Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00568 (ascorbate)
 23,072 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of two different combined treatments with vitamin E acetate and vitamin C on infarct size and recovery of regional myocardial function was investigated in ischemic, reperfused porcine hearts. The left anterior descending coronary artery was distally ligated in 30 thoracotomized pigs for 45 minutes followed by 3 days of reperfusion. Infarct size was determined as the ratio of infarcted (tetrazolium stain) to ischemic (dye technique) myocardium. Regional myocardial function was assessed by sonomicrometry. Ten pigs received vitamin E acetate (12 gm intravenously three times for 1 week) before ischemic and vitamin C (4.4 gm intravenously) before reperfusion (therapy A). Another 10 pigs were treated with vitamin E acetate (12 gm intraarterially) and vitamin C (4.4 gm intravenously) during ischemia (therapy B). An additional 10 pigs served as a control group. Global hemodynamics did not differ significantly among the groups before and during ischemia. Mean plasma concentrations of vitamin E amounted to 107 micrograms/ml in group A, 16 micrograms/ml in group B, and 0.9 micrograms/ml in the control group at the onset of reperfusion. Therapy A reduced the size of the infarct from 73 +/- 12% to 47 +/- 16% of the region at risk (p less than 0.005) and improved regional systolic shortening from 0 +/- 7% to 11 +/- 6% at 3 days after reperfusion (p less than 0.01). Therapy B decreased the size of the infarct to 64 +/- 9% of the region at risk (p = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combined treatment with vitamins E and C in experimental myocardial infarction in pigs. 280 74

To verify the lipid peroxidation in the focal cerebral ischemia, the levels of alpha-tocopherol, ubiquinone and ascorbate were measured in the ischemic center in rats. The former two were endogeneous lipid soluble antioxidants and the last was a water soluble antioxidant. alpha-Tocopherol, reduced ubiquinone-9 and -10, and reduced ascorbate decreased to 79%, 73%, 66%, and 76% 0.5 hour after ischemia, respectively. alpha-Tocopherol decreased to 63% 6 hours after ischemia, and then reached a plateau, while reduced ubiquinones and reduced ascorbate declined further to 16% and 10% 12 hours after ischemia, respectively, and then reached plateau levels. These results suggest their functional and durational differences as antioxidants against lipid peroxidation in this ischemic model. Although the reciprocal increase in oxidized ubiquinones during ischemia was not observed, that in oxidized ascorbate was noted. The complementary antioxidant system between cytoplasmic and membranous components, the combination alpha-tocopherol/ascorbate, was estimated from the calculated consumption ratio of these antioxidants, assuming that the loss of these reduced antioxidants is due to neutralization of free radicals. This system was suggested to play an important role in an early ischemic period. Urate also markedly increased during ischemia. Therefore, xanthine oxidase activity was measured in rats both in normal brain and in ischemic brain induced by four-vessel occlusion method. In the control rat, the enzyme activity was 0.87 +/- 0.13 nmol/g wet brain/min at 25 degrees C (mean +/- S.D.): 92.4% was associated with the NAD-dependent dehydrogenase form and only 7.6% with the oxygen-dependent superoxide-producing oxidase form. However, the ratio of the latter form increased to 43.7% after 0.5 hour of global ischemia despite the same level in total xanthine oxidase activity. This result suggests the involvement of the oxygen free radicals generated from the xanthine oxidase pathway in the pathogenesis of the ischemic injury of the rat brain.
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PMID:[Lipid peroxidation and changes in xanthine oxidase in cerebral ischemia]. 280 15

Incubation of human blood platelets in vitro in Tyrode solution with unsaturated fatty acids, diamide or superoxide (generated in situ) resulted in the oxidation of tocopherol in the platelets. Arachidonate concentrations of (3-5).10(-4) M caused a 50% decrease in platelet alpha-tocopherol. The addition of saturated fatty acids or platelet-active substances such as ADP, dibutyryl cyclic AMP, and some prostaglandins, or peroxidizing agents such as hydrogen peroxide and tert-butylhydroperoxide to the incubation medium did not cause any change in platelet tocopherol content. During incubations of platelets with arachidonate, malonaldehyde as well as alpha-tocopherolquinone were produced. The latter was also produced during incubations with diamide or superoxide. The oxidation of tocopherol induced by unsaturated fatty acids may be one factor responsible for the well-known increase in dietary vitamin E requirements induced by polyunsaturated fatty acids. The oxidative consumption of tocopherol in the membranes could be expected to take place during localized release of oxidants such as superoxide and polyunsaturated fatty acids during normal biological function (e.g., phagocytosis) or pathological processes (e.g., ischemia). Tocopherol utilization is kept low probably by the regeneration of the compound by vitamin C and/or the preferential utilization of the other biological antioxidants.
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PMID:In vitro oxidation of alpha-tocopherol (vitamin E) in human platelets upon incubation with unsaturated fatty acids, diamide and superoxide. 282 39

The effects of several concentrations of amines and reducing agents on the activity of creatine (CK) and adenylate (AK) kinases were determined in homogenates of the brain of the rat at 0 and 37 degrees C. The order of decreasing irreversible inhibition of the enzymes was peroxide, 6-hydroxydopamine, dopamine, norepinephrine, 5-hydroxytryptamine. At 37 degrees C, approx. 50% of the activity of creatine kinase was lost in 30 min in the presence of 20 microM dopamine. 5-Hydroxytryptamine was several orders of magnitude less toxic. The action of dopamine was not prevented by inhibition of monoamine oxidase, chelation of metals or the addition of a catalase, indicating that formation of peroxide by monoamine oxidase was not the primary cause of the loss of enzyme. Although auto-oxidation of dopamine to a toxic quinone was considered, the degree of inhibition of creatine kinase was not affected when auto-oxidation was prevented under anaerobic conditions. Glutathione (GSH), present during the incubation, protected the enzymes but could not restore activity after exposure to amine. Concentrations of glutathione above 5 mM and of oxidized glutathione as low as 10 microM inhibited creatine kinase. Ascorbate protected the enzymes even when present at a concentration much less than that of the amine, but ascorbate was itself toxic. The findings indicate that dopamine, at concentrations attained after drug-induced release or ischemia, can be toxic to a metabolic enzyme present in the synaptosomal membrane.
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PMID:Amine-mediated toxicity. The effects of dopamine, norepinephrine, 5-hydroxytryptamine, 6-hydroxydopamine, ascorbate, glutathione and peroxide on the in vitro activities of creatine and adenylate kinases in the brain of the rat. 300 2

A large amount of biochemical, physiological, and pharmacological data has been obtained which supports a mechanistic role of oxygen free radical-induced lipid peroxidation (LP) in post-traumatic spinal cord degeneration. Biochemical evidence of early and progressive lipid peroxidative reactions occurring in the injured spinal cord includes: an increase in polyunsaturated fatty acid peroxidation products (e.g., malonyldialdehyde), a decrease in cholesterol and the appearance of cholesterol oxidation products, an increase in cyclic GMP presumably due to free radical activation of guanylate cyclase, a decrease in tissue anti-oxidant levels (e.g., alpha tocopherol, reduced ascorbate), and inhibition of membrane-bound enzymes such as Na+ + K+-ATPase. In vitro CNS tissue studies have provided support for the possibility that LP may contribute to other early post-traumatic events including intracellular calcium accumulation and arachidonic acid release. Moreover, spinal tissue lactic acidosis, which occurs early after injury, can exacerbate LP reactions. The involvement of LP in the development of progressive post-traumatic spinal white matter ischemia has been strongly inferred from pharmacological studies in cats with known inhibitors of LP. For example, the dose-response curves for the ability of the glucocorticoid methylprednisolone (MP) to inhibit post-traumatic LP and to retard ischemia development are identical. This relationship between LP and post-traumatic ischemia is more directly implied from studies showing that pretreatment of cats with high doses of anti-oxidants (e.g., d-alpha tocopherol plus selenium p.o. or 1-ascorbic acid i.v.) can also significantly antagonize the progressive decrease in spinal cord blood flow that follows severe blunt injury. However, a similar efficacy of certain calcium and prostaglandin antagonists suggests an interrelationship between aberrant calcium fluxes, vasoconstrictor/platelet aggregating prostanoids, and LP in the post-traumatic ischemic phenomenon. In addition to a role of LP in ischemia development, the action of intensive d-alpha tocopherol and selenium pretreatment to retard anterograde cat motor nerve fiber degeneration after nerve section suggests that LP may also be a fundamental mechanism of "Wallerian" axonal degeneration after neural injury. Finally, a critical role of LP in the acute pathophysiology of CNS injury in general has been supported by the finding of an excellent correlation, in terms of efficacy and potency, between the action of glucocorticoid and nonglucocorticoid steroids to inhibit neural tissue LP in vitro and to promote early neurological recovery in severely head-injured mice.
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PMID:Role of lipid peroxidation in post-traumatic spinal cord degeneration: a review. 355 50

It was shown in experiments in vitro that thermal ischemia of liver tissue leads to disorders in the function of membrane-bound microsomal monooxygenases. Disorders in the structural organization of membranes were also expressed in the inhibition of reactions of ascorbate-depending and fermentative peroxide oxidation of lipids and labilization of lysosomal membranes. Faults in the rate of amidopyrine n-demethylation and aniline n-hydroxylation correlate with the intensification of spontaneous peroxidation of lipids and activation of proteolytic processes in ischemia. The obtained data permitted to ground the approach to pharmacological prophylaxis of ischemic damages of liver microsomal monooxygenases.
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PMID:[Mechanisms of the damage to the liver monooxygenase systems in thermal ischemia]. 370 79

Oxygen-derived free radicals and other oxidizing species are thought to be involved in inflammation and ischemic tissue injuries. Recently, oxygen-derived free radicals also have been implicated in tissue injury of the myocardium subjected to ischemia/reperfusion. The purpose of this investigation was to determine if electrolysis of a physiological buffer would serve as a source of free radicals, and if these radicals would lead to alterations in myocardial function. Isolated Langendorff-perfused rabbit hearts perfused with buffer subjected to a 20 mA D.C. current for 2 min demonstrated significant increases in coronary perfusion pressure (37 +/- 6 mmHg), left ventricular end diastolic pressure (41 +/- 7 mmHg), and loss in left ventricular developed pressure (35 +/- 5%). The free radical scavengers, superoxide dismutase and a combination of tryptophan plus glycine, were effective in protecting the hearts from the effects of electrolysis. The presence of free radicals was semiquantitated with a radical-luminol chemiluminescent assay. In this assay a variety of radical scavengers and antioxidants were effective (i.e., dimethyl sulfoxide, nitro blue tetrazolium, ascorbate, superoxide dismutase, 1, 3-diphenylisobenzofuran, and glycine, catalase), whereas mannitol and tryptophan were not effective. The data indicate that electrolysis of a physiological buffer produces a milieu containing several reactive oxygen species or free radicals that have the potential to produce alterations in a biological system. This method has the advantage over existing protocols for the generation of radicals in that it is a blood-free and an enzyme-free system.
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PMID:Electrolysis-induced myocardial dysfunction. A novel method for the study of free radical mediated tissue injury. 372 1

We previously published results of investigations which indicated that the combination of mannitol, which acts as a free radical scavenger, and perfluorochemicals (PFC), which have a strong oxygen-carrying capacity, can be therapeutic in cases of brain infarction. The present experiment tested the hypothesis that the effectiveness of such treatment could be increased by an optimal combination of such scavengers and other chemicals. Fifty-two dogs were used, employing the "canine model of a completely ischemic brain regulated with the perfusion method." A total of six drugs with free radical scavenger capacities were tested: mannitol, vitamin E, vitamin C, Nizofenone (Y-9197), dexamethasone (DEXA) and suloctidil (MY-103). These drugs were administered intravenously 15 minutes prior to the production of ischemia, when cerebral blood flow was reduced to one-tenth its normal volume. After one hour, recirculation was allowed and the recovery of electrical activity of the brain observed for three hours. Judged by the degree of recovery of brain electrical activity, five drugs were considered to have protective effect against brain ischemia: mannitol, vitamin E, MY-103, DEXA and Y-9197. Among these five drugs, mannitol, vitamin E and DEXA are known to be safe and easily used clinically. The combined administration of these three drugs, together with PFC, was also investigated. It was found that the speed and degree of recovery of brain electrical activity were greater when these drugs were given together than when one was administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The protective effect of combined administration of anti-oxidants and perfluorochemicals on cerebral ischemia. 608 1

The role of lipid peroxidation (LPO) in the damages of the enzymic system of Ca2+ transport in sarcoplasmic reticulum (SR) membranes of skeletal and cardiac muscles under conditions of vitamin E deficiency, ischemia and limb reoxygenation as well as in emotional-pain stress was investigated. It was shown that these processes are associated with activation of endogenous LPO in SR membranes "in vivo" and with simultaneous inhibition of Ca2+ transport, (i. e. decrease of the Ca2+/ATP ratio) and inactivation of Ca-ATPase. The degree of damage of the Ca2+ transport system was correlated with the concentration of LPO products accumulated in SR membranes "in vivo and during LPO induction by the Fe2+ + ascorbate system 'in vitro". Injection of natural and synthetic free radical scavengers (e. g. 4-methyl-2.6-ditretbutylphenol, alpha-tocopherol) to experimental animals resulted in practically complete suppression of LPO activation "in vivo" and in partial protection of the Ca2+-transporting capacity of SR membranes. A comparison of experimental results allowed to estimate the role of LPO in SR damage under pathological conditions. Model experiments with "contraction-relaxation" cycles including isolated components of muscle fibers (SR fragments and myofibrils) demonstrated that LPO induction in SR membranes by the Fe2+ + ascorbate system results in complete elimination of the relaxation step in myofibrils due to the loss of the SR affinity to decrease the concentration of Ca2+ in the incubation medium. This effect can be removed by free radical scavengers. The role of LPO in pathological changes of muscle contractility is discussed.
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PMID:[Modification of an enzymic system of Ca2+ transport in sarcoplasmic reticulum during lipid peroxidation. In vivo damages in the development of pathological changes]. 622 70

Polarographic measurements show that activity of cytochrome oxidase (CO), assayed as ascorbate plus TMPD oxidase, is decreased in the mitochondria (M) from postischemic areas of rabbit heart 1, 6, and 9 days after temporary (1-hr) coronary artery occlusion (CAO). This effect is observable only in the absence of added cytochrome c. Cytochrome oxidase activity in the cytochrome c-containing medium was not different from the control level. Levels of cytochromes c + c1 and a were substantially lower in tissue from postischemic areas and elevated in the intact tissue 1 and 6 days after temporary CAO as compared with control hearts. Stoichiometry of the cytochromes was not changed. After 1 or 4 hr of permanent CAO, CO activity (plus cytochrome c) of ischemic M was equal to that of M from intact area; CO activity (with or without cytochrome c) was reduced after 0.5 and 1 hr but elevated after 3 or 4 hr of in vitro ischemia as compared with control. The changes of CO activity in infarcted human heart M were similar to those in rabbits after temporary CAO; CO activity was restored after addition of cytochrome c. The data suggest that leakage of cytochrome c occurs during isolation of M and is more pronounced in ischemia-damaged M.
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PMID:Cytochrome oxidase activity of mitochondria from ischemic and reperfused myocardium. 630 31


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