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)

A 32 year old patient with refractory complex partial seizures was treated with vigabatrin for 3.5 years. Before starting treatment and at 42 months, lumbar punctures were done and the CSF analyzed for amino acids including GABA. Although the patient experienced a 50% seizure reduction, he underwent a left sided temporal lobectomy, and the tissue sample was also analyzed for amino acid content. It was found that vigabatrin caused a three-fold increase in total and free GABA in both the tissue sample and CSF. There were no other significant changes in the other amino acids analyzed. Seizure reduction seen initially was maintained over the long-term observation period. The finding of a specific increase of GABA in brain tissue and CSF of this patient treated with vigabatrin provides additional support to the concept that the primary effect of vigabatrin is as a selective enzyme activated irreversible inhibitor of GABA transaminase.
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PMID:Effect of long-term vigabatrin therapy on GABA and other amino acid concentrations in the central nervous system--a case study. 811 75

Among some 14 new antiepileptic drugs (AEDs), those most extensively tested in humans include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), vigabatrin (VGB), and zonisamide (ZNS). All are currently marketed in some but not all countries. Although no large, comparative studies on efficacy have been conducted, all of these new AEDs are effective in adult localization-related epilepsies, and some have activity in specific syndromes. Although these drugs all have some CNS side effects, especially when administered in combination with other AEDs, they also all have low toxicity profiles. The availability of AEDs with different mechanisms of action may facilitate rational polytherapy. FBM is not teratogenic in animals. Half-life of FBM in humans is 11-28 h. Daily FBM dosages are 15-45 mg/kg in children and 2,400-4,800 mg in adults. Side effects include insomnia and anorexia, with weight loss. FBM increases phenytoin (PHT) and valproate (VPA) concentrations, and FBM concentration may be affected by other drugs. It is available in the United States for treatment of Lennox-Gastaut syndrome and partial seizures in adults. GBP is very water soluble. Half-life of GBP in humans is 5-7 h and daily dosages range from 900 to 2,400 mg in adults. Few side effects have been observed. GBP is not metabolized by the liver and has no drug interactions. It is available in the United Kingdom and the United States. LTG has no teratogenicity in animal models. Half-life of LTG in humans depends on co-medication: with enzyme inducers it is 15-24 h, and with VPA it is approximately 60 h. LTG dosages are 100-600 mg/day in adults. LTG is available in Europe. OCBZ is rapidly metabolized to 10,11-dihydro-10-hydroxy-carbazepine (MHD), the active compound. Animal studies have shown similar efficacy but superior toxicity to carbamazepine (CBZ) in animal models. For MHD, half-life ranges from 10 to 15 h in patients. OCBZ dosages range from 300 to 1,800 mg/day. VGB is a potent, irreversible inhibitor of GABA transaminase which elevates GABA levels in the CNS. Daily dosages of 2,000-4,000 mg of VGB are needed in adults. Although intramyelinic edema has developed in rats and dogs, it has not yet presented in other mammals or humans. ZNS is a sulfonamide effective in animal models of epilepsy. Half-life of ZNS is 27-36 h. ZNS daily dosage is 400-600 mg. ZNS has been effective in some cases of Baltic myoclonic epilepsy.
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PMID:Antiepileptic drugs in development: prospects for the near future. 817 17

Vigabatrin (gamma-vinyl-GABA), a structural analogue of GABA, is a selective inhibitor of GABA transaminase. Vigabatrin has been effective in patients with refractory epilepsy. We treated patients with complex partial seizures and some of them also with secondary generalized seizures. Vigabatrin was administered as "add on therapy" (Table 1) and monotherapy (Table 2). As to table 1, concerning a variety of treatments and too few patients we could not reach any definitive statistical conclusion (paired Student's t test not significant). In table 2 the paired Student's t test was significant with p < 0.01. Longer follow-up is needed to determine whether the clinical effect is maintained and no severe side effects appear.
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PMID:[Gamma-vinyl-GABA: the first trials in Italy]. 847 29

Localized 1H NMR spectroscopy in conjunction with J editing was used to measure the concentration of gamma-aminobutyric acid (GABA) in the occipital lobe of four control human volunteers and four epileptic volunteers who were receiving the drug vigabatrin. The GABA concentration measured in four nonepileptic subjects was 1.1 +/- 0.1 mumol/cm3 of brain, which is in good agreement with previous values measured in surgically removed human cortex. A dose-dependent elevation of GABA concentration was measured in patients receiving the GABA transaminase inhibitor vigabatrin, with the maximum measured level of 3.7 mumol/cm3 of brain measured at the highest dose (6 g per day) studied. 1H NMR measurements of GABA in those patients receiving GABA-elevating agents such as vigabatrin will be of importance in establishing the relationship between seizure suppression and the concentration of brain GABA.
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PMID:Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo. 851 15

Depending on their mechanism of action, anticonvulsant drugs in clinical use may be divided into three groups: those drugs which facilitate gamma-aminobutryic acid (GABA)ergic neurotransmission; those which block neuronal ion channels; and those whose mechanism of action is unresolved. The compounds acting on GABAergic systems may be further subdivided into those which modulate transmission through chloride channels, e.g. the barbiturates and the benzodiazepines; those compounds, in particular vigabatrin, which reduce the degradation of GABA by blocking GABA transaminase; and those which inhibit the re-uptake of GABA into the presynaptic terminal. The other group of compounds whose mechanism of action is known are those which block neuronal ion channels. Blockage of voltage-operated sodium channels by lamotrigine, phenytoin or carbamazepine leads to decreased electrical activity and, probably, a subsequent reduction in glutamate release. Conversely, ethosuximide, blocks voltage-operated calcium channels, especially those which mediate calcium currents in thalamic neurones. Of those drugs in which the mechanism of action is unknown, sodium valproate is the prime example. An antagonistic action at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor might also be a possibility, which could be the case with some of the newer compounds currently undergoing evaluation.
Seizure 1995 Dec
PMID:Mechanisms of action of antiepileptic drugs. 871 18

gamma-Aminobutyric acid (GABA) was first proposed as a putative inhibitory neurotransmitter by Elliot and van Gelder in 1958. Since then, numerous efforts have been made to find ways to increase GABA at its receptor sites, based on the findings that decreased GABA results in convulsions in animals and that agents enhancing GABA-mediated functions can have antiepileptic effects. However, the relationship between GABA levels and seizures is not simple. Seizures can occur even in the presence of elevated GABA levels. Indeed, it is possible that regional biochemical differences in the brain can be important. The antiepileptic effects of GABA depend on the mechanism whereby GABA-mediated inhibition is enhanced. Since the 1970s, several compounds have been developed that are designed to act in some manner on the GABA system. These compounds affect GABA-mediated inhibition at different levels and appear to have varied effects, depending on their mechanism of action. To date, specific antiepileptic drugs (AEDs) with potential GABA-inhibitory effects have been designed either to have GABA agonist properties, to inhibit GABA catabolism, to inhibit GABA uptake, or to facilitate GABA release or facilitate GABAA receptor activity. Vigabatrin (VGB) was designed specifically to inhibit GABA transaminase and thereby increase the availability of GABA in the brain. Study data and clinical experience over the past 14 years have demonstrated VGB to be an effective AED.
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PMID:Vigabatrin. 878 18

Levetiracetam ((S)-alpha-2-oxo-pyrrolidine acetamide, ucb L059) is a novel anticonvulsant drug presently in clinical development. Its mechanism of action is unknown although a recently novel specific binding site for [3H]levetiracetam, unique to brain, may be involved. This binding site has yet been characterized, but some evidence suggested a possibly indirect interaction with the GABA system. We therefore examined levetiracetam's effects on GABA metabolism and turnover in several rat brain regions after systemic administration of anticonvulsant doses. Furthermore, in order to study functional effects of levetiracetam on a well defined system of GABAergic neurons in a brain region that has been critically involved in anticonvulsant drug action, we examined levetiracetam's action on spontaneous firing of substantia nigra pars reticulata (SNR) neurons in anesthetized rats. Although levetiracetam did not alter the activity of the GABA synthesizing and degrading enzymes glutamic acid decarboxylase (GAD) and GABA aminotransferase (GABA-T) in vitro, systemic administration induced significant alterations in these enzymes in several brain regions, indicating that these enzyme alterations were no direct drug effects but a consequence of postsynaptic changes in either GABAergic or other neurotransmitter-related systems. In the striatum, levetriacetam, 170 mg/kg i.p., induced a significant increase in GABA-T activity while GAD activity markedly decreased. When GABA turnover was estimated after inhibition of GABA-T by aminooxyacetic acid (AOAA), treatment with levetiracetam (given 15 min prior to injection of AOAA) significantly reduced GABA turnover in the striatum. Since the substantia nigra pars reticulata (SNR) receives a strong GABAergic input from the striatum, we examined if the alterations in GABA metabolism and turnover in the striatum led to functional alterations in neuronal activity in the SNR by recording single unit activity of SNR neurons after i.p. injection of levetiracetam. While injection of vehicle did not affect SNR neuronal activity, a significant decrease in spontaneous neuronal firing was recorded after levetiracetam. Since a substantial body of evidence suggests that the SNR is a critical site at which decrease of neuronal firing results in protection against various seizure types, the suppressive effect of levetiracetam on SNR activity may contribute to the anticonvulsant action of this drug.
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PMID:The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata. 891 59

Vigabatrin (VGB) is a recently-released antiepileptic drug which works by a clearly-defined mechanism of action: inhibition of GABA transaminase leading to an elevation of brain GABA concentration. It has been proven effective, mainly as an add-on agent, in complex partial and secondarily generalized seizures in both adults and children as well as in infantile spasms in both short and long-term controlled studies. World-wide experience now includes over 150,000 patients exposed to the drug. VGB has a favorable pharmacokinetic profile since it has little protein-binding, is mainly excreted unchanged by the kidney and has a long effective half-life allowing once or twice daily dosing. It is generally well-tolerated with very few cognitive effects but may cause significant behavioral side effects such as agitation, irritability, depression or psychosis in approximately 2-4% of cases. Mild weight gain and possible exacerbation of absence and myoclonic seizures are other reported adverse effects. The role of VGB in other childhood epileptic syndromes apart from West syndrome is still being defined.
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PMID:Vigabatrin. 895 Dec 15

Limbic motor seizures in animals, analogous to complex partial seizures in humans, result in a consistent activation of the mediodorsal thalamus (MD) and, with prolonged seizures, damage to MD. This study examined the functional role of MD in focally evoked limbic motor seizures in the rat. GABA- and glutamate (Glu)-mediated synaptic transmissions in MD were evaluated for an influence on seizures evoked from area tempestas (AT), a discrete epileptogenic site in the rostral piriform cortex. A GABAA receptor agonist, Glu receptor antagonists, or a GABA-elevating agent were focally microinfused into MD before evoking seizures by focal application of bicuculline methiodide into the ipsilateral AT. Focal pretreatment of MD with the GABAA agonist muscimol (190 pmol) protected against seizures evoked from AT. Seizure protection was also obtained with the focal application of 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (500 pmol), an antagonist of the AMPA subtype of Glu receptors, into MD. In contrast, focal pretreatment of MD with a competitive antagonist of the NMDA receptor 2-amino-7-phosphonoheptanoic acid (500 pmol) did not attenuate seizures. The anticonvulsant effects achieved with intra-MD injections of muscimol and NBQX were site-specific, because no seizure protection was obtained with injections placed 2 mm ventral or lateral to MD. Prolonged seizure protection was obtained following GABA elevation in MD after the application of the GABA transaminase inhibitor vigabatrin (194 nmol). These results suggest the following: (1) MD is a critical participant in the generation of seizures elicited focally from piriform cortex; (2) transmission via AMPA receptors, but not NMDA receptors, in MD regulates limbic seizure propagation; and (3) a GABA-mediated system exists within MD, the enhancement of which protects against focally evoked limbic motor seizures.
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PMID:Mediodorsal thalamus plays a critical role in the development of limbic motor seizures. 978 5

4-Aminobutyrate aminotransferase (GABA-transaminase, GABA-T, EC 2.6.1.19) deficiency (McKusick 137150), an inborn error of GABA degradation, has until now been documented in only a single Flemish child. Compared to the other defects of GABA degradation, succinic semialdehyde dehydrogenase (SSADH, EC 1.2.1.24) deficiency with > 150 patients (McKusick 271980) and pyridoxine-dependent seizures with > 100 patients ('putative' glutamic acid decarboxylase (GAD, EC 4.1.1.15) deficiency; McKusick 266100), GABA-T deficiency is very rare. We present a summary of the clinical, biochemical, enzymatic and molecular findings on the index proband, and a recently identified second patient, with GABA-T deficiency. The phenotype in both included psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures and electroencephalographic abnormalities. In an effort to elucidate the molecular basis of GABA-T deficiency, we isolated and characterized a 1.5 kb cDNA encoding human GABA-T, in addition to a 41 kb genomic clone which encompassed the GABA-T coding region. Standard methods of cloning and sequencing revealed an A-to-G transition at nucleotide 754 of the coding region in lymphoblast cDNAs derived from the index proband. This mutation resulted in substitution of an invariant arginine at amino acid 220 by lysine. Expression of the mutant in E. coli, followed by isolation and enzymatic characterization of the recombinant protein, revealed an enzyme whose Vmax was reduced to 25% of wild-type activity. The patient and father were heterozygous for this allele; the second allele in the patient remains unidentified. Genomic Southern analysis revealed that the second proband most likely harbours a deletion in the 3' region of the GABA-T gene.
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PMID:4-Aminobutyrate aminotransferase (GABA-transaminase) deficiency. 1040 78


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