Cognitive and quality of life effects of differing dosages of tiagabine in epilepsy

Dodrill, Carl B.; Arnett, John L.; Sommerville, Kenneth W.; Shu, Vincent

doi:10.1212/wnl.48.4.1025

Cited by 98 publications

(48 citation statements)

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“…Nervousness describes the clinical side effects of tiagabine (Dodrill et al, 1997(Dodrill et al, , 1998(Dodrill et al, , 2000Adkins and Noble, 1998). In the absence of an accepted test for nervousness in rodents, we assumed that it can be assessed as a mild form of anxiety.…”

Section: Nervousness Versus Anxietymentioning

confidence: 99%

GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

Chiu

Brickley²,

Jensen³

et al. 2005

J. Neurosci.

218

170

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GABA transporter subtype 1 (GAT1) knock-out (KO) mice display normal reproduction and life span but have reduced body weight (female, Ϫ10%; male, Ϫ20%) and higher body temperature fluctuations in the 0.2-1.5/h frequency range. Mouse GAT1 (mGAT1) KO mice exhibit motor disorders, including gait abnormality, constant 25-32 Hz tremor, which is aggravated by flunitrazepam, reduced rotarod performance, and reduced locomotor activity in the home cage. Open-field tests show delayed exploratory activity, reduced rearing, and reduced visits to the central area, with no change in the total distance traveled. The mGAT1 KO mice display no difference in acoustic startle response but exhibit a deficiency in prepulse inhibition. These open-field and prepulse inhibition results suggest that the mGAT1 KO mice display mild anxiety or nervousness. The compromised GABA uptake in mGAT1 KO mice results in an increased GABA A receptor-mediated tonic conductance in both cerebellar granule and Purkinje cells. The reduced rate of GABA clearance from the synaptic cleft is probably responsible for the slower decay of spontaneous IPSCs in cerebellar granule cells. There is little or no compensatory change in other proteins or structures related to GABA transmission in the mGAT1 KO mice, including GAT1-independent GABA uptake, number of GABAergic interneurons, and GABA A -, vesicular GABA transporter-, GAD65-, and GAT3-immunoreactive structures in cerebellum or hippocampus. Therefore, the excessive extracellular GABA present in mGAT1 KO mice results in behaviors that partially phenocopy the clinical side effects of tiagabine, suggesting that these side effects are inherent to a therapeutic strategy that targets the widely expressed GAT1 transporter system.

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Section: Nervousness Versus Anxietymentioning

confidence: 99%

GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

Chiu

Brickley²,

Jensen³

et al. 2005

J. Neurosci.

218

170

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“…When present, the changes were small, and none reached statistically significant differences at the p < 0.01 level. Even if a slight negative impact of TGB with higher doses (56 mg/day) could not be completely discounted, it was considered not likely to be of clinical importance (29). Long-term TGB treatment did not cause cognitive impairment.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Review of Controlled Trials of Gabitril (Tiagabine): A Clinician's Viewpoint

Loiseau

1999

Epilepsia

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Summary: A recent problem for doctors has been the choice of which new antiepileptic drug (AED) to select for treatment of pharmacoresistant epilepsy. This article summarizes the clinical experience to date regarding the efficacy and safety of tiagabine (TGB; Gabitril) as adjunctive therapy in patients with partial-onset seizures. In its early Phase I1 development, TGB was evaluated in two multicenter pilot studies. Each had an open-label enrichment phase followed by a treatment phase with randomized, double-blind, two-period, cross-over phases. Between 24 and 50% of patients experienced reductions in seizure rates of ?500/0, depending on the type of partial seizure. In Phase 111, three double-blind, parallel group, placebocontrolled adjunctive studies determined the efficacy of TGB in patients with refractory partial seizures. The first was a doseresponse study employing doses of TGB-HCI of 16, 32 or 56 mg/day. Significant reductions in seizure rates were found with 32 and 56 mg/day. The second and third studies evaluated the efficacy of dosing TGB twice, three times, and four times daily, all of which showed similar efficacy. TGB efficacy in partial seizures was supported in several open trials, and no tolerance to efficacy was noted in long-term continuation studies. Tolerability was documented in all trials. Most adverse events were mild or moderate and transient, occurring during dose titration. They were clearly dose-related. No relevant changes in hematologic and biochemical tests, vital signs, or body weight were attributable to TGB. TGB appears to be an effective new drug for partial seizures with an acceptable safety profile.

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“…Additional adverse events identified in these and other open trials included tremor, nonconvulsive status epilepticus (absence stupor), emotional lability, vomiting, tiredness, headache, and psychosis. One study with class II evidence 29 showed with neuropsychometric tests that add-on tiagabine regimens were not associated with changes in cognitive functions.…”

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confidence: 99%

Efficacy and tolerability of the new antiepileptic drugs II: Treatment of refractory epilepsy [RETIRED]

et al. 2004

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Abstract-Objective:To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. Methods: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. Results: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. Conclusions: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.

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Cognitive and quality of life effects of differing dosages of tiagabine in epilepsy

Cited by 98 publications

References 1 publication

GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

Review of Controlled Trials of Gabitril (Tiagabine): A Clinician's Viewpoint

Efficacy and tolerability of the new antiepileptic drugs II: Treatment of refractory epilepsy [RETIRED]

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