Absence seizures are reduced by the enhancement of GABA-ergic inhibition in the hippocampus in WAG/Rij rats

Classical theories on absence epilepsy suggest that spike-wave discharge (SWDs) represent thalamo-cortical oscillations, where an abnormally excitable cortex interacts with thalamus and brain stem reticular formation. The limbic system is generally not included in any theory about the pathogenesis of absence seizures. However, some data demonstrated that the alterations in the limbic system attribute to the expression of absence epileptic phenotype in genetic models of absence epilepsy. The present study investigated whether local intrahippocampal administration of progesterone (a GABA_A-mimetic) and tiagabine (an inhibitor of GABA (re)uptake) might affect the occurrence of SWDs. Male WAG/Rij rats were implanted with permanent electroencephalograph (EEG) electrodes and bilateral cannulas in the CA1-CA3 region of the dorsal hippocampus. Control rats had bilateral cannulas in the cortical area above the hippocampus. Rats received intracerebral injections of progesterone (5 mg/ml), 45% β-cyclodextrin (CD), saline, or tiagabine (2 mg/ml). EEG recordings were made before and after injection. Progesterone, CD, and tiagabine administration to the hippocampus reduced SWDs for 60 min following administration without behavioral or electroencephalographic side-effects. Both progesterone administration into the cortex and saline injection into the hippocampus yielded no changes in the occurrence of SWDs. These data suggest that activation of GABA-ergic transmission in the hippocampus has an inhibitory effect on cortico-thalamo-cortical circuits underlying the generation of SWDs and might be critically involved in the regulation of absence seizures.     

Effects of Tiagabine Monotherapy on Abilities, Adjustment, and Mood

Summary: Purpose: We evaluated the dose-related impacts of tiagabine (TGB) on cognition and mood in a monotherapy study.
Methods: Patients were 123 adults with uncontrolled partial seizures, each treated with a single currently available antiepileptic drug (AED) for management of clinical epilepsy. They completed a battery of neuropsychological tests during an 8 week prospective baseline period and once again at the end of the 12-week fixed-dose period (or earlier if they dropped out of the study). Sixty-six patients were randomized to 6 mg/day TGB and 57 were randomized to 36 mg/day TGB.
Results: Few changes in either abilities or adjustment and mood were noted when all patients were considered as a single group. However, analysis of both dose and attainment of TGB monotherapy showed that patients receiving TGB monotherapy did best, improving particularly in the areas of adjustment and mood with low-dose TGB and in the area of abilities with high-dose TGB. Patients who did not attain monotherapy showed no change except that the high-dose group did not perform as well on measures of mood and adjustment. Baseline AED and changes in seizure control did not affect the results.
Conclusions: Patients attainment of TGB monotherapy was associated with their achievement of positive changes of varying degree on psychological tests. Failure to attain TGB monotherapy was associated with no changes on the tests except in patients receiving high-dose TGB where it appeared that some alterations in mood might have been avoided if a slower titration schedule had been used.     

The pharmacokinetic inter-relationship of tiagabine in blood, cerebrospinal fluid and brain extracellular fluid (frontal cortex and hippocampus)

PURPOSE: Tiagabine is a unique antiepileptic drug with a novel mechanism of action. Whilst some limited data are available as to the peripheral blood pharmacokinetics of tiagabine, data regarding the kinetics of tiagabine in the central brain compartment are very limited. We therefore sought to investigate serum, cerebrospinal fluid (CSF) and frontal cortex and hippocampal extracellular fluid (ECF) kinetic inter-relationship of tiagabine in a freely moving rat model. METHODS: Adult male rats were implanted with either a jugular vein catheter and a cisterna magna catheter for blood and CSF sampling, respectively, or a blood catheter and a microdialysis probe in the hippocampus and frontal cortex (for ECF sampling). Tiagabine was administered intraperitoneal (i.p.) at 20 or 40 mg/kg and blood, CSF and ECF were collected at timed intervals for the measurement of tiagabine concentrations by high performance liquid chromatography. RESULTS: Tiagabine concentrations in blood and CSF rose linearly and dose-dependently and time to maximum concentration (Tmax) was 15 and 29 min, respectively. Mean CSF/serum tiagabine concentration ratios (range, 0.008-0.01) were much smaller than the mean free/total tiagabine concentration ratios in serum (0.045 +/- 0.003). Entry of tiagabine into brain ECF (frontal cortex and hippocampus) was rapid with Tmax values of 31-46 min. Distribution of tiagabine in brain was not brain region specific with values in the frontal cortex and hippocampus being indistinguishable. Whilst elimination from CSF was comparable to that of serum, half-life (t(1/2)) values in ECF were three times longer. CONCLUSIONS: Tiagabine is associated with linear kinetic characteristics and with rapid brain penetration. However, CSF concentrations are not reflective of free non-protein-bound concentrations in serum. The observation that tiagabine elimination from the brain is threefold slower than that seen in blood, may explain as to the relatively long duration of action of tiagabine.     

Changes in CCK-4 induced panic after treatment with the GABA-reuptake inhibitor tiagabine are associated with an increase in 3α,5α-tetrahydrodeoxycorticosterone concentrations

There is evidence that gamma-amino-butyric acid type A (GABA_A)-receptor modulating neuroactive steroids play a role in the pathophysiology of panic disorder. Antidepressant treatment has been suggested to stabilize the concentrations of neuroactive steroids. In this pilot study we investigated neuroactive steroid concentrations during GABAergic treatment, which might represent an alternative anxiolytic pharmacotherapeutic strategy. Neuroactive steroid concentrations were determined in 10 healthy subjects treated with tiagabine. To evaluate the anxiolytic effects of tiagabine a cholecystokinine-tetrapeptide (CCK-4) challenge was performed before and after treatment. Treatment with tiagabine led to a significant increase in 3α,5α-tetrahydrodeoxycorticosterone (3α,5α-THDOC) from 0.49 to 1.42 nmol/l (Z = −2.80, p = .005), which was significantly correlated with a decrease of panic symptoms in the CCK-4 challenge. Thus, it might be hypothesized that the anxiolytic effects of GABAergic treatment might in part be mediated by their influence on 3α,5α-THDOC concentrations.     

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

Summary: We review the neurochemical and behavioral profile of the selective γ-aminobutyric acid (GABA) up-take inhibitor, (R)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride [tiagabine (TGB), previously termed NNC 05-0328, NO 05-0328, and NO-328], which is currently in phase III clinical trials for epilepsy. TGB is a potent, and specific GABA uptake inhibitor. TGB lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites. In electrophysiological experiments in hippocampal slices in culture, TGB prolonged the inhibitory postsynaptic potentials (IPSP) and inhibitory postsynaptic currents (IPSC) in the CA1 and CA3 produced by the addition of exogenous GABA. In vivo microdialysis shows that TGB also in-creases extracellular GABA overflow in a dose-dependent manner. Together these biochemical data suggest that the in vitro and in vivo mechanism of action of TGB is to inhibit GABA uptake specifically, resulting in an increase in GABAergic mediated inhibition in the brain. TGB is a potent anticonvulsant agent against methyl-6,7-dimethyox-4-ethyl-B-carboline-3-carboxylate (DMCM)-induced clonic convulsions (mice), subcutaneous pentylenetetrazol (PTZ)-induced tonic convulsions (mice and rats), sound-induced convulsions in DBA/2 mice and genetically epilepsy-prone rats (GEPR), and electrically induced convulsions in kindled rats. TGB is partially efficacious against subcutaneous PTZ-induced clonic convulsions, and photically induced myoclonus in Papio papio. TGB is weakly efficacious in the intravenous PTZ seizure threshold test and the maximal electroshock seizure (MES) test and produces only partial protection against bicuculline (BIC)-induced convulsions in rats. The overall biochemical and anticonvulsant profile of TGB suggests potential utility in the treatment of chronic seizure disorders such as generalized clonic-tonic epilepsy (GTCS), photomyoclonic seizures, myoclonic petit mal epilepsy, and complex partial epilepsy.     

The Challenges of Epilepsy in Children

Summary: Among the most distinct and challenging characteristics of childhood epilepsy are the high incidence, the risk of cognitive function deterioration, the age relationship of various types of epilepsy, and the existence of particular clinical and EEG patterns that characterize epilepsy syndromes. With regard to antiepileptic drug (AED) treatment, one must take into account age-dependent pharmacokinetics, response to treatment according to the type of epilepsy, and ethical constraints in the development of controlled trials that often prevent the early introduction of new AEDs to the pediatric market.     

Occurrence of psychosis in patients with epilepsy randomized to tiagabine or placebo treatment

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 gamma-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 (> or =50% 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 = 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.     

Interlaboratory variability in the quantification of new generation antiepileptic drugs based on external quality assessment data

PURPOSE: To assess interlaboratory variability in the determination of serum levels of new antiepileptic drugs (AEDs). METHODS: Lyophilised serum samples containing clinically relevant concentrations of felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), the monohydroxy derivative of oxcarbazepine (OCBZ; MHD), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were distributed monthly among 70 laboratories participating in the international Heathcontrol External Quality Assessment Scheme (EQAS). Assay results returned over a 15-month period were evaluated for precision and accuracy. RESULTS: The most frequently measured compound was LTG (65), followed by MHD (39), GBP (19), TPM (18), VGB (15), FBM (16), and TGB (8). High-performance liquid chromatography was the most commonly used assay technique for all drugs except for TPM, for which two thirds of laboratories used a commercial immunoassay. For all assay methods combined, precision was <11% for MHD, FBM, TPM, and LTG, close to 15% for GBP and VGB, and as high as 54% for TGB (p < 0.001). Mean accuracy values were <10% for all drugs other than TGB, for which measured values were on average 13.9% higher than spiked values, with a high variability around the mean (45%). No differences in precision and accuracy were found between methods, except for TPM, for which gas chromatography showed poorer accuracy compared with immunoassay and gas chromatography-mass spectrometry. CONCLUSIONS: With the notable exception of TGB, interlaboratory variability in the determination of new AEDs was comparable to that reported with older-generation agents. Poor assay performance is related more to individual operators than to the intrinsic characteristics of the method applied. Participation in an EQAS scheme is recommended to ensure adequate control of assay variability in therapeutic drug monitoring.     

Pharmacodynamic analysis of the interaction between tiagabine and midazolam with an allosteric model that incorporates signal transduction

PURPOSE: The objective of this study was to characterize quantitatively the pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of the gamma-aminobutyric acid subtype A (GABAA) receptor, and tiagabine (TGB), an inhibitor of synaptic GABA uptake. METHODS: The in vivo concentration-response relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence and the presence of a steady-state plasma concentration of MDL. The EEG response in the 11.5- to 30-Hz frequency band was used as the pharmacodynamic end point. RESULTS: Infusion of MDL resulted in a mean steady-state plasma concentration of 66 +/- 3 ng/ml. A significant pharmacokinetic interaction with TGB was observed. MDL inhibited TGB clearance by 20 +/- 7 ml/min/kg from the original value of 89 +/- 6 ml/min/kg. However, no changes in plasma protein binding of both drugs were observed. The concentration-EEG relation of TGB was described by the sigmoid-Emax model. The pharmacodynamic parameter estimates of TGB were: Emax = 327 +/- 10 microV, EC50 = 392 +/- 20 ng/ml, and nH = 3.1 +/- 0.3. These values were not significantly different in the presence of MDL. Factors that may explain the lack of synergism were identified by a mechanism-based interaction model that separates the receptor activation from the signal-transduction process. High efficiency of signal transduction and the presence of a baseline response were shown to diminish the degree of synergism. CONCLUSIONS: We conclude that the in vivo pharmacodynamic interaction between MDL and TGB is additive rather than synergistic. This strongly suggests that allosteric modulation of the antiseizure activity of a GAT-1 inhibitor by a benzodiazepine does not offer a therapeutic advantage.     

Effects of antiepileptic drugs on refractory seizures in the intact immature corticohippocampal formation in vitro

PURPOSE: We developed a new in vitro preparation of immature rats, in which intact corticohippocampal formations (CHFs) depleted in magnesium ions become progressively epileptic. The better to characterize this model, we examined the effects of 14 antiepileptic drugs (AEDs) currently used in clinical practice. METHODS: Recurrent ictal-like seizures (ILEs, four per hour) were generated in intact CHFs of P7-8 rats, and extracellular recordings were performed in the hippocampus and neocortex. AEDs were applied at clinically relevant concentrations (at least two), during 30 min after the third ILE. Their ability to prevent or to delay the next ILE was examined. RESULTS: Valproic acid and benzodiazepines (clobazam and midazolam) but also phenobarbital and levetiracetam prevent the occurrence of seizures. In contrast, usual concentrations of carbamazepine (CBZ), phenytoin, vigabatrin, tiagabine, gabapentin, lamotrigine (LTG), topiramate, felbamate, and ethosuximide did not suppress ILEs. In addition, LTG and CBZ aggravate seizures in one third of the cases. CONCLUSIONS: This intact in vitro preparation in immature animals appears to be quite resistant to most AEDs. Blockade of seizures was achieved with drugs acting mainly at the gamma-aminobutyric acid (GABA)A-receptor site but not with those that increase the amount of GABA. Drugs with a broad spectrum of activity are efficient but not those preferentially used in partial seizures or absences. We suggest that this preparation may correspond to a model of epilepsy with generalized convulsive seizures and could be helpful to develop new AEDs for refractory infantile epilepsies.