allopurinol and Ischemic-Attack--Transient

Topics: Amino Acid Transport System X-AG; Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Astrocytes; Cerebral Cortex; Glutamic Acid; Glycoproteins; Humans; Hydrogen Peroxide; Ischemic Attack, Transient; Oxidation-Reduction; Rats; Reactive Oxygen Species; Xanthine; Xanthine Oxidase; Xanthines

Central blood pressure (CBP) and carotid intima-media thickness (CIMT) are surrogate measures of cardiovascular risk. Allopurinol reduces serum uric acid and oxidative stress and improves endothelial function and may therefore reduce CBP and CIMT progression. This study sought to ascertain whether allopurinol reduces CBP, arterial stiffness and CIMT progression in patients with ischaemic stroke or transient ischaemic attack (TIA).. We performed a randomised, double-blind, placebo-controlled study, examining the effect of 1-year treatment with allopurinol (300 mg daily), on change in CBP, arterial stiffness and CIMT progression at 1 year and change in endothelial function and circulating inflammatory markers at 6 months. Patients aged over 18 years with recent ischaemic stroke or TIA were eligible.. Eighty participants were recruited, mean age 67.8 years (SD 9.4). Systolic CBP [-6.6 mm Hg (95% CI -13.0 to -0.3), p=0.042] and augmentation index [-4.4% (95% CI -7.9 to -1.0), p=0.013] were each lower following allopurinol treatment compared with placebo at 12 months. Progression in mean common CIMT at 1 year was less in allopurinol-treated patients compared with placebo [between-group difference [-0.097 mm (95% CI -0.175 to -0.019), p=0.015]. No difference was observed for measures of endothelial function.. Allopurinol lowered CBP and reduced CIMT progression at 1 year compared with placebo in patients with recent ischaemic stroke and TIA. This extends the evidence of sustained beneficial effects of allopurinol to these prognostically significant outcomes and to the stroke population, highlighting the potential for reduction in cardiovascular events with this treatment strategy.. ISRCTN11970568.

Topics: Aged; Allopurinol; Antihypertensive Agents; Blood Pressure; Body Mass Index; Brachial Artery; Brain Ischemia; Carotid Intima-Media Thickness; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Humans; Ischemic Attack, Transient; Male; Middle Aged; Risk Factors; Smoking; Stroke; Treatment Outcome

To compare cardiovascular (CV) risk among gout patients initiating allopurinol vs febuxostat.. Using 2002-2015 Korean National Health Insurance Service data for the entire Korean population, we conducted a cohort study on gout patients initiating allopurinol or febuxostat. The primary outcome was a composite CV end point of myocardial infarction, stroke/transient ischaemic attack, or coronary revascularization. Secondary outcomes were individual components of the primary outcome, and all-cause mortality. We used propensity score-matching with a 4:1 ratio for allopurinol and febuxostat initiators to control for confounding. Competing risk analyses were done for non-fatal outcomes accounting for deaths.. We included 39 640 allopurinol initiators propensity score-matched on 9910 febuxostat initiators. The mean age was 59.1 years and 78.4% were male. The incidence rate per 100 person-years for the primary outcome was 1.89 for allopurinol and 1.84 for febuxostat initiators. The corresponding hazard ratio comparing allopurinol vs febuxostat initiators was 1.09 (95% CI: 0.90, 1.32). No significant difference was found for the secondary outcomes, including all-cause mortality (hazard ratio 0.96; 95% CI: 0.79, 1.16). Subgroup analyses limited to those at high CV risk and to equipotent-dose initiators (i.e. allopurinol ⩾300 mg/day vs febuxostat ⩾40 mg/day) showed similar results.. Overall, this large Korean population-based study suggests no difference in the risk of non-fatal CV events and all-cause mortality between allopurinol and febuxostat initiators. These findings are consistent with the recent US Medicare population study, although the current study population consisted of younger Asians.

Topics: Aged; Allopurinol; Cardiovascular Diseases; Cohort Studies; Febuxostat; Female; Gout; Gout Suppressants; Humans; Ischemic Attack, Transient; Male; Middle Aged; Mortality; Myocardial Infarction; Myocardial Revascularization; Proportional Hazards Models; Republic of Korea; Stroke

Xanthine dehydrogenase and oxidase activities increased by 87% in rat brain slices after 30 min in vitro ischaemia. A further 41% increase was induced by 30 min simulated reperfusion of ischaemic slices. No conversion from the dehydrogenase to the oxidase activity was observed. The increment of enzyme activity was not due to neosynthesis of the enzyme, since it was not affected by the addition of cycloheximide during the ischaemic incubation. The increased oxygen-dependent form of the enzyme could aggravate the ischaemic brain injury by free radicals production, in particular after reperfusion.

Topics: Animals; Brain; Cycloheximide; In Vitro Techniques; Ischemic Attack, Transient; Male; Models, Biological; Oxygen; Protein Synthesis Inhibitors; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury; Xanthine Dehydrogenase; Xanthine Oxidase

The effect of ad libitum oral-administration of (-)catechin solution on ischemia-reperfusion-induced cell death of hippocampal CA1 in the gerbil was histologically examined. When (-)catechin solution instead of drinking water was orally administered ad libitum for 2 weeks, dose-dependent protection against neuronal death following by transient ischemia and reperfusion was observed. To evaluate the involvement of reduction of reactive-oxygen-species (ROIs) by the antioxidant activity of (-)catechin in this protection, the superoxide scavenging activity of the brain in catechin-treated gerbils was measured by ESR and spin-trapping using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). The superoxide scavenging activities of the brains obtained from catechin-treated gerbils were significantly higher than those of catechin-untreated animals. From these results, it was suggested that orally administered (-)catechin was absorbed, passed through the blood-brain barrier and that delayed neuronal death of hippocampal CA1 after ischemia-reperfusion was prevented due to its antioxidant activities.

Topics: Administration, Oral; Animals; Antioxidants; Blood-Brain Barrier; Catechin; Cell Death; Cyclic N-Oxides; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Neurons; Prosencephalon; Reactive Oxygen Species; Reperfusion Injury; Spin Labels; Superoxides; Xanthine Oxidase

The effects of free radical generating systems on basal and ischemia/reperfusion-evoked release of amino acids into cortical superfusates was examined in the rat using the cortical cup technique. Xanthine oxidase plus xanthine significantly enhanced GABA levels 358 fold over controls during 20 min of four vessel occlusion. Glutamate and phosphoethanolamine release following reperfusion were also elevated. Prostaglandin synthase plus arachidonic acid significantly enhanced the ischemia-evoked release of all amino acids (aspartate 360 fold; glutamate 433 fold; glycine 6 fold; GABA 689 fold; phosphoethanolamine 69 fold) and increased the pre-ischemic levels of glutamate, glycine and phosphoethanolamine. Administration of H2O2 plus ferrous sulfate significantly elevated both pre-ischemic amino acid release and ischemia-evoked release. A role for free radical generating systems in the development of ischemic injury is supported by the ability of superoxide dismutase plus catalase to reduce ischemia-evoked amino acid efflux into cortical superfusates. Thus, the species of free radical produced, as well as the amount generated, may after the pattern of amino acid release under both ischemic and non-ischemic conditions.

Topics: Animals; Basal Metabolism; Cerebral Cortex; Free Radicals; Ischemic Attack, Transient; Male; Neurotransmitter Agents; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Xanthine Oxidase

The present study investigated the effect of the administration of oxypurinol (40 mg/kg), an inhibitor of xanthine oxidase, on adenosine and adenine nucleotide levels in the rat brain during ischemia and reperfusion. The brains of the animals were microwaved before, at the end of a 20-min period of cerebral ischemia, and after 5, 10, 45, and 90 min of reperfusion. Cerebral ischemia was elicited by four-vessel occlusion with arterial hypotension to 45-50 mm Hg. Adenosine and adenine nucleotide levels in the oxypurinol-pretreated (administered intravenously 20 min before ischemia) rats were compared with those in nontreated animals exposed to the same periods of ischemia and reperfusion. Oxypurinol administration resulted in significantly elevated ATP levels at the end of ischemia and 5 min after ischemia, but not at 10 min after ischemia. ADP levels were also elevated, in comparison with those in the control rats, at the end of the ischemic period. Conversely, AMP levels were significantly reduced at the end of ischemia and during the initial (5 min) period of reperfusion. Adenosine levels were lower in oxypurinol-treated rats, during ischemia, and in the initial reperfusion phase. Oxypurinol administration resulted in a significant increase in the energy charge both during ischemia and after 5 min of reperfusion. Physiological indices, namely, time to recovery of mean arterial blood pressure and time to onset of respiration, were also shortened in the oxypurinol-treated animals. These beneficial effects of oxypurinol may have been a result of its purine-sparing (salvage) effects and of its ability to inhibit free radical formation by the enzyme xanthine oxidase. Preservation of high-energy phosphates during ischemia likely contributes to the cerebroprotective potency of oxypurinol.

Topics: Adenine Nucleotides; Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Blood Pressure; Electrochemistry; Hydrogen-Ion Concentration; Ischemic Attack, Transient; Kinetics; Male; Oxypurinol; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Respiration; Xanthine Oxidase

Increases in uric acid follow experimental stroke, which may be related to free radical formation by xanthine oxidase. The present study examined the time course of changes in xanthine and uric acid and their relationship to changes in the free radical scavengers glutathione, cysteine, and ascorbic acid.. Focal ischemia was induced by occluding the middle cerebral artery, followed by transient occlusion of the common carotid arteries for 60 minutes. At varying time points, animals were sacrificed, and ischemic cortex was dissected. Neurochemical measurements were made by high-performance liquid chromatography with 16-sensor electrochemical detection.. Marked increases in uric acid were seen at all time points, with a maximal increase at 1 day and a persistent increase lasting up to 21 days. There were smaller reciprocal decreases in xanthine. Glutathione, cysteine, and ascorbic acid showed significant decreases, consistent with the generation of free radicals. Reductions in levels of cysteine and glutathione were significantly correlated with increases in uric acid levels.. These findings confirm marked alterations in purine metabolism following focal ischemia and suggest that xanthine oxidase contributes to the generation of free radicals.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Cysteine; Free Radicals; Glutathione; Guanosine; Hydroxyindoleacetic Acid; Ischemic Attack, Transient; Rats; Rats, Inbred Strains; Serotonin; Tryptophan; Uric Acid; Xanthine Oxidase

The role of xanthine dehydrogenase and oxidase as a source of free radicals contributing to focal cerebral ischemic injury was evaluated in Long-Evans rats after the middle cerebral artery was permanently occluded and both carotid arteries were clamped for 90 min. The fraction of xanthine dehydrogenase present as the free radical producing oxidase increased slightly from 22% in control cortex to 30% in the ischemic right cortex during the first 3 h of reperfusion and then remained relatively unchanged over the next 24 h. This increase may in part be due to entrapped plasma, which contained 4.5 +/- 0.8 nmol.min-1.ml-1 xanthine oxidase entirely in the free radical-producing form. Infarct volume was unaffected by pretreatment with 50 mg allopurinol/kg per day over 3 days before surgery but was decreased by 8% with 100 mg/kg and 24% with 150 mg/kg of allopurinol (P less than 0.05). However, inhibition of xanthine oxidase by dietary depletion of the essential molybdenum cofactor increased infarct volume by 19%, suggesting that protection by allopurinol at higher dosages was independent of xanthine oxidase inhibition. Neither xanthine oxidase present in rat brain nor circulating in plasma appears to be the primary source of oxygen radicals that contributes to infarction in focal cerebral ischemia.

Topics: Allopurinol; Animals; Brain; Dithiothreitol; Free Radicals; Ischemic Attack, Transient; Male; Molybdenum; Rats; Reperfusion; Tungsten; Xanthine Dehydrogenase; Xanthine Oxidase

Oxypurinol, an inhibitor of the enzyme xanthine oxidase, reduced ischemic hippocampal damage and the associated hypermotility in Mongolian gerbils. Cerebral ischemia was induced in unanesthetized gerbils by a bilateral 5-min occlusion of the carotid arteries. Oxypurinol (40 mg/kg, IP), administered 20 min prior to carotid occlusion, prevented the increase in locomotor activity observed in saline-injected ischemic animals and significantly reduced the damage to, and loss of, CA1 hippocampal neurons observed 5 days postischemia. These findings suggest that oxypurinol may be useful for the prevention of cerebral ischemic damage.

Topics: Animals; Enzyme Inhibitors; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Male; Oxypurinol; Pyrimidines; Xanthine Oxidase

The existence of uric acid in mammalian brain was recently reported, but it has not yet become a consensus. The mammalian brain has been thought to lack xanthine oxidase, which catalyzes hypoxanthine to xanthine and xanthine to uric acid as the last steps of ATP degradation in other tissue. Using high-performance liquid chromatography, we performed assays for hypoxanthine, xanthine, and uric acid in rat brain after cerebral ischemia. It was confirmed that all three substances showed significant augmentation in the removed brains and that the chronological order of those increases corresponded to the order in the metabolic pathway. Allopurinol, a specific inhibitor of xanthine oxidase, significantly suppressed the increases in uric acid and xanthine, and a compensatory accumulation of hypoxanthine was observed. From these results, it was concluded that uric acid does exist in the brain, increases after ischemia, and is possibly the end product of purine degradation in the brain. Furthermore, it is suggested that xanthine oxidase exists in the brain and catalyzes the reaction from hypoxanthine to xanthine and then to uric acid. These reactions catalyzed by xanthine oxidase are considered to be a source of free radicals and may play important roles in the pathogenesis of cerebral ischemic injury.

Topics: Allopurinol; Animals; Chromatography, High Pressure Liquid; Enzyme Inhibitors; Hypoxanthine; Hypoxanthines; Ischemic Attack, Transient; Male; Rats; Rats, Inbred Strains; Uric Acid; Xanthine; Xanthines

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.

Topics: Animals; Ascorbic Acid; Brain; Brain Ischemia; Ischemic Attack, Transient; Lipid Peroxidation; Male; Oxidation-Reduction; Rats; Rats, Inbred Strains; Ubiquinone; Vitamin E; Xanthine Oxidase

In the first part of this experiment, the effects of pharmacotherapy on the neurologic consequences of transient global ischemia were examined in Wistar rats. The control and four experimental groups each contained six rats. In comparison to the control group receiving normal saline (NS) solution, in which no rats survived, all rats given naloxone (Nx) (23 mg/kg), superoxide dismutase (SOD) (10,000 U/kg), or allopurinol (APL) (35 mg/kg), 15 minutes before interruption of cerebral blood flow, survived the 20-minute period of global ischemia (p less than 0.01, p less than 0.01, p less than 0.01, respectively). No rat receiving deferoxamine (DEF) (20 mg/kg) survived the same ischemic period. In the second part of the experiment, the arachidonic acid (AA) content of brain samples was determined by gas chromatography and was used as an indicator of cerebral ischemia. Two control and four experimental groups consisted of six rats each. An ischemia control group received NS, whereas experimental groups were given Nx, SOD, APL, or DEF with the same previous dosage schedule. The animals were decapitated 15 minutes after drug infusion and cerebral ischemia was simulated by incubation of the heads in a 37 degrees C water bath for 60 minutes. AA content of ischemic brain treated with NS was markedly elevated (60.0 +/- 24.1 micrograms/gm of brain tissue), whereas in comparison the AA content of brain treated with Nx (5.1 +/- 3.0 micrograms/gm of brain tissue, p less than 0.05), SOD (3.5 +/- 2.7 micrograms/gm of brain tissue, p less than 0.05), or APL (2.9 +/- 1.5 micrograms/gm of brain tissue, p less than 0.05) all demonstrated much lower levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allopurinol; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Deferoxamine; Ischemic Attack, Transient; Male; Naloxone; Rats; Rats, Inbred Strains; Superoxide Dismutase

Changes of the xanthine and uric acid (UA) levels in rat forebrain following focal cerebral ischemia were studied by reversed-phase HPLC with electrochemical detection. Focal ischemia was induced by occluding the left middle cerebral artery in the rat. The xanthine level in the normal group was 11.50 nmol/g tissue. In the ischemic group, the xanthine concentration in the ischemic hemisphere progressively increased after occlusion and reached a maximum value of 59.42 nmol/g tissue 4 h after operation. The UA level in the normal group was 2.20 nmol/g tissue, whereas in the ischemic group the UA concentration in the ischemic hemisphere gradually increased after occlusion, reaching a value of 38.53 nmol/g tissue 24 h after ischemia. The concentration of UA remained elevated in the ischemic hemisphere until 48 h after occlusion, and reached a maximum value of 38.98 nmol/g tissue. The xanthine and UA levels in the contralateral hemisphere remained unchanged. The xanthine and UA concentrations in the sham-operated group did not show a significant increase after operation. The time course of xanthine and UA levels suggests that in ischemic forebrain UA is formed from xanthine as a product of purine metabolism.

Topics: Animals; Brain; Chromatography, High Pressure Liquid; Ischemic Attack, Transient; Kinetics; Male; Rats; Rats, Inbred Strains; Uric Acid; Xanthine; Xanthine Oxidase; Xanthines

Based on accumulating evidence of the role of xanthine oxidase (XO) in generating oxygen free radicals and causing tissue damage during ischemia, we examined the possible role of XO in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). After inducing SAH in dogs by two autologous blood injections 2 days apart, chronic vasospasm of the basilar artery was reliably produced. There was a 3.5-fold elevation in uric acid (UA), the product of XO, in the cerebrospinal fluid (CSF) of these animals. Parenteral administration of allopurinol (i.v., 25 mg/kg, every 6 hours), a specific blocker of XO, successfully abolished the elevation in CSF uric acid levels due to SAH. However, angiographic vasospasm measured on Day 7, morphological changes observed by electron microscope, and elevated CSF prostaglandin levels were not altered by the treatment. It can be concluded that the observed activation of the enzyme XO, which is a well-known source of oxygen free radicals in ischemia in various organs, is not playing a major role in the pathogenesis of chronic cerebral vasospasm in this animal.

Topics: Allopurinol; Animals; Cerebral Angiography; Dogs; Free Radicals; Ischemic Attack, Transient; Subarachnoid Hemorrhage; Uric Acid; Xanthine Oxidase

Total starvation is effective for acute weight reduction in obesity. However, in 200 patients, most of whom also had internal diseases, 8% exhibited sometimes severe complications, i.e. reversible cerebral ischemia in 3 hypertensive patients when the blood pressure was lowered to the normal range by natriuresis of fasting; breakdown of water and electrolyte homeostasis with circulatory collapse, vomiting and vertigo; acute crises of paroxysmal nocturnal hemoglobinuria and porphyria respectively and increase of transaminases up to 200 mu/ml, or cardiac arrhythmias. Relative (?) contraindications for total fasting appear to be clinical sings of arteriosclerosis such as vascular bruits, angina pectoris and intermittent claudication. In case of doubt, the method should only be used in hospital.

Topics: Acetone; Adult; Allopurinol; Arrhythmias, Cardiac; Diet, Reducing; Edema; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Obesity; Spironolactone; Starvation; Transaminases; Urea; Water-Electrolyte Imbalance