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)

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

Drugs which elevate brain levels of the inhibitory amino acid neurotransmitter GABA by inhibiting the GABA catabolizing enzyme GABA transaminase (GABA-T) have been developed for treatment of brain disease, such as epilepsy. Among all GABA-T inhibitors available, vigabatrin is thought to be the most selective compound, and this drug is the only GABA-T inhibitor in clinical use. However, some previous studies have indicated that vigabatrin might affect the metabolism of several amino acids not directly linked to the GABA shunt. In the present study, various amino acids, involving inhibitory and excitatory neurotransmitters, were determined in 12 brain regions and plasma of rats after treatment with anticonvulsant doses of vigabatrin and the less selective GABA-T inhibitors aminooxyacetic acid (AOAA) and gamma-acetylenic GABA (GAG). Furthermore, the antiepileptic drug valproate, which is also thought to act via the GABA system, was included for comparison. The GABA-T inhibitors markedly enhanced GABA levels in all brain regions examined, while valproate induced only moderate increases in some regions. All drugs, including valproate, significantly decreased aspartate in the brain to a similar extent, and the GABA-T inhibitors but not valproate decreased levels of glutamate. The decreases in aspartate and glutamate levels were not correlated with the different magnitudes of GABA increase produced by GABA-T inhibitors, suggesting that these effects were not simply due to the altered GABA degradation. In addition to glutamate and aspartate, alanine levels were decreased by GABA-T inhibitors but not valproate in several regions. Brain levels of glutamine were decreased by GAG and vigabatrin but increased by valproate and partly also by AOAA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential effects of vigabatrin, gamma-acetylenic GABA, aminooxyacetic acid, and valproate on levels of various amino acids in rat brain regions and plasma. 820 5

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

The novel antiepileptic drug vigabatrin (Sabril) acts by inhibiting degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), increasing the GABA concentrations in the brain. Because the GABA degrading enzyme GABA aminotransferase (GABA-T) is also present in peripheral tissues, including blood platelets, measurement of plasma GABA levels might be a useful indication of the pharmacological response to vigabatrin during therapeutic monitoring. However, because of the very low concentrations of GABA in plasma, the few methods available for plasma GABA analysis are time-consuming, difficult to perform and/or not selective enough because of potential interference with other plasma constituents. In the present study, a rapid, selective and sensitive amino acid analysis HPLC method has been developed for plasma GABA determination with fluorescence detection, using o-phthaldialdehyde as a precolumn derivatizing agent. By employing a 3 microns particle size reversed-phase column and a multi-step gradient system of two solvents, the very low endogenous concentration of GABA in human plasma could be reproducibly quantitated without interference of other endogenous compounds. Incubation of human plasma samples with GABA degrading enzyme(s) resulted in an almost total loss of the GABA peak, thus demonstrating the specificity of the method for GABA analysis. In addition to GABA and other endogenous amino acids, the HPLC method could be used to quantitate plasma levels of vigabatrin. Thus, this improved HPLC amino acid assay might be used to examine whether concomitant monitoring of plasma GABA and vigabatrin is useful for clinical purposes. This was examined in 20 epileptic patients undergoing chronic treatment with vigabatrin. The average plasma GABA level of these 20 patients did not differ significantly from non-epileptic controls. However, when epileptic patients were subdivided according to their clinical response to vigabatrin, vigabatrin responders had significantly higher GABA levels than nonresponders or controls. In contrast to the difference in plasma GABA, vigabatrin responders and nonresponders did not differ in dose or plasma level of vigabatrin. These data may indicate that determination of plasma GABA is a valuable non-invasive method for therapeutic monitoring in patients on medication with vigabatrin.
Epilepsy Res 1993 Mar
PMID:Determination of GABA and vigabatrin in human plasma by a rapid and simple HPLC method: correlation between clinical response to vigabatrin and increase in plasma GABA. 850 95

Gabapentin is a novel anticonvulsant drug. The anticonvulsant mechanism of gabapentin is not known. Based on the amino acid structure of gabapentin we explored its possible effects on glutamate and gamma-aminobutyric acid (GABA) metabolism in brain as they may relate to its anticonvulsant mechanisms of action. Gabapentin was tested for its effects on seven enzymes in the metabolic pathways of these two neurotransmitters: alanine aminotransferase (AL-T), aspartate aminotransferase (AS-T), GABA aminotransferase (GABA-T), branched-chain amino acid aminotransferase (BCAA-T), glutamine synthetase (Gln-S), glutaminase (GLNase), and glutamate dehydrogenase (GDH). In the presence of 10 mM gabapentin, only GABA-T, BCAA-T, and GDH activities were affected by this drug. Inhibition of GABA-T by gabapentin was weak (33%). The Ki values for inhibition of cytosolic and mitochondrial forms of GABA-T (17-20 mM) were much higher than the Km values for GABA (1.5-1.9 mM). It is, therefore, unlikely that inhibition of GABA-T by gabapentin is clinically relevant. As with leucine, gabapentin stimulated GDH activity. The GDH activity in rat brain synaptosomes was activated 6-fold and 3.4-fold, respectively, at saturating concentrations (10 mM) of leucine and gabapentin. The half-maximal stimulation by gabapentin was observed at approximately 1.5 mM. Gabapentin is not a substrate of BCAA-T, but it exhibited a potent competitive inhibition of both cytosolic and mitochondrial forms of brain BCAA-T. Inhibition of BCAA-T by this drug was reversible. The Ki values (0.8-1.4 mM) for inhibition of transamination by gabapentin were close to the apparent Km values for the branched-chain amino acids (BCAA) L-leucine, L-isoleucine, and L-valine (0.6-1.2 mM), suggesting that gabapentin may significantly reduce synthesis of glutamate from BCAA in brain by acting on BCAA-T.
Epilepsy Res 1995 Sep
PMID:Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. 856 62

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

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is not solely located in the CNS, it and the enzymes responsible for its synthesis (glutamic acid decarboxylase, GAD, EC 4.1.1.15) and catabolism (GABA-transaminase, GABA-T, EC 2.6.1.19) are also present in non-neuronal organs. Following 2, 8 and 21 day oral administration of ethanolamine-O-sulphate (EOS) and gamma-vinyl GABA (GVG), two irreversible inhibitors of GABA-T, the GABA content and activities of GAD and GABA-T in rat brain, liver and kidney, and the GABA content of plasma were determined: GABA-T activity was significantly decreased (over 80%) in liver, brain and kidney, although there was 2-3 times the residual activity left in the brain compared with the peripheral organs. GABA content was subsequently significantly elevated in the liver (300-1500%), plasma (200-300%) and brain (200-300%), although, surprisingly, the kidney GABA content was reduced (by 60-70%) compared with control. GAD activity was decreased following 8 day treatment in liver and brain. Kidney GAD was reduced at all time points. These two compounds are anticonvulsant, GVG is used clinically for the treatment of epilepsy but it seems that these drugs have significant peripheral effects.
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PMID:Effects of chronic oral treatment with GABA-transaminase inhibitors on the GABA system in brain, liver, kidney, and plasma of the rat. 893 45

We have used quantitative immunocytochemistry to examine the content of GABA and glutamate in rabbit retinae where the enzyme GABA transaminase has been selectively inhibited. Inhibition of GABA breakdown led not only to the expected rise in GABA levels in neurones and glial cells but also to a reduction in neuronal pools of glutamate, particularly in neuronal elements in the inner plexiform layer. We suggest that a significant proportion of the glutamate pool in nerve terminals is derived from GABA via the GABA shunt. This observation is of practical significance since GABA transaminase inhibitors are used in the treatment of epilepsy; accordingly GABA-transaminase inhibitors may modify uncontrolled excitatory episodes in the brain both by raising levels of GABA, and reducing levels of the excitatory transmitter, glutamate.
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PMID:GABA transamination regulates neuronal glutamate content in the retina. 898 47

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


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