The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes

Noyer, Michel; Gillard, Michel; Matagne, Alain; Hénichart, Jean‐Pierre; Wülfert, Ernst

doi:10.1016/0014-2999(95)00436-o

Cited by 231 publications

(176 citation statements)

References 17 publications

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“…9,10 Seletracetam binds selectively, stereospecifically, and with high affinity (10- 10,11 suggesting a functional correlation between binding and anticonvulsant activity. Seletracetam did not induce a significant displacement (Յ10 mol/L) of radioligands specific for the other known binding sites within the CNS (e.g., receptors, uptake systems, and ion channel proteins).…”

Section: Pharmacological Backgroundmentioning

confidence: 99%

Seletracetam (UCB 44212)

et al. 2007

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Summary:Better pharmacotherapies for epilepsy are needed for patients who are refractory to or have tolerability difficulties with current treatments. Seletracetam, a new drug in epilepsy development, is a pyrrolidone derivative structurally related to levetiracetam (trade name Keppra). It was discovered because of its high binding affinity to the synaptic vesicle 2A (SV2A) protein, which is now known to be the binding site for this family of compounds. Seletracetam shows very potent seizure suppression in models of acquired or genetic epilepsy, as well as high CNS tolerability in various animal models. Pharmacokinetic studies in animals suggest that seletracetam is rapidly and highly absorbed, with linear and time-independent pharmacokinetics. Seletracetam appears neither to inhibit nor to induce the major human drug metabolizing enzymes, and it demonstrates low plasma protein binding (Ͻ10%), which suggests a low potential for drug-drug interactions. Initial studies in humans demonstrated first-order monocompartmental kinetics with a half-life of 8 h and an oral bioavailability of Ͼ90%. Studies in healthy volunteers showed that the treatment emergent adverse events were of mild to moderate severity, were mostly of CNS origin and were resolved within 24 h. Altogether, these results suggest that seletracetam represents a promising new antiepileptic drug candidate, one that demonstrates a potent, broad spectrum of seizure protection and a high CNS tolerability in animal models, with initial clinical findings suggestive of straightforward pharmacokinetics and good tolerability.

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Section: Pharmacological Backgroundmentioning

confidence: 99%

Seletracetam (UCB 44212)

et al. 2007

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“…7 LEV seems to partially inhibit N-type high voltage-activated Ca 2+ currents and reduces Ca 2+ release from intraneuronal stores; it reverses the effects of negative allosteric modulators of gamma aminobutyric acid and glycine-gated currents. [8][9][10] Recently, the LEV binding site was identified as synaptic vesicle protein 2A (SV2A). 11 A very recent study 12 has explored the hypothesis that the antiepileptic mechanism of action of LEV is related to effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels in mouse cortical neurons.…”

mentioning

confidence: 99%

Levetiracetam in juvenile myoclonic epilepsy: long‐term efficacy in newly diagnosed adolescents

Verrotti

Cerminara

Coppola

et al. 2007

Develop Med Child Neuro

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The aim of this study was to evaluate the efficacy and tolerability of levetiracetam (LEV) monotherapy in juvenile myoclonic epilepsy (JME). The study group consisted of 32 patients with epilepsy (20 males, 12 females) with a mean age of 13 years 3 months (SD 7y 11mo) at seizure onset. LEV was administered as the first drug; all patients were followed up at 6 and 12 months. The dose that achieved seizure control ranged from 1000 to 2500mg/daily. At 6-month evaluation: 15 patients were seizure free; 14 patients were responders (>50% reduction in seizures); and three patients had marginal effects (<50% reduction of seizures). At 12-month evaluation: 29 patients were seizure free; three patients were responders. No patients reported adverse events. These data provide preliminary evidence that LEV may be effective for treating patients with newly diagnosed JME.Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy, characterized by irregular myoclonic jerks, tonicclonic seizures, and sometimes typical absences. 1 The main clinical symptoms of JME are myoclonic jerks on awakening, generalized tonic-clonic seizures, typical absences, and photosensitivity. 1,2 This type of epilepsy generally responds to antiepileptic drugs (AEDs) and is, therefore, generally considered a benign type of epilepsy. 3 Physicians have at their disposal many AEDs to treat JME; historically, valproic acid was the first AED used to treat myoclonic seizures, 4 but levetiracetam (LEV) could be a good alternative because of its efficacy against all three JME seizure types and photosensitivity, and because of lack of the endocrine and metabolic side-effects frequently reported in patients receiving valproic acid. 5,6 LEV is a novel AED because its mechanisms of action appear different from other AEDs and seem to be unrelated to known mechanisms of neurotransmission. In fact, it has no significant affinity for gamma-aminobutyric acidergic or glutamatergic receptors and does not interact directly with the benzodiazepine binding site. 7 LEV seems to partially inhibit N-type high voltage-activated Ca 2+ currents and reduces Ca 2+ release from intraneuronal stores; it reverses the effects of negative allosteric modulators of gamma aminobutyric acid and glycine-gated currents. [8][9][10] Recently, the LEV binding site was identified as synaptic vesicle protein 2A (SV2A). 11 A very recent study 12 has explored the hypothesis that the antiepileptic mechanism of action of LEV is related to effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels in mouse cortical neurons. This study reveals that AMPA receptors are modulated by LEV because a significant decrease was found in the kainate and AMPA-induced miniature excitatory postsynaptic currents in cortical neurons.Several reports and open label studies have pointed out the efficacy of LEV in generalized epilepsy. [13][14][15][16] Moreover, LEV has been shown to be effective in preventing the photoparoxysmal response in patients with photosensitive epile...

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“…The results also indicated the affinity of nefiracetam to the neocortex, however, no receptors for this agent have been identified. The synaptic plasma membrane is a possible binding site of levetitacetam in antiepileptic effect (Noyer et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Antiepileptic effect of nefiracetam on kainic acid-induced limbic seizure in rats

et al. 2000

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Nefiracetam is being studied as a novel cognition-enhancing agent; however, it has been suggested from studying its chemical structure that it has a potential anticonvulsive effect. We examined the antiepileptic effect of nefiracetam on kainic acid (KA)-induced seizures. KA was infused into the left basolateral amygdaloid nucleus, and focal limbic seizures were induced in 43 male Wistar rats. During status epilepticus, 10, 50, 100 or 200 mg/kg of nefiracetam was intravenously injected. Nefiracetam inhibited KA-induced limbic seizures at doses over 100 mg/kg while it had a sedative effect on the animals. In [ 14 C] deoxyglucose autoradiographic studies, the propagation of seizure-induced hypermetabolic areas was also suppressed dose-dependently. From the results, it was indicated that nefiracetam has an antiepileptic effect and that its application may suppress seizure propagation. Further study is required whether this agent is available as a novel anticonvulsant.

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The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes

Cited by 231 publications

References 17 publications

Seletracetam (UCB 44212)

Seletracetam (UCB 44212)

Levetiracetam in juvenile myoclonic epilepsy: long‐term efficacy in newly diagnosed adolescents

Antiepileptic effect of nefiracetam on kainic acid-induced limbic seizure in rats

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