A Review of the Preclinical Pharmacology of Tiagabine: A Potent and Selective Anticonvulsant GABA Uptake Inhibitor

Suzdak, Peter D.; Jansen, Jens Aas

doi:10.1111/j.1528-1157.1995.tb02576.x

Cited by 260 publications

(151 citation statements)

References 57 publications

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“…327 In addition, tiagabine exacerbates spike-and-wave discharges in some models of absence epilepsy, prossibly due to enhanced action of GABA at GABA B receptors. 328 Acute studies in hippocampal slices show that tiagabine prolongs inhibitory synaptic potentials. 324 However, in GAT-1 knockout mice, IPSCs are not potentiated, phasic GABA release is downregulated, and GABA-mediated tonic conductance is potentiated.…”

Section: Plasma Membrane Gaba Transportersmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Section: Plasma Membrane Gaba Transportersmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…However, the supposed proconvulsant effect was not observed in studies on animals, even when given in large doses. 40 …”

Section: Tiagabinementioning

confidence: 99%

Aggravation of epilepsy by anti‐epileptic drugs

Gayatri

Livingston

2006

Develop Med Child Neuro

102

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The possibility that so‐called anti‐epileptic drugs (AEDs) may aggravate epilepsy must always be borne in mind by the clinician. Many reports of such aggravation of seizures have been published. Most such reports are anecdotal and speculative, and suggest that many such reactions are idiosyncratic. However, for some there is a sufficient body of evidence to suggest that some AEDs used in certain epilepsies may consistently cause worsening of seizures. Seizure aggravation may include increase in the frequency or severity of existing seizures, emergence of new types of seizure, or the occurrence of status epilepticus. The pathophysiology of seizure aggravation is poorly understood including nonspecific effects such as those associated with sedation, druginduced encephalopathy, and paradoxical or inverse pharmacodynamic effects. For some epilepsies the choice of AEDs may be inappropriate, and although the mechanism of seizure aggravation is not clear, its occurrence may be fairly predictable. This is best documented for the use of carbamazepine in idiopathic generalized and myoclonic epilepsies. Most other AEDs have been reported occasionally to cause seizure aggravation. The lowest risk of seizure aggravation appears to be with valproate. Risk factors for worsening of seizures are epileptic encephalopathy, polytherapy, high frequency of seizures, and cognitive impairment. Advances in pharmacogenomics may in the future enable such adverse effects to be predicted for individual patients. Meanwhile, a systematic approach to reporting AED‐induced seizure aggravation should be developed.

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“…Because tiagabine (TGB), a new GABA-uptake inhibitor, has a similar mechanism of action, concern has been raised about its potential to cause treatment-emergent psychosis in patients with epilepsy. TGB enhances GABA-mediated inhibition by blocking GABA uptake into neurons or glia, resulting in anticonvulsant properties (16). Although controlled clinical trials have shown TGB to be well tolerated and effective as adjunctive treatment in patients with complex partial seizures (CPSs) (17,18), no studies have been designed to assess the specific risk of psychosis.…”

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confidence: 99%

Occurrence of Psychosis in Patients with Epilepsy Randomized to Tiagabine or Placebo Treatment

et al. 2002

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Summary:Purpose: Patients with drug-resistant epilepsy have a higher incidence of psychiatric problems and possibly greater intolerance to antiepileptic drugs (AEDs) than do other patients with epilepsy. Concern has been raised that ␥-aminobutyric acid (GABA)ergic drugs may be associated with treatment-emergent psychosis. Tiagabine (TGB; Gabitril), a new AED that blocks synaptic GABA uptake, was developed in trials of drug-resistant patients with epilepsy. We conducted ad hoc analyses of adverse events, drug intolerance, and treatment response to evaluate the association between TGB treatment and psychosis and whether psychiatric history might be predictive of tolerance or effectiveness of this GABAergic drug.Methods: Data were analyzed from two multicenter, randomized, double-blind, placebo-controlled trials of add-on TGB therapy (32 or 56 mg daily) in 554 adolescents and adults with complex partial seizures (CPSs). After an 8-or 12-week baseline phase, double-blind treatment consisted of a 4-week titration period (with TGB dose gradually increased to 32 or 56 mg daily) and an 8-or 12-week fixed-dose period. Adverse events commonly associated with psychosis were evaluated. Treatment intolerance and effectiveness (Ն50% reduction in CPS rate) were compared among patients with and without psychiatric histories.Results: Psychotic symptoms (hallucinations) were observed in three (0.8%) of 356 TGB-treated patients and none of 198 placebo-treated patients (p ‫ס‬ 0.556, NS). Statistical analysis showed no interaction between psychiatric history and drug intolerance or treatment outcome.Conclusions: TGB administration appears to carry no significant increased risk of treatment-emergent psychosis. Psychiatric history was not predictive of the tolerance or effectiveness of the drug.

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A Review of the Preclinical Pharmacology of Tiagabine: A Potent and Selective Anticonvulsant GABA Uptake Inhibitor

Cited by 260 publications

References 57 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

Aggravation of epilepsy by anti‐epileptic drugs

Occurrence of Psychosis in Patients with Epilepsy Randomized to Tiagabine or Placebo Treatment

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