Lee KJ, Dabrowski K. School of Natural Resources, The Ohio State University, Columbus, OH 43210, USA. Abstract We have conducted studies with juvenile yellow perch (Perca flavescens) over a period of 20 weeks to address the question of the interaction between water- and lipid-soluble antioxidant vitamins. Fish (2.25+/0.14 g) were divided into twelve groups, and triplicate groups were fed one of four casein-based, semi-

purified diets formulated to contain low or high vitamin E levels of either 5 or 160 mg/kg without or with vitamin C supplementation (250 mg/kg). Diets were designated as -C-E, -C+E, +C-E, or +C+E, respectively. The fish fed the +C+E diet showed significantly higher weight gain, feed intake, and feed efficiency than the groups fed vitamin C-deficient diets. Total ascorbate concentrations of liver were significantly higher in fish fed vitamin C-supplemented diets than in fish fed the vitamin C-deficient diet after 16 and 20 weeks. The liver alpha-tocopherol concentrations were increased by supplemental vitamin C in vitamin E-deficient dietary groups which indicates a sparing or regenerating effect of vitamin C on vitamin E. Fish fed vitamin C-deficient diets (-C-E and -C+E) exhibited severe deficiency symptoms, such as scoliosis, lens cataracts, anorexia, and haemorrhages. The cumulative mortality was significantly higher in the -C-E groups. The thiobarbituric acid-reactive substances value was significantly higher in blood plasma of fish fed a diet unsupplemented with both vitamins. The findings in the present study with yellow perch support the hypothesis that vitamin C regenerates and/or spares vitamin E in vivo. SOURCE: PMID: 12720579 [PubMed - indexed for MEDLINE Copyright: National Center for Biotechnology Information, U.S. National Library of Medicine 8600 Rockville Pike, Bethesda MD, 20894 USA **************************************************************************************************************************

RESEARCH STUDY NUMBER 3: Association of vitamin E and C supplement use with cognitive function and dementia in elderly men K.H. Masaki, MD, K.G. Losonczy, MA, G. Izmirlian, PhD, D.J. Foley, MS, G.W. Ross, MD, H. Petrovitch, MD, R. Havlik, MD and L.R. White, MD Author Affiliations: From the HonoluluAsia Aging Study (Drs. MasakiPetrovitch, and White), Kuakini Medical Center, Honolulu, HI; the Division of Geriatric Medicine (Drs. Masaki, Petrovitch, and Ross), University of Hawaii, John A. Burns School of Medicine, Honolulu, HI; the Epidemiology, Demography, and Biometry Program (Drs. Izmirlian, Havlik, and White, and K. Losonczy and D. Foley), National Institute on Aging, National Institutes of Health, Bethesda, MD; and the Department of Veterans Affairs (Dr. Ross), Honolulu, HI. Address correspondence and reprint requests to Dr. Kamal H. Masaki, The Honolulu Heart Program, 347 North Kuakini Street, HPM 9, Honolulu, HI 96817; e-mail: kamal@hhp2.hawaii-health.com Abstract Objective: To determine whether use of vitamin E and C supplements protects against subsequent development of dementia and poor cognitive functioning. Methods: The HonoluluAsia Aging Study is a longitudinal study of Japanese-American men living in Hawaii. Data for this study were obtained from a subsample of the cohort interviewed in 1982, and from the entire cohort

from a mailed questionnaire in 1988 and the dementia prevalence survey in 1991 to 1993. The subjects included 3,385 men, age 71 to 93 years, whose use of vitamin E and C supplements had been ascertained previously. Cognitive performance was assessed with the Cognitive Abilities Screening Instrument, and subjects were stratified into four groups: low, low normal, mid normal, and high normal. For the dementia analyses, subjects were divided into five mutually exclusive groups: AD (n = 47), vascular dementia (n = 35), mixed/other types of dementia (n = 50), low cognitive test scorers without diagnosed dementia (n = 254), and cognitively intact (n = 2,999; reference). Results: In a multivariate model controlling for other factors, a significant protective effect was found for vascular dementia in men who had reported taking both vitamin E and C supplements in 1988 (odds ratio [OR], 0.12; 95% CI, 0.02 to 0.88). They were also protected against mixed/other dementia (OR, 0.31; 95% CI, 0.11 to 0.89). No protective effect was found for Alzheimers dementia (OR, 1.81; 95% CI, 0.91 to 3.62). Among those without dementia, use of either vitamin E or C supplements alone in 1988 was associated significantly with better cognitive test performance at the 1991 to 1993 examination (OR, 1.25; 95% CI, 1.04 to 1.50), and use of both vitamin E and C together had borderline significance (OR, 1.18; 95% CI, 0.995 to 1.39). Conclusions: These results suggest that vitamin E and C supplements may protect against vascular dementia and may improve cognitive function in late life. SOURCE: PMID: 10746596 [PubMed - indexed for MEDLINE] Copyright: National Center for Biotechnology Information, U.S. National Library of Medicine 8600 Rockville Pike, Bethesda MD, 20894 USA **************************************************************************************************************************

RESEARCH STUDY NUMBER 4: Vitamins C and E help stop atherosclerosis KUOPIO, FINLAND. Atherosclerosis is a disease of the arteries in which fatty, often calcified deposits develop on the inside of the arterial wall (intima) and eventually cause blockages that lead to cardiovascular disease (angina, heart attack and stroke). The progression of atherosclerosis can be followed by measurement of the thickness of the intima with ultrasonography. Finnish researchers reported about 3 years ago that supplementing with a combination of vitamin C and vitamin E markedly reduced the increase in intima thickness. The researchers now report the results of a further 3 years of follow-up. The study involved 440 men and women between the ages of 45 and 69 years. All participants had cholesterol levels at or above 5.0 mmol/L (193 mg/dL) and both smokers and non- smokers were included. The participants were randomized into

two groups one receiving 136 IU of natural vitamin E (d-alpha-tocopherol) and 250 mg of slow-release vitamin C (ascorbic acid) twice daily with meals, the other receiving placebos. The researchers observed an average annual increase in intima thickness of 0.014 mm in the placebo group as compared to 0.010 mm in the supplement group corresponding to a substantial 25% treatment benefit. Further analysis showed that the benefit was limited to male participants. Here the treatment benefit was 37% as compared to an insignificant 14% among women. The benefit of supplementation was greatest among participants with low baseline levels of vitamin C and among those with existing plaques in the carotid artery. Plasma levels of vitamin E and vitamin C increased by 57% and 38% respectively over the 6 years of supplementation. The researchers emphasize that vitamins C and E must be taken together as vitamin-C is needed for regeneration of vitamin-E. It would also appear that it may be crucial to use natural vitamin E (d-alphatocopherol) rather than synthetic (dl-alpha-tocopherol) in order to achieve the desired effect. They point out that the treatment effect among participants who had carotid plaques at baseline was more than 50%. This is comparable to the effect of the most effective cholesterol-lowering drugs (statins), but with no adverse effects and at a much lower cost. Researchers at the UC Davis Medical Center suggest that the optimum regimen may well be 600-800 IU/day of natural vitamin E plus 500 mg/day of vitamin C. SOURCE: International Health News database Copyright 2004 by Hans R. Larsen @ www.yourhealthbase.com Salonen, Riitta M., et al. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression. Circulation, Vol. 107, February 25, 2003, pp. 947-53 Jialal, I. and Devaraj, S. Antioxidants and atherosclerosis: Don't throw out the baby with the bath water. Circulation, Vol. 107, February 25, 2003, pp. 926-28 (editorial) **************************************************************************************************************************

RESEARCH STUDY NUMBER 5: Effects of -carotene, vitamin C and E on antioxidant status in hyperlipidemic smokers Jane C.-J Chao a , Chiung-Hui Huanga, Shu-Ju Wua, Suh Ching Yanga, Nen-Chung Changb, MingJer Shieha, Ping Nan Loc Received 26 October 2001; received in revised form 18 February 2002; accepted 12 March 2002. Abstract Smoking can accelerate the consumption of the stored antioxidant vitamins and increase the oxidative stress in the hyperlipidemic patients. The study investigated the effects of combined -carotene, vitamin C, and vitamin E on plasma antioxidant levels, erythrocyte antioxidative enzyme activities, and LDL lipid peroxides. Male hyperlipidemic smokers (3578 years old) were randomly divided into two antioxidant supplemented groups: intervention 1 (I1, n = 22) (15 mg -carotene/day, 500 mg vitamin C/day, and 400 mg -tocopherol equivalent/day) and intervention 2 (I2, n = 20) (30 mg -carotene/day, 1000 mg vitamin

C/day, and 800 mg -tocopherol equivalent/day). After 6-week supplementation, plasma -carotene, vitamin C, vitamin E, and erythrocyte glutathione levels increased significantly by 200%, 98%, 129%, and 39%, respectively, in the I1 group, and by 209%, 216%, 197%, and 32%, respectively, in the I2 group. Plasma Fe+2 concentrations and Fe+2/Fe+3 decreased significantly in both groups. Except erythrocyte glutathione peroxidase activity in the I1 group, erythrocyte catalase, glutathione peroxidase, and superoxide dismutase activities increased significantly in both groups. Lipid peroxides in LDL decreased significantly by 56% and 72% in the I1 and I2 groups, respectively. However, the levels of plasma iron, erythrocyte glutathione, and LDL lipid peroxides, and the activities of erythrocyte antioxidative enzymes did not differ between two groups. In conclusion, combined antioxidant supplements increased plasma antioxidant levels and antioxidative enzyme activities, and lowered LDL lipid peroxides in male hyperlipidemic smokers. Higher dosage of the supplements did not have an additive effect. a Graduate Institute of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan, Republic of China b Department of Cardiology, Taipei Medical University Hospital, Taipei, Taiwan, Republic of China c Department of Experimental Diagnosis, Taipei Medical University Hospital, Taipei, Taiwan, Republic of China SOURCE: The Journal of Nutritional Biochemistry PII: S0955-2863(02)00188-2 2002 Elsevier Science Inc. All rights reserved. **************************************************************************************************************************

RESEARCH STUDY NUMBER 6: Vitamin E and C to Slow Progression of Common Carotid Artery Plaque Build-Up First Received on October 27, 1999, Last Updated on October 25, 2006 History of Changes Sponsor: Information provided by: National Heart, Lung, and Blood Institute (NHLBI) National Heart, Lung, and Blood Institute (NHLBI)

ClinicalTrials.gov Identifier: NCT00000600 Purpose This study will evaluate the effects of vitamin E supplementation in retarding the progression of common carotid artery intima-media thickening in African Americans. Condition Cardiovascular Diseases Intervention Drug: Vitamin E Phase Phase II

Carotid Artery Diseases Intracranial Arteriosclerosis Cerebrovascular Disorders Heart Diseases Vascular Diseases Atherosclerosis Study Type: Study Design: Official Title: Interventional Allocation: Randomized Primary Purpose: Prevention

Drug: Vitamin C

Antioxidants and Prevention of Early Atherosclerosis

Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI): Primary Outcome Measures: Rate of change in average common carotid artery intima-media thickness (measured over 24 months) Study Start Date: June 1995 BACKGROUND: Evidence from epidemiologic studies, and from one unpublished study, suggests that greater intake of antioxidant vitamins is associated with reduced risk of coronary heart disease and stroke. Findings from an animal model indicate that increased intake of antioxidant vitamins prevents progression of aortic fatty streaks induced by an atherogenic diet, but not from more advanced injury-induced lesions. These observations suggest the hypothesis that increased antioxidant vitamin intake may prevent further progression of early atherosclerosis, possibly by means of reduced susceptibility of low density lipoprotein to oxidative modification and consequent cytotoxic, chemotactic, chemostatic, and unregulated uptake effects. A new, automated, low-cost, portable ultrasound system for determining intima-media thickness of the common carotid artery makes it feasible to test the primary prevention impact of antioxidant vitamins on early atherosclerosis. Results of two studies at the University of Southern California suggest that the lowdensity lipoprotein effects on common carotid artery intima-media thickness can be detected by automated methods within 12 to 24 months in small patient samples. Retardation of intima-media thickness progression was achieved in both studies without significant changes in average vessel diameter, which suggests effects on early atherosclerotic lesions. DESIGN NARRATIVE: Patients will be screened for carotid intima-media thickness at home or at schools in mobile vans equipped with portable ultrasound equipment. After 12 months, those patients above the age and sex-adjusted 66th percentile at Screen I will be re-screened (Screen II), and those showing the greatest progression in intimamedia thickness will be invited to participate in a trial run-in to assess vitamin E compliance. Patients will be randomized to the following four groups: 1) vitamin E (573 mg/day); 2) vitamin C; 3) Vitamin E and C combined; and 4) placebo. Common carotid artery intima-media thickness will be observed by ultrasound at

12- and 24-month follow-ups. The primary outcome is 24-month rate of change in average common carotid artery intima-media thickness. Sponsors and Collaborators: National Heart, Lung, and Blood Institute (NHLBI) Principal Investigator: James H. Dwyer, III University of Southern California SOURCE: US National Institute of Health ClinicalTrials.gov processed this record on May 19, 2011 **************************************************************************************************************************

RESEARCH STUDY NUMBER 7: Reduced Risk of Alzheimer Disease in Users of Antioxidant Vitamin Supplements The Cache County Study Peter P. Zandi, PhD; James C. Anthony, PhD; Ara S. Khachaturian, PhD; Stephanie V. Stone, PhD; Deborah Gustafson, PhD; JoAnn T. Tschanz, PhD; Maria C. Norton, PhD; Kathleen A. Welsh-Bohmer, PhD; John C. S. Breitner, MD; for the Cache County Study Group Background: Antioxidants may protect the aging brain against oxidative damage associated with pathological changes of Alzheimer disease (AD). Objective: To examine the relationship between antioxidant supplement use and risk of AD. Design: Cross-sectional and prospective study of dementia. Elderly (65 years or older) county residents were assessed in 1995 to 1997 for prevalent dementia and AD, and again in 1998 to 2000 for incident illness. Supplement use was ascertained at the first contact. Setting: Cache County, Utah. Participants: Among 4740 respondents (93%) with data sufficient to determine cognitive status at the initial assessment, we identified 200 prevalent cases of AD. Among 3227 survivors at risk, we identified 104 incident AD cases at follow-up. Main Outcome Measure: Diagnosis of AD by means of multistage assessment procedures. Results: Analyses of prevalent and incident AD yielded similar results. Use of vitamin E and C (ascorbic acid) supplements in combination was associated with reduced AD prevalence (adjusted odds ratio, 0.22; 95% confidence interval, 0.05-0.60) and incidence (adjusted hazard ratio, 0.36; 95% confidence interval, 0.090.99). A trend toward lower AD risk was also evident in users of vitamin E and multivitamins containing

vitamin C, but we saw no evidence of a protective effect with use of vitamin E or vitamin C supplements alone, with multivitamins alone, or with vitamin Bcomplex supplements. Conclusions: Use of vitamin E and vitamin C supplements in combination is associated with reduced prevalence and incidence of AD. Antioxidant supplements merit further study as agents for the primary prevention of AD. SOURCE: (Reprinted) Arch Neurol/vol 61, Jan 2004 www.archneurol.com Arch Neurol. 2004;61:82-88 2004 American Medical Association. All rights reserved. **************************************************************************************************************************

RESEARCH STUDY NUMBER 8: Six-Year Effect of Combined Vitamin C and E Supplementation on Atherosclerotic Progression The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study Riitta M. Salonen, MD, PhD; Kristiina Nyyssnen, PhD; Jari Kaikkonen, PhD; Elina Porkkala-Sarataho, PhD; Sari Voutilainen, PhD, RD; Tiina H. Rissanen, MScPH, RD; Tomi-Pekka Tuomainen, MD; Veli-Pekka Valkonen, MD; Ulla Ristonmaa, MSc; Hanna-Maaria Lakka, MD, PhD; Meri Vanharanta, PhD, MPH; Jukka T. Salonen, MD, PhD; Henrik E. Poulsen, MD, PhD Background Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. In the first 3 years of the ASAP trial, the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women. This article examines the 6year effect of supplementation on common carotid artery (CCA) intima-media thickness (IMT). Methods and Results The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol _5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom completed the study. Atherosclerotic progression was assessed ultrasonographically. In covariance analysis in both sexes, supplementation reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to 46, P_0.014), in men by 33% (95% CI, 4 to 62, P_0.024) and in women by 14% (not significant). In both sexes combined, the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group (25% treatment effect, 95% CI, 2 to 49, P_0.034). In men, this treatment effect was 37% (95 CI, 4 to 69, P_0.028). The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on HDL cholesterol. Conclusion

These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C slows down atherosclerotic progression in hypercholesterolemic persons. SOURCE: (Circulation.2003;107:947-953.) Received August 2, 2002; revision received November 5, 2002; accepted November 6, 2002. From the Research Institute of Public Health (R.M.S., K.N., E.P.-S., S.V., T.H.R., T.-P.T., V.-P.V., H.-M.L., M.V., J.T.S.) and Department of Public Health and General Practice (T.H.R., H.-M.L., J.T.S.), University of Kuopio, Finland; Oy Jurilab Ltd (J.K., U.R.), Kuopio, Finland; Inner Savo Health Centre (J.T.S.), Suonenjoki, Finland; and Department of Clinical Pharmacology (H.E.P.), Rigshospitalet, University of Copenhagen, Denmark. Dr Poulsen serves as a consultant to Ferrosan A/S. Correspondence to Professor Jukka T. Salonen, Research Institute of Public Health, University of Kuopio, Harjulantie 1, PO Box 1627, 70211 Kuopio, Finland. E-mail jukka.salonen@uku.fi 2003 American Heart Association, Inc.