Neuroprotective activity of tiagabine in a focal embolic model of cerebral ischemia

Gamma aminobutyric acid (GABA) agonists have been shown to have neuroprotective effects when used after focal or global cerebral ischemia. In this study, we evaluated the neuroprotective effects of a GABA re-uptake inhibitory agent, tiagabine, on focal ischemic brain injury in an embolic model in rats. Tiagabine, injected at 1 h after embolization, significantly reduced brain infarction volume, measured with 2,3,5-triphenyltetrazolium chloride (TTC) histological assay. There were varying degrees of neuroprotective effect exhibited in the other experimental groups however this did not reach significance. These results suggest that tiagabine is neuroprotective when administrated at an early period after the ischemic brain injury.     

Basic Mechanisms of Gabitril (Tiagabine) and Future Potential Developments

Summary: Gabitril (tiagabine) is a potent selective inhibitor of the principal neuronal γ-aminobutyric acid (GABA) transporter (GAT-1) in the cortex and hippocampus. By slowing the reuptake of synaptically-released GABA, it prolongs inhibitory postsynaptic potentials. In animal models of epilepsy, tiagabine is particularly effective against kindled (limbic) seizures and against reflexly-induced generalized convulsive seizures. These data are predictive of its efficacy in complex partial seizures in humans. Possible clinical applications outside the field of epilepsy include bipolar disorder and pain.     

Tiagabine does not attenuate alcohol-induced activation of the human reward system

Rationale The rewarding effects of ethanol and other drugs of abuse are mediated by activation of the mesolimbic dopamine system. Recent neuroimaging studies in primates and humans suggest that cocaine-induced dopamine stimulation might be diminished by drugs augmenting γ-aminobutyric acid A (GABA-A) receptor function such as the GABA transaminase inhibitor vigabatrin. Objectives The objective of this study was to test the property of the selective GABA transporter 1 (GAT1) inhibitor tiagabine to block ethanol-induced activation of the mesolimbic reward system in an i.v. ethanol challenge. Materials and methods Twenty nonaddicted healthy volunteers underwent an i.v. ethanol challenge after 1 week of tiagabine (15 mg/day) administration. Neuronal activation was measured using [¹⁸F]-fluoro-deoxyglucose positron emission tomography (PET). Results Tiagabine did not prevent ethanol-induced stimulation of the mesolimbic reward system but augmented ethanol-induced hypometabolism within areas of the visual system and the cerebellum. Tiagabine alone also decreased neuronal metabolism within parts of the right temporal cortex that are highly enriched with GABA-ergic neurons. Conclusions Our ethanol challenge imaging study does not provide supporting evidence that the GAT1 inhibitor tiagabine diminishes the rewarding effects of ethanol. Further PET imaging studies using established anticraving compounds, such as the μ-opioid receptor antagonist naltrexone and antiepileptic drugs affecting the GABA-ergic system more broadly, will provide additional important insights on the interaction between the GABA-ergic and the brain reward system in vivo and the suitability of GABA-ergic drugs as anticraving compounds.     

Utility of the Lethargic (lh/lh) Mouse Model of Absence Seizures in Predicting the Effects of Lamotrigine,Vigabatrin, Tiagabine,Gabapentin, and Topiramate Against Human Absence Seizures

Summary: Purpose: Traditional methods of preclinical screening have predicted the effects of a putative antiepi-leptic drug (AED) against human absence seizures by testing its efficacy against clonic seizures in the high-dose pen-tylenetetrazole (PTZ) model. This high-dose PTZ model correctly predicted the efficacy of ethosuximide (ESM), benzodiazepines, and valproate (VPA) and the lack of efficacy of phenytoin (PHT) and carbamazepine (CBZ). However, the high-dose PTZ model erred in predictions for (a) phenobarbital (PB) (PTZ: efficacy; human: noneffi-cacy); (b) lamotrigine (LTG) (PTZ nonefficacy; human: efficacy); (c) vigabatrin (VGB) (PTZ: nonefficacy; human: proabsence effect); and (d) tiagabine (TGB) (PTZ efficacy; human: possibleproabsence). It also appears to have erred in predictions for gabapentin (GBP) (PTZ efficacy) and topiramate (TPM) (PTZ: efficacy). Because the lh/lh genetic model of absence seizures correctly predicted effects of ESM, clonazepam, VPA, PHT, CBZ, and PB against human absence seizures, we performed this study to test the predictive utility of the lWZh model for LTG, VGB, TGB, GBP, and TPM. Methods: Bipolar recording electrodes were implanted bilaterally into frontal neocortex of 8–week-old male lWZh mice. With the exception of VGB, vehicle or drugs were administered intraperitoneally (i.p.) on alternating days, and an EEG was used to record effects on seizure frequency. With VGB, vehicle was administered i.p. on day 1, and gradually increasing doses of VGB were administered on successive days. Drug and vehicle effects were compared in corresponding lfi-min epochs of the 150–min period after administration. Results: LTG (4.8–144 μmol/kg) significantly (p < 0.04) reduced seizure frequency (by 6.5%) compared with vehicle. In contrast, VGB (0.35–11 mmol/kg) and TGB (0.27–27 μmol/kg) significantly increased seizure frequency (300– 700%) and seizure duration (1,700–1,800%; p ≤ 0.001). GBP (18μmol/kg to 1.8 mmol/kg) and TPM (8.9–29.5 pmol/kg) had no significant effect on seizure frequency. Conclusions: In contrast to the high-dose PTZ model, the lh/lh model correctly predicted the antiabsence effect of LTG, the possible proabsence effects of VGB and TGB, and the lack of effect of GBP and TPM. The lWlh model appears to be superior to the high-dose PTZ model in predicting efficacy of putative AEDs against human absence seizures.     

Clinical Administration of New Antiepileptic Drugs: An Overview of Safety and Efficacy

Summary: Gabapentin, lamotrigine, tiagabine, topira-mate, vigabatrin, and zonisamide are all administered as add-on therapy for treatment of patients with refractory epilepsy. To date, no comparative randomized trials have been performed that could potentially allow an evidence-based choice to be made between these antiepileptic drugs (AEDs). We report a series of meta-analyses of placebo-controlled, randomized add-on trials in patients with partial epilepsy. Results of these meta-analyses are compared, thus giving broad estimates of the comparative efficacy and tolerability of these AEDs. The efficacy out come is the odds ratio for the number of patients with a ≥50% reduction in seizure frequency. Reported side ef fects are also used as tolerability outcomes, and study withdrawal is used as a global outcome measure. Results are summarized as odds ratios with 95% confidence in tervals (CIs). When each outcome is compared among drugs, the 95% CIS overlap. Therefore, no conclusive ev idence of a difference in efficacy or tolerability between these AEDs was derived, even though the apparently most effective agent (topiramate) may be twice as effec tive as the apparently least effective agent (lamotrigine). Comparative randomized studies are needed to further evaluate these drugs.     

Isobolographic profile of interactions between tiagabine and gabapentin: a preclinical study<Superscript>A,B</Superscript>

Combining the use of some antiepileptic drugs (AEDs) in patients with epilepsy can result in interactions of a pharmacodynamic or pharmacokinetic character. To quantify the profile of interactions between tiagabine (TGB) and gabapentin (GBP), two novel AEDs influencing the GABAergic neurotransmitter system, an isobolographic analysis was performed in the maximal electroshock seizure threshold (MEST), pentylenetetrazole (PTZ)-induced seizure and chimney tests in mice. TGB and GBP injected alone dose-dependently raised the electroconvulsive threshold in mice, which allowed the evaluation of TID₂₀ (the dose increasing the threshold by 20% compared with controls) in the MEST-test. TID₂₀ values for TGB and GBP alone were 4.3 mg/kg and 70 mg/kg, respectively. On the basis of isobolographic calculations, TGB was also co-administered with GBP at three fixed ratios (1:3, 1:1 and 3:1) of their respective TID₂₀ doses. The isobolographic analysis showed that all three combinations of TGB with GBP exerted supra-additive (synergistic) interactions in the MEST-test in mice. Likewise, TGB and GBP injected alone suppressed the clonic phase of PTZ-induced seizures, with (effective) doses protecting 50% of the animals tested against clonic convulsions (ED₅₀) for TGB and GBP of 0.9 and 199.3 mg/kg, respectively. Moreover, the two-drug combinations at the same fixed ratios of 1:3, 1:1 and 3:1 in PTZ-induced seizures also showed a tendency towards supra-additive (synergistic) interactions. The adverse (neurotoxic) effects produced by TGB and GBP alone or in combinations at the same fixed ratios of 1:3, 1:1 and 3:1 were evaluated in the chimney test. The (toxic) doses evoking motor impairment in 50% of animals tested (TD₅₀) for TGB and GBP alone were 13.6 and 979.6 mg/kg, respectively. The isobolographic analysis showed the interactions between the AEDs to be additive in this test. From a preclinical point of view, the interactions observed experimentally showed that the combination of TGB and GBP, due to a synergistic anti-seizure activity of the drugs, might provide adequate seizure control in patients with refractory epilepsy.^AThe results of the MEST-test in this study were presented at the 3rd Forum of European Neuroscience, Paris, France, 13–17 July, 2002 (abstract 559).^BThe results of the PTZ-test in this study were presented at the conference: Thirty years of cooperation between German and Polish pharmacologists—new perspectives in the Common Europe, Bialowieza, Poland, 18–21 September, 2003 (abstract: Pol J Pharmacol, 2003, 55:500–501).     

Tiagabine for posttraumatic stress disorder: effects of open-label and double-blind discontinuation treatment

Rationale Preliminary results suggest a potential benefit of agents that enhance gamma-aminobutyric acid (GABA) neurotransmission in treating posttraumatic stress disorder (PTSD). Objectives It is the aim of this study to evaluate the effect of a selective GABA reuptake inhibitor (SGRI), tiagabine, in patients with PTSD. Methods Twenty-nine adult outpatients with PTSD were treated with open-label tiagabine for 12 weeks. Those who responded to treatment (i.e., demonstrated at least minimal clinical improvement) were randomly assigned to double-blind treatment with either tiagabine or matching placebo. Efficacy assessments included measures of PTSD, anxiety, depression, sleep quality, resilience, and disability. Safety evaluation included changes in vital signs and weight and treatment-emergent adverse events. Results In subjects completing open-label treatment (n=19), significant improvement was observed on all outcome measures (P<0.05) and the treatment was well tolerated. Eighteen subjects responded and were randomized into the double-blind phase. Following randomization, benefits of treatment were generally upheld, but there was no greater incidence of relapse in the placebo group. However, continued treatment with tiagabine was associated with a greater trend toward likelihood of remission than if one was switched to placebo (P<0.08). Conclusions These findings suggest a possible role for the SGRI tiagabine in the treatment of PTSD. As the role of GABAergic drugs in PTSD is poorly defined, larger, randomized, double-blind, placebo-controlled trials are needed.     

Tiagabine Pharmacology in Profile

Summary: Tiagabine (TGB) hydrochloride, a nipecotic acid derivative linked to a lipophilic anchor, potently and specifically inhibits uptake of the inhibitory neurotransmitter γ-aminobu-tyric acid (GABA) into astrocytes and neurons. With microdial-ysis, TGB has been shown to increase extracellular overflow of GABA in the midbrain of awake rats. TGB administration prolongs neuronal depolarization induced by iontophoretically applied GABA in hippocampal slices. TGB is effective in a wide range of seizure models, including pentylenetetrazol-induced, methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-car-boxylate (DMCM)-induced tonic, amygdala-kindled and picro-toxin-induced convulsions, and maximal electroshock seizures in rodents. In humans, TGB absorption is rapid and complete. It is metabolized in the liver, largely by isoform 3A of the cytochrome P450 family of enzymes. The process of elimination is linear, with a half-life of 5–8 h. TGB does not induce Or inhibit metabolic processes, although it provides a target for enzyme inducers that can lower its elimination half-life to 2–3 h. Accordingly, TGB does not alter the concentrations of other antiepileptic drugs (AEDs), with the possible exception of a small decrease in valproate levels. A controlled-release formulation of TGB would offset any potential clinical disadvantage of the short elimination half-life, particularly in patients receiving concurrent treatment with enzyme-induced AEDs.     

Tiagabine: The Safety Landscape

Summary: Tiagabine (TGB) hydrochloride is a potential new antiepileptic drug (AED) undergoing clinical development. Experience in humans amounts to 1,810 patient-years of exposure. TGB was found to be tolerated in an integrated safety analysis of five double-blind, add-on therapy trials involving approximately 1,000 patients with epilepsy with difficult-to-control seizures with existing AEDs. Discontinuation resulting from adverse events were infrequent, occurring in 15% of patients receiving TGB compared to 5% receiving placebo. The most frequently reported adverse event was dizziness, which was usually transient and did not require medical intervention. Adverse events that were statistically significantly more common with TGB than placebo were dizziness, asthenia, nervousness, tremor, diarrhea, and depression (not major depression). Adverse events were usually mild to moderate in severity and transient, and most were associated with dose titration. The incidence, type, and severity of adverse events in long-term studies were comparable with those in short-term studies. Serious adverse events were uncommon and no idiosyncratic events were reported.