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Forty-one patients with type II diabetes mellitus were examined, divided into
four groups administered various types of treatment: (1) diets, (2) predian, (3) glibenclamide, and (4) sugar-reducing drugs and insulin. All the patients were prescribed vitamin E in daily doses 600 and 1200 mg. The results indicate that vitamin E in high doses stimulates pancreatic insulin-producing function and is conducive to normalization of lipid peroxidation no matter what kind of therapy is administered.

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.

The impact of diet and specific food groups on aging and age-associated
degenerative diseases has been widely recognized in recent years. The modern
concept of the free radical theory of aging takes as its basis a shift in the
antioxidant/prooxidant balance that leads to increased oxidative stress,
dysregulation of cellular function, and aging. In the context of this theory,
antioxidants can influence the primary "intrinsic" aging process as well as
several secondary age-associated pathological processes. For the latter, several epidemiological and clinical studies have revealed potential roles for dietary antioxidants in the age-associated decline of immune function and the reduction of risk of morbidity and mortality from cancer and heart disease. We reported that long-term supplementation with vitamin E enhances immune function in aged animals and elderly subjects. We have also found that the beneficial effect of vitamin E in the reduction of risk of atherosclerosis is, in part, associated with molecular modulation of the interaction of immune and endothelial cells. Even though the effects of dietary antioxidants on aging have been mostly observed in relation to age-associated diseases, the effects cannot be totally separated from those related to the intrinsic aging process. For modulation of the aging process by antioxidants, earlier reports have indicated that antioxidant feeding increased the median life span of mice to some extent. To further delineate the effect of dietary antioxidants on aging and longevity,
middle-aged (18 mo) C57BL/6NIA male mice were fed ad libitum semisynthetic
AIN-76 diets supplemented with different antioxidants (vitamin E, glutathione,
melatonin, and strawberry extract). We found that dietary antioxidants had no
effect on the pathological outcome or on mean and maximum life span of the mice, which was observed despite the reduced level of lipid peroxidation products, 4-hydroxynonenol, in the liver of animals supplemented with vitamin E and strawberry extract (1.34 0.4 and 1.6 0.5 nmol/g, respectively) compared
to animals fed the control diet (2.35 1.4 nmol/g). However, vitamin
E-supplemented mice had significantly lower lung viral levels following
influenza infection, a viral challenge associated with oxidative stress. These
and other observations indicate that, at present, the effects of dietary
antioxidants are mainly demonstrated in connection with age-associated diseases in which oxidative stress appears to be intimately involved. Further studies are needed to determine the effect of antioxidant supplementation on longevity in the context of moderate caloric restriction.

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 +/- 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 precancerous lesions; high
vitamin E supplements reveal potentials in secondary CVD prevention. Plasma
values desirable for primary prevention: > or = 30 mumol/l lipid-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.

Epidemiological studies have provided evidence that diets rich in antioxidant
nutrients may reduce the risk of cancer. To evaluate the possibility that
dietary phytochemicals with antioxidant potential would create an environment
capable of affecting the differentiation of HL-60 leukemia cells, we measured
the effects of vitamin E and other dietary antioxidants on the differentiation
produced by low levels of vitamin D3 and analogs thereof. Vitamin E succinate
and other antioxidant compounds (ie butylated hydroxyanisole, beta-carotene and lipoic acid) used alone had no significant effect on the differentiation of
HL-60 cells; however, these agents markedly increased the differentiation
produced by vitamin D3. Previous studies from this laboratory have shown that a sequence-specific antisense phosphorothioate oligonucleotide to the Rel A
subunit of NF-kappaB enhanced the differentiation of HL-60 cells produced by
several inducing agents. Consistent with these observations, vitamin E succinate caused a marked reduction in the nuclear content of NF-kappaB both in the presence and absence of vitamin D3. These findings suggest that NF-kappaB may be a factor in regulating the differentiation of myeloid leukemia cells. The results also indicate that combinations of vitamin D3 and analogs thereof with dietary antioxidants may be useful in overcoming the differentiation block present in acute promyelocytic leukemia cells.

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 IU 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.

Epidemiological and clinical studies indicate that vitamin E may reduce the risk
of cardiovascular disease (CVD). Modulation of adhesion molecule expression and chemokine production by vitamin E may contribute to its beneficial effect. In
this study we found that the enrichment of confluent human aortic endothelial
cells (HAEC) or U937 monocytic cells with increasing doses of vitamin E
(d-alpha-tocopherol, 20, 40, and 60 micromol/l for 20 h) inhibited their
adhesion when either or both cell types were stimulated with interleukin
(IL)-1beta. Enrichment of HAEC with the same doses of vitamin E suppressed
IL-1beta-stimulated expression of intercellular adhesion molecule-1 (ICAM-1),
vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin). Supplementation with increasing doses of vitamin E up to 60 micromol/l was not effective in preventing spontaneous production of monocyte chemoattractant protein-1 (MCP-1), but supplementation with vitamin E at 60 micromol/l reduced IL-8 production significantly. However, IL-1beta-induced productions of both MCP-1 and IL-8 were dose-dependently suppressed by enrichment of cells with vitamin E. Vitamin E, at the doses used, did not significantly change the spontaneous production but dose-dependently inhibited the IL-1beta-induced production of inflammatory cytokine IL-6. We concluded that vitamin E could inhibit production of chemokines and inflammatory cytokines, in addition to inhibiting adhesion of HAEC to monocytes by reducing expression of adhesion molecules when cells were activated with an inflammatory cytokine. These mediators are actively involved in the pathogenesis of atherosclerosis. Therefore, their inhibition by vitamin E may contribute to vitamin E's reported reduction in risk of CVD.

Epidemiologic studies have suggested that vitamin E (alpha-tocopherol) may play a 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.

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 Heart Outcomes Prevention Evaluation (HOPE) study found that the ACE
inhibitor ramipril can lower the risk of atherosclerotic disease events and
death in patients without heart failure but with known atherosclerosis or with
diabetes plus at least one cardiovascular risk factor. This benefit was
independent of ramipril's effect on blood pressure. Additional benefits were a
reduced risk of diabetic nephropathy in diabetic patients, and a lower
likelihood of newly diagnosed diabetes. On the other hand, vitamin E in the
doses and duration studied (400 IU/day for 4.5 years) did not lower risk
significantly.