Reduction of Plasma Alanine Aminotransferase During Vigabatrin Treatment

Foletti, G.; Delisle, M.C.; Bachmann, C.

doi:10.1111/j.1528-1157.1995.tb01618.x

Cited by 12 publications

(3 citation statements)

References 14 publications

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“…See Supporting Information Tables 3 and 4 for the summary of testing. There also was no in vitro effect on aspartate aminotransferase, alanine aminotransferase, or succinic semialdehyde dehydrogenase, unlike vigabatrin, which is known to reduce activities of alanine aminotransferase 23,24 and succinic semialdehyde dehydrogenase 25 in vivo. CPP-115 also did not inhibit or induce CYP1A2, CYP2B6 and CYP3A4/5 or inhibit CYP2C8, CYP2C9, CYP2D6, which are the more common human liver microsomal cytochrome P450 enzymes (100 μM).…”

Section: Resultsmentioning

confidence: 93%

(1S, 3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction

Pan

Gerasimov

Kvist³

et al. 2011

J. Med. Chem.

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Vigabatrin, a GABA aminotransferase (GABA-AT) inactivator, is used to treat infantile spasms and refractory complex partial seizures and is in clinical trials to treat addiction. We evaluated a novel GABA-AT inactivator (CPP-115) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. Using in vivo microdialysis techniques in freely moving rats and micro-PET imaging techniques, CPP-115 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at 1/300–1/600th the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose 1/300th that of vigabatrin. Electroretinographic (ERG) responses in rats treated with CPP-115, at doses 20–40 times higher than those needed to treat addiction in rats, exhibited reductions in ERG responses, which were less than the reductions observed in rats treated with vigabatrin at the same dose needed to treat addiction in rats. In conclusion, CPP-115 can be administered at significantly lower doses than vigabatrin, which suggests a potential new treatment for addiction with a significantly reduced risk of visual field defects.

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Section: Resultsmentioning

confidence: 93%

(1S, 3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction

Pan

Gerasimov

Kvist³

et al. 2011

J. Med. Chem.

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“…VGB is not appreciably metabolized, which is consistent with a low likelihood of hepatocellular damage (72). However, VGB, because of its mechanism of transaminase inhibition, causes a reduction in ALT and AST levels (73). It is not known whether this can mask early elevations in transaminases in patients with hepatocellular damage.…”

Section: Idiosyncratic Reactionsmentioning

confidence: 88%

Vigabatrin

French

1999

Epilepsia

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Summary: Vigabatrin (VGB) is a structural analogue of the inhibitory neurotransmitter y-amino butyric acid (GABA), which produces its antiepileptic effect by irreversibly inhibiting the degradative enzyme GABA-transaminase. This produces an increase in central nervous system (CNS) GABA levels. VGB is among the few antiepileptic drugs (AEDs) that was synthesized with a specific targeted mechanism in mind and was subsequently demonstrated to function by that mechanism. Ti- HISTORY AND MECHANISM OF ACTIONVigabatrin (VGB) was first synthesized in the 1970s and was used clinically for the first time in 1979. Therefore, the clinical experience with this drug spans a longer time period than most of the new AEDs. VGB is approved for use in over 50 countries worldwide, and it is estimated that 175,000 patients have been exposed to the drug. The efficacy of VGB is well known, both in partial epilepsy and in some pediatric epilepsy syndromes.VGB consists of a racemic mixture of R-and Senantiomers. The R-enantiomer is completely inactive (1). It is presumed that the pharmacologic and toxic effects of vigabatrin are produced by the S-enantiomer.The primary mechanism of action of VGB is believed to arise from irreversible inhibition of GABA-transaminase, producing an increase in brain GABA. Experimental evidence demonstrates a clear relationship between brain GABA levels and seizures. Patients with partial epilepsy have lower mean brain GABA levels than controls. In investigations performed with magnetic resonance spectroscopy (MRS), there was a significant correlation between low GABA levels and recent seizures. Well-controlled epilepsy patients had higher mean brain GABA levels than those who were poorly controlled (2). In addition, when GABA levels are measured with implanted microdialysis catheters in patients with temporal lobe epilepsy undergoing presurgical evalua-

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“…Deficiency of OAT results in accumulation of ornithine in tissues; however, the pathophysiologic mechanism of ornithine leading to visual field defects is unknown. Nonetheless, ornithine levels have been shown to increase in the brain of VGB‐treated mice, and VGB is known to inhibit other transaminases besides GABA transaminase . Therefore, it is hypothesized that VGB may elevate ornithine levels in tissues by binding to OAT or indirectly via GABA inhibition of OAT.…”

Section: Ornithinementioning

confidence: 99%

Vigabatrin-associated retinal damage - potential biochemical mechanisms

Heim

Gidal

2012

Acta Neurol Scand

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Vigabatrin (VGB), an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase, is approved as adjunct treatment of refractory partial seizures as well as infantile spasms. Although VGB has been proven to be effective, its use is limited by the risk of retinopathy and associated peripheral visual field defects. This review describes and analyzes current literature related to potential pathophysiologic mechanisms underlying VGB-mediated cellular toxicity. Animal data suggest that GABA mediates neural excitotoxicity. The amino acid taurine is concentrated in retinal cells, and deficiency of this amino acid may be involved in VGB-mediated retinal degeneration and possible phototoxicity.

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Reduction of Plasma Alanine Aminotransferase During Vigabatrin Treatment

Cited by 12 publications

References 14 publications

(1S, 3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction

(1S, 3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction

Vigabatrin

Vigabatrin-associated retinal damage - potential biochemical mechanisms

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