γ‐Vinyl GABA: A double‐blind placebo‐controlled trial in partial epilepsy

Gram, Lennart; Klosterskov, Peter; Dam, M.

doi:10.1002/ana.410170307

Cited by 156 publications

(71 citation statements)

References 18 publications

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“…Two diffusion-sensitive gradient pulses of 10-ms duration and 85 mT/m amplitude were separated by 25 ms, which resulted in a gradient factor of 1,062 s/mm2. T,-weighted images were acquired with a multislice single-echo sequence (TE,80 ms;TR,1,200 ms; eight slices; I mm thickness). T, relaxation times were calculated from data acquired with a multiecho sequence (TE, 2 1.6 ms; TR, 1,200 ms; six echoes; three slices; 1-mm thickness).…”

Section: Mr Imagingmentioning

confidence: 99%

Effect of Long‐Term Vigabatrin Administration on the Immature Rat Brain

et al. 2000

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Summary:Purpose: To determine whether the neuropathologic changes produced by vigabatrin (VGB; y-vinyl GABA) administration in the developing rat brain are reversible.Methods: We injected rats daily with VGB (2540 mglkgl day, s.c.) from age 12 days for 2 weeks followed by 2 weeks of a drug-free period. Behavioral testing, magnetic resonance (MR) imaging, biochemical assays, and histologic technique were used to assess the adverse effect of VGB in developing brain and its reversibility.Results: At the end of 2 weeks' VGB administration: (a) there was a hyperactivity and a shortened latency to escape out of cool water; (b) white matter appeared hyperintense in T, and diffusion-weighted MR images with 4-15% increases in T,; (c) microvacuolation, TUNEL-positive nuclei, and swollen axons were observed in the corpus callosum; (d) myelin staining indicated a reduction in myelination, as did the reduction in activities of myelin and oligodendrocyte-associated enzymes and the decrease in myelin basic protein on Western blots. Two weeks after stopping VGB administration: (a) MR images were normal, and microvacuolation was no longer in the white matter; (b) reduction in myelination reversed partially; (c) the T, relaxation time remained elevated in the hypothalamus; and (d) the behavioral response remained abnormal.Conclusions: Long-term VGB administration to young rats causes brain injury, which recovers partially on its cessation. The observed cell death, disrupted myelination, and alterations in behavior indicate a need for further safety assessment in infants and children. Key Words: Development-Magnetic resonance imaging-Vigabatrin-White matter.Vigabatrin (VGB; y-vinyl-aminobutyric acid) elevates tissue levels of GABA by irreversibly binding to GABA transaminase, thereby inhibiting GABA degradation. VGB is considered an effective and safe antiepileptic drug (AED) in both adults and children and now is the preferred treatment for infantile spasms (1 4). However, Holmes ( 5 ) has emphasized that the detrimental effects of AEDs may be greater in the developing brain than in the mature brain. In addition, Marson et al. (6) have drawn attention to the paucity of information on the "new" AEDs in childhood epilepsy and advocated the need for randomized clinical trials at an earlier stage of drug development than is currently the case. Although prolonged administration of VGB to adult animals causes potentially reversible intramyelinic edema or microvacuolation (7,8), we demonstrated recently (9) that the adverse effects of VGB may be greater in immature than mature brains. Treatment of rats at age 12-16 days Accepted February 8, 2000. Address correspondence and reprint requests to Dr. U. Tuor at Institute for Biodiagnostics, National Research Council of Canada, 435 Ellice Ave., Winnipeg, Manitoba R3B 1Y6, Canada. E-mail: Ursula. Tuor@ nrc.ca with 15-50 mglkg of VGB daily for 5 days caused decreased myelin staining, axonal degeneration, glial cell death in the white matter, and reactive astrogliosis in the frontal cortex. Whe...

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Section: Mr Imagingmentioning

confidence: 99%

Effect of Long‐Term Vigabatrin Administration on the Immature Rat Brain

et al. 2000

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“…GABA (3,12,29). Currently, there is no evidence of alterations in clinical (3,11,12,22,29,35,36), electrophysiological (14), and psychometric and psychophysiological tests (30), and brain histology (6,10,12,15,27) (18)(19)(20). Since reduced GAD activity should decrease GABA synthesis, the elevated GABA levels were indicative of vigabatrin's effect on prolonging GABA degradation by its profound inhibition of GABA-T.…”

Section: Histopczthologymentioning

confidence: 99%

Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

Yarrington¹,

Gibson²,

Dillberger³

et al. 1993

Toxicol Pathol

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Vigabatrin (Sabril®) is a γ-aminobutyric acid-transaminase (GABA-T) inhibitor that is effective in the treatment of certain types of drug-resistant or uncontrolled epilepsy but is known to cause microscopic vacuolation (intramyelinic edema) in the brains of treated rats, mice, and dogs. The effects of high oral doses (300 mg/kg/day) of vigabatrin administered orally to Beagle dogs were studied during treatment weeks 1-12 and recovery weeks 13, 14, 16, 20, 24, and 28. Emesis, loose stools, and anorexia and 3 drug-related deaths were observed during the first 4 wk of treatment but were virtually nonexistent thereafter because of adaptation to the drug aided by food supplementation. In more sensitive areas of the brain (columns of the fomix, thalamus, and hypothalamus), microscopic quantitative differences between background vacuolation in controls and drug-related vacuolation in treated dogs could be delineated after 4 wk, generally reached highest levels of severity between 8 and 12 wk, and were reversible upon cessation of dosing. Inhibition of brain GABA-T and elevation of brain GABA were noted after 1 wk of treatment. During the course of treatment vigabatrin ranged between 4-17 nmol/ml (plasma) and 42-1,570 nmol/ml [cerebrospinal fluid (CSF)] while CSF GABA concentrations were 4-32 nmol/ml (treated dogs) and 0.1-0.6 nmol/ml (control dogs). Although the cause of vigabatrin-induced microvacuolation is unknown, the results of the study demonstrated that GABA-T inhibition with subsequent GABA elevation occurred within the first week of treatment and was followed by the onset of detectable microvacuolation several weeks later.

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“…Vigabatrin (-y-vinyl GABA), a specific, enzymeactivated irreversible inhibitor of GABA-transaminase (GABA-T) has been shown to be an effective anti-convulsant agent for complex partial seizures (Gram et al, 1983;Browne et al, 1983;Rimmer & Richens, 1984;Gram et al, 1985;Loiseau et al, 1986;Schechter, 1986;Tartara et al, 1986;Tassinari et al, 1987). In all published studies to date vigabatrin has been administered orally on a twice-daily schedule.…”

Section: Introductionmentioning

confidence: 99%

The effect of different vigabatrin treatment regimens on CSF biochemistry and seizure control in epileptic patients.

Ben‐Menachem

Persson

Schechter

et al. 1989

Brit J Clinical Pharma

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1. Vigabatrin, 50 mg kg‐1, was administered orally as add‐on therapy to 11 patients with drug‐resistant complex partial epilepsy as a single dose, then once every third day for 2 months, every other day for 2 months and daily for 1 month. 2. Lumbar punctures were carried out prior to treatment and at the end of each dosage regimen and cerebrospinal fluid (CSF) evaluated for concentrations of free and total GABA, homocarnosine (GABA‐histidine dipeptide), homovanillic acid (HVA), 5‐hydroxyindole acetic acid (5‐HIAA) and vigabatrin. 3. Each regimen resulted in significant increases in CSF concentrations of free and total GABA and homocarnosine compared with the immediately preceding regimen. 4. CSF concentrations of HVA significantly increased after a single vigabatrin dose but returned to pre‐treatment levels with subsequent dosing schedules. In contrast, 5‐HIAA concentrations also increased with the single dose but were significantly decreased, compared with pre‐treatment values, following alternate day and daily vigabatrin administration. 5. Seizure frequency progressively decreased with decreasing dosing interval. Daily vigabatrin administration was associated with greater than 50% decrease in seizures in 8 of the 10 patients treated.

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γ‐Vinyl GABA: A double‐blind placebo‐controlled trial in partial epilepsy

Cited by 156 publications

References 18 publications

Effect of Long‐Term Vigabatrin Administration on the Immature Rat Brain

Effect of Long‐Term Vigabatrin Administration on the Immature Rat Brain

Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

The effect of different vigabatrin treatment regimens on CSF biochemistry and seizure control in epileptic patients.

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