Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tiagabine (TGB) is indicated as adjunctive therapy for partial seizures in adults and children aged 12 years and older. Double-blind, placebo-controlled studies of TGB treatment are under way in younger children with various forms of epilepsy. The results of pediatric pharmacokinetic trials indicate patterns similar to those seen in adults. An open-label study was conducted in the United States in 31 children with refractory complex partial seizures, with doses escalated every 2 weeks by 0.25 mg/kg up to a maximal daily dose of 1 mg/kg. Twenty-nine patients were treated with TGB for >1 year; 26 completed the study, of whom 18 were receiving monotherapy at study completion. A European dose-escalation study evaluated TGB (0.25-1.5 mg/kg/day) as add-on therapy in 52 children aged 2-15 years. TGB appeared to be more effective in localization-related epilepsy syndromes, with 17 of 23 patients with localization-related epilepsy having a 33% median reduction of seizure rate compared with baseline in the fourth month of treatment, and six patients having > or =50% seizure rate reduction. In this study, myoclonic seizures and spasms showed a poor response as opposed to encouraging findings reported by other groups with these seizure types. The adverse effect profile of TGB in children with epilepsy is similar to that in adults. In the U.S. study, most common adverse events were related to the central nervous system (CNS) and decreased over time. In the European study, mostly mild to moderate adverse events, including asthenia (19%), nervousness (19%), dizziness (17%), and somnolence (17%), were reported by 83% of TGB-treated children (39% of children reported adverse events during the single-blind placebo period). In summary, preliminary pediatric data with TGB suggest particular efficacy against epilepsy characterized by partial seizures or other syndromes, and further investigation is warranted.
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PMID:Tiagabine (gabitril) experience in children. 1152 Mar 24

Tiagabine is a relatively new anticonvulsive agent. Data concerning safety and efficacy come from randomised controlled trials whose relation to everyday clinical practice is poorly defined. We analysed retrospectively the data of 56 patients to whom tiagabine was routinely prescribed in a special clinic. Effect and adverse events were registered according to documentation of routine visits in the outpatient clinic. After a median of 89 weeks, 22 patients (39%) still received tiagabine. All of them noted a reduction in seizure frequency, and eight (14%) became seizure-free. Reasons for stopping the medication were: an increase in seizure frequency, lack of efficacy, tiagabine-associated non-convulsive status epilepticus and sudden and short episodes of mental chang. However, tiagabine seems to be an effective anticonvulsant in clinical practice but should remain in the hands of experienced prescribers until further clarification of possible risk factors for proconvulsive effects.
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PMID:[Experience with tiagabine in the clinical practice; new insights as to the efficacy and safety profile]. 1168 77

Tiagabine, a novel GABA reuptake inhibitor, has been reported to induce non-convulsive status epilepticus (NCSE) in patients with epilepsy. We report a 27 year old female with history of pseudoseizure documented by video-EEG monitoring who presented confusion while on 56 mg per day of tiagabine. Electroencephalography showed generalized sharp and slow wave discharges, consistent with NCSE. The NCSE was terminated by lorazepam and did not recur after tiagabine was discontinued. This case report suggests that tiagabine may induce NCSE in patients without epilepsy.
Seizure 2002 Jan
PMID:Non-convulsive status epilepticus induced by tiagabine in a patient with pseudoseizure. 1188 62

The inhibitory effect of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and its N-methylated (N-methyl-exo-THPO) and N-ethylated (N-ethyl-exo-THPO) analogs, derived from gamma-aminobutyric acid (GABA) and 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO) on GABA transport was investigated using cultured neocortical neurons (GABA-ergic) and astrocytes and cloned mouse GABA transporters GAT1-4 expressed in human embryonic kidney (HEK) 293 cells. Anticonvulsant activity was assessed after i.c.v. administration to Frings audiogenic seizure-susceptible mice. Anticonvulsant activity of the O-pivaloyloxymethyl prodrug of N-methyl-exo-THPO was assessed after i.p. administration. Results from these studies were compared with those obtained from similar studies with the novel anticonvulsant drug tiagabine, which acts via inhibition of GABA transport. exo-THPO and its N-alkyl analogs inhibited neuronal, astrocytic, and GAT1-mediated GABA transport but not GABA uptake mediated by GAT2-4. N-Methyl-exo-THPO was 8-fold more potent as an inhibitor of astrocytic versus neuronal GABA uptake. The IC(50) value for inhibition of GABA uptake by GAT1 closely reflected its IC(50) value for inhibition of neuronal uptake. Tiagabine was approximately 1000-fold more potent than exo-THPO and its alkyl derivatives as an inhibitor of GABA uptake in cultured neural cells and GAT1-expressing HEK 293 cells. exo-THPO, its alkylated analogs, and tiagabine displayed a time- and dose-dependent inhibition of audiogenic seizures after i.c.v. administration. N-Methyl-exo-THPO was the most potent anticonvulsant among the exo-THPO compounds tested and only slightly less potent than tiagabine. The findings suggest a correlation between anticonvulsant efficacy and selective inhibition of astroglial GABA uptake. Furthermore, results obtained with the N-methyl-exo-THPO prodrug demonstrate the feasibility of developing a glial-selective GABA uptake inhibitor with systemic bioavailability.
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PMID:Correlation between anticonvulsant activity and inhibitory action on glial gamma-aminobutyric acid uptake of the highly selective mouse gamma-aminobutyric acid transporter 1 inhibitor 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole and its N-alkylated analogs. 1213 Jul 26

High seizure susceptibility in El mice is associated with disinhibition in the dentate gyrus (DG) and paired-pulse facilitation in the CA3 area in hippocampal slices [Brain Res. 745 (1997) 165; Brain Res. 779 (1998) 324]. A decrease in gamma-aminobutyric acid (GABA)-mediated inhibition and an increase in excitatory inputs to the major neurons seem to be the responsible mechanisms, respectively, for these phenomena. In this study, we examined the effects of tiagabine, an inhibitor of GABA transporter, on hyperexcitation in vivo and in slice preparations. Tiagabine (0.3-0.5 mg/kg) suppressed the occurrence of seizures to about 20% of controls with an ED(50) value of about 0.17 mg/kg. In addition, perfusion of hippocampal slices with tiagabine (20 microM) counteracted the paired-pulse facilitation in the CA3 region over the entire range of interpulse intervals (P<0.05, two-way ANOVA) and reduced the disinhibition in the DG measured at 10 and 20 ms during short interpulse intervals (P<0.005, paired t-test). The CA1 region in the El mice, as well as in a non-epileptic parental strain of ddY mice did not respond to the drug. However, frequency potentiation of CA3 was enhanced in both strains (P<0.05, paired t-test). Our results suggest that within the hippocampus the antiepileptic action of tiagabine is selectively suppressive for hyperexcitability of DG and CA3, which are responsible for seizure-susceptibility in El mice.
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PMID:Selective suppression of hippocampal region hyperexcitability related to seizure susceptibility in epileptic El mice by the GABA-transporter inhibitor tiagabine. 1217 63

The stability of tiagabine hydrochloride in two extemporaneously prepared oral suspensions stored at 4 and 25 degrees C for three months was studied. Tiagabine is used for adjunctive therapy for the treatment of refractory partial seizures. It is currently available in a tablet dosage form, which cannot be used in young children who are unable to swallow and given doses in milligrams per kilogram of body weight. No stability data are available for tiagabine in any liquid dosage form. Five bottles contained tiagabine 1 mg/mL in 1% methylcellulose:Simple Syrup, NF (1:6), and another five bottles had tiagabine 1 mg/mL in Ora-Plus:Ora-Sweet (1:1). Three samples were collected from each bottle at 0, 7, 14, 28, 42, 56, 70, and 91 days and analyzed by a stability-indicating high-performance liquid chromatographic method (n = 15). At 4 degrees C, the mean concentration of tiagabine exceeded 95% of the original concentration for 91 days in both formulations. At 25 degrees C, the mean concentration of tiagabine exceeded 90% of the original concentration for 70 days in Ora-Plus:Ora-Sweet formulation and for 42 days in 1% methylcellulose:syrup formulation. No changes in pH or physical appearance were seen during this period. The stability data for two formulations would provide flexibility for compounding tiagabine. Tiagabine hydrochloride 1 mg/,mL in extemporaneously prepared liquid dosage forms and stored in plastic bottles remained stable for up to three months at 4 degrees C and six weeks at 25 degrees C.
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PMID:Stability of tiagabine in two oral liquid vehicles. 1253 80

Tiagabine was used as add-on therapy in the treatment of epilepsy with partial and/or secondarily generalised seizures to evaluate tolerability and efficacy. Five hundred and seventy-four patients (299 men and 275 women, mean age 38.1 years), with refractory partial seizures, were enrolled in this prospective, open-label study. Tiagabine was added to one (44.1%) or more (up to nine) antiepileptic drugs. The median daily dose of tiagabine was 30 mg (mean 29.1, SD 12.0). The mean duration of follow-up was 94.9 42.7 days. 12.3% of patients were completely seizure-free at the end of the observation period. Median total seizure frequency decreased from 4.5 to 2.0 seizures/4 weeks. Adverse events occurred in 78 patients (13.6%). Tiagabine proved to be a well-tolerated AED.
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PMID:Tolerability of tiagabine: a prospective open-label study. 1260 Aug 12

Epilepsy, a functional disturbance of the CNS and induced by abnormal electrical discharges, manifests by recurrent seizures. Although new antiepileptic drugs have been developed during recent years, still more than one third of patients with epilepsy are refractory to treatment. Therefore, the search for new mechanisms that can regulate cellular excitability are of utmost importance. Three currently available drugs are of special interest because they have novel mechanisms of action and are especially effective for partial onset seizures. Vigabatrin is a selective and irreversible GABA-transaminase inhibitor that greatly increases whole-brain levels of GABA. Tiagabine is a potent inhibitor of GABA uptake into neurons and glial cells. Topiramate is considered to produce its antiepileptic effect through several mechanisms, including modification of Na(+)-and/or Ca(2+)-dependent action potentials, enhancement of GABA-mediated Cl- fluxes into neurons, and inhibition of kainate-mediated conductance at glutamate receptors of the AMPA/kainate type. This review will discuss these mechanisms of action at the cellular and molecular levels.
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PMID:Novel mechanisms of action of three antiepileptic drugs, vigabatrin, tiagabine, and topiramate. 1260 6

Epilepsy is a common comorbidity among developmentally disabled (DD) patients, and special considerations apply to its treatment. In particular, clinicians should try to avoid antiepileptic drugs (AEDs) with sedating properties or adverse cognitive effects that might further diminish quality of life for DD patients. Behavioral changes due to medication and significant pharmacokinetic interactions with other medications are also concerns. The newer AEDs, approved in the 1990s, offer new options for the treatment of individuals with developmental disability and epilepsy. Gabapentin does not interact with the hepatic metabolism of other AEDs or psychotropic agents, results in a statistically significant reduction in seizure frequency in mentally retarded children, and is generally well tolerated. Felbamate is an effective broad-spectrum AED, but has serious toxicity issues limiting its use. Lamotrigine has been extensively studied in the DD population, achieving seizure reduction rates of up to 50% in some trials. Although it is usually well tolerated in this population, its pharmacokinetic profile is influenced by concomitant medications. Levetiracetam has been found to be effective against kindled seizures and has been approved as adjunctive therapy for partial epilepsies. It does not cause any pharmacokinetic interactions, but may have behavioral side effects. Oxcarbazepine is a homologue of carbamazepine that has fewer drug interactions. It is approved for mono- or adjunctive therapy in patients with partial seizures, and its use in DD individuals appears to be worthwhile. Tiagabine is extensively bound to plasma proteins and is therefore subject to protein-binding displacement interactions by other highly protein-bound drugs, such as sodium valproate. While there are trial data showing its efficacy as adjunctive therapy in partial epilepsy in adults and children, there is a paucity of data specific to the DD population. Common side effects include sedation. Topiramate is a broad-spectrum AED approved as adjunctive therapy for partial and primary generalized tonic-clonic seizures. It appears to be particularly effective in patients with Lennox-Gastaut syndrome and those with cognitive disabilities. It appears to be better tolerated in the DD population than in the general population. Zonisamide has been effective in the DD population, yielding a seizure reduction of 50% in 41% of children in 1 trial. It has been associated with renal stone formation, sedation, and cognitive effects, however. The new AEDs have a role in treating seizures in the DD. Side effects that limit their use include anorexia, behavioral changes, and sedation. Seizure exacerbation can occur with the new AEDs and success is defined empirically and by improvements in quality of life.
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PMID:Antiepileptic drug treatment in the developmentally disabled: treatment considerations with the newer antiepileptic drugs. 1260 9

Tiagabine (TGB), a novel GABA reuptake inhibitor antiepileptic drug, has been reported to induce nonconvulsive status epilepticus (NCSE) in patients with generalized or partial onset seizures. We describe six patients with refractory partial epilepsy treated with add-on TGB. They developed acute intermittent or progressive chronic confusion associated with diffuse slowing of the electroencephalogram (EEG), shortly after an increase in dose of TGB. This remitted in each situation after reduction of the daily dose. The possibility of nonconvulsive status epilepticus or toxic encephalopathy is discussed.
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PMID:Clinical and EEG findings in six patients with altered mental status receiving tiagabine therapy. 1279 36


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