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

Martin A.; Foxall T.; Blumberg J.B.; Meydani M.
Arteriosclerosis, Thrombosis, and Vascular Biology (USA), 1997, 17/3 (429-436)

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

alpha-Tocopherol inhibits aggregation of human platelets by a protein kinase C-dependent mechanism.

Freedman J.E.; Farhat J.H.; Loscalzo J.; Keaney J.F. Jr.
Whitaker Cardiovascular Institute, Boston University School of Medicine, 80 E Concord St, Boston, MA 02118-2394 USA
Circulation (USA), 1996, 94/10 (2434-2440)

Background: Epidemiological studies indicate that vitamin E (alpha tocopherol) exerts a beneficial effect on cardiovascular disease. The effect of vitamin E has generally been attributed to its antioxidant activity and the antioxidant protection of LDL. Distinct from its effect on LDL, vitamin E is also known to inhibit platelet aggregation and adhesion in vitro, but the mechanism(s) responsible for these observation are not known. Methods and Results: Using gel-tiltered platelets derived from platelet-rich plasma treated with alpha-tocopherol (500 micromol/L) or vehicle (0.5% ethanol), we found that inhibition of platelet aggregation by alpha-tocopherol was closely linked to its incorporation into platelets (r=-.78; P&lt.02). Platelet incorporation of alpha-tocopherol was associated with a significant reduction in platelet sensitivity to aggregation by adenosine 5'-diphosphate, arachidonic acid, and phorbol ester (PMA) by approximately 0.15-, 2-, and 100-fold, respectively. In contrast, platelets treated similarly with butylated hydroxytoluene, another potent lipid-soluble antioxidant, did not demonstrate any change in sensitivity to these agents. Platelet incorporation of alpha-tocopherol inhibited PMA-induced stimulation of platelet protein kinase C (PKC) as determined by phosphorylation of the 47-kD PKC substrate. In 15 normal subjects, oral supplementation with alpha-tocopherol (400 to 1200 IU/d) resulted in an increase in platelet alpha-tocopherol content that correlated with marked inhibition of PMA-mediated platelet aggregation (r=.67: P&lt.01). Platelets derived from these subjects after supplementation also demonstrated apparent complete inhibition of PKC stimulation by PMA. Conclusions: These data indicate that platelet incorporation of alpha-tocopherol at levels attained with oral supplementation is associated with inhibition of platelet aggregation through a PKC-dependent mechanism. These observations may represent one potential mechanism for the observed beneficial effect of alpha-tocopherol in preventing the development of coronary artery disease.

Changes in atherosclerotic aorta of rabbit fed with high cholesterol diet: The effect of vitamin E.

Sirikci O.; San T.; Ozer N.
Biyokimya Anabilim Dali, Tip Fakultesi, Marmara Universitesi, Istanbul Turkey
Klinik Gelisim (Turkey), 1996, 9/2 (4063-4068)

Background and design: Atherosclerosis call be triggered by a multiplicity of risk factors, but its common feature is intimal thickening caused by the proliferation of smooth muscle cells which have migrated from the media. Hypercholesterolemia is one most important risk factors of the disease. Proteinkinase C is a pivotal enzyme which relays signals of proliferation and differentiation in smooth muscle cells. The protective role of vitamin E as an antioxidant in cardiovascular disease has long been recognized. RRR-alpha-Tocopherol was shown to inhibit the proteinkinase C activity and proliferation of cultured smooth muscle cells independently of its antioxidant properties. Methods: In the present study, we investigated the molecular changes in aortic smooth muscle cells of rabbits fed with high cholesterol diet. In addition, we investigated if we would observe a parallel relation between proteinkinase C activity, smooth muscle cell proliferation and vitamin E in an experimental model of atherosclerosis at microscopical and biochemical levels ex-vivo. Results: The group receiving a cholesterol-rich diet had serum cholesterol levels of 875 plus or minus 573 mg/dL, the group received cholesterol rich-diet + vitamin E 811 plus or minus 300 mg/dL and the control group 64 plus or minus 11 mg/dL. Serum vitamin E levels were 3.2 plus or minus 1.3 microg/mL for the control group, 9.8 plus or minus 2.9 microg/mL for the cholesterol group, and 122.6 plus or minus 42.7 microg/mL for the cholesterol + vitamin E group. Our light microscopy results showed that hypercholesterolemia induced a prominent intimal thickening. Proteinkinase C activities of the aortic homogenates were 10.55 plus or minus 2.12 for the cholesterol group, 9.41 plus or minus 0.94 for the cholesterol + vitamin E group and 5.42 plus or minus 1.89 Delta absorbance/min/microg protein for the control group. Vitamin E was shown to protect from smooth muscle cell proliferation at microscopical level and partially effect the signal transduction cascade of smooth muscle cell proliferation.

The effect of modest vitamin E supplementation on lipid peroxidation products and other cardiovascular risk factors in diabetic patients.

Jain S.K.; McVie R.; Jaramillo J.J.; Palmer M.; Smith T.; Meachum Z.D.; Little R.L.
Department of Pediatrics, LSU Medical Center, 1501 Kings Highway, Shreveport, LA 71130 USA
Lipids (USA), 1996, 31/3 SUPPL. (S87-S90)

Among many factors, elevated lipids and lipid peroxide levels in blood are major risk factors in the development of cardiovascular disease in diabetic patients. This study has examined whether oral supplementation of vitamin E, an antioxidant, has any effect on blood lipid peroxidation products (LP) and lipid profile of diabetic patients. Thirty-five diabetics(D) were supplemented with DL-alpha-tocopherol (E) capsule (orally, 100 IU/d) or placebo (P) for three months in double-blind clinical trials. Plasma E was analyzed by HPLC and LP by the thiobarbituric acid-reactivity; serum lipids by auto analyzer. Data were analyzed using paired t-test and Wilcoxon Signed Rank Test. Vitamin E supplementation significantly lowered LP and lipid levels in diabetic patients; there were no differences in these parameters after P supplementation. There were no differences in the duration of diabetes and ages of D between P- and E- supplemented groups. This study suggests that vitamin E supplementation significantly lowers blood LP and lipid levels in diabetic patients.

Effects of various fatty acids alone or combined with vitamin E on cell growth and fibrinogen concentration in the medium of HepG2 cells.

Thromb Res (UNITED STATES) Oct 1 1995, 80 (1) p75-83

Dietary intake of fish oils, rich in the polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has given inconsistent results as to their influence on the plasma fibrinogen level (1, 2, 3, 4, 5, 6). In the present study we have examined the effects of various fatty acids, the PUFAs and the saturated fatty acid palmitic acid (PA), alone or combined with the antioxidant vitamin E (Vit.E), on the fibrinogen concentration in the growth medium of human hepatoma (HepG2) cells. Vit.E alone decreased the amount of fibrinogen in the medium in a dose dependent fashion, where fibrinogen was measured as Fibrinopeptide A (FPA) releasable by thrombin. EPA and Vit.E decreased the amount of fibrinogen additively. PUFAs alone increased the fibrinogen concentration in a dose dependent manner. PUFAs combined with a fixed dose of Vit.E decreased the fibrinogen concentration, also dose dependently. OA and PA had an inhibitory effect, both alone and combined with Vit.E. These results indicate that Vit.E may be necessary for PUFAs to have a fibrinogen lowering effect, whereas both OA and PA apparently may decrease the fibrinogen concentration in the cell medium of HepG2 cells, both alone and combined with Vit.E. Possibly, peroxidation of the PUFAs may increase the fibrinogen production, that may be counteracted and reversed by the simultaneous presence of Vit.E.

[The role of platelets in the protective effect of a combination of vitamins A, E, C and P in thrombinemia]

Gematol Transfuziol (RUSSIA) Sep-Oct 1995, 40 (5) p9-11

White rat experiments have shown that combination of vitamins A, E, C and P diminishes thrombin-induced thrombocytopenia and low platelet aggregation. This is explained by limited activation of free radical processes initiated by thrombin in plasma, red cells and platelets. It was found that thrombin ability to activate lipid peroxidation is not related to coagulatory transformation of fibrinogen, but is rather due to a direct contact of the enzyme with platelets. A protective effect of vitamins-antioxidants in thrombinemia is likely to rest on their ability to restrict activation of free radical oxidation in platelets

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

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

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

Erythrocyte and plasma antioxidant activity in type I diabetes mellitus

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.

[Erythrocyte and plasma antioxidant activity in diabetes mellitus type I] Activite anti-oxydante erythrocytaire et plasmatique dans le diabete de type I.

Presse Med (FRANCE) Feb 10 1996, 25 (5) p188-92

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 I diabetes.

[Patients with type-II diabetes mellitus and neuropathy have nodeficiency of vitamins A, E, beta-carotene, B1, B2, B6, B12 and folic acid]

Med Klin (GERMANY) Aug 15 1993, 88 (8) p453-7

The present study was aimed to determine the vitamin status of vitamins A, E, beta-carotene, B1, B2, B6, B12 and folate in plasma using HPLC and vitamins B1, B2 and B6 in erythrocytes using the apoenzyme stimulation test with the Cobas-Bio analyzer in 29 elderly type II diabetic women with (G1: n = 17, age: 68.6 ± 3.2 years) and without (G2: n = 12, age: 71.8 ± 2.7 years) diabetic polyneuropathy. The basic parameters as age, hemoglobin A1c, fructosamine and duration of the disease did not differ in both groups. Furthermore, retinopathy was assessed with fundoscopy and nephropathy with creatinine clearance. The creatinine clearance (G1: 50.6 ± 3.4 vs. G2: 63.6 ± 3.7 ml/min, 2p < 0.025) and the percentage of retinopathy (G1: 76.5% vs. G2: 16.7%, 2p = 0.002) were different indicating that G1 had significantly more severe late complications than G2. Current plasma levels of all measured vitamins (A, E, beta-carotene, B1, B2, B6, B12 and folate) and the status of B1, B2 and B6 in erythrocytes did not vary between the two groups (2p > 0.1). In summary, we found a lack of association between the actual vitamin condition in plasma and erythrocytes and diabetic neuropathy.

[Vitamin status in diabetic neuropathy (thiamine, riboflavin, pyridoxin, cobalamin and tocopherol)]

Z Ernahrungswiss (GERMANY, WEST) Mar 1980, 19 (1) p1-13

Investigations on the vitamin pattern of diabetic neuropathy: thiamine, riboflavin, pyridoxine, cobalamin and tocopherol. The contents of the vitamins mentioned above have been measured in the blood of 119 patients (53 diabetic neuropathies, 66 diabetics without neuropathy). The incidence of neuropathy shows a strong correlation with the duration of the diabetic state, but not with sex, nor with concomitant diseases such as adipositas, hypertension, heart and circulatory diseases, except retinopathia diabetica. Most of the diabetics in our study are well supplied with vitamins B1, B2, and E; B6 and B12 are occasionally low, but there is no statistically relevant difference between diabetic controls and neuropathies. Adipose patients have neither a markedly different vitamin content nor a different calory uptake from non-adipose patients. A general trend towards reduced total calory uptake is seen in old age, men (lower protein intake) and women (lower carbohydrate intake) obviously differing somewhat in their habits. The influence of therapy on the vitamin pattern is not clear cut, except for patients under diet and biguanide-therapy showing a higher proportion of low or subnormal B12 values. The increased frequency of neuropathies in patients treated with sulfonyl-urea approaches only the limits of significance and needs further investigations.

Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering.

Circulation (UNITED STATES) Nov 15 1996, 94 (10) p2369-72

BACKGROUND: There is accumulating experimental, epidemiological, and clinical evidence of an association between anti-oxidant vitamin intake and reduced risk of coronary heart disease. Using data from the Cholesterol Lowering Atherosclerosis Study (CLAS), we explored the association of self-selected supplementary antioxidant vitamin intake on the rate of progression of early preintrusive atherosclerosis. METHODS AND RESULTS: CLAS was an arterial imaging trial in which nonsmoking 40- to 59-year-old men with previous coronary artery bypass graft surgery were randomized to colestipol/niacin plus diet or placebo plus diet. The rate of progression of early preintrusive atherosclerosis was determined in 146 subjects using high-resolution B-mode ultrasound quantification of the distal common carotid artery far wall intima-media thickness (IMT). From the nutritional supplement database, 22 subjects had an on-trial average supplementary vitamin E intake of > or = 100 IU per day (high users) and 29 subjects had an average on-trial supplementary vitamin C intake of > or = 250 mg per day (high users). Within the placebo group, less carotid IMT progression was found for high supplementary vitamin E users when compared with low vitamin E users (0.008 versus 0.023 mm/y, P = .03). No effect of vitamin E within the drug group was found. No effect of vitamin C within the drug or placebo group was found. CONCLUSIONS: Supplementary vitamin E intake appears to be effective in reducing the progression of atherosclerosis in subjects not treated with lipid-lowering drugs while the process is still confined to the arterial wall (early preintrusive atherosclerosis).

The age-associated decline in immune function of healthy individuals is not related to changes in plasma concentrations of beta-carotene, retinol, alpha-tocopherol or zinc

Mechanisms of Ageing and Development (Ireland), 1997, 94/1-3 (55-69)

The decline in the lymphoproliferative response to mitogenic stimuli shows marked heterogeneity in elderly individuals. Adequate nutriture is required for optimal immune function, yet nutritional status may be compromised in the elderly. To address whether this variation in the proliferative response of elderly individuals is related to their nutritional status, we studied 61 elderly (80.5 plus or minus 5.7 year-old) and 27 young (27.3 plus or minus 3.8 year-old) individuals participating in an ongoing assessment of their immune response to influenza vaccine. Ambulatory elderly individuals were recruited from five different retirement communities and were in good health upon enrollment in the study. Thirty-three percent of young and 54% of elderly subjects reported consuming micronutrient supplements daily during the study. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from fasting individuals twice, 4-6 weeks apart. At both times, proliferative responses to the mitogens phytohemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM) were significantly lower (P < 0.004) in the elderly compared to the young. However, at both times, elderly participants had plasma concentrations of beta-carotene, retinol, alpha-tocopherol and zinc that were either significantly greater than, or equal to, those of young subjects. No significant correlations between plasma concentrations of beta-carotene, retinol, alpha-tocopherol and zinc and level of proliferative responses to each stimuli were observed in elderly individuals at either time. Thus, the heterogeneity in the proliferative response to mitogenic stimuli exhibited by a healthy elderly population cannot be attributed to differences in these nutritional parameters.

Recommended dietary allowance: support from recent research.

J Nutr Sci Vitaminol (Tokyo) (JAPAN) 1992, Spec No p173-6

Increasing evidence is accumulating that a synergistic role of the so-called antioxidant vitamins (C, E, beta-carotene) may have a dominant role in the prevention of cancer, cardiovascular diseases and cataract formation. Controversy still exists regarding the optimum intake of vitamin C. This is partly due to lack of accurate and easily accessible health-relevant end-points, and lack of knowledge of the role of vitamin C in biochemical functions. Today, it is clearly recognized and broadly accepted that optimal health is a consequence of dietary optimization. Attainment of optimal health rather than prevention of deficiency symptoms is the goal. There can be little doubt that in this respect the requirements for vitamin C are greater than the amount required for the mere prevention of overt or classical scurvy. The recommendation of varying levels of requirement could overcome the controversy. The following is therefore proposed: The lowest level is that value which prevents deficiency symptoms. The second level is valid for healthy populations (< 200 mg/d). This level would take into account needs which differ according to age, sex, physical activity, physiological status (e.g. pregnancy or lactation) and environmental factors such as smoking, pollution and alcohol intake. Finally, a third level should be determined for the prevention of the above-mentioned non-communicable diseases. These diseases are an important cause of disability, resulting in costs of billions of dollars annually in medical costs. Many of the above-mentioned diseases can be prevented by supplementation with vitamin C. Medical costs could thereby also be dramatically reduced.

Modelling cortical cataractogenesis VII: Effects of vitamin E treatment on galactose-induced cataracts.

Exp Eye Res (ENGLAND) Feb 1985, 40 (2) p213-22

The possibility that vitamin E or other antioxidants might prevent cataracts was tested by incubating rat lenses in vitro in galactose-enriched medium or by treating rats fed a diet containing 50% galactose (w/w). The vitamin E was added to the medium at 2.4 microM, and to the diet at a level of 5 g kg-1 diet. In vitro, lenses incubated with 55.6 mM galactose underwent globular degeneration, which was partially prevented by addition of vitamin E (2.4 microM). Even in such vitamin E-protected lenses, which appeared clear, many small globules could be seen in the region of interdigitation at the 'corners' where hexagonal cells intersected. In vivo, in dietary experiments, a dense nuclear opacity of the lens was observed after approximately 5 weeks; unlike diabetic cataracts, this was not prevented by the addition of vitamin E to the diet. The extensive globular degeneration observed was typical of that found in long-term (21-week diabetic) cataracts. Although no significant difference in cataract incidence was observed, the extent of damage in vitamin E-treated rat lenses appeared to be less. The difference in effectiveness of vitamin E in galactose-induced cataracts, as compared to diabetic cataracts, is tentatively ascribed to (1) the more severe osmotic stress expected from the products of the aldose reductase pathway for galactose and (2) the greater depletion of reduced pyridine nucleotides (NADPH + NADH) expected of galactose as compared to glucose.

Modeling cortical cataractogenesis. V. Steroid cataracts induced by solumedrol partially prevented by vitamin E in vitro.

Exp Eye Res (ENGLAND) Jul 1983, 37 (1) p65-76

Rat lenses incubated in tissue culture medium (M 199) maintain their transparency for a long period of time. The soluble corticosteroid, solumedrol (methyl prednisolone sodium succinate) was added to the medium, at concentrations including the range expected during rejection episodes following organ transplantation (3.8 X 10(-9) M-3.8 X 10(-6) M). At the lowest level used (3.8 X 10(-9) M), five lenses of 12 became opaque following a 48 hr incubation, while at higher concentrations of solumedrol almost all lenses developed opacities. Addition of vitamin E to the medium resulted in partial prevention of the cataract as judged by the smaller proportion of lenses becoming opaque. Examination of the lenses by scanning and transmission electron microscopy (SEM and TEM, respectively), indicated that in untreated lenses the initial location of the cataract is at the anterior pole of the lens where a deepening area of degeneration formed, followed by a uniform subcapsular layer of degeneration spreading over the remainder of the lens. Damage at this location is not typical of most in vitro cortical cataracts. In the presence of vitamin E the extent of damage was less, involving, initially, an equatorial wedge of globular degeneration and spreading anteriorly and posteriorly in a thinner subcapsular layer. This type of damage was more typical of that seen previously for cataracts induced by cytochalasin D, elevated glucose and hygromycin B.

Biochemical and morphological changes in the lenses of selenium and/or vitamin E deficient rats.

Biomed Environ Sci (UNITED STATES) Jun 1994, 7 (2) p109-15

The activities of glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), superoxide dismutase (SOD) and the contents of malondialdehyde (MDA) and free radicals were measured, and the morphological changes were observed in the lens of control rats, selenium-deficient (SeD) and/or vitamin E deficient (VED) rats. The activities of GSH-Px in the lens of SeD rats decreased significantly. The GSH-Px activities of lens were positively related to erythrocytes selenium level. There was a free radical at g = 2.0015 in the rat lens of all groups, but the content of free radicals in the lens of SeD group was significantly higher than that of the control group. The free radical content of lens was negatively related to erythrocytes selenium level, as well as the GSH-Px activities in the lens. In vitro, ultraviolet radiation caused the generation of another kind of free radical (g = 2.0097) in the lens of all groups, but the amount of the free radical in the lens of the SeD group was also significantly higher than that of the control group. The activities of SOD and GSSG-R in VED rat lens were significantly decreased. The amount of MDA in the lens of SeD and/or VED rats were significantly increased. The results showed that the decrease of antioxidative capability in the lenses of SeD and/or VED rats accelerated the lipid peroxidation and generation of free radicals. Although only early morphological changes in SeD and/or VED rat lens were observed, it is considered that selenium and vitamin E deficiency may be involved in the occurrence of cataract.

Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants

EMBO Journal (United Kingdom), 1996, 15/8 (1753-1765)

Muscle wasting is a critical feature of patients afflicted by AIDS or cancer. In a murine model of muscle wasting, tumor necrosis factor alpha (TNFalpha) induces oxidative stress and nitric oxide synthase (NOS) in skeletal muscle, leading to decreased myosin creatinine phosphokinase (MCK) expression and binding activities. The impaired MCK-E box binding activities resulted from abnormal myogenin-Jun-D complexes, and were normalized by the addition of Jun-D, dithiothreitol or Ref-1, a nuclear redox protein. Treatment of skeletal muscle cells with a phorbol ester, a superoxide-generating system, an NO donor or a Jun-D antisense oligonucleotide decreased Jun-D activity and transcription from the MCK-E box, which were prevented by antioxidants, a scavenger of reducing equivalents, a NOS inhibitor and/or overexpression of Jun-D. The decreased body weight, muscle wasting and skeletal muscle molecular abnormalities of cachexia were prevented by treatment of TNFalpha mice with the antioxidants D-alpha-tocopherol or BW755c, or the NOS inhibitor nitro-L-arginine.

Protective role of orally administered selenium and vitamin E towards cardiotoxicity induced by anthracyclines in the rat

Nutrition Clinique et Metabolisme (France), 1996, 10/2 (69-76)

Adriamycin-induced cardiotoxicity could be due to free radical formation, which induces lipid peroxidation and membrane damage. We have studied the effect of oral supplementation with selenium (Se) and/or vitamin E (Vit. E) on myocardiopathy in rats treated by adriamycin (ADM). Animals were divided intby ADM (ADM) or NaCl 0.15 M solution (Control group = C); standard diet (SD); ADM I and C I; SD with Se; ADM II and C II; SD with Vit. E; ADM III and C III; SD with Se and Vit. E; ADM IV and C IV. All rats received ADM or saline solution by the intraperitoneal route. Ascitis and survival were observed throughout 18 weeks and hearts were studied histologically. Survival was 100% for controls while median survival was 12 (ADM I and II), 14 (ADM III) and 16 weeks (ADM IV) in treated rats. Ascitis was significantly less marked in ADM IV compared with ADM I (p = 0.02). Heart weight was decreased in ADM I, II and III compared with those of controls (p = 0.001) while it was similar to controls in ADM IV. Cardiac lesions studied by semi-quantitative histology were less severe in ADM IV. Se associated with Vit. E could prevent cardiac toxicity induced by ADM treatment and may be helpful to clinicians in chemotherapy using anthracycline.

[Electrocardiogram analysis of adriamycin cardiotoxicity in 160 cases]

Chung Hua Chung Liu Tsa Chih. 1991 Jan. 13(1). P 71-3

From January 1986 to May 1989, 160 cancer patients proven by pathology were treated by combined chemotherapy with adriamycin (ADM) as the chief agent. Of them, 20 were given simultaneous cyclophosphamide (CTX) and 14 had received mediastinal irradiation. 40 mg/m2 of ADM was given by rapid IV bolus injection which was repeated every 3 weeks. All but 9 had normal electrocardiogram (ECG) before ADM administration. In these 9 patients, when ADM reached certain accumulated dose, ECG showed no further changes. Thirty-seven (24.5%) cases had various types of abnormal ECG, manifested as arrhythmia in 11, non-specific ST-T changes in 12 and low voltage in 14. Of these 37 patients, fatal congestive heart failure developed in 4 cases. To reduce ADM cardiotoxicity, its indication should be strictly adhered to; ADM may be divided to two fractions on Day 1 and 2, for those patients receiving simultaneous CTX or who had had mediastinal irradiation, ADM accumulated dose should be limited to 400 mg/m2; ADM should never be given to patients with lowered QRS voltage greater than or equal to 30% of the normal value or with obvious ST-T changes; the accumulated doses should range from 450 to 550 mg/m2, simultaneous anti-histamines, anti-adrenaline, coenzyme Q10 and vitamin E are indicated.

Effect of antioxidants on adriamycin-induced microsomal lipid peroxidation.

Biol Trace Elem Res. 1995 Jan-Mar. 47(1-3). P 111-6

Adriamycin (25 microM) stimulated NADPH-dependent microsomal lipid peroxidation about fourfold over control values. The tested antioxidants, zinc, superoxide dismutase, vitamin E, and desferrioxamine (Desferal) inhibited Adriamycin-enhanced lipid peroxidation to varying degrees. Others antioxidants, e.g., glutathione, catalase, and selenium, were found to have no effects. Our in vitro studies suggest that adriamycin effect is mediated by a complex oxyradical cascade involving superoxide, hydroxyl radical, and small amounts of iron.

Alpha tocopherol improves focal glomerulosclerosis in rats with adriamycin-induced progressive renal failure.

Nephron. 1994. 68(3). P 347-52

The effect of d-alpha-tocopherol on the progression of renal dysfunction was investigated in rats injected with adriamycin (ADR), a model of progressive glomerulosclerosis associated with the nephrotic syndrome. Treatment with d-alpha-tocopherol was started 1 day before or 1 day after ADR injections (BE-TOC or AF-TOC rats). When compared to rats without d-alpha-tocopherol treatment (ADR-CON rats), the serum total cholesterol and triglyceride levels were significantly lower in the BE-TOC and AF-TOC groups. In week 16, the LDL cholesterol level and the atherogenic index were both significantly lower in BE-TOC and AF-TOC rats than in ADR-CON rats. The urinary protein, serum creatinine, blood urea nitrogen, malondialdehyde, and systolic blood pressure levels as well as the glomerulosclerosis score were high in ADR-CON rats, and reduced in BE-TOC or AF-TOC rats. There were no significant differences in body weight and serum albumin between the three groups in week 16. It is concluded that d-alpha-tocopherol can improve hyperlipidemia and ameliorate glomerulosclerosis in rats with ADR-induced progressive renal failure. Thus, d-alpha-tocopherol may have the potential for clinical application to treat focal glomerulosclerosis.

Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer.

Br J Cancer. 1995 Mar. 71(3). P 587-91

A phase III randomised study, comparing treatment with fluorouracil, epidoxorubicin and methotrexate (FEMTX) with the best supportive care, was conducted in patients with unresectable or metastatic gastric cancer. During the period from July 1986 to June 1992, 41 patients were randomised to receive FEMTX or best supportive care. MTX was given in a dose of 1500 mg m-2 intravenously (i.v.) followed after 1 h by 5-FU 1500 mg m-2 i.v. on day 1; leucovorin rescue was started after 24 h (30 mg orally every 6 h for 48 h) and epidoxorubicin 60 mg m-2 i.v. was administered on day 15. In addition both groups received tablets containing vitamins A and E. Response rates for FEMTX were as follows: complete response (CR), 19% (4/21); partial response (PR), 10% (2/21); no change (NC), 33% (7/21); and progressive disease (PD), 24% (5/21). Response rates in the control group were: NC, 20% (4/20); and PD, 80% (16/20). Increased pain was observed in one patient in the treated group and in 11 patients in the control group within the first 2 months. WHO grade III/IV toxicity in the chemotherapy group was as follows: nausea/vomiting 40%, diarrhoea 10%, stomatitis 15%, leucopenia 50% and thrombocytopenia 10%. One possible treatment-related death was due to sepsis. The median time to progression in the FEMTX group was 5.4 months [95% confidence interval (CI) 3.1-11.7 months], but only 1.7 months in the control group (95% CI 1.2-2.7 months) (P = 0.0013). Similarly, the FEMTX group displayed significantly (P = 0.0006) prolonged survival compared with the control group, i.e. median survival 12.3 months (95% CI 7.1-15.6 months) vs 3.1 months (95% CI 1.6-4.6 months). In conclusion, FEMTX combined with vitamin A and E is a fairly well-tolerated treatment, giving a response rate of 29% in patients with advanced gastric cancer, and also prolonging patients' survival. It can be used as a reference treatment in testing new investigational combinations.

Enhancement of the antineoplastic effect of anticarcinogens on benzo[a]pyrene-treated Wistar rats, in relation to their number and biological activity.

Cancer Lett. 1994 Jul 29. 82(2). P 153-65

Naturally occurring anticarcinogens, such as vitamins C and E, and the microelement selenium were found to inhibit the induction of benzo[a]pyrene-induced malignant tumors in Wistar rats to various extends. The antineoplastic effect of the tested anticarcinogens is gradually increased according to the number of inhibitors selected. To date the maximum action against malignancy is manifested by use of the above three inhibitors. In the group of rats receiving vitamins C, E and selenium, the prolongation of life induced by adding more than one anticarcinogen to the treatment regime reached, and in some cases surpassed, the normal life expectancy of the rats. It is expected that by adding even more anticarcinogens, the antineoplastic potency (Ap) of the inhibitors will be further improved. These results encouraged us to conduct a clinical trial in terminal human cancer cases, in conjunction with the usual treatments of surgery or chemotherapy and irradiation.

Critical reappraisal of vitamins and trace minerals in nutritional support of cancer patients.

Support Care Cancer. 1993 Nov. 1(6). P 295-7

The potential of a high intake of fresh fruits and vegetables in cancer prevention is well established. Epidemiological studies support carotene, vitamins A, C, E and selenium as the active compounds. Antioxidant properties and direct effects (e.g. inhibition of N-nitrosamine formation or cell-to-cell interactions) are invoked. The role of other trace elements is less clear. The modulation of immune function by vitamins and trace elements remains important and affects survival. In established cancers, the site-specific differences in the diet/cancer relation require appropriate dietary changes, e.g. low fat (20% by energy) in breast cancer, or high vegetable or fruit intake in lung cancer. Single high-dose supplements (e.g. vitamin C) have proved to have no curative or life-prolonging effect. Chemotherapy and radiation increase the requirements for antioxidant compounds. Supplementation can diminish the damage induced by peroxidation. Carefully planned and monitored trials that establish the optimal intake of micronutrients as adjuvants in cancer patients are required.

Chemotherapy-induced alopecia: new developments

South Med J. 1993 May. 86(5). P 489-96

Alopecia (hair loss) is one of the most physically and psychologically distressing side effects of cancer chemotherapeutic drugs. Since its first recognition as a common outcome to most chemotherapeutic agents, only a few trials have been reported, using either a method to temporarily reduce the scalp blood flow (scalp tourniquet or hypothermia) or vitamin E, with undocumented and variable efficacy. The lack of progress in the treatment and prevention of chemotherapy-induced alopecia is in part due to the lack of a reproducible animal model. In the past 2 years, we reported on the following observations: (1) treatment of 8-day-old rats with vidarabine (ara-C), doxorubicin, and cyclophosphamide consistently produced either total body alopecia (ara-C and cyclophosphamide) or alopecia confined to the head and proximal part of the back (doxorubicin); (2) Imuvert, a biologic response modifier derived from the bacterium Serratia marcescens, uniformly produced complete protection against alopecia induced by ara-C and doxorubicin but not that produced by cyclophosphamide; (3) the protective effect of Imuvert against chemotherapy-induced alopecia is mediated by a monocyte-mediated cytokine; and (4) this monocyte-derived cytokine is, possibly, interleukin-1. These observations constitute important progress in the understanding and prevention of chemotherapy-induced alopecia.

Vitamin E enhances the chemotherapeutic effects of adriamycin on humanprostatic carcinoma cells in vitro

J. UROL. (BALTIMORE) (USA), 1986, 136/2 (529-531)

Vitamin E (tocopherol) enhances the growth inhibitory effects of adriamycin ADR) on a variety of cancer cells in vitro. The role of vitamin E (d-alpha-tocopheryl) acid succinate in adjuvant chemotherapy with ADR was assessed in DU-145 human prostatic carcinoma cells in culture. Adriamycin produced a dose-dependent growth inhibition of DU-145 cells. The IDsub 5sub 0 of DU-145 cells on the criteria: a) of clonal assay was 13 ng./ml. and b) of cell count assay was 14 ng./ml. Vitamin E succinate also inhibited the growth of DU-145 human prostatic carcinoma cells in a dose-dependent manner, 4.4 mug./ml. and 5.4 mug./ml. vitamin E succinate in the culture medium produced inhibition of growth of 50 per cent of control (IDsub 5sub 0) in the clonal and the cell count assays respectively. When adriamycin and vitamin E succinate were used in combination, both additive and synergistic effects were observed, depending on the concentration of vitamin E succinate used. Doses of vitamin E succinate greater than its IDsub 5sub 0 had a synergistic effect while doses smaller than its IDsub 5sub 0 had an additive effect. In either case, the presence of vitamin E succinate caused an enhancement of tumor cell cytotoxicity of adriamycin while decreasing its IDsub 5sub 0. Equivalent concentrations of sodium succinate and ethanol used to dissolve vitamin E succinate did not have any effect on DU-145 cells. Thus, it is concluded that the effect of vitamin E succinate is due to vitamin E and not due to succinate or ethanol. These results suggest that vitamin E may have a role in the treatment of human prostatic cancer as an adjuvant agent to adriamycin.

Hematological aspects of vitamin E, continued. Adriamycin cardiotoxicity amelioration by alpha-tocopherol

AM. J. PEDIATR. HEMATOL. ONCOL. (USA), 1979, 1/2 (151-153)

Adriamycin has become a potent member of the cancer chemotherapeutic program. However, the full utilization of adriamycin is limited by its cardiotoxicity. In experimental animals, alpha-tocopherol has been shown by some to ameliorate or prevent cardiac dysfunction without impairing antitumor effectiveness. During adriamycin therapy, future clinical research should consist of biochemical measurements of vitamin E in plasma, lipoperoxidation in red cells and platelets, while cardiac status is being monitored. Replacement with vitamin E, if there are parameters to indicate deficiency, should be considered as one method of ameliorating toxicity.

Treatment of cutaneous radiation fibrosis with pentoxifylline and vitamin E. A case report

Strahlentherapie und Onkologie (Germany), 1996, 172/1 (34-38)

Background: Radiation fibrosis represents a severe complication of radiation therapy; standardized treatment protocols are lacking so far. Surgical excision rarely results in complete healing. Patient and Methods: We report on a 58-year-old female patient who developed a squamous cell carcinoma within the fibrotic area of the irradiation field on the right chest, resulting from a radiotherapy following mastectomy for breast cancer 17 years ago. After surgical excision of the carcinoma a combined treatment with pentoxifylline tablets (3 x 400 mg/d p.o.) and vitamin-E capsules (1 x 400 mg/d p.o.) was initiated. Skin thickness was quantified by 20 MHz-ultrasound before and during treatment. Results: The patient noted an increasing improvement of the condition of the affected skin starting from 4 months. A continuing decrease of skin thickness as documented by 20 MHz-ultrasound could be demonstrated from the 6th month on. The treatment was tolerated well, no side effects were observed. Conclusion: The data indicate a beneficial therapeutic effect of pentoxifylline and vitamin E on radiation-induced fibrosis. Little is known about the mechanism of action of this combined treatment protocol including pentoxifylline and vitamin E. Controlled clinical trials should be performed to confirm this observation.

Few aspects of bacterial colonies in the stomach during the treatment with acidoinhibitors

BOLL. CHIM. FARM. (Italy), 1992, 131/8 (302-303)

On this paper are stated the reasons why a prolonged gastric-acid inhibition causes bacterial and/or mycotic colonizations in the stomach. Instead, the surgical operations, that now became obsolete, are only casual occasions of intragastric colonizations. This paper ends with some rules to be followed in order to avoid risks connected to a pH increase, and with a short hint to two important vitamins (i.e. Vitamin C and Vitamin E) for the complementary treatment of ulcerous patients.

Effects of vitamins A, C, and E on aflatoxin Bsub 1-induced mutagenesis in Salmonella typhimurium TA-98 and TA-100

TERATOG. CARCINOG. MUTAG. (USA), 1985, 5/1 (29-40)

The effects of retinoids (vitamin A analogs) and vitamins C and E on the aflatoxin Bsub 1-(AFBsub 1)-induced mutagenesis in Salmonella typhimurium TA-98 and TA-100 were investigated. The bioassay was performed under conditions that permitted the effects of vitamins on carcinogen metabolism to be assessed separately from effects on the expression of the mutated bacterial cell. Both retinoic acid and retinol inhibited (up to 50%) AFBsub 1-induced mutagenesis in S. typhimurium TA-98, but only retinol inhibited (up to 75%) mutagenesis in TA-100. Retinoic acid inhibition of mutagenesis in S. typhimurium TA-98 was pronounced over a wide concentration range (i.e., 2 x 10sup -sup 1sup 0 to 2 x 10sup -sup 8 M); however, at the higher concentrations (i.e., 2 x 10sup -sup 8 to 2 x 10sup -sup 6 M range) the predominant effect was the inhibition of the metabolism of AFBsub 1 to its mutagenic metabolites. Vitamin E was more potent in inhibiting the expression of AFBsub 1-induced mutagenesis than vitamin C. However, the major inhibitory effects of vitamin E were related to the metabolism of AFBsub 1, whereas vitamin C was inhibitory at both metabolic and the post-metabolic levels of the AFBsub 1 mutagenesis assay. The results of these investigations suggest that vitamins A, C, or E inhibit both AFBsub 1 metabolism to its mutagenic metabolites as well as the expression of AFBsub 1-induced mutated bacterial cells.

Effects of n-3 and n-6 fatty acids on the activities and expression of hepatic antioxidant enzymes in autoimmune-prone NZBxNZW F1 mice

LIPIDS (USA), 1994, 29/8 (561-568)

Menhaden fish oil (FO) containing n-3 fatty acids dramatically extends the life span and delays the onset and progression of autoimmune disease in (NZBxNZW)F1 (B/W) female mice as compared to those fed corn oil (CO) rich in n-6 lipids. As an inefficient antioxidant defense system has been linked to autoimmune diseases, the present study was undertaken to determine whether the protective action of n-3 lipids is mediated through their antioxidant defense system. Weanling B/W mice were fed a nutritionally adequate, semipurified diet containing CO or krill oil (KO) or FO at 10% level (w/w) ad libitum until the mice were 6.5 months old. All diets contained the same level of vitamin E (21.5 mg/100 g diet). We compared the effects of feeding D-6 and n-3 lipids on survival, kidney disease, hepatic microsomal lipid composition, peroxidation, and on the activity and mRNA expression of the antioxidant enzymes catalase, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in 6.5-month-old B/W mice. The results showed that when compared to livers from CO-fed mice, livers from KO- and FO-fed mice showed: (i) significantly higher (P < 0.001) activities and expression of CAT, GSH- Px and SOD; (ii) significantly lower (P < 0.001) arachidonic acid (20:4n-6) and linoleic acid (18:2n-6) and higher (P < 0.001) eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3) levels in hepatic microsomes; and (iii) significantly lower (P < 0.001) estimated peroxidation indices and thiobarbituric acid reactive substances generation. The data indicate that one of the mechanisms through which the n-3 lipids delay the onset of autoimmune diseases in B/W mice may be through maintenance of higher activities and expression of hepatic antioxidant enzymes.

Effect of (n-3) polyunsaturated fatty acids on cytokine production and their biologic function

Nutrition (USA), 1996, 12/1 SUPPL. (S8-S14)

Cytokines are important biologic mediators with tightly regulated production. Overproduction contributes to pathogenesis of acute and chronic inflammatory, autoimmune, atherosclerotic, and neoplastic diseases. Animal and human studies have shown that production of cytokines can be reduced by long-chain (n-3) polyunsaturated fatty acids (PUFA). This, in turn, results in reduction of the severity of certain autoimmune, inflammatory, and atherosclerotic diseases and reduces cytokine-induced anorexia. Because these cytokines are also involved in control of the host defense, substantial reduction in their production could impair normal immune response. In addition, increased intake of (n-3) PUFAs without adequate antioxidant protection could result in increased free radical formation and lipid peroxidation, leading to a reduction in T cell-mediated function, natural killer cell activity, and macrophage cytotoxicity. These risks associated with the intake of (n-3) PUFAs may be minimized without compromising its beneficial effects by the intake of appropriate levels of antioxidants such as vitamin E.

Lipid peroxidase and erythrocyte redox system in systemic vasculitides treated with corticoids. Effect of vitamin E administration

Romanian Journal of Internal Medicine (Romania), 1994, 32/4 (283-289)

The level of plasma lipid peroxidation was followed up in 66 patients with systemic vasculitides with autoimmune pathogeny (SLE and SV) treated with corticoid compounds. The effect of vitamin E associated to this treatment was also studied. The change of the redox cycle, of the red cell glutathione, and of the glutathionperoxidase activity, an enzyme supplying antioxidant protection, were studied in parallel. The results obtained demonstrated: an increased level of lipid peroxidation in the patients treated with corticoid substances, an increase that can be explained by the dyslipidemias induced by these compounds; a decrease of the red cell G-SH concentration owing to the continuous oxidative stress in this group of diseases. This decrease was associated with a concomitant increase of oxidated glutathion. The decrease of GSH, a substrate for glutathionperoxidase, induces an inhibition of this enzyme activity. The GSH/GSSH ratio may represent a useful marker of the evolution of disease. Administration of vitamin E in association with corticotherapy has a relatively reduced effect due to the complex metabolic disturbances with a continuous character in the autoimmune pathogenic processes. The chronic disturbance of the oxidants-antioxidants balance in patients with systemic vasculitides seems to create favourable conditions for the early onset of a process of atherogenesis with severe vascular effects

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.

Smoking, plasma antioxidants and essential fatty acids before and after nutratherapy

Canadian Journal of Cardiology (Canada), 1996, 12/7 (665-670)

OBJECTIVE: To study the effect of smoking on plasma antioxidants with and without antioxidant vitamin nutratherapy. DESIGN: Chronic smokers (n = 10, 16plus or minus4 cigarettes a day) and nonsmokers (n = 17) of both sexes were recruited from patients with arthritis-like symptoms. After baseline studies of plasma antioxidant vitamins Q (ubiquinone) and E (alpha-tocopherol) and essential fatty acids (EFA, vitamin F), three months' nutratherapy with vitamins Q (90 mg) and E (350 mg) was administered and plasma reanalyzed. RESULTS: No sex differences were seen in smoking habits or plasma nutrients. Smokers had normal Q (0.71plus or minus 0.07 mg/L) but depressed E (9.4plus or minus0.6 mg/L, P < 0.01). EFA were the same in both groups. Nutratherapy increased Q by about 90% in both groups and E by 47% in smokers and 101% in nonsmokers (P < 0.01). In nonsmokers, nutratherapy protected omega-3 fatty acids (vitamin F1)-plasma docosahexaenoic acid increased by 39%. The vitamin F index (omega-6:omega-3 ratio) remained unchanged in the smokers but decreased in the nonsmokers and became related to the individual plasma vitamin Q but not to vitamin E. CONCLUSIONS: There was no difference between smokers and nonsmokers before nutratherapy. Nonsmokers may have suffered from passive smoking. After nutratherapy the quantitatively most important antioxidant, ie, vitamin E, increased more in nonsmokers than in smokers. This resulted in less vitamin F1 peroxidation. Nutratherapy cannot overcome disadvantages associated with smoking. Nonsmokers might achieve an antioxidant protection with nutratherapy, which could mean a possible reduced risk of developing cardiovascular disease.

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 active oxygen species in tissue injury in rheumatoid arthritis. Methods: We examined 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.

[Effect of vitamin E deficiency on the development of cardiac arrhythmias as affected by acute ischemia]

Biull Eksp Biol Med (USSR) Nov 1986, 102 (11) p530-2

Malonic dialdehyde content was increased by 53% in the myocardium of male Wistar rats (250-300 g) devoid of vitamin E for 2 months, as compared to the control rats (animals receiving an optimal amount of vitamin E). Transitory ischemia (10 min) with subsequent reoxygenation (5 min) was induced during open heart surgery under urethan anesthesia. Ischemia was induced by the occlusion of the descending branch of the left coronary artery. In ischemic rats with vitamin E deficiency the incidence of ventricular fibrillation, tachycardia, extrasystoles and the additive duration of arrhythmias were significantly increased as compared to the control.

Antioxidant protection against adrenaline-induced arrhythmias in rats with chronic heart hypertrophy.

Can J Cardiol (CANADA) Mar 1990, 6 (2) p71-4

Effects of vitamin E on adrenaline-induced arrhythmias were examined in rats with chronic heart hypertrophy subsequent to narrowing of the abdominal aorta. After 60 weeks of pressure overload, the rats showed an increase of about 21% in heart/body weight ratio and a small but significant rise in left ventricular end diastolic pressure (LVEDP) (sham control 1.7 > 0.67 mmHg; hypertrophy 7.1 ± 2.7 mmHg) without any change in left ventricular peak systolic pressure (LVSP). Intravenous infusion of adrenaline caused rhythm disorders in a dose-dependent manner and pathological arrhythmias (occurrence of six premature ventricular complexes/min) were observed at doses of 2.9 ± 0.6 and 3.8 ± 1.0 micrograms/kg of the drug in control and hypertrophy animals, respectively. Administration of two doses of vitamin E (50 mg/kg intraperitoneally), given 24 h and 1 h before adrenaline infusion, significantly increased the amount of adrenaline required to produce pathological arrhythmias (control 8.0 +/- 3.0; hypertrophy 7.7 ± 2.0 micrograms/kg). Vitamin E pretreatment did not have any detrimental effect on the pressure readings nor did it have any influence on adrenaline-induced pressure changes. The data suggest that a combination therapy with vitamin E may allow therapeutic use of higher concentrations of adrenaline required to improve function in failing hearts with a reduced risk of arrhythmias

Effects of dietary supplementation with alpha-tocopherol on myocardial infarct size and ventricular arrhythmias in a dog model of ischemia-reperfusion

J. AM. COLL. CARDIOL. (USA), 1994, 24/6 (1580-1585)

Objectives. We investigated whether dietary supplementation with the antioxidant vitamin alpha-tocopherol (500 mg daily) might reduce lethal ventricular arrhythmias and infarct size. Background. Previous studies suggested that dietary supplementation with alpha-tocopherol may be associated with a reduced risk of ischemic heart disease. However, the mechanism of this protection remains unknown. Methods. Beagle dogs were randomized to either a supplemented or a control group. Because of the low mortality rate in the supplemented group, five dogs were added to the control group. After 2 months, dogs were anesthetized and underwent a 2-h coronary artery occlusion and 6-h reperfusion. Plasma vitamin E, retinol and malondialdehyde concentrations were assessed in all dogs. Results. Fourteen dogs (11 of 25 control vs. 3 of 19 supplemented dogs, p < 0.05) developed ventricular fibrillation during either ischemia or reperfusion. Malondialdehyde concentrations were higher in dogs that subsequently developed arrhythmias (2.7 plus or minus 0.2 micromol/liter, mean plus or minus SEM) compared with dogs that did not (2.1 plus or minus 0.2 micromol/liter, p = 0.03). Among survivors with significant ischemia, infarct size was larger in supplemented (n = 12, 58.5 plus or minus 3.3% of area at risk) than in control (n = 11, 41.9 plus or minus 6.5%, p < 0.04) dogs. In addition, for a given collateral flow, supplemented dogs (n = 16) developed larger infarct size than control dogs (n = 15, p < 0.001, analysis of covariance). Conclusions. The data suggest that dietary alpha-tocopherol supplementation prevented lethal ventricular arrhythmias associated with ischemia and reperfusion. However, its influence on infarct size and long-term prognosis warrants further investigation.

Diminished production of malondialdehyde after carotid artery surgery as a result of vitamin administration

Medical Science Research (United Kingdom), 1996, 24/11 (777-780)

The objective of this study was to establish the antioxidative effect of the vitamins E, C and retinyl palmitate (vitamin A), contained in a multivitamin solution, in carotid artery revascularisation surgery. 57 patients, 67.84 plus or minus 5.72 years of age, 39 men and 18 women, were divided into a control group (27 subjects) and a group with 30 subjects (mean age 68.46 plus or minus 5.09 years) who received the vitamin treatment immediately before the start of reperfusion of the brain. The control group (mean age 67.14 plus or minus 6.37 years) received physiological sodium chloride as placebo. All of the patients suffered from ischaemic cerebrovascular insufficiency manifested as TIA (transitory ischaemic attack) due to haemodynamically significant stenosis of the extracranial part of the ICA (internal carotid artery). Oxidative burst was measured by malondialdehyde (MDA) - thiobarbituric acid reactive substances (TBARS) perioperatively before and 0.5, 1, 2 and 3 h after revascularisation. In the control group MDA-TBARS significantly increased from 0.91 plus or minus 0.49 to 1.15 plus or minus 0.41 nmol mL-1 (p < 0.003) 1 h after reperfusion onset and returned to baseline after 2-3 h. In the vitamin-treated group MDA-TBARS steadily decreased during the reperfusion period (1.11 plus or minus 0.39, 0.91 plus or minus 0.42, 0.81 plus or minus 0.29, 0.78 plus or minus 0.39, 0.72 plus or minus 0.24 nmol mL-1). The significant difference in MDA-TBARS between control and treatment groups, 1 h after the start at reperfusion was 1.15 plus or minus 0.41 vs 0.81 plus or minus 0.29 nmol mL-1; (p < 0.001). As an indirect parameter of reperfusion injury 13% (4/30 patients) of the patients in thetreatment group suffered... The perioperative use of antihypertensive drugs was 20% (6/30) in the treatment group, as compared to 78% (21/27) in the control group. These results suggests that vitamin treatment prior to reperfusion might be of beneficial effect, alleviating lipid peroxidation and leading to a better clinical course as regards the central nervous system.

[The efficacy of using alpha-tocopherol during ftorotan anesthesia]

Eksp Klin Farmakol (RUSSIA) Jul-Aug 1996, 59 (4) p3-4

Halothane monoanesthesia in hypoxia leads to activation of lipolysis with increase in the content of NEFA and POL products. The administration of alpha-tocopherol in a dose of 50 mg/liter in such cases was conductive to a statistically significant decrease in the content of peroxidation products in the blood.

Effect of antioxidants on postoperative hyperamylasemia in coronary bypass surgery

Pancreas (USA), 1996, 13/3 (236-240)

Antioxidants may reduce pancreatic cellular injury after coronary artery bypass grafting (CABG). Twenty patients (Group A) received vitamin E (600 mg/day) for 28 days and vitamin C (2 g/day) and allopurinol (600 mg/day) for 2 days before and 1 day after CABG. Seventeen patients (Group C) received all drugs for 3 days, and 25 (Group B) and 19 (Group D) patients served as corresponding controls. The pre- and postoperative pancreatic isoamylase (P- amylase), creatinine, and antioxidant concentrations were measured. Serum hyperamylasemia was highest on the first postoperative day and occurred in 73% of the patients. After surgery serum P-amylase increased in all study groups and urine P-amylase decreased. Postoperative serum hyperamylasemia, whether primarily renal or pancreatic, cannot be decreased by pretreatment with allopurinol, vitamin C, and vitamin E.

Antioxidant drugs block in vitro the neurotoxicity of CSF from atients with amyotrophic lateral sclerosis

NeuroReport (United Kingdom), 1996, 7/12 (1970-1972)

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterized by upper and lower motoneurone degeneration. Excitotoxicity and oxidative stress have been proposed as possible aetiological factors. We measured the neuronal death induced in rat cortical cell cultures by CSF taken from seven ALS patients and seven control subjects with lumbar radiculopathies. Cultures were exposed to CSF for 48 h at a dilution of 1:4. Some cultures were also exposed to antioxidant drugs, the free radical scavenger vitamin E (250 microM) and the xanthine oxidase inhibitor allopurinol (50 microM), alone or combined. The mean neuronal death rate was 31.8 plus or minus 3.4% in cultures exposed to ALS CSF and 10.9 plus or minus 1.8% in cultures exposed to control CSF. The cytotoxicity of ALS CSF was partially blocked by vitamin E (21.6 plus or minus 3%) or by allopurinol (18.6 plus or minus 2.7%). The combination of these two antioxidants reduced the toxicity from 31.8 plus or minus 3.4% to 10.6 plus or minus 1.7%. The present work suggests that neurotoxicity induced by CSF from patients with ALS indirectly involves free radicals. A combination of allopurinol and vitamin E may be useful in ALS therapy.