Double-blind Study of Vigabatrin in the Treatment of Drug-Resistant Epilepsy

Tassinari, C. A.; Michelucci, Roberto; Ambrosetto, G.; Salvi, Fabrizio

doi:10.1001/archneur.1987.00520210009010

Cited by 137 publications

(87 citation statements)

References 16 publications

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“…Animal studies have shown that elevation of brain GABA by this mechanism can prevent experimental seizures (2 1- 23,29), and clinical trials have shown vigabatrin to have beneficial eKects in 'certain types of drug re-sistant or uncontrolled epilepsy (4,8,20,26,31,32).…”

Section: Introductionmentioning

confidence: 99%

Chronic Toxicity Studies with Vigabatrin, A GABA-Transaminase Inhibitor

Gibson¹,

Yarrington²,

Loudy³

et al. 1990

Toxicol Pathol

118

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The GABA-transaminase inhibitor, vigabatrin, has been shown to have a rather low degree ofacute toxicity in several animal species. Oral administration ofthe drug at 1,000 mg/kg/day for 2 4 weeks caused decreased food consumption and weight loss with resultant prostration and death in both rats and dogs. Dosages of 200 mg/kg/day were tolerated for a year without clinical signs in dogs, although rats suffered reduced weight gains and convulsions after 3-4 months when given the drug in the diet. The convulsions continued to occur frequently throughout the one-yr study, but abated 3 4 months after cessation of treatment. The only consistent histopathologic evidence of toxicity in rats and dogs has been the finding of intramyelinic edema (microvacuolation) in the brain, most notably in certain areas ofwhite matter (cerebellum, reticular formation and optic tract in rats and columns of fornix and optic tract in dogs). No lesions were found in the spinal cord or peripheral nervous system. It took several weeks for the microvacuolation to develop, even at high dosages, but it did not continue to progress thereafter, even though a slight effect was noted at dosages as low as 30-50 mg/kg/day after one yr of treatment. The intramyelinic edemia disappeared within a few weeks after treatment was withdrawn. No residual effects were observed in dogs, whereas rats exhibited swollen axons and microscopic mineralized bodies in the cerebellum. Monkeys exhibited no adverse clinical effects except for occasional loose stools at 300 mg/kg/day. After 16 months of oral treatment at 300 m&g/day any suggestion of intramyelinic edema was considered to be equivocal, and there was no evidence of any erect in the 50 or 100 mg/kg/day monkeys after 6 yr of treatment. Higher doses caused chronic diarrhea, thus limiting the dosage in this species. Vigabatrin was shown to be well absorbed in rat, dog and man, whereas dose-limited absorption occurred in the monkey. Metabolism is practically nil in all 4 species and the primary elimination pathway is by glomerular filtration. Because vigabatrin is an irreversible inhibitor of GABA-transaminase and the enzyme has a slow turnover rate, plasma levels of the drug are not indicative of its pharmacologic activity. For this reason cerebrospinal fluid levels ofGABA and vigabatrin were evaluated, with considerable species differences being noted. The significance of these differences in relation to the differences in toxic response is discussed.

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Section: Introductionmentioning

confidence: 99%

Chronic Toxicity Studies with Vigabatrin, A GABA-Transaminase Inhibitor

Gibson¹,

Yarrington²,

Loudy³

et al. 1990

Toxicol Pathol

118

View full text Add to dashboard Cite

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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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“…This was demonstrated in an adjunctive crossover study in which seizures worsened in some patients crossing over from VGB to placebo but not in those changing from placebo to VGB (20)(21)(22). A withdrawal rate of 0.5-1 @week is usually safe.…”

Section: Effect Of Age and Disease Statementioning

confidence: 96%

“…In most studies, responder (50% seizure reduction) rates were between 40 and 50%, as were mean overall seizure reduction rates. All controlled trials have shown statistically significant seizure reductions in VGB treated patients (20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Efficacymentioning

confidence: 99%

“…The most common adverse events reported in patients receiving VGB add-on therapy are drowsiness and fatigue, dizziness, anxiety, headache, irritability, and gastrointestinal disorders (25,45,46). Drowsiness, the most common CNS side effect, is reported in 1340% of patients and tends to be most pronounced during initiation of therapy, diminishing with continued use (22,25,34,27). Weight gain has been reported in some long-term VGB studies (31,32,34).…”

Section: Dose-related Side Effectsmentioning

confidence: 99%

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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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Double-blind Study of Vigabatrin in the Treatment of Drug-Resistant Epilepsy

Cited by 137 publications

References 16 publications

Chronic Toxicity Studies with Vigabatrin, A GABA-Transaminase Inhibitor

Chronic Toxicity Studies with Vigabatrin, A GABA-Transaminase Inhibitor

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

Vigabatrin

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