Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of ATP-ase and acetylcholinesterase (AChE) in crude mitochondrial fraction (CMF) and microsomal fraction of rat brain cortex and the spinal cord was studied in clonic seizures evoked by electroshock and 5 min after them. Inhibition of the Na, K-ATP-ase activity of the CMF of the brain at the clonic phase of convulsions and an increase in the activity of this enzyme in all the fractions of the tissues under study at the postconvulsive period were revealed. The activity of Ca-ATP-ase in the CMF of the brain increased during the convulsions and decreased at the postconfulsive period. The activity of Mg-ATP-ase remained unchanged. The AChE activity, as a rule increased during the convulsions, and grew even more during the postconvulsive period; the spinal cord tissue displayed a reduction of the activation effect. A possibility of structural reconstructions in the excitable neuron membranes during the convulsive activity is discussed.
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PMID:[Na, K-ATP-ase and acetylcholinesterase activity of the membrane structures of the rat brain and spinal cord during the seizure process]. 13 79

A lyophilized liver extract (FLR) lengthens hexobarbital action in control rats ; it decreases slightly the induction of hepatic microsomal enzymes and normalizes diphenylhydantoin protection against electroshock seizure in phenobarbital-treated animals ; in the event of a CC14 intoxication, this extract reestablishes values close to normal for mebubarbital metabolism in mice and for BSP clearance in rats. FLR could act in regularizing drug metabolism.
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PMID:[Liver extract effect on liver microsomal system and on an experimental model of intoxication]. 14 49

Three liver microsomal enzyme inhibitors, proadifen, 2,4-dichloro-6-phenylphenoxyethyldiethylamine, and 2,4-dichloro-6-phenylphenoxyethylamine, and a hepatotoxic agent, carbon tetrachloride, were tested for anticonvulsant activity in adult male albino rats using the maximal electroshock seizure technique. All four substances exhibited significant anticonvulsant activity 1 hr after intraperitoneal administration. This protection was absent when tested 24 hr later.
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PMID:Anticonvulsant activity of enzyme inhibitors in rats. 97 47

This study reproduces in experimental animals the sequential development of all the liver lesions seen in the human alcoholic: in 15 baboons fed ethanol, all developed fatty liver, five progressed to hepatitis, and five had cirrhosis. Maintenance of a nutritionally adequate regimen despite the intake of inebriating amounts of ethanol (50% of total calories) was achieved by incorporation of the ethanol in a totally liquid diet. Upon ethanol withdrawal, signs of physical dependence, such as seizures and tremors, developed. Ultrastructural changes of the mitochondria and the endoplasmic reticulum were already present at the fatty liver stage and persisted throughout the hepatitis and cirrhosis. The lesions were similar to those observed in alcoholics (including the inflammation and the central sclerosis) and differed from the alterations produced by choline and protein defiencies. At the fatty liver stage, some "adaptive" increases in activity of microsomal enzymes [aniline hydroxylase (EC 1.14.14.1) and the microsomal ethanol oxidizing system] were observed, but these tended to disappear with the development of hepatitis and cirrhosis. Fat accumulation was also much more pronounced in the animals with the hepatitis as compared with those with simple fatty liver (an 18-fold compared with 3- to 4-fold increase in liver triglycerides). The demonstration that these lesions can develop despite an adequate diet indicates that in addition to correction of the nutritional status, control of alcohol intake is mandatory for the management of patients with alcoholic liver injury.
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PMID:Sequential production of fatty liver, hepatitis, and cirrhosis in sub-human primates fed ethanol with adequate diets. 105 27

The s.c. implantation of a 75 mg pentobarbital pellet in the back of a conscious mouse resulted in a much more rapid development of tolerance to barbiturates than that produced in mice receiving daily i.p. injections of 75 mg/kg sodium pentobarbital. Acceleration in tolerance development by pentobarbital pellet implantation was evidenced by a decrease in sleeping time after the challenge with either sodium pentobarbital or sodium barbital. The degree of hepatic microsomal drug enzyme induction after pentobarbital pellet implantation also was found to be significantly higher than that produced by the injection technique. Further studies demonstrated that the threshold for pentylenetetrazol-induced seizures was significantly reduced compared to that of the sodium pentobarbital daily injected and control groups. These studies provide an animal model for studying the mechanism of barbiturate tolerance and dependence.
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PMID:A model for the rapid development of dispositional and functional tolerance to barbiturates. 116 76

The intracellular accumulation of PAF following cell stimulation suggests an intracellular signal transduction pathway. High affinity binding sites for PAF in microsomal membranes and displacement of PAF from these sites by structurally distinct PAF antagonists suggests the existence of an intracellular receptor. Suppression of primary genomic responses by a PAF antagonist selective for the intracellular Ca2+ and arachidonic acid metabolites, is linking the intracellular generation of PAF to immediate-early transcription. Several of the metabolites that transiently accumulate after injury may elicit beneficial effects on regenerative processes. The membrane metabolite PAF, which accumulates after seizure and ischemia, may initiate reparative processes by promoting transcriptional activation of immediate-early transcription factors. The long-term effects of these immediate-early gene transcription factors may provide a synthetic mechanism to replenish and rebuild cells following traumatic events.
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PMID:Second messengers derived from excitable membranes are involved in ischemic and seizure-related brain damage. 130 97

We examined the activity and phosphorylation level of (Na+,K+)-ATPase (E.C. 3.6.1.3) partially purified from normal and epileptic human cortices. Control patients (n = 11) were operated on for a non-epileptogenic deep brain lesion, while epileptic patients (n = 10) were operated on for temporal or frontal originating partial seizures, resistant to medications or secondary to evolutive brain tumors. No differences in the specific activity of microsomal (Na+,K+)-ATPase were observed between the two groups of patients. After partial purification of the enzyme followed by SDS-polyacrylamide gel electrophoresis, (Na+,K+)-ATPase catalytic subunit had a decreased affinity for K+ in human epileptic cortex and lost its sensitivity to phenytoin dephosphorylation. Indirect evidence suggests that those abnormalities of (Na+,K+)-ATPase in human epileptic cortex hold preferentially true for the alpha(-) enzymatic subunit. Those results indicate that, in human epileptic cortex, (Na+,K+)-ATPase and most probably its glial subtype is altered in its K+ regulation and phenytoin sensitivity and could be responsible for ictal transformation and seizure spread.
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PMID:Phosphorylation of brain (Na+,K+)-ATPase alpha catalytic subunits in normal and epileptic cerebral cortex: II. Partial seizures in human epilepsy. 165 59

Studies conducted by Fisons Pharmaceuticals and the Antiepileptic Drug Development Program (ADD Program) of the Epilepsy Branch (NINDS, NIH) revealed that 'remacemide' (FPL 12924, formerly PR 934-423) was effective orally in the prevention of maximal electroshock seizures (MES) in rats. In this context (-)stereoisomer (FPL 14145) was of equal potency to the racemate (remacemide), while the (+)stereoisomer (FPL 14144) was 54% less potent. With respect to neurotoxicity, remacemide and its enantiomers possessed more favorable therapeutic indices than phenobarbital and valproate and less favorable indices than phenytoin and carbamazepine. The duration of protection of rats in the MES test at the ED50 or 3 x ED50 of remacemide and the (+)isomer was better or on par with the best reference compounds, phenytoin and phenobarbital. After subchronic administration of either the ED50 or the ED97 of remacemide, no tolerance developed in the hexobarbital sleep test, however, the activities of 3 hepatic microsomal enzymes were elevated. In naive rats high doses of remacemide or its (-)isomer and low doses of phenobarbital caused an increase in spontaneous motor activity. Alternatively, motor activity was depressed subsequent to high doses of phenobarbital and phenytoin. Remacemide was inactive against pentylenetetrazol and 'kindling' seizures. It was without effect in 5 electrophysiological tests (evoked responses, recurrent inhibition, long-term potentiation, penicillin-induced discharge rate and veratridine-induced depolarization) employing the in vitro hippocampal slice technique. Moreover, remacemide failed to demonstrate potent binding in vitro to neuronal L-glutamate, gamma-amino-butyrate A, adenosine A1, benzodiazepine, N-methyl-D-aspartate (strychnine-insensitive glycine and ion channel subsites) or muscarinic receptors. In conclusion, remacemide specifically prevents seizures elicited by MES, an action predicting utility in patients with generalized tonic/clonic convulsions.
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PMID:Preclinical profile of the anticonvulsant remacemide and its enantiomers in the rat. 166 Mar 99

Clozapine is a neuroleptic agent whose structure consists of a dibenzodiazepine derivative with a piperazinyl side chain. It has been classified as an atypical neuroleptic drug due to its unique neuropharmacologic profile. Clozapine has a weak binding affinity for dopamine D-1 and D-2 receptors by its slightly greater preference for D-1 receptors, as noted with a D-1:D-2 receptor binding ratio of 1.3. Other neuroreceptors are involved, as the drug has potent binding affinity for serotonin receptors 5-HT1A and 5-HT2. Clozapine also has antihistaminic, anticholinergic, and alpha-adrenergic antagonistic properties. Electrophysiologic studies show that it differs from other typical neuroleptics in that its actions appear to be specific for the cortical-limbic dopamine A-10 tract. In animal paradigms, in contrast to typical neuroleptics, clozapine did not produce catalepsy and had only transient effects in antagonizing other dopamine agonists. The drug is rapidly absorbed orally with a bioavailability of 0.27. After a single oral dose the elimination half-life was approximately 8-10 hours, but with several doses it increased to 14.1 hours. The agent is extensively metabolized by hepatic microsomal enzymes that forms the N-desmethyl and N-oxide metabolites. It is an effective neuroleptic that has been studied in short-term and long-term clinical trials, and multicenter trials. Clozapine was superior to chlorpromazine in the treatment of refractory schizophrenia that failed to respond to previous neuroleptic therapy. Reports of extrapyramidal side effects are minimal, and no case reports of tardive dyskinesia have been published. Indeed, clozapine has been used to treat tardive dyskinesia and other movement disorders. Agranulocytosis is the major adverse effect and its prevalence appears to differ among various ethnic groups. Other adverse effects that have been reported include hypersalivation, orthostatic hypotension, and constipation. Clozapine can lower the seizure threshold in a dose-dependent manner. The drug represents a significant advancement in the treatment of mental illness.
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PMID:Clozapine. 167 65

Anticonvulsants are commonly used empirically to prevent seizures in patients receiving high-dose busulfan in preparation for bone marrow transplantation. This study evaluates the effects of two anticonvulsants with enzyme-inductive properties, phenytoin and phenobarbital, and an enzyme inducer without anticonvulsant properties, Aroclor 1254, on the myelotoxicity and acute neurotoxicity of busulfan in a murine model. To assess the neuroprotective effects of these agents, we studied the effects of a single dose of 100 mg/kg i.p. busulfan, previously shown in this model to be uniformly lethal due to neurotoxicity. A significantly greater proportion of mice survived when pretreated with phenytoin or phenobarbital as compared with Aroclor 1254 pretreatment or an untreated control group. Busulfan myelotoxicity was studied in another group of mice treated with 135-150 mg/kg given in divided doses over 6 days. The proportion of animals surviving the otherwise myeloablative effects of this regimen were significantly improved by Aroclor 1254, high-dose phenytoin, and phenobarbital pretreatment. We conclude that anticonvulsants offer protection from the acute neurotoxicity of busulfan. However, these enzyme-inducing agents may reduce the myelosuppressive effects as well. These results suggest that an inducible enzyme system such as microsomal or glutathione S-transferases plays an important role in busulfan metabolism, warranting concern over concomitant administration of agents that either induce or inhibit these enzymes.
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PMID:The effect of hepatic enzyme inducers on busulfan neurotoxicity and myelotoxicity. 226 59


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