Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00512 (Phenytoin)
 1,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebral angiography, performed after a seizure in a patient with a life-long history of typical hemiplegic migraine, disclosed markedly dolichoectatic anterior and middle cerebral arteries. No abnormality of the adjacent capillary or venous structures was present. A positive brain scan was attributed to ischemia induced by vasospasm rather than to the corresponding large tortuous anterior and middle cerebral arteries. There were no permanent sequelae and the patient has been free of seizures on Dilantin and phenobarbital over a 3-year follow-up period. Angiographic demonstration or description of a similar ectatic set of anterior and middle cerebral arteries could not be found in the literature. The concurrence of seizures and hemiplegic migraine adds to the peculiarity of this case.
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PMID:Cerebral arterial dolichoectasia with seizure. Case report. 125 41

The 21-aminosteroid antioxidant U-74006F (1) is being developed as an iv injectable agent for the treatment of human CNS trauma and ischemia. Because of its poor water solubility, the plasma compatibility of the parenteral formulation of 1 was evaluated using three models: (I) static solubility, (II) aggregometric, and (III) dynamic flow. The flow model was designed to mimic an iv infusion into the human antecubital vein, which was assumed to have plasma flow of 10 mL/min. Dilantin (phenytoin), the positive control, produced a precipitate in all three models from a 10% (v/v) mixture with human plasma, which approximates the in vivo ratio when the drug is infused at the recommended rate of 1 mL/min. Approximately 39% of the phenytoin dose in the flow model was retained on a downstream 3-microns filter as crystals. In comparison, the parenteral formulation of 1 produced minimal precipitate in models I and II from 40% mixtures with plasma, but higher percentages produced unstable suspensions with time-dependent precipitation. The percentage of the dose of the parenteral formulation of 1 retained on the filter in the flow model was 0.5% or less at infusion rates as high as 10 mL/min and 3% at 19 mL/min. At the 10-mL/min infusion rate, the mass of 1 retained on the filter per minute was less than 1% of the mass of phenytoin retained at the 1-mL/min infusion rate for Dilantin. The acceptable plasma compatibility of the parenteral formulation of 1 appears to be related to the solubilizing effects of plasma protein binding and pH suppression by the citric acid vehicle.
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PMID:Plasma compatibility of injectables: comparison of intravenous U-74006F, a 21-aminosteroid antioxidant, with Dilantin brand of parenteral phenytoin. 186 39

Recent in vitro and in vivo experiments have suggested that excitatory amino acid antagonists, particularly those active at the N-methyl-D-aspartate receptor subtype, are effective in ameliorating ischemic injury due to their antiexcitotoxic activity. However, these drugs are also potent and effective in vivo anticonvulsants. The present experiments compared the noncompetitive N-methyl-D-aspartate antagonists phencyclidine and MK-801 with the anticonvulsant phenytoin in a model of focal brain ischemia. Fisher F-344 rats were subjected to tandem occlusion of the middle cerebral and ipsilateral common carotid arteries under halothane anesthesia. Compounds were administered intravenously 30 minutes and 24 hours after arterial occlusion; infarct size was assessed at 48 hours after occlusion. Phencyclidine had no effect on infarct volume at 1 mg/kg, significantly reduced (by 36%) infarct volume at 3 mg/kg, and produced a nonsignificant 26% decrease at 10 mg/kg. The more potent and selective noncompetitive antagonist MK-801 reduced (by 32%) infarct volume significantly at 0.1 mg/kg, produced a nonsignificant 23% decrease at 0.3 mg/kg, and had no effect at 0.5 mg/kg. Phenytoin, which is not a glutamate antagonist, reduced the infarct volume by 45% at 28 mg/kg. A single dose of phenytoin (28 mg/kg) administered 30 minutes after occlusion was neuroprotective, but delaying drug administration for more than 2 hours was ineffective. These data suggest that blockade of the N-methyl-D-aspartate receptor is effective in reducing the infarct size after focal cerebral ischemia. The neuroprotective activity of phenytoin suggests that this may be related to the common anticonvulsant action.
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PMID:Comparison of phenytoin with noncompetitive N-methyl-D-aspartate antagonists in a model of focal brain ischemia in rat. 223 85

We investigated the effects of phenytoin on the rate of enzymatic release of free fatty acids and on the levels of energy metabolites and nucleoside phosphates in ischemic brain. Phenytoin (10 mg/kg i.v.) was administered 30 minutes before the onset of ischemia induced in 30 male Wistar rats by occluding the basilar and both common carotid arteries. The rats' brains were frozen in situ after 0, 5, or 30 minutes of ischemia or 10, 30, or 60 minutes of recirculation following 30 minutes of ischemia (n = 5 at each time). Nucleoside triphosphate levels were higher in the phenytoin-treated rats than in corresponding untreated rats at each time during and after ischemia. Phenytoin significantly attenuated the accumulation of lactate and free fatty acids (arachidonic acid and stearic acid) during ischemia and accelerated their recovery during recirculation. These results suggest that phenytoin has favorable protective effects on ischemic brain and that phenytoin may inhibit calcium-mediated phenomena, especially the inositol cycle, in cerebral ischemia.
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PMID:Phenytoin affects metabolism of free fatty acids and nucleotides in rat cerebral ischemia. 239 70

A case of Isaacs' syndrome with Trousseau's phenomenon is reported. Myokymia, pseudomyotonia (difficulty relaxing after forceful contraction), and ischemia-induced carpal spasm (Trousseau's phenomenon) were not abolished by nerve block distal to the cuff or by intravenous infusion of calcium. Inhalation of oxygen suppressed the pseudomyotonia and Trousseau's phenomenon, but myokymia persisted. Phenytoin abolished all types of abnormal discharges. The morphological abnormality in biopsied short peroneal muscle consisted of intraterminal and ultraterminal sprouting. We postulate that the trigger zone for abnormal discharge in our case is in the distal segment of the intramuscular nerve axon, including the nerve terminal. Hypoxia-sensitive hyperexcitability of the axon membrane might be responsible for the generation of pseudomyotonia and Trousseau's phenomenon, although the mechanism underlying myokymia remains unknown.
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PMID:Hypoxia-sensitive hyperexcitability of the intramuscular nerve axons in Isaacs' syndrome. 253 95

Ischemia gives rise to severe energy depletion and imbalance of Ca2+ homeostasis. This condition leads to activation of phospholipases A2, A1 and to attenuation of ATP dependent reacylation. As a result, free fatty acid (FFA) especially arachidonic acid accumulates. Phenytoin has been reported to blockade the various Ca2+ channels. In this study, we could investigate the effect of phenytoin on the liberation of FFA, energy metabolites, various nucleotides metabolism, Na+, K+-ATPase activity, and water and electrolyte contents in the ischemic brain. Inhibitory effects of phenytoin against FFA accumulation in the ischemia, and increase of parietal cortex water content in the recirculation were brought about. In addition, Na+,K+-ATPase activity in the ischemia was accelerated by phenytoin. Phenytoin may reduce intracellular Ca2+ by blocking the Ca2+ channel into the cytoplasma, or by activation of Na+-Ca2+ exchange transport system following the acceleration of Na+,K+-ATPase activity. Another conceivable way for this acceleration of Na+,K+-ATPase may be derived from the preservation of the energy state, protein metabolism, and lipid metabolism.
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PMID:[A study on the protective mechanism of phenytoin in transient global ischemia]. 255 Aug 30

We looked at FiO2, choice of anesthetic, nutritional status, and body temperature in a gerbil model of forebrain ischemia to determine their effect on data interpretation, ischemic outcome, and extent of pharmacologic protection. We subjected 484 gerbils to 5 minutes of forebrain ischemia under different experimental conditions. The gerbils were anesthetized with 3% halothane and inspired 21% O2, 37% O2 and 60% N2O, or 97% O2. Six groups of gerbils pretreated with 200 mg/kg phenytoin or 2 ml/kg polyethylene glycol (vehicle) underwent ischemia in the fasted or fed state. Three groups of gerbils receiving no pretreatment underwent ischemia with rectal temperatures of 32-33 degrees C, 34-35 degrees C, or 37 degrees C. We counted intact neurons in the CA1 hippocampal sector in brains fixed on Day 7 after ischemia. t tests of square-root-transformed cell counts were used to assess the effect of hypothermia, and analysis of variance of the transformed data was used to test for the effects of phenytoin, FiO2, and nutritional status. Phenytoin pretreatment provided significant protection from CA1 neuron loss in all groups tested (p less than 0.001), but the degree of protection varied from 20% to 44%. In spite of significantly higher serum glucose concentrations in fed than in fasted gerbils (173 and 118 mg/dl, respectively), we found no significant effect of nutritional status upon neuron loss in phenytoin- or vehicle-pretreated gerbils. An FiO2 of 21% significantly decreased the number of viable neurons in both vehicle- and phenytoin-pretreated groups (p less than 0.03), despite the lack of an effect of hypoxemia on arterial blood gases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Conditions for pharmacologic evaluation in the gerbil model of forebrain ischemia. 281 90

Phenytoin is well known as the anticonvulsant agent and also said to protect the brain against ischemic damage. The purpose of the present experiment is to study the therapeutic effect of phenytoin on cerebral ischemia and confirm whether the effectiveness of phenytoin could be enhanced by combination of free radical scavengers such as mannitol and vitamin E. In this experiment, twenty-five dogs were subjected to ischemia, using the "canine model of complete ischemic brain regulated with a perfusion method" in which it is possible to control the degree of blood flow to a cerebral hemisphere via a perfusion pump at will. Five animals served as untreated control, fifteen received treatment with phenytoin (7 mg/kg in five dogs, 10 mg/kg in five dogs and 30 mg/kg in five dogs) and five treated with 10 mg/kg phenytoin, 2 g/kg of mannitol and 30 mg/kg of vitamin E. These drugs were administered intravenously 20 minutes prior to the production of ischemia, when cerebral blood flow was reduced to one-tenth its normal volume. After one hour, cerebral blood flow was restored and the recovery of electrical activity of the brain and the degree of brain swelling were observed for three hours. With regard to the recovery of EEG, no recovery of EEG was seen subsequent to recirculation except one dog in the control group. Whereas in the group treated with phenytoin, gradual emergence of slow wave ws observed soon after recirculation. The higher the administered dosage is, the better the degree of recovery of EEG was seen. Thus, the dose-related recovery of EEG was observed within the dose ranges tested.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Protective effect of phenytoin and its enhanced action by combined administration of mannitol and vitamin E in cerebral ischemia]. 308 96

Ischemia gives rise to severe energy depletion and influx of Ca from the extracellular space, and it is suggested that increased intracellular Ca leads to the activation of phospholipase C and A, and to liberation of free fatty acids (FFA) in particular arachidonic acid. Phenytoin has been reported not only to maintain the intra- and extracellular cation balance but blockade the Ca channel. The purpose of the present study is to investigate the effect of phenytoin on the liberation of FFA, energy metabolism and mononucleotide metabolism in ischemic brain. Male Wistar rats were subjected to global cerebral ischemia induced by the occlusion of basilar and bilateral common carotid arteries. The brains were frozen in situ by the funnel technique after 5 or 30 min of ischemia or after 10, 30, or 60 min of recirculation following 30 min of ischemia. Purine and pyrimidine nucleotides, FFA, and glycolytic intermediates were measured by HPLC, GLC, and fluoro-enzymatic method. In non-treated rats, ATP reached a nadir after 5 and 30 min of ischemia. Phenytoin significantly attenuated ATP depletion after 5 and 30 min of ischemia. And also E.C. is higher in phenytoin treated rats than in non-treated rats in ischemia. After 60 min of recirculation, ATP recovered to 1.93 +/- 0.02 mumol (72.3% of pre-ischemia) in treated rats but 1.60 +/- 0.07 mumol/g (60% of pre-ischemia) in non treated rats. In E.C., there are significant differences between non-treated and treated rats after 10 and 30 min of recirculation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The effect of phenytoin on free fatty acid liberation and mononucleotide metabolism in transient ischemia]. 321 41

Protection of the brain and spinal cord against ischemia is a goal of vast clinical importance. One approach to this objective is to reduce the tissue's functional activity in order to preserve energy for the metabolic processes that are essential to viability. Experiments to explore ways of reducing function-related energy demands were performed on isolated rabbit retina, a well-characterized model of organized adult mammalian central nervous system (CNS) tissue. The retina was maintained in a nearly physiological state in a miniature "heart-lung" apparatus. Energy metabolism (oxygen consumption and glycolysis) and electrophysiological function (determined by electroretinogram) of the in vitro retina were monitored, and their responses to a series of agents that may reduce energy requirements were determined. Large reversible reductions in O2 consumption, glycolysis, and electrophysiological function were seen in response to mild hypothermia (-3 degrees to -6 degrees C), phenytoin (Dilantin, 100 to 200 mg/kg), chlordiazepoxide (Librium, 200 microM), lithium (1 to 4 mM), Mg++ (6 to 20 mM), strophanthidin (0.15 to 0.25 microM), CO2 (25% to 30%), 2-amino-5-phosphonovaleric acid (APV, 500 microM), amiloride (1 mM), and dantrolene (1 mM). One retina was exposed simultaneously to a combination of six of these agents, which reduced its oxidative and glycolytic metabolism to less than 50% of the control level. The retina recovered metabolic and electrophysiological function after a 2 1/2-hour exposure period. Other agents tested (diphenhydramine, midazolam, nifedipine, nimodipine, and quercetin) had effects on energy metabolism and electrophysiological function that were poorly reversible. Surprisingly little effect was seen in response to general anesthetic agents (thiopental and Althesin) and other CNS depressants (chlorpromazine, ethanol, lidocaine, paraldehyde, valproic acid, and baclofen). The presumed mechanisms through which these agents reduce cellular energy requirements, as well as their potential roles in the treatment of CNS ischemia, are discussed.
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PMID:Reduction of cellular energy requirements. Screening for agents that may protect against CNS ischemia. 341 90


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