Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P80404 (GABA transaminase)
 786 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Nearly three-fourths of all newly diagnosed cases of epilepsy are easily controlled with our current drug armamentarium. Further progress will undoubtedly come with use of three new drugs, gabapentin, lamotrigine, and vigabatrin now in diverse stages of clinical trials. Gabapentin is a gamma-aminobutyric acid (GABA) analog which passes the blood-brain barrier. Its mode of action is unknown. The anti-convultion effect of lamotrigine apparently results from its capacity to stabilize voltage-dependent sodium channels and thus limit release of the excitory neuromediator glutamate. Vigabatrin produces irreversible inhibition of GABA transaminase, increasing the concentration of this neurotransmittor inhibitor in the brain. The pharmacokinetic properties of these three anti-epileptics are more favorable than those of earlier drugs. Renal excretion is proportional to creatinine clearance allowing better dose adjustment and all three can be associated with oral contraception. They are as effective as the classical agents although indications may vary. There are fewer adverse effects and no teratogenic effect has been observed in animal studies. Clinical surveillance is usually sufficient without laboratory tests. One handicap is the increased cost although it has been demonstrated that the overall cost for the society for a patient with well controlled epilepsy is less. The prescription of a third-generation anti-epileptic drug is justified immediately whenever treatment with one of the classical drugs has been unsuccessful; however, in case of failure the new drug should not be continued.
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PMID:[New medical treatment of epilepsy]. 868 6

Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, gamma-aminobutyric acid type A (GABAA) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABAA receptor-mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium-channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T-type) calcium-channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high-affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high-frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underline the clinical efficacy of VGB.
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PMID:Antiepileptic drug mechanisms of action. 878 10

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

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

Great progress has been made in the development of antiepileptic drugs (AEDs) from their early empirical stage until the current scientifically-founded advancement based on our greater understanding of the genesis of epilepsy. Available AEDs decrease neuronal membrane excitability, acting on ion channels or synaptic receptors. The classic AEDs act on sodium channels (phenytoin and carbamazepine); increase GABA-A receptor-mediated inhibition (benzodiazepines and barbiturates); and on T-type Ca2+ channels (sodium valproate and ethosuximide). Many patients are resistant to these AEDs. The introduction of new drugs whose mechanisms of action are not well established has improved therapeutic prospects. Four promising new AEDs are now available in many countries. Vigabatrin is an irreversible inhibitor of GABA transaminase. Lamotrigine blocks Na+ channels, thereby inhibiting the presynaptic release of excitatory neurotransmitters. Gabapentin increases GABAergic inhibition and Felbamate acts on the NMDA receptor and Na+ channels. New techniques in molecular biology are likely to facilitate the design of better AEDs.
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PMID:[Antiepileptic drugs: mechanism of action]. 905 61

The antiepileptic drug, vigabatrin, inhibits GABA transaminase, thus elevating GABA levels in the brain. In adult animal experiments, high-dose (200 mg/kg/day) chronic vigabatrin administration is associated with potentially reversible myelin vacuolation, a phenomenon not documented in humans. We hypothesized that vigabatrin might adversely affect myelination in the developing brain. Rats were given vigabatrin in doses comparable to those used clinically (15-50 mg/kg/day), from age 12 to 16 days. The rats were killed at age 19-20 days. We observed decreased myelin staining in the external capsule, axonal degeneration in white matter, evidence of glial cell death in the white matter, and reactive astrogliosis in the frontal cortex. We did not detect myelin vacuolation. These findings indicate that vigabatrin can have adverse and potentially irreversible effects on the developing rat brain. The mechanism of damage could be direct toxicity of vigabatrin or an indirect effect mediated through elevated GABA levels. Vigabatrin has been recommended as a treatment for some forms of childhood epilepsy; therefore, further studies are needed to assess the risks in children.
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PMID:Low-dose vigabatrin (gamma-vinyl GABA)-induced damage in the immature rat brain. 916 39

Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed prior to 1980 appear to act on sodium channels. gamma-amino butyric acid type A (GABAA) receptors (GABARs) or calcium channels. Benzodiazepines and barbiturates enhance GABAR-mediated inhibition. Phenytion, carbamazepine and possibly sodium valproate decrease high-frequency repetitive firing of action potentials by enhancing sodium channel inactivation. Ethosuximide and sodium valproate reduce a low threshold (T-type) calcium channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin binds to a high affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of gabapentin into neurons; however, this has not been proven and the mechanism of action of gabapentin remains uncertain. Lamotrigine decreases sustained high-frequency repetitive firing of voltage-dependent sodium actin potentials that may result in a preferential decreased release of presynaptic glutamate. Oxcarbazepine's mechanism of action is not known; however, its similarity in structure and clinical efficacy to that of carbamazepine suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underlie the clinical efficacy of vigabatrin. The potential mechanistic bases for rational polypharmacy are reviewed.
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PMID:Is there a mechanistic basis for rational polypharmacy? 929 30

Vigabatrin (gamma-vinyl GABA) is an antiepileptic drug and blocks GABA transaminase activity resulting in elevations in cellular GABA levels in the brain. Nipecotic acid (NPA) promotes release of GABA from neonatal optic nerve astrocytes, resulting in a bicuculline-sensitive depolarization of the optic nerve axons. The NPA-induced depolarization of vigabatrin-treated rats (100 mg/kg, i.p.) more than doubled, suggesting an elevation in free GABA levels; the GABA transporter inhibitor, NO-711 reduced the depolarization. These results are consistent with the known ability of vigabatrin to block the GABA degradation enzyme GABA-transaminase, suggesting that vigabatrin elevates astrocytic GABA levels, thereby favoring greater release of GABA through the GABA transporter.
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PMID:Vigabatrin enhances promoted release of GABA in neonatal rat optic nerve. 955 81

Previous studies have demonstrated that the expression of one of the isoforms of glutamate decarboxylase, GAD67, is selectively reduced in cultured cortical neurons and in rat cerebral cortex when the concentration of GABA is elevated. We asked whether the expression of GAD67 was similarly affected by elevated GABA throughout the brain. The concentration of GABA in rat brain was increased by inhibiting GABA transaminase (GABA-T) with vigabatrin (gamma-vinylGABA, GVG), an antiepileptic drug and selective inhibitor of GABA-T. Rats were injected with saline or vigabatrin (150 mg/kg) daily for 5 days, and the effects of accumulated GABA on total GAD activity and the expression of GAD65 and GAD67 proteins were determined in twelve brain regions. The GABA concentration was significantly elevated in all regions except amygdala and olfactory bulb after vigabatrin treatment. Total GAD activity was significantly lower than controls in six regions: cerebellum, frontal cortex, thalamus, substantia nigra, ventral tegmentum, and the remaining midbrain. The decrease in GAD activity was largest in cerebellum and thalamus (33% and 29%), while the changes in the other four areas were 15-18%. Vigabatrin treatment significantly reduced GAD67 protein in all regions except olfactory bulb, whereas GAD65 protein decreased significantly only in cerebellum. The failure to detect significant changes in GAD activity in regions having a significant change in GAD67 levels is attributable to the small contribution of GAD67 to total GAD in those regions. It is evident that there are marked regional differences in the effects of tissue GABA levels on the expression of GAD67.
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PMID:Elevation of brain GABA levels with vigabatrin (gamma-vinylGABA) differentially affects GAD65 and GAD67 expression in various regions of rat brain. 966 22


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