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)

The effect of systemic administration of the gamma-aminobutyric acid (GABA) uptake inhibitor, R(-)N-(4,4-di(3-methyl-thien-2-yl)-but-3-enyl) nipecotic acid, hydrochloride (tiagabine) (previously NO-328), on extracellular GABA levels in the globus pallidus, ventral pallidum and substantia nigra of awake Sprague-Dawley rats was investigated using in vivo microdialysis. Tiagabine was administered in doses of 11.5 or 21.0 mg/kg i.p. (ED50 and ED85 doses, respectively, for inhibiting pentylenetetrazole-induced tonic seizures). Tiagabine increased the extracellular concentrations of GABA in globus pallidus with peak values 310% of basal level (after 21 mg/kg) and 240% of basal level (after 11.5 mg/kg). A significant increase in extracellular GABA levels was also found in the ventral pallidum (280% increase after 11.5 mg/kg and 350% increase after 21 mg/kg) and in the substantia nigra where the ED85 dose of tiagabine (21 mg/kg) produced a peak value of 200% compared to the basal level. Thus, tiagabine acts as a GABA uptake inhibitor in vivo also.
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PMID:The gamma-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats. 142 91

Tiagabine (NO-328) (R(-)-N-[4,4-bis(3-methylthien-2-yl)but-3-enyl]nipecotic acid, hydrochloride) is a new centrally acting GABA uptake inhibitor. The anticonvulsant activity of tiagabine was evaluated against seizures induced by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), pentylenetetrazol, bicuculline, maximal electrostimulation (MES), or high intensity sound. The sedative actions of tiagabine were evaluated in tests for traction, rotarod performance and exploratory behavior. Finally, interoceptive properties of tiagabine were assessed using diazepam-, CGS 9896-, pentylenetetrazol-, or amphetamine-discriminating rats. Tiagabine was an effective anticonvulsant in doses which did not produce sedation or motor debilitation, although it was not potent against MES. In a manner similar to other anti-epileptic drugs, tiagabine potentiated dopaminergic function (methylphenidate-induced gnawing in mice) although it did not substitute for amphetamine in amphetamine-trained animals. Furthermore, although tiagabine antagonized DMCM-induced convulsions, it exhibited neither CGS 9896 or diazepam-like interoceptive effects, nor did it block (or potentiate) pentylenetetrazol-discrimination. Thus, GABA uptake inhibition represents a novel rationale for a valproate-like anticonvulsant drug therapy.
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PMID:Characterization of tiagabine (NO-328), a new potent and selective GABA uptake inhibitor. 183 36

Effects of the anticonvulsant tiagabine in doses of 1, 3 and 10 mg/kg were investigated on electroencephalogram (EEG), spike-wave discharges and behaviour of WAG/Rij rats. These rats are considered as an animal model of generalized, non-convulsive, absence epilepsy. WAG/Rij rats spontaneously show a considerable number of spike-wave discharges in their EEG. These discharges can be facilitated by GABA agonists. The facilitatory effects of these agonists are completely opposite to their effects on convulsive seizures, which are reduced by these drugs. Tiagabine enhances the effects on the GABA system, since it acts as a GABA re-uptake inhibitor. According to expectations, tiagabine enhanced in a dose-related way both the number and mean duration of spike-wave discharges. The low dose of 1 mg/kg had almost no effects, but doses of 3 and 10 mg/kg were effective. Furthermore, tiagabine in the latter two doses increased the power in the higher beta band of the background EEG, whereas no significant changes in behavioural parameters were found. An unexpected finding was the occurrence of a second type of spike-wave discharges. These were again seen with the two higher doses of tiagabine, while 1 mg/kg had no effect. An assumption is that this second type of discharges are forerunners of genuine spike-wave discharges. In general, this experiment supports that non-convulsive epilepsy is associated with a GABA hyperfunction. It also underlines the biochemical differences of convulsive and non-convulsive animal models of epilepsy. Tiagabine, with its GABA-mimetic properties, belongs to the category of drugs effective in convulsive animal models and not in non-convulsive models of epilepsy.
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PMID:Effects of the GABA-uptake inhibitor tiagabine on electroencephalogram, spike-wave discharges and behaviour of rats. 758 92

Tiagabine is a new antiepileptic drug which acts by a novel mechanism, inhibiting the reuptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into neurons and glia. A double-blind, placebo-controlled, crossover trial was undertaken, based upon a response-dependent design. Ninety-four patients with complex partial seizures with or without secondary generalised tonic-clonic seizures were recruited into an open screening phase and tiagabine was added to their existing drug therapy in doses titrated to reduce seizure frequency by > or = 25% or to the limit of tolerance. Forty-six responders were subsequently randomised to a double-blind crossover trial in which tiagabine was compared with placebo. Forty-two patients completed the trial. A significant reduction in the frequency of complex partial and secondary generalised tonic clonic seizures was seen. Twenty-six percent had a reduction of > or = 50% in the frequency of their complex partial seizures, and of the 27 patients who also had secondary generalised tonic clonic seizures, 63% experienced a reduction of > or = 50%. No interactions with baseline antiepileptic drugs were detected and no serious adverse reactions occurred. The commonest adverse events were tiredness, dizziness and headache. We conclude that tiagabine has promising antiepileptic effects. Further trials are underway.
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PMID:Adjunctive treatment of partial seizures with tiagabine: a placebo-controlled trial. 764 74

Tiagabine is a novel antiepileptic drug which acts by decreasing gamma aminobutyric acid uptake in astrocytes and neurones. Here the first case of deliberate overdose with this compound in a patient on concomitant phenytoin is reported. On admission to hospital his conscious level deteriorated to grade III coma. No changes in the electrocardiogram were noted. Recovery from the initial effects was rapid, and there were no sequelae. Plasma levels of tiagabine (3.1 micrograms/ml) 4 hours after ingestion were 30 times higher than at typical steady state during therapeutic dosing. The effects of poisoning with current first-line antiepileptic drugs are reviewed. The newer agents, particularly those with greater biochemical specificity, may be safer in overdose than the more established anticonvulsants.
Seizure 1995 Jun
PMID:Deliberate overdose with the novel anticonvulsant tiagabine. 767 Jul 69

The potential clinical efficacy of tiagabine for control of status epilepticus was evaluated in an experimental model. Tiagabine was administered to cobalt-lesioned rats in which status epilepticus was induced by injection of homocysteine thiolactone. Tiagabine was effective in controlling status epilepticus in this model; the median effective dose for control of generalized tonic-clonic seizures in the model was 8.3 mg/kg. Tiagabine administration produced an abnormal, hypo-reactive behavioral state which was accompanied by an EEG pattern of high-amplitude, frontally dominant, rhythmic, 3-5-Hz spike-wave activity. This EEG and behavioral syndrome could be reproduced by administration of tiagabine to normal, non-epileptic rats. The exact nature of this syndrome remains unclear, but whether it is an epileptic or encephalopathic phenomenon, further study is clearly required before this drug should be considered for use in the treatment of human status epilepticus.
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PMID:Treatment of experimental status epilepticus with the GABA uptake inhibitor, tiagabine. 769

The effects of i.p. administration of the gamma-aminobutyric acid (GABA) uptake inhibitors R(-)N-(4,4-di(3-methylthien-2-yl)-but-3-enyl) nipecotic acid hydrochloride (tiagabine; molecular weight 412.0), (1-(2-(((diphenylmethylene)-amino)oxy)ethyl)-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride (NNC-711; molecular weight 386.9), and (+/-)-nipecotic acid (molecular weight 128.2) are compared with those of carbamazepine (molecular weight 236.3) on sound-induced seizures and locomotor performance in genetically epilepsy-prone (GEP) rats. The ED50 value against clonic seizures (in mumol kg-1 at the time of maximal anticonvulsant effect) for tiagabine was 23 (0.5 h), and for NNC-711 was 72 (1 h), and for carbamazepine was 98 (2 h). (+/-)-Nipecotic acid (0.4-15.6 mmol kg-1) was not anticonvulsant. High doses of NNC-711 (207-310 mumol kg-1) and of (+/-)-nipecotic acid (39-78 mmol kg-1) induced ataxia and myoclonic seizures 0.25-1 h. Tiagabine and carbamazepine did not induce myoclonic seizures and had similar therapeutic indices (locomotor deficit ED50/anticonvulsant ED50) ranging from 0.4 to 1.9. In Papio papio, we observed a reduction in photically induced myoclonic seizures with tiagabine (2.4 mumol kg-1 i.v.) accompanied with neurological impairment. Tiagabine has comparable anticonvulsant action to carbamazepine in rats and has anticonvulsant effects in non-human primates supporting the potential use of inhibitors of GABA uptake as therapy for epilepsy.
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PMID:The gamma-aminobutyric acid uptake inhibitor, tiagabine, is anticonvulsant in two animal models of reflex epilepsy. 773 33

Tiagabine is a new anticonvulsant drug that blocks the uptake of GABA, prolonging the action of this inhibitory transmitter. In the present study the effects of systemically administered tiagabine [30 mg/kg, ip (ED50)] were examined on audiogenic seizure (AGS) severity and neuronal firing in the inferior colliculus (IC) in the freely moving genetically epilepsy-prone rat (GEPR-9). The IC is known to be critical to AGS initiation. The effects of focal microinjection of tiagabine into the IC were also examined. Bilateral focal microinjection of tiagabine into the IC significantly reduced seizure severity in the GEPR-9. Systemically administered tiagabine also produced a significant reduction in seizure severity in the GEPR-9. Tiagabine produced a reduction in IC (central nucleus) neuronal firing, which was significant only at high acoustic intensities (90-105 dB), concomitant with the considerable reduction in seizure severity. These data are consistent with enhancement by tiagabine of gamma-aminobutyric acid (GABA)-mediated inhibition in IC, which is most prominent at high acoustic intensities. The time course of the reduction in neuronal firing of IC neurons paralleled the reduction in seizure severity. Previous studies have shown that two forms of GABA-mediated inhibition (intensity-induced and offset inhibition) in IC neurons are most prominent at high stimulus intensities, which are required to induce AGS. The blockade of GABA uptake by tiagabine may act to inhibit audiogenic seizures, in part, by intensifying these naturally occurring forms of acoustically evoked inhibition in inferior colliculus neurons.
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PMID:Blockade of GABA uptake with tiagabine inhibits audiogenic seizures and reduces neuronal firing in the inferior colliculus of the genetically epilepsy-prone rat. 792 22

No new antiepileptic drugs (AEDs) were licensed in the United States from 1978 to 1992. In late 1992, felbamate and gabapentin were recommended for approval, and in early 1993, lamotrigine. In July 1993, felbamate was licensed, and gabapentin and lamotrigine may soon follow. Lamotrigine, vigabatrin and clobazam are in use outside the US. Tiagabine, oxcarbazepine, fosphenytoin, topiramate, vigabatrin and zonisamide are in Phase II clinical testing in the US. All of the new AEDs are effective against partial and tonic-clonic seizures. Few controlled clinical trials have been done in patients with absence and myoclonic seizures. Mechanisms of action of the new drugs have not been clearly defined. The new AEDs will provide an opportunity to improve the care of epileptic patients. Even with optimal management with currently available drugs, some 30% of patients remain refractory to medical management.
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PMID:How about the new antiepileptic drugs? 800 Sep 69

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.
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PMID:Tiagabine: the safety landscape. 859 87


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