Status epilepticus and tiagabine therapy revisited

PURPOSE: To determine whether antiepileptic treatment with tiagabine (TGB) is associated with an increased frequency of nonconvulsive status epilepticus (NCSE) in patients with refractory epilepsy. METHODS: We reviewed retrospectively the medical and EEG records of all inpatients with refractory localization-related epilepsy at the National Society for Epilepsy treated with TGB between January 1997 and December 2000. Clinical and electroencephalographic (EEG) data before, during, and after TGB therapy were evaluated in those patients who experienced a deterioration in seizure control suggestive of NCSE. Frequency of NCSE was determined in a comparable, non-TGB-treated patient population. RESULTS: Seven (7.8%) of 90 TGB-treated patients were identified who experienced episodes of electroclinically confirmed NCSE. Serial EEGs showed deterioration during TGB treatment, with resolution of abnormality on discontinuation of TGB in all seven patients. During the same observation period, 32 (2.7%) of 1,165 non-TGB-treated patients developed electroclinically defined NCSE. CONCLUSIONS: Treatment with TGB is associated with an increased frequency of NCSE in patients with refractory localization-related epilepsy.     

Effects of antiepileptic drugs on working memory as assessed by spatial alternation performance in rats

Patients with epilepsy can have impaired cognitive abilities. Many factors contribute to this impairment, including the adverse effects of antiepileptic drugs (AEDs). However, there are few systematic data on the effects of AEDs on specific cognitive domains, such as working memory. The purpose of the present study was to evaluate the effects of AEDs on working memory as measured by delayed spatial alternation behavior in nonepileptic rats. The GABA-related AEDs triazolam and phenobarbital significantly disrupted performance, whereas tiagabine, valproate, and gabapentin did not. The sodium channel blockers carbamazepine and topiramate produced modest but significant disruption of performance, whereas the effects of lamotrigine were not significant and phenytoin produced a modest but significant improvement in performance but at doses that abolished responding in some animals. Levetiracetam had no effect on working memory. In contrast, ethosuximide significantly disrupted working memory. The disruptions produced by triazolam and phenobarbital were similar in magnitude to the effects of the muscarinic antagonist scopolamine. The present results indicate that AEDs can disrupt working memory, but there are differences among AEDs in the magnitude of the disruption that do not appear to be correlated with mechanism of action.     

Population Analysis of the Pharmacokinetics of Tiagabine in Patients with Epilepsy

Summary: Purpose: In two open-label long-term safety studies, we determined tiagabine (TGB) pharmacokinetics in patients with epilepsy.
Methods: In all, 2,147 plasma samples from 511 patients who participated in the studies were available. The total daily dose ranged from 2 mg administered once daily to 80 mg administered in four doses. A one-compartment model with first-order absorption and elimination was used to fit the TGB plasma concentration-time data, with a population pharmacokinetic approach.
Results: The patients'average (±SD) weight and age were 73.8 ± 20.7 kg and 32.1 ± 12.3 years. The most significantly factor affecting TGB pharmacokinetics was concomitant administration of other antiepileptic drugs (AEDs). The central clearance value in patients receiving AEDs known to induce hepatic drug metabolism was 21.4 L/h, a value 67% higher than the central clearance estimate obtained for the patients receiving AEDs not known to affect hepatic drug metabolism (12.8 L/h). There was no evidence of any dose or time effect, indicating that TGB pharmacokinetics are linear. TGB pharmacokinetics were not different in white, black, or Hispanic patients, although our ability to explore racial effects was limited since 90% of the patients were white. No other demographic variables (including age and smoking) or any clinical chemistry measurements (including bilirubin, SGOT, and SGPT) were important in explaining the variability in the clearance estimates.
Conclusions: TGB pharmacokinetics are linear, influenced by enzyme-inducing AEDs, and largely unaffected by other demographic variables.     

Pharmacodynamic analysis of the anticonvulsant effects of tiagabine and lamotrigine in combination in the rat

PURPOSE: The pharmacodynamic interaction between the antiepileptic drugs (AEDs) tiagabine (TGB) and lamotrigine (LTG) was characterized on basis of the anticonvulsant effect in the cortical stimulation model in the rat. METHODS: The study was conducted according to a partial crossover design, in which both drugs were infused intravenously to achieve linear increases in the plasma concentration in the absence and presence of a steady-state concentration of the second drug. The anticonvulsant effect was quantified by counts of four specific ictal signs (eye closure, forelimb clonus, forelimb extension, and head jerk). A potential pharmacokinetic interaction was accounted for by determination of total plasma concentrations of both drugs. RESULTS: When given separately, both TGB and LTG suppressed all ictal signs in a concentration-dependent manner, with the exception of eye closure, which was not suppressed by LTG. The interaction between both drugs was estimated by response surface analysis by using the difference between the observed effect and the additive effect to identify synergistic drug concentrations. This analysis showed that the pharmacodynamic interaction between TGB and LTG is synergistic for the ictal signs of eye closure and head jerk. In contrast, the interaction was additive for the ictal signs of forelimb clonus and forelimb tonus. CONCLUSIONS: This study demonstrates the usefulness of ictal-component analysis for studying the pharmacodynamic interaction between AEDs. Quantification of both the nature and the magnitude of the interaction between TGB and LTG led to the identification of two ictal signs that were synergistically suppressed. This approach offers a theoretical basis to identify and optimize drug combinations that are useful to treat refractory epilepsy.     

Pre- rather than co-application of vigabatrin increases the efficacy of tiagabine in hippocampal slices

PURPOSE: The antiepileptic drug vigabatrin (VGB) increases intracellular availability of the inhibitory transmitter gamma-aminobutyric acid (GABA) by inhibition of GABA-transaminase. A blockade of the GABA uptake is the main mechanism of action of tiagabine (TGB). Based on this, the two antiepileptic drugs (AEDs) can be speculated to act synergistically so that their combined antiepileptic efficacy is supraadditive. METHODS: To test this, experiments were performed on hippocampal slices of guinea-pigs. As an epilepsy model, epileptiform field potentials (EFPs) were induced by omission of Mg2+ from the bath solution and recorded in stratum pyramidale of the CA3 region. VGB (7.5 microM) and TGB (0.75 microM) were added to the superfusate. RESULTS: VGB, given alone, failed to decrease the repetition rate of EFPs. Similarly, TGB applied alone only transiently led to a nonsignificant reduction of the EFP frequency. Combining VGB and TGB, their suppressive efficacy increased, yielding a significant reduction of EFP frequency, which, however, again did not persist. Pretreatment of the preparations with VGB for 2 h, followed by additional application of TGB, or TGB alone, drastically and persistently potentiated the effects. CONCLUSIONS: These results demonstrate that VGB and TGB show favorable pharmacodynamic interactions, provided VGB is allowed to block intracellular GABA degradation before GABA uptake block by TGB.     

Adjunctive Tiagabine Treatment of Psychiatric Disorders: Three Cases

Anticonvulsants which effectively treat complex partial seizures are noted to have mood stabilizing effects (carbamazepine, valproate, lamotrigine, gabapentin). Tiagabine, a novel GABA uptake inhibitor anticonvulsant with similar indications, was used as adjunctive therapy to control psychiatric symptoms in three patients—two with bipolar disorder and one with schizoaffective disorder, bipolar type. All three patients improved during adjunctive low dosage tiagabine treatment and no untoward side effects were noted. Clinicians are advised to consider this new anticonvulsant as a potential adjunctive agent in the treatment of bipolar and schizoaffective disorders. Controlled trials are indicated.     

Overview of the Safety of Newer Antiepileptic Drugs

Summary: Standard antiepileptic drugs (AEDs) are associated with a wide variety of acute and chronic adverse events and with many interactions with each other and with non-AEDs that complicate patient management. The safety and interaction profiles of the newer AEDs have also been intensively studied. Safety data are available for six of the newer AEDs, lamotrigine (LTG), vigabatrin (VGB), gabapentin (GBP), tiagabine (TGB), felbamate (FBM), and topiramate (TPM). The potential for the most recently developed AEDs for producing rare idiosyncratic reactions cannot be ascertained until additional patient exposures have been reported from careful postmarketing surveillance.     

Antiepileptic Effects of Tiagabine, a Selective GABA Uptake Inhibitor, in the Rat Kindling Model of Temporal Lobe Epilepsy

Summary: Purpose: We determined the antiepileptic profile of tiagabine (TGB), a selective γ-aminobutyric acid (GABA) uptake inhibitor, in the rat kindling model of temporal lobe epilepsy (TLE).
Methods : The anticonvulsant and adverse effects of TGB were examined in amygdala- or hippocampal-kindled rats and compared with those of other GABA uptake inhibitors (SKF89976A and NNC-7 1 1) and conventional antiepileptic drugs [AEDs: valproate (VPA) and carbamazepine (CBZ)]. In addition, the antiepileptogenic effects of TGB on amygdala kindling development were examined.
Results : TGB (2.5–40 mgkg intraperitoneally, i.p.) had potent and dose-dependent anticonvulsant effects on both amygdala-and hippocampal-kindled seizures. The order of anticonvulsant potency of the three GABA uptake inhibitors tested was: NNC-711 > TGB > SKF-89976A and paralleled the in vitro GABA uptake efficacy. In addition, daily treatment with TGB 10 mgkg for 10 days significantly retarded kindling development. Although adverse effects of TGB on motor systems were significantly less than those of VPA and CBZ, high toxic doses of TGB often caused EEG paroxysm and myoclonus.
Conclusions : Our results indicate the clinical usefulness of TGB for treatment of drug-resistant TLE.     

Intrinsic activation of GABAA receptors suppresses epileptiform activity in the cerebral cortex of immature mice

Purpose: Activation of ionotropic γ‐aminobutyric acid type A (GABA_A) receptors induces in immature neocortical neurons a membrane depolarization that may contribute to the higher epilepsy susceptibility in newborns. To elucidate whether depolarizing GABAergic responses enhance or attenuate epileptiform activity in the immature neocortex, we investigated the effect of agonists, antagonists, and positive modulators of GABA_A receptors on epileptiform activity. Methods: We performed in vitro field potential recordings on isolated whole neocortex preparations and whole cell recordings of identified pyramidal neurons in 400‐μm slices of immature (postnatal day 1–7) mice. Epileptiform activity was induced by low Mg²⁺ solutions with or without 50–100 μm 4‐aminopyridine. Results: Bath application of GABA (3–100 μm , in the presence of tiagabine) attenuated epileptiform activity. The GABA transporter isoform 1 (GAT‐1) inhibitor tiagabine (30 μm ) and the GAT‐2/3 specific inhibitor SNAP 5114 (40 μm ) reduced the frequency of epileptiform activity. The benzodiazepines midazolam (0.2 μm ) and zolpidem (0.5 μm ) as well as the barbiturate phenobarbital (30 μm ) slightly attenuated epileptiform activity. Continuous bath application of the GABAergic antagonist gabazine (SR‐95531, 2–3 μm ) or picrotoxin (15 μm ) induced epileptiform discharges. Discussion: These results demonstrate, that (1) the activation or positive modulation of GABA_A receptors attenuates epileptiform activity, (2) GABA_A antagonists mediate a disinhibition, and (3) GABA uptake contributes to the regulation of extracellular GABA in immature neocortex. We conclude from these findings that a constant inhibition via GABA_A receptors is required to suppress epileptiform activity already in the immature neocortex.