Life Extension Final Clerance Sale


Table of Contents
image Rationales for micronutrient supplementation in diabetes
image Contraction and relaxation of aortas from diabetic rats: effects of chronic anti-oxidant and aminoguanidine treatments.
image Antioxidant vitamins in hospitalized elderly patients: Analysed dietary intakes and biochemical status
image Antioxidant depletion, lipid peroxidation, and impairment of calcium transport induced by air-blast overpressure in rat lungs
image The use of antioxidants in healing
image Update on the biological characteristics of the antioxidant micronutrients: vitamin C, vitamin E, and the carotenoids.
image Dietary intake and plasma levels of antioxidant vitamins in health and disease: A hospital-based case-control study
image Supplementation with vitamins C and E suppresses leukocyte oxygen free radical production in patients with myocardial infarction
image Antioxidant therapy using high dose vitamin C: Reduction of postburn resuscitation fluid volume requirements
image Effect of antioxidant vitamin supplementation on muscle function after eccentric exercise
image Modification of the daily photoreceptor membrane shedding response in vitro by antioxidants
image Tirilazad mesylate protects vitamins C and E in brain ischemia-reperfusion injury
image Biochemical basis of ozone toxicity
image Decreases in tissue levels of ubiquinol-9 and -10, ascorbate and alpha-tocopherol following spinal cord impact trauma in rats
image An in vitro model to test relative antioxidant potential: Ultraviolet-induced lipid peroxidation in liposomes
image Antioxidants, fat and skin cancer
image Photoprotective effect of superoxide scavenging antioxidants against ultraviolet radiation-induced chronic skin damage in the hairless mouse
image Impairment of enzymic and nonenzymic antioxidants in skin by UVB irradiation
image Diminished production of malondialdehyde after carotid artery surgery as a result of vitamin administration
image Spermine partially normalizes in vivo antioxidant defense potential in certain brain regions in transiently hypoperfused rat brain
image Positron-labeled antioxidant 6-deoxy-6-(18F)fluoro-L-ascorbic acid: Increased uptake in transient global ischemic rat brain
image Maternal infusion of antioxidants (Trolox and ascorbic acid) protects the fetal heart in rabbit fetal hypoxia
image Poor plasma status of carotene and vitamin C is associated with higher mortality from ischemic heart disease and stroke: Basel Prospective Study
image Antioxidant vitamins and disease - Risks of a suboptimal supply
image Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: An epidemiological update with special attention to carotene and vitamin C
image Oxidative protein damage in human diabetic eye: evidnal participation.
image Abnormalities in diabetes or experimental galactosemia. IV. Antioxidant defense system.
image Nutritional antioxidants, red cell membrane fluidity and blood viscosity in type 1 (insulin dependent) diabetes mellitus.
image [Prospective biochemical study of the antioxidant defense capacity in retinopathy of premokemiai vizsgalata retinopathia preamaturorumban.
image [Antioxidants for prophylaxis of eye diseases]
image [Erythrocyte and plasma antioxidant activity in diabetes mellitus type I]
image Oxidative protein damage in human diabetic eye: Evidence of a retinal participation
image Abnormalities of retinal metabolism in diabetes or experimental galactosemia. III. Effects of antioxidants
image Oxidative stress and diabetic vascular complications
image Pharmacological prevention of diabetic microangiopathy
image Erythrocyte and plasma antioxidant activity in type I diabetes mellitus
image Status of antioxidants in patients with diabetes mellitus with and without late complications
image Effectiveness of antioxidants (vitamin C and E) with and without sunscreens as topical photoprotectants.
image Role of oxidant stress in the adult respiratory distress syndrome: evaluation of a novel antioxidant strategy in a porcine model of endotoxin-induced acute lung injury.
image Prevention of dopamine-induced cell death by thiol antioxidants: possible implications for treatment of Parkinson's disease.
image [The dose-dependent effects of a combination of different classes of antioxidants exemplified by dibunol and beta-carotene]
image Oxidative damage and defense.
image The effect of dietary fat, antioxidants, and pro-oxidants on blood lipids, lipoproteins, and atherosclerosis.
image Reliability of a food frequency questionnaire to assess dietary antioxidant intake.
image Dietary antioxidants and Parkinson disease. The Rotterdam Study.
image Association of serum vitamin levels, LDL susceptibility to oxidation, and autoantibodies against MDA-LDL with carotid atherosclerosis. A case-control study. The ARIC Study Investigators. Atherosclerosis Risk in Communities.
image Antioxidant flavonols and ischemic heart disease in a Welsh population of men: the Caerphilly Study.
image [Prevalence and risk factors in the population of Graz (Austrian Stroke Prevention Study)]
image Beta-2-agonists have antioxidant function in vitro. 2. The effect of beta-2-agonists on oxidant-mediated cytotoxicity and on superoxide anion generated by human polymorphonuclear leukocytes.
image Antioxidants in the prevention of atherosclerosis.
image Bronchial reactivity and dietary antioxidants.
image Antioxidant actions of beta-carotene in liposomal and microsomal membranes: role of carotenoid-membrane incorporation and alpha-tocopherol.
image [Alcohol and free radicals: from basic research to clinical prospects]
image Oxidized low-density lipoprotein and atherosclerosis.
image Serum levels of antioxidant vitamins in relation to coronary artery disease: a case control study of Koreans.
image Antioxidants in food and chronic degenerative diseases.
image Randomized trials of dietary antioxidants in cardiovascular disease prevention and treatment.
image Basic research in antioxidant inhibition of steps in atherogenesis.
image Oxidative susceptibility of low-density lipoproteins--influence of regular alcohol use.
image Do hydroxy-carotenoids prevent coronary heart disease? A comparison between Belfast and Toulouse.
image Antioxidants in cardiovascular disease: randomized trials.
image Randomized trial of antioxidants in the primary prevention of Alzheimer disease warranted?
image Lipid peroxidation and antioxidant vitamins C and E in hypertensive patients.
image Update on dietary antioxidants and cancer.
image Antioxidants in health and disease
image Multicenter ophthalmic and nutritional age-related macular degeneration study--part 2: antioxidant intervention and conclusions.
image Multicenter ophthalmic and nutritional age-related macular degeneration study--part 1: design, subjects and procedures.
image Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis?
image The role of oxidized lipoproteins in atherogenesis.
image [Bronchopulmonary dysplasia]
image Oxidative stress as a mechanism of cardiac failure in chronic volume overload in canine model.
image [The significance of oxidized low density lipoprotein in atherosclerosis]
image In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation.
image Antioxidants and age-related eye disease. Current and future perspectives.
image [Free radicals in the central nervous system]
image Protection by multiple antioxidants against lipid peroxidation in rat liver homogenate.
image Inhibition of Ca2+-pump ATPase and the Na+/K+-pump ATPase by iron-generated free radicals. Protection by 6,7-dimethyl-2,4-DI-1-pyrrolidinyl-7H-pyrrolo[2,3-d] pyrimidine sulfate (U-89843D), a potent, novel, antioxidant/free radical scavenger.
image Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women
image Oxidative stress and antioxidant therapy in Parkinson's disease
image In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia.
image Antioxidant mechanism and protection of nigral neurons against MPP+ toxicity by deprenyl (selegiline)
image Parkinson's disease: a chronic, low-grade antioxidant deficiency?
image Free radicals in brain metabolism and pathology.
image Free radicals and their scavengers in Parkinson's disease.
image Role of dietary lipid and antioxidants in bone metabolism
image [Preventive treatment of diabetic microangiopathy: blocking the pathogenic mechanisms]
image COSMETICS -- Marketing
image Measurement of low-molecular-weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis.
image On the causes of multiple sclerosis
image Alpha-tocopherol and hydroperoxide content in breast adipose tissue from patients with breast tumors.
image Interaction of family history of breast cancer and dietary antioxidants with breast cancer risk (New York, United States)
image Extraocular, limb and diaphragm muscle group-specific antioxidant enzyme activity patterns in control and mdx mice.
image Free radicals, lipid peroxides and antioxidants in blood of patients ith myotonic dystrophy.
image Antioxidants and angiogenetic factor associated with age-related macular degeneration (exudative type)
image Studies on the mechanism of early onset macular degeneration in c ynomolgus monkeys. II. Suppression of metallothionein synthesis in the retina in oxidative stress
image Association of zinc and antioxidant nutrients with age-related maculopathy.
image Antioxidant enzymes of the human retina: Effect of age on enzyme activity of macula and periphery
image Antioxidant enzymes in RBCs as a biological index of age related macular degeneration
image Antioxidant defenses in metal-induced liver damage
image Antioxidant status in controlled and uncontrolled hypertension and its relationship to endothelial damage.
image The role of antioxidants in the prevention of cardiovascular diseases
image Essential antioxidants in cardiovascular diseases--lessons for Europe
image Antioxidant vitamin intake and coronary mortality in a longitudinal population study.
image Can anti-oxidants prevent ischaemic heart disease?
image Antioxidant therapy in the aging process.
image Anti-oxidants show an anti-hypertensive effect in diabetic and hypertensive subjects.
image Micronutrient profiles in HIV-1-infected heterosexual adults
image Antioxidant-micronutrients and HIV infection
image Can antioxidants prevent ischemic heart disease?
image Antioxidant therapy in the aging process.
image Acute phase response and plasma carotenoid concentrations in older women: Findings from the nun study.
image Endothelial dysfunction: Clinical implications.
image Use of antioxidant vitamins in the cardiovascular disease. A review of epidemiological study and clinical trials.
image The effect of dietary treatment on lipid peroxidation and antioxidant status in newly diagnosed noninsulin dependent diabetes.
image Smoking, plasma antioxidants and essential fatty acids before and after nutratherapy.
image Reduction of plasma peroxide levels by oral antioxidants.
image Systemic oxidative stress in asthma, COPD, and smokers
image Role of oxidants/antioxidants in smoking-induced lung diseases
image Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus
image Spice constituents scavenging free radicals and inhibiting pentosidine formation in a model system.
image Potential therapeutic approaches to the treatment or prevention of diabetic neuropathy: evidence from experimental studies.
image Prevention of postischemic cardiac injury by the orally active iron chelator 1,2-dimethyl-3-hydroxy-4-pyridone (L1) and the antioxidant (+)-cyanidanol-3
image Iron-load increases the susceptibility of rat hearts to oxygen reperfusion damage. Protection by the antioxidant (+)-cyanidanol-3 and deferoxamine
image Nutritional antioxidants and the modulation of inflammation: theory and practice.
image Antioxidant vitamins in cataract prevention.
image Free radical tissue damage: protective role of antioxidant nutrients.
image Free radical tissue damage: protective role of antioxidant nutrients.
image [Antioxidative vitamins and cataracts in the elderly]
image Prevention of cataracts by nutritional and metabolic antioxidants.
image Free radicals, exercise, and antioxidant supplementation
image Fibronectin fragment mediated cartilage chondrolysis. I. Suppression by anti-oxidants
image Overview of conditioning related life-threatening toxicities of marrow transplantation
image [Cardioprotection in chemo- and radiotherapy for malignant diseases--an echocardiographic pilot study]
image Place of antioxidants in active photoprotection
image Indicators of free radical activity in patients developing radiation pneumonitis
image The effect of antioxidants on bleomycin treatment in in vitro and in vivo genotoxicity assays
image Serum concentrations of alpha tocopherol, beta carotene, and retinol preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus.
image Free radical tissue damages in the anterior segment of the eye in experimental autoimmune uveitis
image Intervention at diagnosis of type I diabetes using either antioxidants or photopheresis
image Free radical theory of aging: Beneficial effect of antioxidants on the life span of male NZB mice: Role of free radical reactions in the deterioration of the immune system with age and in the pathogenesis of systemic lupus erythematosus
image Reduced superoxide dismutase in lung cells of patients with asthma
image Antioxidant protection against adrenaline-induced arrhythmias in rats with chronic heart hypertrophy.
image The effects of antioxidants on reperfusion dysrhythmias
image [Essential antioxidants in cardiovascular diseases--lessons for Europe]
image Muscle ubiquinone and plasma antioxidants in effort angina
image Effect of antioxidants on postoperative hyperamylasemia in coronary bypass surgery
image Antioxidant depletion during aortic aneurysm repair
image Free radical reaction products and antioxidant capacity in arterial plasma during coronary artery bypass grafting
image Evaluation of antioxidants, protein, and lipid oxidation products in blood from sporadic amiotrophic lateral sclerosis patients.
image Antioxidants in peripheral nerve.
image Free Radicals and Neuroprotection
image Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases.
image Experience over 17 years with antioxidant treatment in Spielmeyer-Sjogren disease.
image Antioxidant of the coronary diet and disease
image Enhanced capacity of n-3 fatty acid-enriched macrophages to oxidize low density lipoprotein mechanisms and effects of antioxidant vitamins
image The mechanism of apolipoprotein B-100 thiol depletion during oxidative modification of low-density lipoprotein
image Polyunsaturated fatty acids, antioxidants, and cognitive function in very old men
image Animal studies on antioxidants
image Abnormal antioxidant vitamin and carotenoid status in chronic renal failure
image Antioxidants in cardiovascular disease: Randomized trials
image Dietary antioxidants and cognitive function in a population-based sample of older persons: The Rotterdam study
image Oxidized low density lipoproteins in atherogenesis: Role of dietary modification
image Antioxydant vitamins and risk of cardiovascular diseases
image The significance of oxidised low-density lipoprotein in atherosclerosis
image Prevention of atherosclerosis with dietary antioxidants: Fact or fiction?
image Randomized, controlled trial of antioxidant vitamins and cardioprotective diet on hyperlipidemia, oxidative stress, and development of experimental atherosclerosis: The diet and antioxidant trial on atherosclerosis (DATA)
image Optimal diet for reducing the risk of arteriosclerosis
image Prevention of atherosclerosis: The potential role of antioxidants
image Advanced glycation endproducts in ageing and Alzheimer's disease
image Molecular basis of Alzheimer's disease.
image New therapeutic approaches to Alzheimer's disease.
image A pilot study of blood antioxidant and free radical marker profiles in patients awaiting coronary artery bypass grafting
image Oxygen free radical-induced histamine release during intestinal ischemia and reperfusion
image Antioxidant drugs block in vitro the neurotoxicity of CSF from atients with amyotrophic lateral sclerosis
image The role of antioxidant agents on experimental ulcerative colitis
image Rutoside as mucosal protective in acetic acid-induced rat colitis
image Inhibitory effect of a traditional Chinese medicine, Juzen-taiho-to, on progressive growth of weakly malignant clone cells derived from murine fibrosarcoma.


[Cardioprotection in chemo- and radiotherapy for malignant diseases--an echocardiographic pilot study]

Schweiz Rundsch Med Prax. 1995 Oct 24. 84(43). P 1220-3

AIM: Pilot study, examining the cardioprotective effect of an antioxidant regimen in patients with malignancies receiving high dose chemo- or radiotherapy. PATIENTS AND METHODS: 14 patients with chemotherapy and 10 patients with radiotherapy were randomized in a double-blind fashion (placebo versus vitamin E and C and N-acetylcysteine). Systolic and diastolic echocardiographic parameters were determined before and within three weeks of treatment completion. RESULTS: Left ventricular ejection fraction fell significantly in patients receiving placebo (radiotherapy: 67 +/- 6 to 56 +/- 2%, p = 0.008, chemotherapy: 67 +/- 7 to 60 +/- 8%, p = 0.05). Patients on antioxidants showed no significant fall in EF (radiotherapy: 63 +/- 8 to 61 +/- 7%, chemotherapy: 67 +/- 5 to 64 +/- 6%). CONCLUSION: The small number of patients in the study precludes a definitive statement. The preliminary results, however, suggest efficient cardioprotection by this cheap and safe antioxidant combination, so that larger studies are warranted for confirmation.

Place of antioxidants in active photoprotection

Nouvelles Dermatologiques (France), 1996, 15/5 (335-337)

Reactive oxygen species produced in the skin by ultraviolet radiations participate in acute and chronic cutaneous solar damages. Endogen antioxidant systems exist in skin cells and allow free radicals elimination. However, when irradiations are important, these defense mechanisms can't any longer face radical attacks. Molecules such as selenium permit an optimum glutathion peroxidase activity. Pre-treatment with agents such as heat or ultraviolet radiations induces new antioxidant proteins synthesis. So, objectives of active photoprotection are to optimise pre-existent antioxidant defenses and to induce new defense mechanisms to protect cutaneous cells. Few studies have evaluated the effects of antioxidant molecules in human photoprotection. Promising experimental data still remain to demonstrate in double-blind controlled studies.

Indicators of free radical activity in patients developing radiation pneumonitis

International Journal of Radiation Oncology Biology Physics (USA), 1996, 34/1 (149-154)

Purpose: Radiation pneumonitis is thought to occur as the result of excess free radical generation following radiotherapy. Various in vitro studies have shown that large doses of irradiation can cause membrane lipid peroxidation and the oxidation of protein sulphuryl groups. We, therefore, studied two circulating markers of lipid peroxidation and an indicator of 'catalytic iron' (potentially available iron to catalyze the generation of free radicals) in patients undergoing radiotherapy. Methods and Materials: The 9,11 diene conjugate of 9,12 linoleic acid, expressed as their molar ratio (percentage molar ratio (MR)) and thiobarbituric acid reactive acid- substances (TBARS), as well as levels of circulating desferrioxamine- chelatable iron assay, were assayed. Serial blood samples were taken over a 3-month period in 25 patients with inoperable nonsmall cell lung cancer. Results: Ten patients developed radiation pneumonitis. The patients who developed pneumonitis showed a tendency for the serum percentage molar ratio to increase after a week. The change in the percentage molar ratio between Time 0 and 1 week of radiotherapy was significantly higher in the group that subsequently developed pneumonitis compared to the group that did not (p = 0.002). The initial serum TBARS levels in patients were not significantly elevated compared to controls and there was no difference in the serum TBARS levels in the pneumonitis and nonpneumonitis groups throughout the study period. After 1 week of radiotherapy the group that subsequently developed pneumonitis had a significantly higher level of desferrioxamine-chelatable iron (DFx-iron) compared with the nonpneumonitis group (p = 0.05). Conclusion: These data suggest that both the percentage MR and DFx-iron appear to reflect an increased susceptibility to develop radiation pneumonitis and after 1 week of radiotherapy they indicate patients who are likely to subsequently develop pneumonitis. Hence, these indicators could indicate the group of patients that could benefit from intervention therapies with antioxidants.

The effect of antioxidants on bleomycin treatment in in vitro and in vivo genotoxicity assays

Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis (Netherlands), 1995, 329/1 (37-47)

Antioxidants are thought to be important in protecting against damage from active oxygen species. The effects of the antioxidant nutrients vitamins C and E have been investigated after bleomycin treatment in the Salmonella typhimurium bacterial mutation assay, in the human peripheral lymphocyte chromosome aberration assay, and in the mouse micronucleus assay in peripheral blood and bone marrow cells. There were no protective effects from vitamins C and E in the bacterial mutation assay, but vitamin C and not vitamin E abolished chromosome damaging responses in human peripheral lymphocytes, and both vitamins reduced responses in micronuclei from peripheral blood cells in mice. This would suggest that in human cells in vitro and mouse cells in vivo these vitamins could have a protective role.

Serum concentrations of alpha tocopherol, beta carotene, and retinol preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus.

Ann Rheum Dis (ENGLAND) May 1997, 56 (5) p323-5

OBJECTIVES: Because oxidative damage has been implicated in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus, this study was designed to see if serum concentrations of alpha tocopherol, beta carotene, and retinol, substances believed to be involved in the prevention or repair of oxidative damage, might be lower among persons who develop rheumatoid arthritis or systemic lupus erythematosus than among those who do not. METHODS: For this prospective case-control study, persons with rheumatoid arthritis and systemic lupus erythematosus that developed two to 15 years after donating blood for a serum bank in 1974 were designated as cases. For each case, four controls were selected from the serum bank donors, matched for race, sex, and age. Stored serum samples from cases and controls were assayed for alpha tocopherol, beta carotene, and retinol. RESULTS: Cases of both diseases had lower serum concentrations of alpha tocopherol, beta carotene, and retinol in 1974 than their matched controls. For rheumatoid arthritis, the difference for beta carotene (-29%) was statistically significant. CONCLUSIONS: These findings support those of a previous study that low antioxidant status is a risk factor for rheumatoid arthritis. They suggest a similar association for systemic lupus erythematosus.

Free radical tissue damages in the anterior segment of the eye in experimental autoimmune uveitis

Investigative Ophthalmology and Visual Science (USA), 1996, 37/4

Purpose. To investigate increased free radical activity and the accumulation and localization of lipid peroxidation in the anterior segment of the eye with uveitis. Methods. Experimental autoimmune uveitis (EAU) was induced in rats using human S-antigen peptide. Conjugated dienes (CD) and keto-dienes (KD) were then extracted from the cornea, iris-ciliary body and lens of the EAU eyes. The quantity of CD and KD were determined by measuring ultraviolet absorption and estimating by means of a molar extinction coefficient. Frozen sections of EAU eyes were reacted with 3-hydroxy-2- naphthoic acid hydrazide (NAH), and NAH-carbonyl compounds were detected using a confocal laser scanning microscope. Statistical comparisons of CD and KD products between the EAU groups and controls were performed using the Student's t-test. Results. Compared to controls, CD and KD were significantly increased in the cornea and iris-ciliary body of EAU eyes. Lenses of EAU eyes showed a tendency to elevated levels of CD and KD. In EAU, primarily the anterior border layer and the posterior epithelium of the iris-and, to a lesser extent, the trabecular meshwork and corneal endothelium-revealed positive fluorescence staining for peroxidized carbonyl products. No staining was observed on the ciliary epithelium. Conclusions. Free radicals and lipid peroxidation products are generated in the anterior segment of the eye in EAU. Because the individual tissues in the anterior segment are composed of various levels of fatty acids and different concentrations of antioxidants, the extent of tissue damage from lipid peroxidation may represent a balance between the fatty acid composition and the antioxidant distribution in each of the tissues.

Intervention at diagnosis of type I diabetes using either antioxidants or photopheresis

DIABETES METAB. REV. (United Kingdom), 1993, 9/4 (329-336)

Two main hypotheses support the contention that type I diabetes is an autoimmune disease, namely 'the cytokine hypothesis' and 'the T-lymphocyte hypothesis'. Various strategies can be used at diagnosis with a view to stopping beta-cell destruction or at least attenuating the process. This review discusses the use of antioxidants based on the idea that free oxygen radicals are important mediators. Experimental animal models have indicated that several antioxidants may prevent diabetes, although in humans only nicotinamide has been shown to have some effect on preventing the disease in high-risk individuals and to produce a slight effect on residual insulin secretion in newly diagnosed patients. Bearing in mind these considerations, we tried a cocktail of several antioxidants at high dosage. As the code of this randomized double-blind study is not broken, results cannot be given, but preliminary observations indicates that there has been no dramatic increase of complete remission. Based on the hypothesis that type I diabetes is a T-lymphocyte-mediated disease, lymphocyte photopheresis may be useful. Photopheresis, comprising the treatment of lymphocytes by a combination of the light-activated drug methoxypsoralen and UVA irradiation, has been shown to be effective in the treatment of some other autoimmune disease. One hypothesis regarding its efficacy holds that the method causes changes in the antigenicity of the treated lymphocyte clones which cause a vaccination-like effect when these cell lines are retransfused at repeated intervals into the patient. Nothing to date is known about its effect in diabetes, although a double-blind randomized placebo-controlled study has been commenced.

Free radical theory of aging: Beneficial effect of antioxidants on the life span of male NZB mice: Role of free radical reactions in the deterioration of the immune system with age and in the pathogenesis of systemic lupus erythematosus

AGE (USA), 1980, 3/3 (64-73)

Autoimmune manifestations increase with age. Tolerance to self-antigens appears to be actively maintained mainly by T-suppressor cells derived from radiosensitive precursors. Since endogenous free radical reactions seem to increase with age the associated increase in autoimmunity could be due, at least in part, to a disproportionate decrease in suppressor cell function, as compared to the other cells of the immune system. This possibility was evaluated using New Zealand Black (NZB) mice; this strain loses T-cell suppressor function early in life and develops autoimmune manifestations which mimic those seen in old mice of normal strains. Addition of 0.25%w (percent by weight) alpha-tocopherol acetate, 0.25%w Santoquin (a quinoline derivative), or 1.0%w NaHsub 2POsub 2 to the diet of NZB male mice, starting shortly after weaning, increased the average life span by 7.1, 32.1 and 1.2 percent, respectively, by comparison with the control life span of 16.8 months. These data support the above-suggested explanation for the rise in autoimmunity with age. The NZB mouse serves as a model for systemic lupus erythematosus (SLE). The present study led to the suggestion that the basic defect in SLE is an abnormality(s) which enhances the tendency for nuclear antigens to be formed from nuclear components by a free radical pathway. The nuclear antigens in turn give rise to immune complex disease. Thus the beneficial effect of antioxidants in the present study can be attributed to a decrease in the rate of: 1) formation of nuclear antigens, 2) free radical damage initiated by aggregating neutrophils, and 3) free radical reaction-induced loss of T-suppressor cell function with age owing to a reduction in damage from both 'normal' endogenous free radicals and those of neutrophil origin.

Reduced superoxide dismutase in lung cells of patients with asthma

Free Radical Biology and Medicine (USA), 1997, 22/7 (1301-1307)

Lung cells recovered from symptomatic patients with asthma generate increased amounts of reactive oxygen species (ROS). Animal and in vitro studies indicate that ROS can reproduce many of the features of asthma. The ability of ROS to produce the clinical features of asthma may depend on an individual's lung antioxidant defenses. Patients with asthma are reported to have reduced antioxidant defenses in peripheral blood, but little is known about the antioxidant defenses of their lung cells. To define lung cell antioxidant defenses in asthma, the glutathione concentration and the glutathione reductase, glutathione peroxidase, catalase, and superoxide dismutase (SOD) activities were measured in cells recovered by bronchoalveolar lavage (BAL cells) and by bronchial brushing (bronchial epithelial cells, HBEC) from normal subjects and patients with asthma. Superoxide dismutase activity was reduced 25% in BAL cells (p < .05) and nearly 50% in HBEC (p < .02) from patients with asthma. Alterations in the other antioxidants were not identified. A direct relationship was found between airway reactivity to methacholine, measured as PC20FEV1, and HBEC SOD activity (r2 = 89; p < .005), but not between airway reactivity and the other antioxidants. The finding of reduced SOD activity in lung cells of patients with asthma suggests that diminished SOD activity serves as a marker of the inflammation characterizing asthma. Alternatively, it may play a role in the development or severity of the disease.

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

The effects of antioxidants on reperfusion dysrhythmias

Ceska a Slovenska Farmacie (Czech Republic), 1995, 44/5 (257-260)

The present study aims to investigate the effects of the lipophilic antioxidant Trolox C (a vitamin E analogue) and stobadine, a scavenger of free oxygen radicals, on reperfusion dysrhythmias. Experiments were performed on isolated perfused rat hearts subjected to global stop-flow ischaemia followed by reperfusion. Trolox C (10-4 mol.l-1) and stobadine (10-5 mol.l-1) were infused immediately prior to ischaemia. Trolox C (10-4 mol.l-1) and stobadine (10-5 mol.l-1) decreased the incidence and duration of reperfusion-induced dysrhythmias (quantified by the dysrhythmia score) in comparison to the ischaemic-reperfusion damaged hearts. There was an improvement in the recovery of contraction force and left ventricular diastolic pressure in Trolox or stobadine pretreated hearts. No significant changes in coronary flow resistance were observed. The results suggest that both substances protect the myocardium during ischaemic-reperfusion injury probably by affecting the generation and activity of reactive oxygen species.

[Essential antioxidants in cardiovascular diseases--lessons for Europe]

Ther Umsch (SWITZERLAND) Jul 1994

Complementary epidemiological studies consistently reveal a substantially increased risk of cardiovascular disease (CVD) at suboptimal plasma levels of essential antioxidants in comparison with optimum ranges of vitamin C (> 50 mumol/l), of lipid-standardized vitamin E (> 30 mumol/l or a tocopherol/cholesterol ratio > 5.2 mumol/mmol), beta-carotene (> 0.4 mumol/l). The poor level of any single essential antioxidant can increase the risk, and the combination of suboptimal levels has additive or even overmultiplicative effects on the risk for CVD. Suboptimal antioxidant levels are stronger predictors of the severalfold regional differences of CVD in Europe than classical risk factor such as hypercholesterolemia, hypertension, etc. Scotsmen and Fins tend to suboptimal levels of essential antioxidants, whereas German-speaking regions may mostly reveal a fair vitamin E status, but at least one out of four subjects can reveal suboptimal levels of vitamin C and carotene, particularly in smokers. This deficit can be avoided by 'prudent diets' rich in fruits and vegetables as practiced by Frenchmen, Italians and Spaniards. The simultaneous correction of all suboptimal antioxidant levels appears to be a promising new means for CVD prevention, particularly in the northern parts of Europe. In the USA the risk of CVD could substantially be reduced without dietary modifications by voluntary daily supplements as follows: vitamin C > 140 mg, vitamin E > 100 IU (100 mg d,l- or 74 mg d-alpha-tocopherylacetate), and in current smokers by gamma-carotene > 8.6 mg. Hence, these antioxidants may be crucial constituents of diets rich in fruits and vegetables, which are by consensus associated with a lower risk of premature death from CVD (and cancer as well).

Muscle ubiquinone and plasma antioxidants in effort angina

Journal of Nutritional and Environmental Medicine (United Kingdom), 1996, 6/3 (255-266)

Twelve male patients with effort angina had needle muscle biopsies taken from their vastus lateralis the day before coronary bypass and during surgery from gastrocnemius muscles for fibre typing and muscle ubiquinone (vitamin Q) determinations. They also had blood samples saved for analyses of ubiquinone (UQ, blood and plasma), alpha-tocopherol (AT, vitamin E, plasma) and free cholesterol (FC, plasma). FC marks for the lipophilic compound deposition volume and is used to calculate standardized UQ and AT (SUQ and SAT). Vastus lateralis muscle had a decreased percentage distribution of slow twitch muscle fibres (39 plus or minus 4 (SEM) %ST) for the age group but a normal proportion of the fast twitch (FT) 'intermediate oxidative' subgroup FTa (35 plus or minus 5%FTa). Muscle UQ was normal, whereas SUQ and SAT were reduced in relation to healthy individuals. Muscle UQ, SUQ and SAT normalized for oxidative muscle fibre types decreased the higher the muscle oxidative fibre proportion. It was concluded that the antioxidative potential in plasma and muscle was interrelated. This reflects an increased reactive radical species formation related to oxygen metabolism and turnover and a subsequent toll on antioxidant capacity.

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 depletion during aortic aneurysm repair

British Journal of Surgery (United Kingdom), 1996, 83/3 (401-403)

Ischaemia-reperfusion injury generates oxygen-derived free radicals leading to local and distant damage. A simple method of following oxidative activity is to measure the consumption of endogenous scavenging antioxidants; an enhanced chemiluminescent assay was used to study this phenomenon in 21 patients undergoing surgery for abdominal aortic aneurysm (AAA). Samples of peripheral venous blood were taken before induction of anaesthesia and then from a central venous line and the inferior mesenteric vein before, during, and after clamping of the aorta. Further specimens were taken from the central line at 2, 6 and 24 h after operation. Antioxidant concentration in the peripheral, central and inferior mesenteric blood were similar, indicating that anaesthesia and surgical dissection had no effect. Levels decreased significantly in central and inferior mesenteric blood during and after clamping, but returned to normal by 24 h. These results confirm ischaemia-reperfusion phenomena in AAA repair.

Free radical reaction products and antioxidant capacity in arterial plasma during coronary artery bypass grafting

J. THORAC. CARDIOVASC. SURG. (USA) 1994, 108/1 (140-147)

Oxygen free radicals mediate the ischemia-reperfusion damage in animal hearts, but their role in human beings is still controversial because of the low xanthine oxidase level in the human heart. Besides ischemia-reperfusion, cardiac operation also includes other major interventions that might generate free radicals but have not been systematically studied. We studied the cases of nine patients throughout coronary artery operations, including general anesthesia, heparin, protamine and administration of cardioplegic solution, extracorporeal circulation, and heart reperfusion. Arterial plasma was assayed for malondialdehyde, diene conjugates, and fluorescent chromolipids, and plasma antioxidant activity was estimated from the ability to trap peroxyl radicals. Anesthesia, surgical procedures, or heparin administration did not change these parameters. Extracorporeal circulation decreased the plasma concentration of diene conjugates immediately, whereas other compounds remained unaltered. When these concentrations were corrected for hemodilution, the amount of fluorescent chromolipids actually increased after 5 minutes of extracorporeal circulation to 177% plus or minus 14% (mean plus or minus standard error of the mean), diene conjugates increased to 138% plus or minus 12%, and plasma antioxidant capacity increased to 144% plus or minus 12% of the awake value. Fluorescent chromolipid values remained at 156% to 177% throughout the perfusion and decreased to 130% plus or minus 13% 1 hour after perfusion. Diene conjugate levels and antioxidant capacity were 123% to 144% and 143% to 161%, respectively, from baseline during perfusion and 119% plus or minus 5% and 135% plus or minus 9%, respectively, 1 hour after perfusion. Heart reperfusion or protamine administration showed no additional increases. Malondialdehyde concentrations varied and showed no statistically significant alterations. We conclude that extracorporeal circulation devices induce generation of free radicals and plasma antioxidant activity, which are different from the damage caused by ischemia-reperfusion.

Evaluation of antioxidants, protein, and lipid oxidation products in blood from sporadic amiotrophic lateral sclerosis patients.

Neurochem Res (UNITED STATES) Apr 1997, 22 (4) p535-9

Several parameters indicators of oxidative stress were evaluated in blood from individuals with the sporadic form of amiotrophic lateral sclerosis (SALS) and compared to healthy controls. Plasma levels of 2-thiobarbituric-reactive substances (TBARS), products of lipid peroxidation, were significantly higher (p < 0.03) in the SALS patients compared to controls. The concentration of plasma antioxidants (alpha-tocopherol, beta-carotene, ubiquinol-10 and glutathione) and the activity of red blood cell CuZn superoxide dismutase were not significantly different between the groups. The ratio TBARS/alpha-tocopherol was 47% higher in the SALS individuals than in controls. Protein thiols and protein-associated carbonyls in red blood cell membranes and supernates were similar for both groups. A positive correlation (r2 = 0.91) was found between the concentration of protein-associated carbonyls in red blood cells and the onset of clinical symptoms. These findings are in agreement with several reports showing higher levels of oxidative damage to cell components in ALS.

Antioxidants in peripheral nerve.

Free Radic Biol Med (UNITED STATES) 1996, 20 (7) p925-32

Oxidative stress and antioxidants have been related in a wide variety of ways with nervous tissue. This review attempts to gather the most relevant information related to a) the antioxidant status in non pathologic nervous tissue; b) the hypothesis and evidence for oxidative stress (considered as the disequilibrium between prooxidants and antioxidants in the cell) as the responsible mechanism of diverse neurological diseases; and c) the correlation between antioxidant alterations and neural function, in different experimental neuropathies. Decreased antioxidant availability has been observed in different neurological disorders in the central nervous system, for example, Parkinson's disease, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, cerebral ischaemia, etc. Moreover, the experimental manipulation of the antioxidant defense has led in some cases to interesting experimental models in which electrophysiological alterations are associated with the metabolic modifications induced. In view of the electrophysiological and biochemical effects of some protein kinase C inhibitors on different neural experimental models, special attention is dedicated to the role of this kinase in peripheral nervous tissue. The nervous tissue, central as well as peripheral, has two main special features that are certainly related to its antioxidant metabolism: the lipid-enriched membrane and myelin sheaths, and cellular excitability. The former explains the importance of the glutathione (GSH)-conjugating activity towards 4-hydroxy-nonenal, a biologically active product of lipid peroxidation, present in nervous tissue and in charge of its inactivation. The impairment of the latter by oxidative damage or experimental manipulation of antioxidant metabolism is discussed. Work on different experimental neuropathies from author's laboratory has been primarily used to provide information about the involvement of free radical damage and antioxidants in peripheral nerve metabolic and functional impairment.

Free Radicals and Neuroprotection

By B, J. Wilder, M. D., Professor Emeritus of Neurology University of Florida College of Medicine and Consultant in Neurology Department of Veterans Affairs Medical Center

A free radical is a molecule, atom or molecular fragment which contains an unpaid electron in its outer orbital shell (R ). Each atomic nucleus is surrounded by one or more orbitals containing a maximum of 2 electrons All compounds contain 2 electrons in each of its orbitals which spin in opposite directions. The covalent bonds of organic compounds share two electrons spinning in opposite directions one supplied by each atom or molecule pan in the bond. Any molecule can become a free radical by gaining or losing an electron in the outer shell. O2 + e Organic compounds also form free radicals

RH2 -e- - RH. O2

Organic molecules are held together by covalent bonds. Normally, when covalent bonds split one fragment becomes a positively charged ion by losing an electron and the other becomes a negatively charged ion by holding both of the shared pair of electrons (heterolytic splitting). Free radicals are formed from organic compounds when a covalent bond is split symmetrically and each retains an unpaired electron in its outer shell (homolytic splitting). Homolytic splitting produces free radicals which result in lipid peroxidation.

Free radicals are also formed as a product of normal cellular chemical reactions. Oxidative metabolism is a major contributor of free radicals. As O2 is reduced to water, over SO% is univalently reduced with the production of the superoxide radical O2.

O2 is combined spontaneously or dismutated with H+ to produce H2O2 which readily breaks down in the presence of the metals Fe++ &Cu+ or O2 to form OH. radicals which are highly injurious to adjacent structures: lipid membranes, proteins, DNA and precellular matrix 2 O2. + 2 H+

H202 + Fez+

O2 + H2O2

-SOD-> H2O2 + O2

- OH + OH + Fe3+

-, 0H + OH- + O2

(SOD = Superoxide dismutase)

The autoxidation of transition metals can produce superoxide radicals:

O2 + Fe++ > Fe+++ + O2

O2 + Cu+ > Cu++ + O2

Free radical formation and cellular damage is greatly accelerated in situations of oxidative stress such as tissue injury, viral and bacterial infections and also accompanies phagocytosis autoimmune disorders and degenerative diseases by yet unknown mechanisms. Some neoplasms may occur as a result of oxidative or free radical damage. Free radical damage is also accelerated by various deficiency states and inborn errors or genetic defects of metabolism

Defects in antioxidant or free radical scavenge systems result in oxidative stress and cellular damage. Parkinson's Alzheimer's and Huntington's disease, multiple sclerosis, progressive myoclonic epilepsy, familial ALS, post-traumatic epilepsy, ant arteriosclerosis, arc diseases which are now thought to be at least partly due to oxidative stress and free radical damage.

All living cells have developed mechanisms for protection against oxidative stress.Mammalian cells have very specific and elaborate antioxidant mechanisms which prevent free radical damage. Superoxide dismutase (SOD), a ubiquitous superoxide scavenging enzyme. is present in both intra- and extracellular fluid (ECF) compartments. Copper and Zinc SOD's are present in ECF and cytosol and manganese SOD is present in mitochondria. These SOD's dismutate 0~ and H+ to H~O~. H.O. is a potential cellular toxin because of its reactivity with 0 and transition metals, however, in the normal situation it is readily converted to 0. and H.0 by catalase (CAT) and glutathione peroxidase (GPX). CAT is present in mitochondna and cyrosolic peroxisomes of most tissues, however, it is found in very low concentrations in brain. GPX is the major antioxidant enzyme in the brain, being present in mitochondria and in the cytosol. GPX requires selenium as a necessary cofactor and is decreased in selenium deficient states. Glutathione transferase (GST) conjugates glutathione (GSH) to reactive organic compounds which become pharmacologically inactive. GPX requires reduced GSH which is oxidized (GSSH) during the conversion of H2O2 to 0. and H,O. GSSH is reconverted to reduced GSH by glutathione reductase which requires vitamin B, (riboflavin) as a cofactor.

Vitamin E is an important membrane antioxidant which prevents membrane peroxidation by scavenging OH'. Oxidized vitamin E is reconverted to active E by vitamin C which is another important antioxidant free radical scavenger. Beta carotene is an antioxidant which works most effectively in low oxygen tensions and is an important retinal antioxidant.

From the above, one can appreciate that the balance between cellular oxidation and free radical production is most important in maintaining homeostasis and preventing cellular damage and death. Elaborate systems have developed to accomplish this. However, a number of disease processes and defects in antioxidant mechanisms can lead tO both progression and initiation of tissue injury and cell death.

We (B.J Wilder. M. D. and Russell Hurd. M.S.) over a number of years have been working on drug injury and tissue protection with a number of antioxidants. Concurrent with our work and that of others, techniques for measuring free radical scavenging enzymes assays ( FRESA) have been developed.

In 1992 we measured FRESA levels in patients with progressive myoclonic epilepsy and familial progressive cerebellar degeneration and found abnormalities in SOD. GPX, GSH and lipid peroxidation (LP). We initiated treatment with selenium. antioxidant vitamins and N-acetylcysteine, a potent free radical and H,O. scavenger and supplier of GSH. After observing favorable clinical effects we have expanded our studies to include other progressive degenerative neurological diseases. We have been joined by other interested investigators, Drs. Basim Uthman Wendell Helveston and Jean Cebula..

We are now studying the effects of N-Acetylcysteine and antioxidant vitamins and trace metals in patients with: Friedreich's ataxia, spinocerebellar ataxia, ataxia telangiectasia, olivopontocerebellar degeneration. amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, and others.

We will soon initiate studies in other degenerative diseases and in the prevention of post traumatic epilepsy and' in the amelioration of post ischemic brain injury.

Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases.

Adv Pharmacol (UNITED STATES) 1997, 38 p601-28

The main pathway for the hepatic oxidation of ethanol to acetaldehyde proceeds via ADH and is associated with the reduction of NAD to NADH; the latter produces a striking redox change with various associated metabolic disorders. NADH also inhibits xanthine dehydrogenase activity, resulting in a shift of purine oxidation to xanthine oxidase, thereby promoting the generation of oxygen-free radical species. NADH also supports microsomal oxidations, including that of ethanol, in part via transhydrogenation to NADPH. In addition to the classic alcohol dehydrogenase pathway, ethanol can also be reduced by an accessory but inducible microsomal ethanoloxidizing system. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans, and is accompanied by increased oxidation of NADPH with resulting H2O2 generation. There is also a concomitant 4- to 10-fold induction of cytochrome P4502E1 (2E1) both in rats and in humans, with hepatic perivenular preponderance. This 2E1 induction contributes to the well-known lipid peroxidation associated with alcoholic liver injury, as demonstrated by increased rates of superoxide radical production and lipid peroxidation correlating with the amount of 2E1 in liver microsomal preparations and the inhibition of lipid peroxidation in liver microsomes by antibodies against 2E1 in control and ethanol-fed rats. Indeed, 2E1 is rather "leaky" and its operation results in a significant release of free radicals. In addition, induction of this microsomal system results in enhanced acetaldehyde production, which in turn impairs defense systems against oxidative stress. For instance, it decreases GSH by various mechanisms, including binding to cysteine or by provoking its leakage out of the mitochondria and of the cell. Hepatic GSH depletion after chronic alcohol consumption was shown both in experimental animals and in humans. Alcohol-induced increased GSH turnover was demonstrated indirectly by a rise in alpha-amino-n-butyric acid in rats and baboons and in volunteers given alcohol. The ultimate precursor of cysteine (one of the three amino acids of GSH) is methionine. Methionine, however, must be first activated to S-adenosylmethionine by an enzyme which is depressed by alcoholic liver disease. This block can be bypassed by SAMe administration which restores hepatic SAMe levels and attenuates parameters of ethanol-induced liver injury significantly such as the increase in circulating transaminases, mitochondrial lesions, and leakage of mitochondrial enzymes (e.g., glutamic dehydrogenase) into the bloodstream. SAMe also contributes to the methylation of phosphatidylethanolamine to phosphatidylcholine. The methyltransferase involved is strikingly depressed by alcohol consumption, but this can be corrected, and hepatic phosphatidylcholine levels restored, by the administration of a mixture of polyunsaturated phospholipids (polyenylphosphatidylcholine). In addition, PPC provided total protection against alcohol-induced septal fibrosis and cirrhosis in the baboon and it abolished an associated twofold rise in hepatic F2-isoprostanes, a product of lipid peroxidation. A similar effect was observed in rats given CCl4. Thus, PPC prevented CCl4- and alcohol-induced lipid peroxidation in rats and baboons, respectively, while it attenuated the associated liver injury. Similar studies are ongoing in humans. (188 Refs.)

Experience over 17 years with antioxidant treatment in Spielmeyer-Sjogren disease.

Am J Med Genet Suppl (UNITED STATES) 1988, 5 p265-74

During the last 17 yr, 74 patients with Spielmeyer-Sjogren disease were treated in Finland with antioxidant supplementation. Twenty-seven patients received a combination of vitamin E, vitamin C, methionine and BHT. As the disease began to progress, the treatment was changed to a combination of sodium selenite and vitamin E in 14 of the 27 patients. The same combination was also given to 47 children (During the last 5-6 yr, vitamins B2 and B6 were also added.) who had not received previous antioxidant supplementation. The latter combination (called the Westermarck formula) appeared to be helpful to some patients. Statistical correlations between various neurological items and relevant laboratory data were sought. In the older patients a significant correlation was found between neurological dysfunction and ceruloplasmin, and also between epilepsy and ceruloplasmin, while a negative correlation was noticed between neurological dysfunction and glutathione peroxidase. In the younger patients, a negative correlation was observed between superoxide dismutase and epilepsy. Serum apolipoprotein B levels were below the normal range in the 6 patients investigated. So far the Westermarck formula seems to have been the best treatment devised yet in Spielmeyer-Sjogren disease, but further studies are needed for a better understanding of the pathogenesis of neuronal ceroid-lipofuscinoses disorders.

Antioxidant of the coronary diet and disease

Clinica Cardiovascular (Spain), 1996, 14/2 (29-38)

High levels of cholesterol and Low Density Lipoproteins (LDL) in plasma are related to high risk to develop Coronary Heart Disease (CHD). LDL-chosterol is a primary ingredient of the atherosclerotic plaque; its accumulation in the subendothelial space is due to peroxidative reactions. Natural antioxidants such as carotenes, polyphenolic flavonoids, vitamin E and C show defensive properties against lipid peroxidation, hence it is possible to apply these molecules in clinical therapy in the prevention of the CHD. On the other hand, alcohol, and special red wine, as well as the intake of selenium can afford a cardioprotective effect. Blood cholesterol reduction, dietary and/or due to pharmacological interventions, could modulate lipid peroxidation through a decreased production of O2.-, pivotal step in the peroxidative chain of reactions. The importance of other dietary components (fresh fruits, nuts, garlic and other vegetables as well as olive oil) have been analyzed to assess its influence and protective action in the prevention of CHD.

Enhanced capacity of n-3 fatty acid-enriched macrophages to oxidize low density lipoprotein mechanisms and effects of antioxidant vitamins

Atherosclerosis (Ireland), 1996, 124/2 (157-169)

We have investigated possible mechanisms by which n-3 fatty acid-enriched macrophages enhance the oxidation of low density lipoprotein (LDL), and the ability of antioxidant vitamins to prevent this. Macrophages were enriched with n-3 fatty acids (eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid) following incubation with fish oil. These macrophages produced large amount of TEARS in medium containing metals, and showed enhanced capacity to oxidize LDL (3-4 fold increase compared to control cells) and to accumulate the modified LDL. 5,8,11,14-eicosatetraynoic acid (ETYA, 15-lipoxygenase inhibitor) and superoxide dismutase (SOD) did not inhibit the enhanced capacity of n-3 fatty acid-enriched cells to oxidize LDL. However antioxidants, (vitamin E-enriched macrophages or vitamin C in the medium), inhibited this enhanced capacity. Medium conditioned by n-3 fatty acid-enriched cells had pro-oxidant effects on metal-initiated LDL oxidation. We conclude that n-3 fatty acid-enriched macrophages display increased oxidant capacity which is not inhibited by ETYA or SOD, and that antioxidant vitamins inhibit the enhanced capacity to oxidize LDL.

The mechanism of apolipoprotein B-100 thiol depletion during oxidative modification of low-density lipoprotein

Archives of Biochemistry and Biophysics (USA), 1997, 341/2 (287-294)

Oxidation of low-density lipoprotein (LDL) is recognized to be a key step in atherogenesis. Previous studies show that LDL contains low-molecular- weight antioxidants such as vitamin E, beta-carotene, and ubiquinol, which can retard oxidative modification. In this report, we have evaluated the antioxidant potential of apolipoprotein B-100 (apo-B) thiols during LDL oxidation. Bath apo-B thiols and vitamin E were depleted concomitantly during the lag phase of Cu2+ -mediated LDL oxidation. The rate of thiol depletion was significantly inhibited by the lipophilic spin trap N-tert-butyl-alpha- phenylnitrone (PBN) but not by the water-soluble spin trap alpha-(4-pyridyl-1- oxide)-N-tert-butylnitrone (POBN). Blocking apo-Bthiols with sulfhydryl modifying agents increased the oxidizability of LDL. As with Cu2+, peroxynitrite also caused depletion of apoB thiols, and again thiol depletion was inhibited by PBN but not by POBN. A PBN/lipid-derived radical adduct was observed by the electron spin resonance technique during oxidation of LDL with peroxynitrite. We conclude that apo-B thiol depletion is mediated by lipid peroxidation, prior to the onset of the propagation phase of LDL oxidation. The implications of apoB thiols as intrinsic antioxidants of LDL are discussed.

Polyunsaturated fatty acids, antioxidants, and cognitive function in very old men

American Journal of Epidemiology (USA), 1997, 145/1 (33-41)

Atherosclerosis and thrombosis may lead to cognitive impairment through cerebral infarcts or white matter hyperintensities. Oxidative stress is now seen as a major contributor to the process of atherogenesis. High intake of polyunsaturated fatty acids, e.g., linoleic acid, or low intake of antioxidants can increase oxidative stress. High intake of n-3 polyunsaturated fatty acids and its main source, fish, may reduce the risk of thrombosis. Little is known, however, about the relation between these dietary factors and cognitive function. The authors investigated this relation with data derived from a cohort of men, aged 69-89 years, who were participants in the Zutphen Elderly Study. The 30-point Mini-Mental State Examination was used to assess cognitive impairment in 1990 (score less than or equal to25 in 153/476 men, 32%) and cognitive decline from 1990 to 1993 (drop >2 points in 51/342 men, 15%). Food intake was estimated in 1985 and 1990 by the cross- check dietary history method. High linoleic acid intake was associated with cognitive impairment after adjustment for age, education, cigarette smoking, alcohol consumption, and energy intake (odds ratio (OR) for highest vs. lowest tertile = 1.76, 95% confidence interval (CI) 1.04-3.01). Intake of n- 3 polyunsaturated fatty acids was not associated with cognitive impairment, whereas high fish consumption tended to be inversely associated with cognitive impairment (OR = 0.63, 95% CI 0.33-1.21) and cognitive decline (OR = 0.45, 95% CI 0.17-1.16). Intakes of beta-carotene, vitamins C and E, and flavonoids were not inversely associated with cognitive impairment or decline. This study raises the possibility that high linoleic acid intake is positively associated with cognitive impairment and high fish consumption inversely associated with cognitive impairment.

Animal studies on antioxidants

Journal of Cardiovascular Risk (United Kingdom), 1996, 3/4 (358-362)

The wealth of existing epidemiologic evidence suggests that antioxidant intake limits the clinical expression of coronary artery disease. Because the oxidative modification of low-density lipoprotein is an important event in atherogenesis, it has been attractive to speculate that antioxidants act by limiting low-density lipoprotein orientation and, as a consequence, atherosclerotic lesion development. Early studies on animals also suggested that a number of structurally distinct antioxidant compounds could limit the extent of lesion development in animal models of atherosclerosis. More recently, however, secure evidence linking the antioxidant protection of low-density lipoprotein with a reduction in atherosclerosis has been elusive. This discrepancy may be explained by emerging evidence demonstrating that antioxidants may prove beneficial through tissue-specific effects that are not strictly related to the antioxidant protection of low-density lipoprotein.

Abnormal antioxidant vitamin and carotenoid status in chronic renal failure

QJM - Monthly Journal of the Association of Physicians (United Kingdom), 1996, 89/10 (765-769)

Oxidative modification of plasma lipoproteins increases their atherogenicity. Nutritive antioxidants, including carotenoids, can prevent such lipoperoxidation and may protect against atherosclerosis. Plasma retinol, ascorbate, alpha-tocopherol and four carotenoids (lutein, lycopene, alpha-carotene and beta-carotene) were measured using HPLC in 45 patients with chronic renal failure (CRF) and in 21 controls. Plasma retinol was significantly increased in patients with CRF (conservative therapy mean of 3.7micromol/l vs. 1.9micromol/l; p < 0.001). Plasma lycopene was significantly lower in patients with CRF (healthy mean 0.44 micromol/l vs. conservative therapy mean 0.27 micromol/l and haemodialysis mean of 0.17 micromol/l; p < 0.001), a finding that persisted even after adjusting for plasma cholesterol. Low circulating antioxidant lycopene levels may contribute to an already impaired antioxidant defence system in patients with CRF. The process of haemodialysis further compromises antioxidant defences, principally by removing water-soluble ascorbate and urate, but does not appear to affect circulating carotenoid concentrations.

Antioxidants in cardiovascular disease: Randomized trials

Nutrition (USA), 1996, 12/9 (583-588)

The hypothesis that antioxidant vitamins might reduce cardiovascular disease risk is based on a large body of both basic and human epidemiologic research. One of the most consistent findings in dietary research is that those who consume higher amounts of fruits and vegetables have lower rates of heart disease and stroke as well as cancer. Recent attention has focused on the antioxidant content of fruits and vegetables as a possible explanation for the apparent protective effects. Basic research provides a plausible mechanism by which antioxidants might reduce the risk of atherosclerosis. A large number of descriptive, case-control and cohort studies provide data suggesting that consumption of antioxidant vitamins is associated with reduced risks of cardiovascular disease. These data raise the question of a possible role of antioxidants, such as vitamins C and E, and beta carotene, in the primary prevention of cardiovascular disease but do not provide a definitive answer. Results from several large-scale randomized trials of antioxidant supplements are now available; however, results are not entirely consistent. The results of the major trials do not prove or disprove the value of antioxidant vitamins, nor do they incriminate them as harmful. They do, however, raise the possibility that some of the benefits from observational epidemiology may have been overestimated and that there may be some adverse effects. At this point randomized trial data are not yet sufficient to fully assess the risk-to-benefit ratios for antioxidant supplements. More reliable data should be forthcoming in the near future which will better define the role of antioxidants in the primary and secondary prevention of atherosclerotic disease as well as cancer.

Dietary antioxidants and cognitive function in a population-based sample of older persons: The Rotterdam study

American Journal of Epidemiology (USA), 1996, 144/3 (275-280)

Antioxidants have been implicated in processes related to atherosclerosis, aging, and selective neuronal damage, all of which may ultimately affect cognitive function. In a sample of older persons, the authors examined the cross-sectional relation between cognitive function and dietary intake of beta-carotene and vitamins C and E. The data were derived from 5,182 community participants aged 55-95 years in the population-based Rotterdam Study in the period 1990 to 1993. Dietary intake was estimated from a semi-quantitative food frequency questionnaire and categorized into five levels of intake. Cognitive function was measured with the 30-point Mini- Mental State Examination (MMSE) and characterized as unimpaired (>25 points) or impaired (less than or equal to25 points). Logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for cognitive impairment. After adjustment for age, education, sex, smoking, total caloric intake, and intake of other antioxidants, a lower intake of beta-carotene was associated with impaired cognitive function (<0.9 mg vs. less than or equal to2.1 mg intake, OR = 1.9, 95% CI 1.2-3.1; p for trend < 0.04). There was no association between cognitive function and intake of vitamins C and E. These cross-sectional observations are compatible with the view that beta-carotene-rich foods may protect against cognitive impairment in older people. The finding could also reflect unmeasured confounding, measurement error, or a change in food habits that resulted from rather than preceded the onset of cognitive impairment.

Oxidized low density lipoproteins in atherogenesis: Role of dietary modification

Annual Review of Nutrition (USA), 1996, 16/- (51-71)

The development of atherosclerosis is a complex and multistep process. There are many determinants in the pathogenesis of this condition, with different factors presumably playing key roles at different times in the evolution of the atherosclerotic plaque. It has been suggested that oxidation of low density lipoproteins (LDL) by cells in the artery wall leads to a proatherogenic particle that may help initiate early lesion formation. For this reason, understanding the determinants of LDL susceptibility to oxidation is essential for developing therapeutic strategies to inhibit this process. Oxidation of LDL begins with the abstraction of hydrogen from polyunsaturated fatty acids; thus, LDL fatty acid composition undoubtedly contributes to the process of LDL oxidation. Since dietary fatty acids influence the fatty acid composition of LDL and cell membranes, the amount and type of fat in the diet may effect susceptibility of LDL and cells to oxidative damage. Additionally, since cell membrane fatty acid composition also influences cellular formation of reactive oxygen species, dietary fatty acids may help determine the prooxidant activity of artery wall cells. Both cells and lipoproteins contain a variety of antioxidants that provide protection against oxidative stress. A major source of these antioxidants is the diet. Enrichment of the diet with foods high in such antioxidants as vitamin E, beta-carotene, or vitamin C, or supplementation of the diet with antioxidant vitamins, may inhibit oxidation and the process of atherosclerosis.

Antioxydant vitamins and risk of cardiovascular diseases

In recent years, an increasing number of basic and clinical research reports have pointed out the role of reactive metabolites of oxygen, the free radicals, in the processes of atherogenesis and also the protective and/or preventive effects of antioxidant molecules such as beta-carotene, vitamin C, vitamin E, selenium and zinc. Epidemiological data obtained by cross-sectional, case-control and prospective studies also provide strong supportive arguments in favour of the relationship between intake of antioxidant vitamins (or biological status in antioxidant vitamins) and cardiovascular risk. However, the epidemiological nature of the studies does not enable confirmation of a causal role. Cause-effect relationships would require controlled intervention trials of antioxidant vitamins versus placebo to assess potential effects on cardiovascular morbidity and mortality.

The significance of oxidised low-density lipoprotein in atherosclerosis

Ugeskrift for Laeger (Denmark), 1996, 158/19 (2706-2710)

The 'oxidation hypothesis' states that oxidised low-density lipoprotein (ox-LDL) plays a central role in atherogenesis. LDL oxidation is a chaotic process initiated by reactive oxygen species. Enhanced uptake of in macrophages leads to foam cell formation in vitro, and ox-LDL has a variety of other experimental proatherogenic effects, e.g., endothelial cell activation, immunogenicity, platelet aggregation, and inhibition of endothelium-dependent vasorelaxation. There are methodological limitations in the current laboratory methods aimed at characterization of the oxidative state of LDL. However, considerable evidence indicates ths, and atheromatous plaques of humans, although the significance of this phenomenon is unknown. Antioxidants may inhibit atherosclerosis in experimental animals, and epidemiological data suggest an inverse relation between the intake of antioxidant vitamins and the risk of coronary artery disease. Randomised prospective trials are in progress, and until their conclusion, the clinical effect of antioxidant therapy in man remains unknown.

Prevention of atherosclerosis with dietary antioxidants: Fact or fiction?

Journal of Nutrition (USA), 1996, 126/4 SUPPL. (1067S-1071S)

The notion that oxidation of lipids and lipoproteins may contribute to the pathogenesis of atherosclerosis is supported by a large body of evidence. It is hypothesized that dietary antioxidants may help prevent development and progression of atherosclerosis. The available evidence helps substantiate this hypothesis but is not yet conclusive. The results of several ongoing large randomized intervention trials will provide valuable information about the efficacy and safety of supplemental dietary antioxidants in prevention of atherosclerosis.

Randomized, controlled trial of antioxidant vitamins and cardioprotective diet on hyperlipidemia, oxidative stress, and development of experimental atherosclerosis: The diet and antioxidant trial on atherosclerosis (DATA)

Cardiovascular Drugs and Therapy (USA), 1995, 9/6

The effects of administration of guava and papaya fruit (100 g/day), vegetables, and mustard oil (5 g/day) (group A); antioxidant vitamins C (50 mg/day) and E (30 mg/day) plus betacarotene (10 mg/day) (group B); a high-fat (5-10 g/day) (group C); or a low-fat (4-5 g/day) diet (group D) were compared over 24 diet weeks in a randomized fashion, while all groups of rabbits (five in each of four groups) received a hydrogenated fat diet (5-10 g/day) for a period of 36 weeks. After 12 weeks on the high fat diet, each group of rabbits had an increase in blood lipoproteins. The fruit and vegetable-enriched prudent diet (group A) caused a significant decline in blood lipids at 24 and 36 weeks, whereas the lipid levels increased significantly in groups C and D. Group A also had a significant rise in vitamin E (2.1 Umol/l), C (10.5 Umol/l), A (0.66 Umol/l), and carotene (0.08 Umol/l) and a decrease in lipid peroxides (0.34 nmol/ml at 36 weeks, whereas the levels were unchanged in groups C and D. Group B rabbits had a significant and greater increase than group A in plasma vitamins E, C, A, and carotene; a rise in HDL cholesterol; and a greater decrease in lipid peroxides after 24 and 36 weeks of treatment. After stimulation of lipid peroxidation in all rabbits, 3 of 5 group C and 2 of 5 group D rabbits died due to coronary thrombosis, whereas in groups A and B there were no deaths, indicating that antioxidant therapy can provide protection against lipid peroxidation and free radical generation. Aortic lipids and sudanophilia, indicating atherosclerosis, were significantly higher in groups C and D than in groups A and B. Fatty streaks and atheromatous and fibrous plaques were noted in all the rabbits in groups C and D. Intimal fibrosis and medial degeneration were also present in the group C rabbits. While group A (36.4 plus or minus 4.4 microm) and group B (37.1 plus or minus 4.2 microm) rabbits had minimal coronary artery plaque sizes, group C (75.4 plus or minus 10.6 microm) and group D rabbits (69.5 plus or minus 6.2 microm) had significantly greater plaque sizes. Aortic plaque sizes were also greater in groups C and D than in groups A and B. It is possible that combined therapy with antioxidant vitamins C, E, and carotene, and a diet rich in antioxidants, could independently inhibit free radical generation and the development of atherosclerosis.

Optimal diet for reducing the risk of arteriosclerosis

Canadian Journal of Cardiology (Canada), 1995, 11/SUPPL. G

The primary objectives of current dietary advice for those at risk from coronary artery disease (CAD) focus on progressive restriction of dietary saturated (and trans) fatty acids and cholesterol intake, combined with exercise-and achievement of ideal body weight. These principles are endorsed by the official bodies of most western nations concerned with reducing CAD mortality and have recently been reaffirmed by the Adult Treatment Panel of the National Cholesterol Education Program. There has been concern, however, in view of the increasing use of drug therapy, that additional strategies should supplement the primary goals to increase the palatability and effectiveness of the diet. These additional strategies include increased intake of foods high in soluble viscous fibres, vegetable proteins, possibly antioxidants such as vitamin E and the isoflavonoids, increased intake of alpha-linolenic acid and, for those with low high density lipoprotein cholesterol levels, increased monounsaturated fat intake. These strategies translate into advice to significantly increase consumption of specific plant foods such as green leafy vegetables, nuts and seeds, and dried legumes, all of which improve the overall nutritional quality of the diet and contain specific active ingredients. These changes represent a regression to a more primitive diet on the evolutionary scale.

Prevention of atherosclerosis: The potential role of antioxidants

Postgraduate Medicine (USA), 1995, 98/1

Evidence is increasing that oxidation of low-density lipoprotein cholesterol may be instrumental in atherogenesis. As a result a number of studies have been undertaken to evaluate the effects of antioxidant vitamins, beta carotene, selenium, and monounsaturated fat on coronary artery disease. Results in many instances have been promising, particularly in the case of vitamin E supplements. Studies of pro-oxidants, such as iron and copper, are inconclusive at this time, and a trial to assess the value of probucol in hypercholesterolemic patients is currently under way.

Advanced glycation endproducts in ageing and Alzheimer's disease

Munch G.; Thome J.; Foley P.; Schinzel R.; Riederer P.


Brain Research Reviews (Netherlands), 1997, 23/1-2 (134-143)

Accumulation of advanced glycation endproducts (AGE) in the brain is a feature of ageing and degeneration, especially in Alzheimer's disease (AD). Increased AGE levels explain many of the neuropathological and biochemical features of AD such as extensive protein crosslinking (beta-amyloid and MAP-tau), oxidation stress and neuronal cell death. Oxidative stress and AGEs initiate a positive feedback loop, where normal age-related changes develop into a pathophysiological cascade. Combined intervention using antioxidants, metal chelators, anti-inflammatory drugs and AGE-inhibitors may be a promising neuroprotective strategy.

Molecular basis of Alzheimer's disease.

Am J Health Syst Pharm (UNITED STATES) Jul 1 1996, 53 (13) p1545-57; quiz 1603-4

Information on the molecular biology of Alzheimer's disease (AD) pointing to new methods of diagnosis and drug therapies is explored. AD is the most common cause of dementia in the elderly and is characterized by senile plaques and neurofibrillary tangles in the brain and loss of cholinergic neurons in the basal forebrain. The disease has a strong genetic component. A definitive diagnosis can be made only by neuropathologic examination at autopsy or biopsy; however, the accuracy of diagnosis based on standard neuropsychological testing and inclusion criteria has improved considerably. Senile plaques consist of a central core of amyloid fibrils surrounded by dystrophic axons. The main component of senile plaque amyloid is a 39-to 42-amino-acid segment referred to as beta-amyloid, which is derived from amyloid precursor protein (APP). APP exists as multiple isoforms encoded by a single gene on chromosome 21. Factors that may influence APP metabolism include activation of phospholipase C, phosphorylation, and the cholinergic system. The microtubule-associated protein tau may contribute to the neurofibrillary tangles of AD. In AD all six adult isoforms of tau can become maximally phosphorylated and can, rather than binding to microtubules, bind to each other, destabilizing the neuronal cytoskeleton. One of the most important discoveries in AD research was the linking of apolipoprotein E phenotype to familial late-onset AD. Acetylcholinesterase inhibitors appear to improve cognitive function but may be limited in utility by adverse effects. Nicotinic agonists are also being investigated as symptomatic therapies. Other possible strategies include nerve growth factor, agents that potentiate the action of endogenous glutamate, antioxidants, nonsteroidal anti-inflammatory drugs, and estrogens. Research into the molecular biology of Alzheimer's disease has begun to point to possible causes of and treatments for this condition.

New therapeutic approaches to Alzheimer's disease.

J Clin Psychiatry (UNITED STATES) 1996, 57 Suppl 14 p30-6

Therapeutic approaches to treat the cognitive impairment in dementia and to treat slow decline are making their way into clinical practice. Cholinergic agents are currently the most promising treatment, and several cholinesterase inhibitors will soon be available for prescription. As physicians learn more about dosing, side effects, and mechanisms of action, they can prescribe these drugs more efficiently. Evidence suggests that certain patients with dementia may be particularly responsive to such intervention, and other medications may enhance response. Current experimental approaches to slowing the rate of cognitive decline include the use of antioxidants, monoamine oxidase-B inhibitors, cholinesterase inhibitors, and anti-inflammatory agents. Psychosocial interventions appear to help delay institutionalization. Drugs that improve cognition also may affect behavioral symptoms and severe dementia as well as non-Alzheimer dementia. (51 Refs.)

A pilot study of blood antioxidant and free radical marker profiles in patients awaiting coronary artery bypass grafting

Clinica Chimica Acta (Netherlands), 1996, 252/2 (181-195)

Coronary artery bypass grafting (CABG) carries a high risk of acute pancreatitis. We report a pilot study to investigate whether pre-existing oxidative stress might underlie this susceptibility, in that a burst of free radical activity not only accompanies the reperfusion stage of CABG but seems to be a pivotal step in the pathogenesis of pancreatitis. Samples of peripheral venous blood were obtained on the morning of surgery from 8 consecutive patients (age, median and range, 62, 35-70 years) with > 75% stenosis in at least three coronary vessels and a further 8 (64, 49-70 years) who had received 1200 mg allopurinol in divided doses in the previous 48 h: the results were compared with profiles of 8 healthy controls (56, 50-60 years) with normal exercise ECG. None of the patients or controls currently smoked cigarettes and the majority drank alcohol on a social basis. Compared with controls, untreated patients had lower levels of glutathione (P < 0.001) and ascorbate (P < 0.05) in plasma, alpha-tocopherol (vitamin E as molar ratio of cholesterol, P < 0.025) and beta-carotene (P < 0.05) in serum. There was no difference in serum selenium levels, but values in patients and controls were lower than in younger controls from this area (P < 0.02). Samples from the patients contained higher concentrations of lipid peroxides than normal samples (P < 0.025) but there was no evidence of excessive isomerisation of linoleic acid or oxidation of ascorbate and erythrocytes showed normal ATP and energy charge with no increase in membrane lipid peroxidisability. Treatment with allopurinol did not alter this pattern, such that the ratio of oxidised to total glutathione in plasma was higher among the 16 patients than 8 controls (P < 0.025). Habitually inadequate intakes are the best explanation for the patients' deficits in aqueous phase antioxidants; prescribed low cholesterol diets would exacerbate any prior insufficiency of lipid-phase antioxidants. Correction of these deficits during the months leading up to surgery should reduce the risk of CABG-induced acute pancreatitis.

Oxygen free radical-induced histamine release during intestinal ischemia and reperfusion

EUR. SURG. RES. (Switzerland), 1989, 21/6 (297-304)

Acute mesenteric ischemia is highly lethal and therefore a serious problem for surgery and intensive care medicine; accordingly its pathophysiology warrants further study. Oxygen free radicals (OFR) play a role in the intestinal mucosal damage that develops during reperfusion after ischemia. Histamine (H) is generally released in various types of tissue ischemia. The link between H release and OFR has only been studied in in vitro systems. We tested the hypothesis that OFR may be involved in H release following reperfusion of the ischemic gut. The artery supplying a segment of the ileum was occluded for 1 or 2 h in anesthetized dogs. On reperfusion, a release of H into the venous effluent of the segment was demonstrated. Pretreatment of the animals with allopurinol (an inhibitor of xanthine oxidase), or with MTDQ-DA (6,6'-methylene-bis(2,2-dimethyl-4-metha nesulfonic acid sodium-1, 2-dihydroquinoline)), a superoxide anion scavenger, or with a combination of allopurinol and MTDQ-DA resulted in an inhibition of H release. We conclude that OFR may play a role in the local H release following intestinal ischemia.

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.

The role of antioxidant agents on experimental ulcerative colitis

Cetiner S.; Gorgulu S.; Kaymakcioglu N.; Sen D.

Genel Cerrahi Anabilim Dali, GATA, 06018 Etlik, Ankara Turkey

Bulletin of Gulhane Military Medical Academy (Turkey) , 1994, 36/4 (452-457)

One of mediators which have been implicated as the cause of tissue injury in ulcerative colitis is the free oxygen radicals. In this study, it is investigated to induce experimental ulcerative colitis in this group. Vitamin E was administered IP at the same time with, before, before and after Mitomycin C in groups 3, 4 and 5 respectively. In group 2 than group 1, it was observed significantly meaningful histopathological alterations in colonic mucosa and meaningful decrease superoxide dismutase (SOD) levels in plasma (p < 0.01). While meaningful histopathological alterations in colonic mucosa were observed in groups 3 and 5 than group 1 (p < 0.05), but it is not as severe as group 2 and there was not meaningful difference SOD levels in plasma (p < 0.05). In group 4, histopathological alterations in colonic mucosa which were not as severe as group 2, but more severe than groups 3 and 5 and meaningful decrease SOD levels in plasma were observed (p > 0.05). As a result, free oxygen radicals are effective in the pathogenesis of experimental ulcerative colitis. Vitamin E, an antioxidant agent, appears to be a good choice in the treatment of the experimental ulcerative colitis.

Rutoside as mucosal protective in acetic acid-induced rat colitis

Galvez J.; Cruz T.; Crespo E.; Ocete M.A.; Lorente M.D.; Sanchez de Medina E.; Zarzuelo A.

J. Galvez, Department of Pharmacology, School of Pharmacy, University of Granada, Poligono de Cartuja s/n, E-18071, Granada Spain

Planta Medica (Germany) , 1997, 63/5 (409-414)

The effect of the flavonoid rutoside on acetic acidinduced rat colitis was studied. Rats were pretreated orally with different doses of the flavonoid (10, 25, and 100 mg/kg) 48, 24, and 1 hour prior to colitis induction and examined for colonic damage 24 hours later. Colonic inflammation was characterized by gross and microscopical injury, bowel wall thickening, abolition of fluid absorption, glutathione depletion, enhanced leukotriene B4 synthesis, and increased levels of myeloperoxidase and alkaline phosphatase activities. Rutoside treatment (25 and 100 mg/kg) reduced histologic injury and prevented the increase in alkaline phosphatase activity, but it had no effect on myeloperoxidase levels or leukotriene B4 synthesis. In addition, glutathione depletion was effectively counteracted at the dose of 25 mg/kg, whereas fluid absorption was achieved at the highest dose assayed. It is concluded that rutoside has an acute antiinflammatory activity in this model which may be related to a putative direct protective effect on intestinal cells, mainly enterocytes, in which the antioxidative properties of the flavonoid may play a role.

Inhibitory effect of a traditional Chinese medicine, Juzen-taiho-to, on progressive growth of weakly malignant clone cells derived from murine fibrosarcoma.

Ohnishi Y; Fujii H; Kimura F; Mishima T; Murata J; Tazawa K; Fujimaki M; Okada F; Hosokawa M; Saiki I

Department of Pathogenic Biochemistry, Research Institute for Wakan-Yaku, Toyama, Japan.

Jpn J Cancer Res (JAPAN) Oct 1996, 87 (10) p1039-44

We have investigated the inhibitory effect of oral administration of Juzen-taiho-to, a Kampo (Chinese herbal) medicine, on progressive growth of a mouse fibrosarcoma. Spontaneously regressive QR-32 tumor cells were able to grow progressively in vivo when coimplanted s.c. with a foreign body, gelatin sponge, whereas QR-32 cells alone gradually grew for over 15 days after inoculation and thereafter regressed for up to 25 days. Oral administration of Juzen-taiho-to (40 mg/day/mouse) for 7 days after inoculation of QR-32 cells with gelatin sponge resulted in significant inhibition of tumor growth and prolongation of the survival of the tumor-bearing mice. This growth-inhibitory effect of Juzen-taiho-to observed on day 25 was dose-dependent over the dose range from 4 to 40 mg/day. Treatment with Juzen-taiho-to for 7 days before tumor inoculation with gelatin sponge also significantly suppressed tumor growth examined on day 25, as did the administration of bismuth subnitrate, which is well known to induce metallothionein, an antioxidant. On the other hand, inoculation of progressed tumor cells (QRsP) resulted in growth without gelatin sponge, leading to death in syngeneic mice. Administration of Juzen-taiho-to for 7 days after inoculation of QRsP cells resulted in a decrease of the tumor growth and prolongation of the survival of mice, but the effect was less than that on the growth of QR-32 regressor tumor after coimplantation with gelatin sponge. These results suggest that the inhibitory effect of Juzen-taiho-to is partly associated with prevention of gelatin sponge-elicited progressive growth, probably mediated by endogenous factors including antioxidant substances, in addition to the augmentation of host-mediated antitumor activity.