Tiagabine: A potent antiepileptic drug with selective GABA uptake inhibitory effect
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abstract
Tiagabine is a nipecotic acid derivative discovered through mechanistic- based drug design program for the treatment of epilepsy. Tiagabine is a specific and potent -aminobutyric acid (GABA)-uptake inhibitor whose anticonvulsant activity has been demonstrated in several widely used animal experimental models including methyl-6,7-dimethoxy-4-ethyl--carboline-3- carboxylate induced clonic convulsions, pentylene tetrazol (PTZ)-induced tonic convulsions, sound-induced convulsions in DBA/2 mice, genetically epilepsyprone rats, electrically induced convulsions in kindled rats and status epilepticus in cobalt-lesioned rats. However, tiagabine is weakly efficacious in intravenous PTZ seizure threshold test, bicuculline-induced seizure test, and maximal electroshock seizure test. In vivo microdialysis shows that tiagabine increases the extracellular GABA overflow in a dose- dependent manner. Four GABA transporter molecules known as GAT-1 to GAT-4 have been cloned and sequenced in brain. Tiagabine is a selective inhibitor of GAT-1, which is predominantly localized in presynaptic terminals of neurons, with little or no affinity for other three transporters. The drug has shown potent antiepileptic activity when given orally thrice daily at a dose of 24-54 mg/day with a half-life of 5-8 h. Tiagabine was clinically evaluated using a novel enrichment (Amery) design which rapidly established the efficacy of tiagabine in adjunctive partial seizures. The tiagabine monotherapy may provide a new approach to the treatment of patients with partial seizures refractory to other antiepileptic drugs. The results of numerous multicentre add-on, open label, placebo-controlled long-term clinical trials established the efficacy of tiagabine as add-on therapy in patients with epilepsy difficult-to-control. Efficacy of the drug is also sustained with long-term treatment without any tolerance to anticonvulsant activity. The drug was well tolerated in an integrated safety analysis of several double-blind, add-on therapy trials in patients with epilepsy with difficult-to-control seizures. Tiagabine does not induce or inhibit metabolic processes of other antiepileptic agents. The adverse events reported include dizziness, asthenia, nervousness, tremor and mild depression. Further clinical experience will not only confirm efficacy but also optimize the dosage of tiagabine for monotherapy and add-on therapy in seizure control. These data suggest that tiagabine is a potent and broad spectrum anticonvulsant with a novel mode of action but without causing tolerance to the anticonvulsant effect.
