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), a recently approved antiepileptic drug (AED), has a specific mechanism of action that is unique among AEDs. A potent AED with linear, predictable pharmacokineties, it inhibits gamma-aminobutyric acid (GABA) reuptake into neurons and glia. Tiagabine does not have any clinically relevant effects on hepatic metabolism or on serum concentrations of other AEDs, nor does it interact with commonly used non-AEDs. The most common side effects of TGB in controlled studies are dizziness, asthenia, somnolence, accidental injury, infection, headache, nausea, and nervousness. These events are usually mild to moderate in severity and generally do not require medical intervention. At dosages of 30-56 mg daily, TGB is an effective add-on treatment for partial seizures. Although patients who have medically refractory epilepsy can be converted to TGB monotherapy, more controlled studies are necessary to confirm the efficacy of TGB as monotherapy and to determine the effective dosage range.
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PMID:A review of the antiepileptic drug tiagabine. 1062 90

The present study examines the effect of tiagabine (a selective inhibitor of GABA transporter 1, GAT-1), SNAP-5114 (a semi-selective inhibitor of rat GAT-3/mouse GAT4) and NNC 05-2045 (a non-selective GABA uptake inhibitor) in modulating GABA levels in the hippocampus and thalamus. Anticonvulsant effects of the same compounds were assessed (after intranigral administration) after maximal electroshock (MES) in juvenile rats. Anticonvulsant effects were also tested after intraperitoneal (i.p.) administration against audiogenic seizures in DBA/2 mice and against pentylentetrazole (PTZ)-induced tonic convulsions or MES in NMRI mice. Tiagabine (30 microM, perfused through the microdialysis probe in halothane anaesthetized rats) increased GABA levels to (% basal+/-SEM) 645+/-69 in the hippocampus and 409+/-61 in the thalamus. SNAP-5114 (100 microM) increased GABA levels in the thalamus (% basal+/-SEM) to 247+/-27 but had no effect on hippocampal GABA-levels. NNC 05-2045 (100 microM) increased GABA levels both in the hippocampus (% basal+/-SEM, 251+/-51) and in the thalamus (298+/-27). All compounds protected against tonic hindlimb extension (THE) in juvenile male rats after intranigral administration. Sound induced convulsions in DBA/2 mice were dose-dependently inhibited by all compounds (administered intraperitoneal, i.p.) with ED(50) values of 1, 6 and 110 micromol/kg, for tiagabine, NNC 05-2045 and SNAP-5114, respectively. Tiagabine and NNC 05-2045 but not SNAP-5114 protected against PTZ-induced tonic convulsions whereas only NNC 05-2045 protected against MES-induced tonic convulsions in NMRI mice. However, tiagabine and NNC 05-2045 exerted a synergistic effect in the MES model. These findings substantiate and extend previous findings of different effects of selective versus non-selective GABA uptake inhibitors in animal models of epilepsy.
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PMID:GABA-level increasing and anticonvulsant effects of three different GABA uptake inhibitors. 1097 24

Multifocal independent spike syndrome (MISS) is an identifiable electroclinical syndrome, which combines intractable motor seizures, mental retardation and multifocal independent spike discharges. Similarities to the Lennox Gastaut syndrome cause frequent misdiagnosis; however, MISS is a distinct electroclinical syndrome in children with a better prognosis and a different EEG pattern. We report an 8-year-old boy with MISS, whose intractable seizures were completely controlled for the first time with tiagabine as add-on therapy. Tiagabine should be studied further in the treatment of intractable multiple seizures of childhood.
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PMID:The role of tiagabine in the treatment of intractable epilepsy of childhood with multifocal independent spikes: a case report. 1105 44

Tiagabine, a specific gamma-aminobutyric acid-uptake inhibitor, has been shown to be reasonably well tolerated and efficacious as adjunctive treatment for partial seizures in adults and is now being investigated in children. This 4-month, single-blind study evaluated the tolerability, safety and preliminary efficacy of ascending doses (0.25-1.5 mg/kg/day) of tiagabine add-on therapy in 52 children over the age of 2 years with different syndromes of refractory epilepsy. Adverse events, mostly mild to moderate, were reported by 39% of children during the single-blind placebo period and by 83% of children during tiagabine treatment. The events predominantly affected the nervous system with asthenia (19%), nervousness (19%), dizziness (17%) and somnolence (17%) being the most common. Only three children (6%) withdrew because of adverse events. Tiagabine appeared to reduce seizures more in localisation-related epilepsy syndromes than in generalised epilepsy syndromes. Twenty-three patients with localisation-related epilepsy syndromes were included and 17 of these patients entered the fourth dosing period. The 17 patients had a median reduction of seizure rate in the fourth month of treatment of 33% compared with baseline. In comparison, 13 of 22 children with seven different generalised epilepsy syndromes entered the fourth dosing period with a median change of seizure rate of 0%. Two patients experienced single episodes of status epilepticus during treatment; both cases resolved. Tiagabine showed efficacy mainly in localisation-related syndromes and was well tolerated by most children in a group of very refractory patients and warrants further study in children with epilepsy.
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PMID:Tiagabine adjunctive therapy in children with refractory epilepsy: a single-blind dose escalating study. 1107 88

For pure childhood absence epilepsy (CAE), ethosuximide (ESM) remains the drug of first choice. Although valproic acid (VPA) is of equal efficacy, it is more toxic, and is reserved for those patients with accompanying convulsions. Lamotrigine (LTG) is effective as both add-on and monotherapy for CAE. If any of these three drugs fails, one of the other two can be used as monotherapy. Rarely, when ESM, VPA, or LTG does not effectively control CAE, phenytoin (PHT), primidone (PRM), and phenobarbital (PB) may be partially effective, although carbamazepine (CBZ) may worsen absence seizures. Experience is limited with the newer AEDs. Tiagabine (TGB) may induce absence status epilepticus in PGE. Oxcarbazepine (OXC) and vigabatrin (VGB) may worsen absence seizures. Felbamate (FBM) is probably effective, but is potentially fatal. Lifelong therapy is not anticipated. For juvenile absence epilepsy (JAE), VPA is the drug of first choice. LTG is also of proven efficacy. The risks of VPA-induced teratogenicity (possibly lessened by the concurrent use of folic acid) and weight gain are potentially unacceptable in young women of childbearing age. Not enough data exists on the safety of LTG in pregnancy. A combination of VPA and LTG can be used if either drug alone is unsuccessful. For juvenile myoclonic epilepsy (JME), VPA is the traditional drug of first choice in most patients. As in JAE, side effects may make VPA an unacceptable choice in many patients, especially young women. In clinical practice, TPM is being increasingly used as monotherapy for JME. Many patients appreciate the accompanying weight loss seen with TPM, but it has potentially troubling side effects, has not been well studied as monotherapy for JME, and its safety in pregnancy has yet to be confirmed. PHT and CBZ may worsen myoclonus when used alone, but they may have a role as add-on treatment to VPA, LTG, or TPM, especially when generalized tonic-clonic seizures (GTCSs) are not controlled. PB and PRM may also be useful as add-on treatment, but often have unacceptable side effects. Clonazepam may be useful as adjunctive treatment for resistant myoclonic jerks. OXC and VGB both worsen myoclonic seizures. GBP is not useful in JME and can make seizures worse. The efficacy of FBM and TGB in JME is largely unknown. Lifelong AED therapy is necessary. In epilepsy with generalized tonic-clonic seizure (GTCS) on awakening (EGA), VPA is the drug of choice, especially if other seizure types (absence and myoclonic) are present. If only GTCSs are present, then PB, PHT, and CBZ may be as effective as VPA; however, the use of PHT and CBZ may "unearth" other seizure types (absence and myoclonic) in those patients with EGA, although PB is poorly tolerated. As for JME, LTG, and TPM may both be effective monotherapy for EGA, although the use of other AEDs in EGA has not been well studied. Lifelong AED treatment is necessary.
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PMID:Primary Generalized Epilepsies. 1109 77

Epilepsy is common in the elderly. The incidence of epilepsy is age-dependent, with a peak during the first year of life and higher incidence in those older than 75 years. Cerebrovascular disease is a common cause of epilepsy in the elderly. Drug treatment of the elderly is a challenge because of pharmacokinetic changes with aging, including impaired drug protein binding or displacement of drug from protein binding sites, potentially causing drug toxicity as a result of increased free drug concentrations. With aging, hepatic mass and blood flow decline along with renal function. Established anticonvulsant drugs have adverse effects and drug interactions that can make treating the elderly difficult. Newly available anticonvulsants cause fewer drug-drug interactions and less toxicity. Gabapentin is not metabolised, is not bound to protein, and has a favourable adverse effect profile and thus may be useful in the treatment of elderly patients. Lamotrigine reduced seizures between 20 and 30% in trials. Dose response was between 300mg per day and 500mg per day. This drug was well tolerated in open-label trials. Rash occurred in younger patients. Oxcarbazepine is rapidly absorbed and is converted to a monohydroxy derivative. Use with hepatic enzyme-inducing drugs necessitates an increase in dose. This drug may be substituted for carbamazepine. Hyponatraemia has been reported and monitoring is suggested. Topiramate blocks voltage-dependent sustained repetitive firing and has an effect on the gamma-aminobutyric acid (GABA) receptors. It affects glutamate responses and inhibits carbonic anhydrase. Topiramate has a dose response pattern up to 400mg per day. Cognitive effects limits its use in some patients. Nephrolithiasis has occurred with this drug. Tiagabine blocks GABA transporter proteins. Clearance is rapid and metabolism complete. Hepatic dysfunction prolongs clearance. The use of tiagabine has not been reported in the elderly. Zonisamide is rapidly absorbed and protein binding is 50%. Plasma half-life is 55 hours but is reduced to about 30 hours by hepatic enzyme-inducing drugs. Responder rate is 45%. Adverse effects include drowsiness, altered thinking and nephrolithiasis. Treatment of the elderly requires obligatory polypharmacy with potential drug interactions. Changes in body physiology alter absorption, binding, metabolism and elimination of drugs. Concomitant illness and sensitivity to drug effects narrow the therapeutic range and complicate pharmacokinetics in elderly patients. Newer anticonvulsant drugs have advantages that may outweigh risks and have therapeutic profiles that may aid in the treatment of this special population of patients.
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PMID:Choice and use of newer anticonvulsant drugs in older patients. 1120 Mar 5

Tiagabine (Gabitril, Sanofi Synlhelabo) new antiepileptic drug was used in add-on therapy in 25 children with resistant partial complex and secondary generalized seizures. Treatment was carried out in children aged 4-17 years with low dose escalation from 5 to 45 mg/day, in three doses until good clinical effects were obtained. In 3 patients aged 4 years, in 11 children aged 5-12 years and in 11 children aged above 17 years Gabitril was used. Follow up period was 8-10 months. Frequency of epileptic seizures before implementation of Gabitril treatment, even during polytherapy with 2 or more antiepileptic drugs was several to hundred per day (status epilepticus was observed in 2 children with Rasmussen syndrome). During the observation 5 children became seizure free, in 11 patients reduction in seizures frequency above 50% was observed and in 9 children effects of treatment were not good enough. Gabitril was well tolerated, and any adverse events were observed in add-on therapy. Preliminary observation and good results of add-on therapy with Gabitril are positive. Drug is safe and generally well-tolerated with good effects at add-on therapy in 64% children with resistant partial complex and secondary generalized seizures.
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PMID:[Gabitril as an additive drug in therapy of intractable epileptic seizures in children]. 1125 89

Tiagabine (TGB), a recently approved anti-epileptic drug (AED), has a specific and unique mechanism of action involving the inhibition of gamma-aminobutyric acid (GABA) re-uptake into neurones and glia. TGB is potent and has linear and predictable pharmacokinetics. It does not induce or inhibit hepatic metabolism and has no clinically significant effects on the serum concentrations of other AEDs or commonly used non-AEDs. Double-blind, placebo-controlled studies in primarily hepatic enzyme-induced patients showed that TGB 30 - 56 mg/day is an effective add-on treatment for all subtypes of partial seizures. The most common adverse effects in the trials were dizziness, asthenia (weakness), somnolence, accidental injury, infection, headache, nausea and nervousness. These side effects were usually mild to moderate in severity and generally did not require medical intervention. Long-term safety studies show continued efficacy of TGB over time and no evidence of tolerance for efficacy. Open studies confirm that patients with medically refractory partial epilepsy can be successfully converted to TGB monotherapy and that TGB may be effective for other seizure types, such as infantile spasms.
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PMID:Pharmacology and clinical experience with tiagabine. 1133 78

1. Trimethylolpropane phosphate (TMPP) is a potent cage convulsant, reported to act through binding to the picrotoxinin and/or benzodiazepine receptor sites of the gamma-aminobutyricA (GABA(A)) ionophore complex. 2. Adult male Fischer-344 rats were pretreated by intraperitoneal (i.p.) injection with either diazepam (DZP) [0.5-5.0 mg/kg], Phenobarbital (PB) [5-20 mg/kg], dizocilpine maleate (MK-801) [0.5-3.0 mg/kg], Tiagabine (TGB) [0.5-5.0 mg/kg], 6,7-dinitro-quinoxaline-2,3-dione (DNQX), [5-20 mg/kg], or scopolamine [SCP] (0.25-1.0 mg/kg) 30 min prior to i.p. injection with a convulsive dose of TMPP (0.6 mg/kg). 3. Rats were rated for occurrence of convulsive activity for 120 min post-injection. Time from TMPP injection to observation of subclinical seizures, generalized (tonic-clonic) seizures, and lethality was rated for each pretreatment group. 4. In general, DZP = PB > TGB in reduction of TMPP subclinical and/or clinical seizures. MK-801, at dose levels inducing near sedation, was also effective in modulation of TMPP-induced seizures. SCP or DNQX were generally ineffective in reducing or eliminating TMPP-induced seizures.
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PMID:Reduction of motor seizures in rats induced by the ethyl bicyclophosphate trimethylolpropane phosphate (TMPP). 1147 48

The choice of an antiepileptic drug depends firstly on its efficacy in specific seizure types and epilepsies. However, it is imperative to consider whether possible adverse events will outweigh any benefits. The advantages and disadvantages of vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine and felbamate are considered in some detail, and oxcarbazepine, stiripentol, remacemide, zonisamide and levetiracetam more briefly. Vigabatrin is effective for partial seizures and infantile spasms, but visual field defects are limiting its use. Lamotrigine has a wide spectrum, needs to be prescribed with care. Gabapentin is unlikely to cause adverse effects, but has relatively poor efficacy. Topiramate is widely effective, but can be poorly tolerated. Tiagabine is relatively untried in childhood epilepsies. The use of felbamate is restricted to severe refractory epilepsies. Stiripentol can be effective in severe myoclonic epilepsy in infancy. Zonisamide has a special place in the progressive myoclonus epilepsies. Levetiracetam, remacemide and oxcarbazepine have been used mainly for partial seizures: further studies of their roles in other circumstances are required.
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PMID:Newer antiepileptic drugs: advantages and disadvantages. 1150 96


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