Tiagabine Therapy for Complex Partial Seizures

Sachdeo, Rǎjesh C.; Leroy, Robert; Krauss, Gregory L.; Drake, Miles E.; Green, Philip M.; Leppik, Ilo E.; Shu, Vincent; Ringham, Gary L.; Sommerville, Kenneth W.

doi:10.1001/archneur.1997.00550170069016

Cited by 108 publications

(44 citation statements)

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“…The data from two multicenter, randomized, doubleblind, placebo-controlled trials of TGB (Gabitril) in 554 patients were analyzed (17,18). To be eligible for entry into either study, patients had to have CPSs for which they were being treated with one to three concomitant AEDs, and be at least 12 years old.…”

Section: Methodsmentioning

confidence: 99%

“…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. We conducted an ad hoc analysis of two doubleblind, randomized, placebo-controlled multicenter studies of TGB in the United States to evaluate whether there was an association between TGB administration and the occurrence of psychosis.…”

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confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

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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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“…Overall, it is a well-tolerated medication, the most common AEs being dizziness, asthenia, amnesia, nervousness, and abdominal pain [Kalviainen et al 1998;Schacter et al 1998;Sachdeo et al 1997]. Three studies [Uthman et al 1998;Sachdeo et al 1997;Richens et al 1993] were included in the QSS and TTA meta-analysis; tiagabine doses ranging from 15 to 56 mg/day were used as add-on therapy in patients with partial epilepsy. The discontinuation rate due to AEs from tiagabine ranged from 8% to 20% in patients on drug, compared to 8 to 9% for patients on placebo [French et al 2004].…”

Section: Topiramatementioning

confidence: 99%

New generation antiepileptic drugs: what do they offer in terms of improved tolerability and safety?

French

Gazzola

2011

Therapeutic Advances in Drug Safety

107

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Over the last two decades a total of 11 antiepileptic drugs (AEDs) have been introduced to the US market. Randomized, placebo-controlled trials have yielded information about each drug's efficacy, tolerability, and safety profile; however, few studies have compared the newer generation AEDs directly with the older generation. Comparative studies are not always straightforward in their interpretation, as many characteristics of drugs, both favorable and unfavorable, may not be highlighted by such studies. In general, findings from the literature suggest that the newer generation AEDs (including vigabatrin, felbamate, gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, zonisamide, pregabalin, rufinamide, and lacosamide) enjoy both improved tolerability and safety compared with older agents such as phenobarbital, phenytoin, carbamazepine, and valproate. This is partially supported by some of the findings of the QSS and the TTA Committee of the American Academy of Neurology (AAN), whose review of four AEDs (gabapentin, lamotrigine, topiramate, and tiagabine) is discussed. Briefly, when compared with carbamazepine, lamotrigine was better tolerated; topiramate adverse events (AEs) were fairly comparable to carbamazepine and valproate; and tiagabine compared with placebo was associated with a higher discontinuation rate due to AEs. The findings of the SANAD trial are also presented; when administered to patients with partial epilepsy, carbamazepine was most likely to fail due to AEs, and lamotrigine and gabapentin were least likely to fail due to AEs. When administered to patients with idiopathic generalized epilepsy, topiramate was most frequently associated with AE-related discontinuation, followed by valproate; and while valproate was the most efficacious drug in this arm of the study, lamotrigine was more tolerable. What makes the SANAD study valuable and somewhat unique is its head-to-head comparison of one drug with another. Such comparative trials are overall lacking for new AEDs, although some conclusions can be drawn from the available data. In the end, however, AED selection must be based on individual patient and drug characteristics.

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“…Tiagabine [R(À)-N-(4,4-di(3-methyl-thien-2-yl)-but-3-enyl)nipecotic acid, hydrochloride; TGB], a novel AED lately introduced into the therapy of partial seizures in humans, is a potent GABA uptake inhibitor into neurons and glia, which by blocking the GABA transporter 1 (GAT-1) in mice, significantly prolongs the duration of GABArelated inhibitory synaptic potentials (Czuczwar and Patsalos, 2001;Nielsen et al, 1991). The net effect of the increment in synaptic GABA concentration is evidently related to the reduction of seizure frequency in patients with partial-onset seizures (Richens et al, 1995;Sachdeo et al, 1997;Uthman et al, 1998). Tiagabine is efficacious either as an adjuvant drug in adult patients and children with partial seizures with/without secondary generalization (Ben-Menachem, 1995;Pellock, 2001) or the drug, applied in monotherapy (Schachter, 1995).…”

Section: Introductionmentioning

confidence: 99%

Tiagabine Synergistically Interacts with Gabapentin in the Electroconvulsive Threshold Test in Mice

Łuszczki

Świąder

Parada-Turska

et al. 2003

Neuropsychopharmacol

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Polytherapy, based on the rational combining of antiepileptic drugs (AEDs), is required for patients with drug-resistant epilepsy. In such cases, the combinations of AEDs usually offer a significant enhancement of their protective effects against seizures. There has appeared a hypothesis that combining two AEDs, influencing the same neurotransmitter system, results in the potentialization of their anticonvulsant effects. For corroborating this hypothesis, a pharmacological character of interaction between tiagabine (TGB) and gabapentin (GBP)Ftwo novel AEDs affecting the GABA-ergic system, in the maximal electroshock seizure threshold (MEST)-test in mice was evaluated. TGB at the dose of 4 mg/kg and GBP at 75 mg/kg significantly raised the electroconvulsive threshold. Further, using the isobolographic calculations, TGB was coadministered with GBP at three fixed-ratios (1 : 3, 1 : 1, and 3 : 1) of their respective protective drug doses. All examined combinations of TGB with GBP exerted supra-additive (synergistic) interactions against MEST-induced seizures in mice. The interaction index, describing the strength and magnitude of interaction, ranged between 0.25 and 0.50 indicating supraadditivity. Adverse (neurotoxic) effects were evaluated in the chimney (motor performance) and the step-through, light-dark passive avoidance (long-term memory) tests in mice. The examined combinations of TGB with GBP did not affect the motor coordination, except for the fixed-ratio of 1 : 1, at which significant impairment of motor performance was observed. Moreover, all combinations selectively impaired the acquisition of the task in the passive avoidance test, having no impact on consolidation and retrieval in the longterm memory test. The pain threshold test revealed that the observed disturbances in the passive avoidance testing resulted presumably from the antinociceptive activity of these AEDs in combinations. After lengthening the exposing time to the direct current stimulus in the passive avoidance test from 2 to 6 s, the acquisition of the task, in animals receiving the combinations of TGB and GBP was not impaired. Neither the plasma, nor brain concentrations of GBP were affected by TGB application, so pharmacokinetic events that might negatively influence the observed effects are not probable. Results of this study clearly indicate that the activation of the same neurotransmitter system (GABA-ergic) leads to a synergistic interaction. The pain threshold test is a very good paradigm for screening the antinociceptive properties of AEDs, which may disturb the long-term memory testing in animals. Combinations of TGB with GBP (very promising from a preclinical point of view) should be clinically verified for elaborating the most effective treatment regimen in patients with intractable seizures.

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Tiagabine Therapy for Complex Partial Seizures

Abstract: Tiagabine administered 2 and 4 times daily as add-on pharmacotherapy was effective in reducing CPSs in patients with epilepsy whose conditions were refractory to treatment with other antiepileptic agents, and it was well tolerated.

Cited by 108 publications

References 8 publications

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

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

New generation antiepileptic drugs: what do they offer in terms of improved tolerability and safety?

Tiagabine Synergistically Interacts with Gabapentin in the Electroconvulsive Threshold Test in Mice

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