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August 2000


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Vitamin E

Chronic vitamin E administration improves brachial reactivity and increases intracellular magnesium concentration in type II diabetic patients

Vascular disease accounts for the majority of the clinical complications in diabetes mellitus. As an exaggerated oxidative stress degree has been postulated as the link between diabetes mellitus and endothelial function, a possible positive effect of plasma vitamin E (Vit.E) administration on brachial reactivity could be postulated. Our study aims at investigating the possible effect of chronic Vit.E administration on brachial reactivity, oxidative stress indexes, and intracellular magnesium and calcium content in type II diabetic patients free of diabetic complications. Forty adult, type II diabetic patients were enrolled in the study, which was deigned as a double blind, randomized vs. placebo trial. At baseline all patients underwent the following tests: I) anthropometric and metabolic examinations, 2) evaluation of oxidative stress indexes, 3) intracellular magnesium and calcium measurements, and 4) determination of arterial compliance and distensibility .Then, all patients were randomly assigned to Vit.E treatment at a dose of 600 mg/day (Evion Forte; n = 20) or placebo (n = 20) over 8 weeks. At the end of this treatment period, a complete reevaluation of the patients was made. Vit.E treatment was associated with a significant improvement in the percent change in brachial artery diameter (P<0.03) and oxidative stress indexes (P< 0.005). In the Vit.E group, the percent change in brachial artery diameter correlated positively with the percent change in oxidative stress indexes ( oxidized/reduced glutathione, TrolQx-equivalent antioxidant capacity, thiobarbituric acid reaction products, lipid peroxides) and intracellular cation content (magnesium and calcium). After adjustment for age, sex, body mass index, and wait/hip ratio, all of these correlations remained significant (P<O.O3 for all). Furthermore, adjusting for glycosylated hemoglobin, plasma total cholesterol, and homeostatic model index, brachial artery diameter was still correlated with the percent change in oxidative stress indexes (P<O.O4 for all). Nevertheless, the relationship between the percent change in brachial artery diameter and oxidative stress indexes was no longer significant after adjustment for intracellular Mg and Ca2+. In conclusion, our study demonstrates that chronic administration of Vit.E improves brachial artery reactivity in patients with type II diabetes mellitus. Such an effect seems mediated by a reduction in oxidative stress and a regulation of intracellular calcium and magnesium contents.

J Clin Endocrinol Metab 2000 Jan,'85(1):109-15

Reversal of defective nerve conduction with vitamin E supplementation in type 2 diabetes: a preliminary study

OBJECTIVE: The present study has examined the effect of vitamin E, the principal modulator of free radical activity , on electrophysiological parameters in patients with diabetic peripheral sensorimotor polyneuropathy, matched for duration of disease and metabolic control. RESEARCH DESIGN AND METHDS: A total of 21 subjects with type 2 diabetes were enrolled in this double-blind randomized placebo-controlled study (vitamin E, 11 patients; placebo, 10 patients). Patients were randomly assigned to receive either 900 mg vitamin E or placebo for 6 months. The average dietary vitamin E consumption of the subjects was similar during the study. The main outcome measure was the electrophysiological tests assessing nerve conduction. Fasting plasma glucose, HbA1, postprandial plasma glucose, and electro- physiological parameters in the basal state and after 6 months of treatment were studied. RESULTS: Glycemic indexes did not show any significant changes during the study, whereas nerve conduction improved significantly in 2 of the 12 studied electrophysiological parameters after 6 months in patients on vitamin E supplementation. The changes in the electrophysiological parameters were obvious in the median motor nerve fibers and tibial motor nerve fibers. Nerve conduction velocity in the median motor nerve fibers (P = 0.0019) and tibial motor nerve distal latency (P = 0.0284) improved significantly after 6 months of vitamin E supplementation.

CONCLUSIONS: This study shows that defective nerve conduction in diabetic subjects with mild-to-moderate peripheral neuropathy may be improved by pharmacological doses of vitamin E supplementation. Further studies with a larger number of patients for longer periods of time are needed.

Diabetes Care 1998 Nov; 21(11):1915-8

Reducing lipid peroxidation stress of erythrocyte membrane by alpha-tocopherol nicotinate plays an important role in improving blood rheological properties in type 2 diabetic patients with retinopathy

The effects of alpha-tocopherol nicotinate on blood viscoelasticity and viscosity and on lipid peroxidation stress in erythrocyte membranes in patients with Type 2 DM were investigated. Thirteen Type 2 diabetic subjects with retinopathy were given alpha-tocopherol nicotinate 300 mg tds, after meals, for 3 months. The treatment resulted in significant reductions of blood viscosity at different shear rates (e.g. -2.23 2.82 p<0.015, gamma = 1.5 s(-l)) and viscoelasticity (p<0.004); resistance of erythrocyte deformation (p<0.001) and lipid peroxidation stress in red cell membrane (malondialdehyde or MDA reduced by 0.17 0.13 nmoll(-l) p<0.005). Plasma viscosity, red cell rigidity, and HbA1c were unchanged. There were negative linear correlations between the indices of red cell deformability and the levels of MDA of red cell membrane both pre- and post-treatment ( e.g. R = -0.79, p<0.001; R = -0.78, p<0.002, n = 13; pre- and post-, respectively). We suggest that the improvements of rheolagical properties of blood and red cell deformability by alpha-tocopherol nicotinate are mainly attributed to reducing lipid peroxidation stress on membrane of red blood cells. The treatment may be useful in slowing deterioration of micro angiopathy in Type 2 DM.

Debate Bed 1998 May;15(5):380-5

Vitamin E and Immunity

OBJECTIVE: To determine whether long-term supplementation with vitamin E enhances in via, 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 OUT - COME 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.

JAMA (1997 May 7) 277(17):1380-6

Vitamins E plus C and interacting conutrients required for optimal health. A critical and constructive review of epidemiology and supplementation data regarding cardiovascular disease and cancer

Antioxidants are crucial components of fruit/vegetable rich diets preventing cardiovascular disease ( CVD ) and cancer: plasma vitamins C, E, carotenoids from diet correlate prevalence of CVD and cancer inversely, low levels predict an increased risk of individuals which is potentiated by combined inadequacy ( e.g., vitamins C + E, C + carotene, A + carotene ); self -prescribed rectification of vitamins C and E at adequacy of other micronutrients reduce forthcoming CVD, of vitamins A, C, E, carotene and conutrients also cancer; randomized exclusive supplementation of beta-carotene + 1- vitamin A or E lack benefits except prostate cancer reduction by vitamin E, and overall cancer reduction by selenium; randomized intervention with synchronous rectification of vitamins A + C + E + B + minerals reduces CVD and counteracts pre- cancerous lesions; high vitamin E supplements reveal potentials in secondary CVD prevention. Plasma values desirable for primary prevention: > or = 30 mumol/llipid- standardized vitamin E ( alpha-tocopherol/cholesterol > or = 5.0 mumol/mmol); > or = 50 mumol/l vitamin C aiming at vitamin C/vitamin E ratio > 1.3-1.5; > or = 0.4 mumol/l beta- (> or = 0.5 mumol/l alpha+ beta-) carotene.

CONCLUSIONS: In CVD vitamin E acts as first risk discriminator, vitamin C as second one; optimal health requires synchronously optimized vitamins C + E, A, carotenoids and vegetable conutrients.

Biofactors 1998;7(1-2);113-74

Therapeutic uses of vitamin E in prevention of atherosclerosis

The purpose of this review is to present the evidence- based pharmacotherapeutic properties of vitamin E and provide clinical recommendations for use in the arena of atherosclerosis. Methods: A literature search was conducted from 1966 through March 1999. All usable papers were retrieved, with large, randomized, double-blinded, clinical trials and epidemiological trials receiving emphasis.

Results: Vitamin E, a lipid soluble vitamin, is a potent antioxidant. Several epidemiological studies have demonstrated positive relationships between vitamin E intake and the prevention of atherosclerotic heart disease; however, only one, large randomized clinical trial (The CHAOS Trial) has been conducted using more than 400 IU per day of vitamin E. Positive outcomes included a 77- percent reduction in nonfatal myocardial infarction (MI), but no corresponding reduction in mortality. Several large clinical trials are ongoing, investigating vitamin E for the prevention of atherosclerosis. Much less work has been undertaken studying vitamin E for prevention of cerebro- and peripheral vascular disease, but there appears to be promise in these areas as well.

Conclusions: On the basis of the literature search, the authors recommend 400 ill or more per day of vitamin E to patients at high risk or already diagnosed with coronary artery disease. Vitamin E supplementation may also be beneficial in the prevention of cerebro- and peripheral vascular diseases.

Altern Med Rev 1999 Dec;4(6);414-23

Cost-effectiveness of vitamin E therapy in the treatment of patients with angiographically proven coronary narrowing (CHAOS trial) - Cambridge Heart Antioxidant Study

Epidemiologic studies have suggested that vitamin E (alpha-tocopherol) may playa preventive role in reducing the incidence of atherosclerosis. The aim of this paper was to conduct a cost- effectiveness analysis of vitamin E supplementation in patients with coronary artery disease using data from the Cambridge Heart Antioxidant Study (CHAOS). The study compared cost-effectiveness in the context of Australian and United States (US) health care utilization. The main clinical outcome used in the economic evaluation was the incidence of acute myocardial infarction (AMI) which was nonfatal. Utilization of health care resources was estimated by conducting a survey of Australian clinicians and published Australian and US cost data. Cost savings of $127 (A$181) and $578/patient randomized to vitamin E therapy compared with patients receiving placebo were found for Australian and US settings, respectively. Savings in the vitamin E group were due primarily to reduction in hospital admissions for AMI. This occurred because the vitamin E group had a 4.4% lower absolute risk of AMI than did the placebo group. Less than 10% of health care costs in the Australian evaluation was due to vitamin E ($150 (A$214/patient]). Our economic evaluation indicates that vitamin E therapy in patients with angiographically proven atherosclerosis is cost-effective in the Australian and US settings.

Am J Cardiol 1998 Aug 15;82(4):414-7

Neurologic findings in vitamin E deficiency

Vitamin E is one of the most important lipid-soluble antioxidant nutrients. Severe vitamin E deficiency can have a profound effect on the central nervous system. Cystic fibrosis, chronic cholestatic liver disease, abetalipoproteinemia, short bowel syndrome, isolated vitamin E deficiency syndrome and other malabsorption syndromes all may cause varying degrees of neurologic deficits due to related vitamin deficiencies. The classic abnormalities in vitamin E deficiency progress from hyporeflexia, ataxia, limitations in upward gaze and strabismus to long-tract defects, profound muscle weakness and visual field constriction. Patients with severe, pro- longed deficiency may develop complete blindness, dementia and cardiac arrhythmias. Treatment must be tailored to the underlying cause of vitamin E deficiency and may include oral or parenteral vitamin supplementation. The more advanced the deficits, the more limited the response to therapy. Therefore, a good neurologic examination and periodic serum vitamin E levels are essential in patients at risk of vitamin E deficiency.

Am Pam Physician 1997 Jan;55(1):197-201

Partners in defense, vitamin E and vitamin C

In addition to the enzymic mechanism of free-radical removal, essential nutrients that can scavenge free radicals, such as vitamins E and C, constitute a strong line of defense in retarding free radical induced cellular damage. Distinct pathways for the repair of oxidized vitamin E in human cells have been recently identified. Within 0.5 min after the addition of arachidonic acid to a human platelet homogenate, over half of the platelet vitamin E and added arachidonate were metabolized by platelet cyclooxygenase and lipoxygenase pathways. After adding nordihydroguaiaretic acid, a lipoxygenase inhibitor and a strong reductant, over 60% of the oxidized vitamin E was regenerated. To test other physiological, water-soluble reductants that may help regenerate vitamin E, eicosatetraynoic acid, a lipoxygenase inhibitor that is not an antioxidant, was used. In this system, both ascorbate and glutathione provided significant vitamin E regeneration. Kinetic analysis and studies of vitamin E regeneration in a protein-denaturing system revealed that ascorbate regenerates vitamin E by a nonenzymic mechanism, whereas glutathione regenerates vitamin E enzymatically. These studies suggest that significant interaction occurs between water- and lipid-soluble molecules at the membrane-cytosol interface and that vitamin C may function in vivo to repair the membrane-bound oxidized vitamin E.

Can J Physiol Pharmacol 1993 Sep;71 (9):725-31


Vitamin C

Scurvy-a mistakenly forgotten disease

Four cases of scurvy diagnosed within a period of two years are reported. They comprised 2 male patients with heavy nicotine and alcohol abuse, a 35-year-old woman with malnutrition due to food supplements phobia, and a 69-year-old woman with malnutrition due to dementia and social isolation. All four patients were adynamic and anemic. Three patients showed typical dermatologic signs with hemorrhagic hyperceratosis, suffusions or cork-screw hair. Two patients complained of parodontol disorders. Other symptoms were gastrointestinal bleeding, sicca syndrome, retinal bleeding, subdural hematoma, edema and arthralgia. Associated disorders were folic acid and vita- min B12 depletion in two cases, and nephropathy and pneumonia with pneumothorax in one case each. In all cases the serum ascorbic acid concentration was below the scorbutic level of 11 mumol/l. Historical data, pathogenesis, incidence, clinical presentation, diagnosis and therapy of scurvy are discussed. We conclude that scurvy can be observed even in a developed country such as Switzerland at the end of the 20th century. The real incidence may be underestimated because symptoms are not well known and disappear rapidly after admission because of sufficient vitamin C content in normal diet. Patients at risk are socially isolated alcoholics, old people, psychiatric patients and diet enthusiasts. Usually scurvy occurs in con- junction with other deficiencies. Smoking and acute illness enhance ascorbic acid depletion. With a knowledge of the symptomatology of scurvy, it is easy to diagnose and treatment is simple and effective.

Schweiz Med Wochenschr 1994 Aug 9;124(31-32):1373-80

Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase

After exposure to many toxic chemicals, NK function can be decreased significantly. Weeks or months later, natural killer (NK) function can rebound to normal levels in some and can be suppressed for prolonged periods of time in other patients. In view of this, we decided to study the effect of buffered vitamin C on NK, T and B cell function in patients who had been exposed to toxic chemicals. After the first blood draw, 55 patients immediately ingested granulated buffered vitamin C in water at a dosage of 60 mg/Kg body weight. Exactly 24 hours later, blood was again drawn for a follow-up study of NK, T and B cell function. Vitamin C in high oral dose was capable of enhancing NK activity up to ten-fold in 78% of patients. Lymphocyte blastogenic responses to T and B cell mitogens were restored to the normal level after vitamin C usage. Signal transduction enzyme protein kinase C (PKC) appeared to be involved in the mechanism of induction of NK activity by vitamin C. We conclude that immune functional abnormalities can be restored after toxic chemical exposure by oral usage of vitamin C.

Immunopharmacol lmmunotoxicol 1997 Aug;19(3);291-312

Serum carotene, vitamin A, and vitamin C levels in breast cancer and cancer of the uterine cervix

Levels of carotene, vitamin A, and vitamin C measured in the serum of patients with cancer of the breast and uterine cervix were compared with levels in healthy controls and patients with benign diseases of the breast and cervix. Serum ascorbate levels were significantly lower in patients with benign diseases of the breast and cervix than in controls. In cancer patients, there was a significant . trend of lower serum vitamin levels with increasing stage of the disease.

Nutr Cancer 1996;25(2);173-7

Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer

Ascorbic acid metabolism is associated with a number of mechanisms known to be involved in host resistance to malignant disease. Cancer patients are significantly depleted of ascorbic acid, and in our opinion this demonstrable biochemical characteristic indicates a substantially increased requirement and utilization of this substance to potentiate these various host resistance factors. The results of a clinical trial are presented in which 100 terminal cancer patients were given supplemental ascorbate as part of their routine management. Their progress is compared to that of 1000 similar patients treated identically, but who received no supplemental ascorbate. The mean survival time is more than 4.2 times as great for the ascorbate subjects (mote than 210 days) as for the controls (50 days). Analysis of the survival-time curves indicates that deaths occur for about 90% of the ascorbate-treated patients at one-third the rate for the controls and that the other 10% have a much greater survival time, averaging more than 20 times that for the controls. The results clearly indicate that this simple and safe form of medication is of definite value in the treatment of patients with advanced cancer.

Proc Natl Acad Sci USA 1976 Oct;73(10);3685-9

Vitamin C and oral health

Maintaining natural dentition is a realistic goal given today's improved caries control and attention to good oral hygiene. Expanding knowledge in the area of periodontal diseases provides further insight into health pro- motion practices which can be effective in preventing tooth loss. Vitamin C's role in maintaining the health of teeth and gingivae remains unchallenged. Now clinical evidence indicates that vitamin C functions in improving host defense mechanisms and is thereby implicated in preserving periodontal health. Common sense tells us that the monitoring of the vitamin C status of individuals, especially those at high risk ( e.g., diabetics, smokers, elderly, etc.) for inadequate intakes, will yield positive results for periodontal health. Patient education pro- grams that stress the importance of good nutrition, while at the same time providing practical information for the selection of a well balanced diet, are simple measures that will benefit many.

J Can Dent Assoc 1989 Sep,55(9);705-7

Effects of high doses of vitamins C and E against doxorubicin-induced chromosomal damage in Wistar rat bone marrow cells

Doxorubicin (DXR) is one of the major antitumoral agents available for clinical use. In addition to intercalating into the DNA molecule, this drug generates free radicals. Vitamins C (VC) and E (YE) can protect normal cells from the damage caused by radicals without interfering with the cytotoxicity of DXR against tumors. The objective of the present study was to investigate the possible protective effect of VC and/or YE on mammalian cells treated with DXR in vivo. Animals treated with the lowest doses of VC and/or YE, alone or in combination, plus a single dose of DXR presented a statistically significant reduction in total number of chromosome aberrations and in number of abnormal metaphases. The highest vitamin doses tested caused no changes in the parameters analyzed when compared with control. Under the present experimental conditions, the efficiency of VC and/or YE in protecting against chromosome damage was dependent on the dose used.

Mutat Res 1998 Nov 9;419(1-3):137-43

Ascorbic acid may protect against human gastric cancer by scavenging mucosal oxygen radicals

High dietary ascorbic acid intake appears to protect against gastric cancer. This may be due to its action as a scavenger of reactive radical species formed in the gastric mucosa, resulting in a reduced level of radical-mediated DNA damage. We have studied 82 patients, of whom 37 had Helicobacter pylori-associated gastritis, a condition which predisposes to gastric cancer. Using electron paramagnetic resonance (EPR) spectroscopy we have demonstrated, for the first time, that ascorbyl radicals are generated in human gastric mucosa, presumably as a result of scavenging of free radicals by ascorbic acid Quantification of ascorbyl radicals demonstrates that there is a higher concentration in those patients with H.pylori gastritis compared with subjects with normal his- tology (P < 0.01). We also found gastric mucosalluminol-enhanced chemiluminescence and malondialdehyde concentrations (which are believed to be markers of radical generation and tissue damage) to be higher in patients with H.pylori gastritis compared with those with normal histology (P < 0.001 and P < 0.01 respectively). The observed concentrations of the ascorbyl radical correlate with the level of luminol-enhanced chemiluminescence (r = 0.41, P < 0.001 ), but not with malondialdehyde concentrations (r = 0.08, P = 0.47). Mucosal ascorbic acid and total vitamin C concentrations did not vary between histological groups, nor did they correlate with mucosal levels of the ascorbyl radical, chemiluminescence or malondialdehyde. These data suggest that ascorbic acid is acting as a scavenger of free radicals generated in human gastric mucosa. The experiments therefore provide direct supportive evidence for the hypothesis that ascorbic acid protects against gastric cancer by scavenging reactive radical species which would otherwise react with DNA, with resultant genetic damage.

Carcinogenesis 1996 Mar;17(3):559-62

Interaction of ascorbate and alpha-tocopherol

Vitamins C and E function as water-soluble and lipid- soluble chain-breaking antioxidants, respectively, and protect lipids, proteins, and membranes from oxidative damage. Vitamin C scavenges oxygen radicals in the aqueous phase, whereas vitamin E scavenges oxygen radicals within the membranes. Vitamin C regenerates vitamin E by reducing vitamin E radicals formed when vitamin E scavenges the oxygen radicals. This interaction between vitamin C and vitamin E radicals can take place not only in homogeneous solutions but also in liposomal membrane systems where vitamins C and E reside separately outside and within the membranes respectively, and vitamin C can act as a synergist.

Ann N Y Acad Sci 1987;498:186-99

Vitamin C improves endothelial function of epicardial coronary arteries in patients with hypercholesterolaemia or essential hypertension--assessed by cold pressor testing

AIMS: There is evidence that formation of free radicals increases in patients with hypertension or hypercholesterolaemia, which may contribute to endothelial dysfunction of epicardial coronary arteries due to inactivation of the vasodilator NO. The present study was designed to test whether the abnormal constriction of epicardial coronary arteries due to sympathetic stimulation by the cold pressor test in patients with essential hypertension or hypercholesterolaemia could be reversed by administration of the antioxidant vitamin C. METHODS and RESULTS: In 28 patients without relevant coronary artery stenosis the cold pressor test was performed before and after a 3 g infusion of vitamin C. In five normal controls the cold pressor test led to a similar increase in lumi- nal area before and after vitamin C (3.7+/-1.3% and 1.9+/-0.8%, ns vs before vitamin C). In nine hypercholesterolaemic patients the cold pressor test led to a -14.1 +/- 2.8% reduction in cross-sectional area before vitamin C. This constriction was significantly improved after vitamin C to -7.6%+/-2.0, P=0.027 Vs before vitamin C. In nine hypertensive patients, the cold pressor test led to a 17.1+/-3.2% decrease in cross-sectional area before vitamin C, which was improved to -7.1 + /-3.1 after vitamin C, P=O.OO4 Vs before vitamin C. This increase in luminal area was significant in each group in comparison with normal controls (each P<O.O5). Administration of saline (placebo group, five patients) had no significant effect on cold pressor test-induced constriction ( -6.9+/-3.9% before and -6. 8+/-3.7% after saline). CONCLUSION: The antioxidant vitamin C reverses cold pressor test- induced vasoconstriction of epicardial coronary arteries in patients with hypertension or hypercholesterolaemia. Our data suggest that enhanced oxidative stress contributes to impaired endothelial function in this patient population.

Eur Heart J 1999 Nov;20(22):1676-80