Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy of valproic acid (VPA) in control of generalized convulsive status epilepticus was tested in a rat model. Rats with cortical cobalt lesions were injected with homocysteine thiolactone to induce secondarily generalized tonic-clonic seizures (GTCS). The median effective dose (ED50) for control of GTCS was 211.9 mg/kg (270 micrograms/ml in serum 30 min post dose) when treatment was given intraperitoneally after the second GTCS. VPA entered both serum and brain very rapidly after injection, with little change in concentration from 5 to 30 min post dose. In earlier experiments with phenytoin, phenobarbital, diazepam and lorazepam in this model, we found that the serum concentrations produced by the ED50s versus GTCS were very similar to those which have been reported to be effective in treating human status epilepticus. If this same relationship holds true for VPA, we would predict that a serum concentration of around 270 micrograms/ml VPA would be required for control of generalized convulsive status epilepticus in human patients. The safety of this high a concentration of VPA has not been tested.
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PMID:Valproic acid treatment of experimental status epilepticus. 139 45

Review of 60 electroencephalograms recorded during episodes of generalized convulsive status epilepticus suggested that there are 5 identifiable EEG patterns which occur in a predictable sequence during the course of generalized convulsive status epilepticus in man: (1) discrete seizures; (2) merging seizures with waxing and waning amplitude and frequency of EEG rhythms; (3) continuous ictal activity; (4) continuous ictal activity punctuated by low voltage 'flat periods'; and (5) periodic epileptiform discharges on a 'flat' background. We confirmed our hypothesis that this sequence represents the natural history of electroencephalographic changes in untreated generalized convulsive status epilepticus by observing the same sequence in the EEGs of rats in which status epilepticus had been induced by 3 different methods: (1) systemic administration of kainic acid, (2) injection of homocysteine thiolactone to cobalt-lesioned rats; and (3) injection of lithium chloride followed 24 h later by injection of pilocarpine.
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PMID:A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. 230 22

Status epilepticus was induced by injection of homocysteine thiolactone to rats with epileptogenic cortical cobalt lesions. Either standard phenytoin or ACC-9653 (a phenytoin prodrug) was injected after the second generalized tonic-clonic seizure. Rats treated with ACC-9653 had significantly poorer treatment outcomes than rats treated with standard phenytoin, although no differences were found in the concentration of phenytoin in plasma or brain 65 min after injection.
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PMID:Efficacy of ACC-9653 (a phenytoin prodrug) in experimental status epilepticus in the rat. 232 17

The study of mechanisms of the epilepsies requires employment of animal models. Choice of a model system depends upon several factors, including the question to be studied, the type of epilepsy to be modelled, familiarity and convenience. Over 50 models are reviewed. Major categories of models are those for simple partial seizures: topical convulsants, acute electrical stimulation, cortically implanted metals, cryogenic injury; for complex partial seizures: kainic acid, tetanus toxin, injections into area tempesta, kindling, rodent hippocampal slice, isolated cell preparations, human neurosurgical tissue; for generalized tonic-clonic seizures: genetically seizure-prone strains of mouse, rat, gerbil, fruitfly and baboon, maximal electroshock seizures, systemic chemical convulsants, metabolic derangements; and for generalized absence seizures: thalamic stimulation, bilateral cortical foci, systemic penicillin, gamma-hydroxy-butyrate, intraventricular opiates, genetic rat models. The lithium-pilocarpine, homocysteine and rapid repetitive stimulation models are most useful in studies of status epilepticus. Key findings learned from each of the models, the model's strengths and weaknesses are detailed. Interpretation of findings from each of these models can be difficult. Do results pertain to the epilepsies or to the particular model under study? How important are species differences? Which clinical seizure type is really being modelled? In a model are behavior or EEG findings only similar superficially to epilepsy, or are the mechanisms comparable? The wealth of preparations available to model the epilepsies underscores the need for unifying themes, and for better understanding of basic mechanisms of the epilepsies.
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PMID:Animal models of the epilepsies. 267 41

Secondarily generalized convulsive status epilepticus was induced by intraperitoneal (i.p.) injection of D,L-homocysteine thiolactone to rats with actively epileptogenic cobalt lesions in motor cortex. This induced focal motor seizures which secondarily generalized. Control animals not treated with antiepileptic drugs had a mean of 18.3 generalized convulsions over a mean period of 103.8 min. Electrographic patterns seen during status epilepticus are described and are very similar to those seen during human status epilepticus. Phenytoin, phenobarbital, diazepam and lorazepam were all effective in arresting the generalized seizures when given i.p. after the second such seizure. Efficacy was serum drug concentration dependent. Concentrations effective in arrest of generalized seizures in this model are similar to those reported to be effective in the treatment of human status epilepticus. Diazepam ED50s for control of generalized tonic-clonic seizures and for arrest of all seizure activity were determined.
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PMID:Experimental secondarily generalized convulsive status epilepticus induced by D,L-homocysteine thiolactone. 319 90

The potential clinical efficacy of tiagabine for control of status epilepticus was evaluated in an experimental model. Tiagabine was administered to cobalt-lesioned rats in which status epilepticus was induced by injection of homocysteine thiolactone. Tiagabine was effective in controlling status epilepticus in this model; the median effective dose for control of generalized tonic-clonic seizures in the model was 8.3 mg/kg. Tiagabine administration produced an abnormal, hypo-reactive behavioral state which was accompanied by an EEG pattern of high-amplitude, frontally dominant, rhythmic, 3-5-Hz spike-wave activity. This EEG and behavioral syndrome could be reproduced by administration of tiagabine to normal, non-epileptic rats. The exact nature of this syndrome remains unclear, but whether it is an epileptic or encephalopathic phenomenon, further study is clearly required before this drug should be considered for use in the treatment of human status epilepticus.
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PMID:Treatment of experimental status epilepticus with the GABA uptake inhibitor, tiagabine. 769

The newly introduced antiepileptic drug, lamotrigine, has been reported to have a mechanism of action similar to that of phenytoin. Because phenytoin is a standard clinical treatment for convulsive status epilepticus, we compared the efficacy of lamotrigine to that of phenytoin in a model of secondarily generalized convulsive status epilepticus in rats that responds to drug concentrations similar to those that have been reported to be clinically useful for this purpose. Status epilepticus was induced in rats with actively epileptogenic cortical cobalt lesions by administration of homocysteine thiolactone. While phenytoin-controlled generalized tonic clonic seizures in this model with a median effective dose of 100.5 mg/kg (16.0 micrograms/ml in serum), lamotrigine was ineffective at doses ranging from 10 to 100 mg/kg, with serum drug concentrations (2.5-43.5 micrograms/ml) within or above the reported 'therapeutic' concentration for LTG treatment of chronic epilepsy. Lamotrigine also failed to prevent the onset of generalized tonic clonic seizures when given prior to homocysteine, while phenytoin was effective in this test. Studies of lamotrigine kinetics in serum and brain revealed that the drug was well-absorbed following i.p. injection and that it entered brain rapidly enough to have exerted an anti-status effect in these experiments. These results suggest that lamotrigine and phenytoin have differences in their mechanisms of anticonvulsant action, leading to very different abilities to control status epilepticus.
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PMID:Lamotrigine vs. phenytoin for treatment of status epilepticus: comparison in an experimental model. 880 Jun 32

In this paper, we utilize a measure of brain dynamics, namely the short-term largest Lyapunov exponent (STLmax) to evaluate the efficacy of treatment in epileptic animals and humans with known antiepileptic drugs (AED) like diazepam and phenobarbital during status epilepticus (SE). This measure is estimated from analysis of electroencephalographic (EEG) recordings at multiple brain locations in both an SE patient and a cobalt/homocysteine thiolactone SE-induced animal. Techniques from optimization theory and statistics are applied to select optimal sets of brain sites, whose dynamics are then measured over time to study their entrainment/disentrainment. Results from such analysis indicate that the observed abnormal spatio-temporal dynamical entrainment in SE is reversed by AED administration (resetting of brain dynamics). These results may provide a potential use of nonlinear dynamical measures in the evaluation of the efficacy of AEDs and the development of new treatment strategies in epilepsy.
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PMID:Brain dynamical disentrainment by anti-epileptic drugs in rat and human status epilepticus. 1727 34

A 23-year-old man using Na-Valproic acid (VPA) was admitted to our clinic due to convulsion. The neurological examination revealed right hemiparesis. From the exitus notes, we learned that his two siblings had died from status epilepticus. Magnetic resonance imaging (MRI), MRI spectroscopy, and diffusion-weighted investigations (DWI) showed acute-subacute ischemic stroke in the left temporo-parieto-occipital region. The patient had an ischemic stroke. Heterozygote methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphism was determined on genetic examination. The homocysteine (Hcy) level was 18.2 mmol/l (5-15 mmol/l). So VPA treatment was stopped and oxcarbazepine treatment was started. MTHFR 677C/T polymorphism is associated with the risk of vascular diseases due to hyperhomocysteinemia. Heterozygote (MTHFR) 677C/T polymorphism has not been reported to be associated with epilepsy. In patients with heterozygote (MTHFR) 677C/T polymorphism and under long-term use of certain drugs the determination of Hcy plasma levels may be useful to prevent the development of atherothrombotic disease.
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PMID:Na VPA-induced acute ischemic stroke in an epileptic patient with methylenetetrahydrofolate reductase gene polymorphism. 1964 48

Patients affected by recurrent seizures frequently present increased homocysteine plasma levels in consequence of treatment with antiepileptic drugs. Homocysteine is proconvulsant and can affect the response to antiepileptic drugs. In addition, high homocysteine plasma levels represent a risk factor for cardiovascular and neurodegenerative diseases. To better define the role of increased homocysteine in epilepsy, we analyzed the effects of homocysteine pretreatment in the pilocarpine model of status epilepticus (SE), which is used to mimic temporal lobe epilepsy (TLE) in rodents. Precisely, we investigated whether a moderate hyperhomocysteinemia, unable to cause seizures, could sensitize rats to pilocarpine and cooperate in inducing brain lesions. We found that a subthreshold dose of pilocarpine (200 mg/kg) is sufficient to induce SE in the majority (approximately 90%) of rats pretreated with homocysteine for 2 weeks, whereas only 40% of saline-treated controls developed SE following the same pilocarpine dose. Furthermore, homocysteine pretreatment led to a significant increase in neuronal cell loss evaluated by counting toluidine blue-stained or Fluoro-Jade-positive cells in hippocampal and parahippocampal regions. Pilocarpine augmented amyloid beta expression in both animal groups. However, pretreatment with homocysteine favored the intraneuronal fibrillar conformation of amyloid beta, thus promoting neurodegeneration. These findings indicate that increased homocysteine levels enhance seizure activity and neurodegeneration in pilocarpine-treated rats and suggest that similar detrimental effects may occur in patients affected by TLE.
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PMID:Homocysteine potentiates seizures and cell loss induced by pilocarpine treatment. 2003 27


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