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 efficacy and tolerability of vigabatrin (gamma-vinyl GABA, GVG), given as add-on therapy to 23 adult outpatients with severe drug-resistant epilepsy (17 with partial seizures), were studied using a double-blind, placebo-controlled, crossover design. The study consisted of two 7-week periods during which vigabatrin and placebo were administered in random sequence. Dosage was 1.0 g twice daily for patients weighing less than or equal to 65 kg and 1.5 g twice daily for patients weighing greater than 65 kg. Three patients were dropped from the study, two for reasons unrelated to treatment and one because of the appearance of vertigo, headache, dysarthria, and ataxia, which subsided rapidly when vigabatrin was stopped (3 g daily). Sixteen of the 20 patients available for analysis showed a decrease in the total number of seizures as compared with the placebo period. Of these, 12 showed a greater than 50% reduction in seizure frequency and 4 of the 12 showed a greater than 75% reduction. Both the total number of seizures and the number of partial seizures were significantly reduced by vigabatrin (p less than 0.01). Only in the patient who dropped out were severe adverse effects seen. The most frequently reported unwanted effect was mild drowsiness, which developed in seven patients on vigabatrin and in one on placebo. Positive effects, however, were also seen with six patients who reported an improved sense of well-being while receiving vigabatrin as compared with only 1 during the placebo period. No consistent changes in electrocardiogram (ECG), electroencephalogram (EEG), and visual-, auditory-, and somatosensory-evoked potentials were seen during the study.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vigabatrin in the treatment of epilepsy: a double-blind, placebo-controlled study. 353 69

The effects of microinjection of various neuroactive compounds into the anterior thalamic nucleus (AN) and other selected subcortical regions of guinea pig brain on the expression of pentylenetetrazol (PTZ)-induced behavioral and electrical seizure activity were examined. Excitatory agents, kainic acid (KA), bicuculline (BIC) or PTZ, injected into the AN or other thalamic nuclei, striatum, but not the mammillary bodies (MB), facilitated the EEG convulsant action of systemically administered PTZ. Injection of muscimol into the AN protected against the expression of PTZ-induced repetitive high-voltage EEG seizure discharges and inhibited the facilitatory effects of subcortically applied KA or BIC. Injection of muscimol into the AN was also able to terminate established ongoing seizure discharges. Unilateral application of muscimol to the AN did not prevent the repetitive hypersynchronous EEG discharges following systemic PTZ but did result in the delay in the onset of cortical hypersynchrony in the ipsilateral hemisphere. Muscimol injections into other thalamic nuclei, MB, cortex, striatum or directly into the CSF space had no anticonvulsant effect, however. Microinjection of gamma-vinyl-gamma-aminobutyric acid, a selective GABA transaminase inhibitor, resulted in protection from the behavioral convulsant action and lethal effects of PTZ when administered into the thalamus, especially the AN, but not when injected into the striatum or CSF. These data demonstrate that the AN is an important subcortical nucleus for the mediation of both cortical EEG synchrony and behavioral seizure expression induced by PTZ. In light of previous results establishing a role for the brainstem and diencephalon in PTZ seizure expression, the AN may serve, in part, as a gating mechanism for the propagation of paroxysmal activity between subcortical areas and the cerebral cortex.
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PMID:Anterior thalamic mediation of generalized pentylenetetrazol seizures. 354 79

Studies were undertaken to determine whether enhancement of GABAergic transmission within the substantia nigra could inhibit seizures caused by the novel, long latency convulsant, L-methionine, sulfoximine (MSO; 200 mg/kg i.p.). Bilateral injections of gamma-vinyl GABA (10 micrograms/side) into several brain sites resulted in varying degrees of protection against MSO-induced seizures. However, significant protection was afforded only when gamma-vinyl GABA was infused into the nigra. The protective effect was reduced when injections were made at sites 2 mm dorsal to the nigra, and was further diminished when the drug was injected into the striatum. These results further support the hypothesis that elevation of cerebral GABA levels is protective against a range of experimentally induced seizures, particularly when the substantia nigra is the target of such manipulations.
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PMID:Suppression of methionine sulfoximine seizures by intranigral gamma-vinyl GABA injection. 360 44

Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra.
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PMID:Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. 370 28

Injection of gamma-vinyl aminobutyric acid (GVG) into the anterior thalamus protected rats against pentylenetetrazol (PTZ) seizures but not against maximal electroshock (MES) seizures. Injection of GVG into the substantia nigra protected against MES seizures but not against PTZ seizures. Both types of seizures were prevented by injections into both of the above brain regions. These data indicate that separate neuronal circuits mediate PTZ and MES seizures.
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PMID:Anterior thalamus and substantia nigra: two distinct structures mediating experimental generalized seizures. 380 76

The effects of bilateral microinjections into the substantia nigra pars reticulata of gamma-vinyl GABA and isoniazid, i.e., drugs which manipulate GABA-mediated inhibition, were studied on kindling and kindled seizures induced by daily stimulation of the amygdala in rats. In comparison to saline-injected controls, both gamma-vinyl GABA (5 or 10 micrograms) and isoniazid (150 micrograms/side) retarded the rate of kindling development as measured by the increase in seizure severity. The duration of the motor seizures and the duration of afterdischarges recorded from the stimulated amygdala were less sensitive to the anticonvulsant effect of both drugs, although significant reductions were measured during kindling acquisition. In fully kindled rats, only gamma-vinyl GABA exerted significant effects on kindled seizures, whereas isoniazid was ineffective after intranigral injection, suggesting that the kindling acquisition period is more sensitive to alterations in GABA-mediated transmission than the fully kindled state. The data provide further evidence that the substantia nigra is involved in the development and expression of kindled seizures.
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PMID:Effect of microinjections of gamma-vinyl GABA or isoniazid into substantia nigra on the development of amygdala kindling in rats. 381 84

The antiepileptic effect of gamma-vinyl gamma-aminobutyric acid (GABA), an irreversible GABA-transaminase inhibitor, was investigated in an add-on, placebo-controlled, double-blind, cross-over, fixed-dose trial. Twenty-one patients suffering from difficult to control complex partial seizures participated; 18 patients completed the trial. Serum levels of concomitant antiepileptic drugs were kept constant throughout the trial. Three patients (17%) experienced a 75% reduction in seizure frequency and in 8 (44%) the seizures were reduced by at least 50%. Two patients developed a moderate and 1 patient a marked increase in seizure frequency during treatment with gamma-vinyl GABA. Except for 2 patients who had to discontinue the trial because of adverse effects of gamma-vinyl GABA, the participants were unable to discriminate between treatment regimens with regard to side effects. gamma-vinyl GABA seems to be a promising new antiepileptic drug, and the first one to present convincing evidence of a GABAergic mechanism of action.
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PMID:gamma-Vinyl GABA: a double-blind placebo-controlled trial in partial epilepsy. 392 82

The high seizure susceptibility in epileptic chickens is due to an autosomal recessive mutation. In 3-day-old chicks homozygous for the epilepsy gene (epileptics), elevation of body temperature using microwave diathermy evoked an initial febrile seizure resembling the clonic seizures evoked in epileptic chicks by photic stimulation. After complete recovery, this was followed by a clonic-tonic seizure. In nonepileptic heterozygote hatchmates (carriers) of the same age, only the latter seizure pattern was observed. In 16- to 17-day-old chicks of either phenotype, both seizure patterns were observed during hyperthermia. In all cases, the temperature at which seizures occurred was significantly lower in epileptic than in nonepileptic chicks, indicating a lower threshold for febrile seizures when there is an inherited predisposition to convulse. The occurrence of seizures was dependent on the body temperature and not on the rate of rise of temperature. Elevation of the brain gamma-aminobutyric acid (GABA) concentrations by administration of the GABA transaminase inhibitor gamma-vinyl GABA reduced the incidence of the initial febrile seizures and increased the latency in those birds that were not fully protected.
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PMID:Experimental febrile convulsions in epileptic chickens: the anticonvulsant effect of elevated gamma-aminobutyric acid concentrations. 404 16

The purpose of this study was to investigate the long-term efficacy and tolerability of gamma-vinyl GABA (GVG) in the treatment of epilepsy. 36 patients with severe therapy resistant epilepsies participated, the majority exhibiting complex partial seizures. The mean follow-up period was 9.3 months. GVG was administered as add-on therapy, to keep serum levels of concomitant treatment constant. The mean dose of GVG was 2.6 g's per day. Fifty-six per cent of the patients, including three patients with juvenile myoclonic epilepsy, experienced more than a 50% reduction in seizure frequency. No signs of tolerance development to the antiepileptic effect of GVG was demonstrated. Two patients were withdrawn from GVG treatment due to increased seizure frequency, and two due to side effects in the form of vomiting and nausea. Incidentally, the side effects observed were harmless and transient. Fifty per cent of the patients experienced no side effects at all. GVG seems to be a valuable antiepileptic compound. The results of this long-term study confirm observations from several short controlled trials.
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PMID:Long-term study of gamma-vinyl GABA in the treatment of epilepsy. 406 Oct 51

Twenty-four patients with frequent drug-resistant seizures took part in a randomised double-blind placebo-controlled crossover trial of the GABA-transaminase inhibitor, gamma-vinyl GABA. It was added to their usual drug treatment in a dose of 3 g daily. The total number of seizures during the 9-week active treatment period was less than that in the placebo period (p less than 0.001, two-way analysis of variance). The greatest effect was on complex partial seizures. Mean weekly seizure frequency (complex partial and tonic-clonic) was 6.2 fits/week for the placebo period and 3.5 fits/week for the gamma-vinyl GABA period. Adverse effects, particularly drowsiness and mood changes, occurred more often during administration of active drug. Serum concentrations of phenytoin were lower during gamma-vinyl GABA treatment than during placebo (p less than 0.05), but the concentrations of other anticonvulsants given concomitantly did not change. These results suggest that gamma-vinyl GABA is an effective antiepileptic compound.
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PMID:Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy. 614 35


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