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1. The effects of repeated administration of the anticonvulsant compounds, vigabatrin (VGB) and tiagabine (TGB), on gamma-aminobutyric acid (GABA) concentration and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD) were investigated in mouse cortex. 2. VGB alone increased GABA levels and decreased GABA-T and GAD activities. 3. TGB alone was essentially without effect. 4. Low doses of VGB and TGB in combination increased GABA levels when neither drug had such an effect alone. 5. Despite this observation, this study failed to establish any conclusive evidence for an interaction between VGB and TGB that might help to explain their reported clinical synergism.

Tiagabine (TGB) and vigabatrin (VGB) are two novel anticonvulsant compounds reported to exert their pharmacological effects via an action on the gamma-aminobutyric acid (GABA) system. We have investigated the effects of acute exposure of these drugs on the uptake of GABA into rat cortical astrocytes in primary culture. Astrocytes were prepared from the cerebral cortices of one day-old rat pups by a mechanical dissociation technique and were assayed for GABA uptake activity after 21 days in culture. Tiagabine (100-300 nM) and VGB (100 microM) reduced GABA uptake when compared to control at four hours post-exposure. GABA uptake was also reduced following eight and 24 hour exposures to 200 nM TGB. A combination of TGB (200 nM) and VGB (100 microM) treatments reduced GABA uptake when compared to both control and VGB treated cultures. These results support the efficacy of TGB as a GABA uptake inhibitor and suggest that VGB may also exert an effect by this mechanism.

Tiagabine is a novel antiepileptic drug which acts by decreasing gamma aminobutyric acid uptake in astrocytes and neurones. Here the first case of deliberate overdose with this compound in a patient on concomitant phenytoin is reported. On admission to hospital his conscious level deteriorated to grade III coma. No changes in the electrocardiogram were noted. Recovery from the initial effects was rapid, and there were no sequelae. Plasma levels of tiagabine (3.1 micrograms/ml) 4 hours after ingestion were 30 times higher than at typical steady state during therapeutic dosing. The effects of poisoning with current first-line antiepileptic drugs are reviewed. The newer agents, particularly those with greater biochemical specificity, may be safer in overdose than the more established anticonvulsants.