Mechanisms of Antiepileptic Drug Action

Walker, Matthew; Fisher, AJ

doi:10.1002/9780470752463.ch9

Cited by 13 publications

(10 citation statements)

References 297 publications

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“…ESL is a novel VGSC blocker to be administered once‐daily. Two of the concomitant AEDs most frequently used by the combined study population (carbamazepine and lamotrigine) were also VGSC blockers (Walker et al., 2009). Suggestion has been made that combining AEDs with different mechanisms of action should be beneficial (Brodie & Yuen, 1997).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of eslicarbazepine acetate as add‐on treatment in patients with focal‐onset seizures: Integrated analysis of pooled data from double‐blind phase III clinical studies

et al. 2012

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SUMMARYPurpose: To evaluate the efficacy and safety profile of eslicarbazepine acetate (ESL) added to stable antiepileptic therapy in adults with partial-onset seizures. Methods: Data from 1,049 patients enrolled from 125 centers, in 23 countries, in three phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2-week titration period, ESL was administered at 400 mg, 800 mg, and 1,200 mg once-daily doses for 12 weeks. Key Findings: Seizure frequency was significantly reduced with ESL 800 mg (p < 0.0001) and 1,200 mg (p < 0.0001) compared to placebo. Median relative reduction in seizure frequency was, respectively, 35% and 39% (placebo 15%) and responder rate was 36% and 44% (placebo 22%). ESL was more efficacious than placebo regardless of gender, geographic region, epilepsy duration, age at time of diagnosis, seizure type, and number and type of concomitant antiepileptic drugs (AEDs). Incidence of adverse events (AEs) and AEs leading to discontinuation were dose dependent. AEs occurred mainly during the first weeks of treatment, with no difference between groups after 6 weeks. Most common AEs (>10% patients) were dizziness, somnolence, and headache. The incidence of AEs in ESL groups compared to placebo was generally consistent among different subpopulations. Significance: Once-daily ESL 800 mg and 1,200 mg showed consistent results across all efficacy and safety end points. Results were independent of study population characteristics and type and number of concomitant AEDs.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of eslicarbazepine acetate as add‐on treatment in patients with focal‐onset seizures: Integrated analysis of pooled data from double‐blind phase III clinical studies

et al. 2012

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“…Mathias et al (13) suggested that the tonic stimulation of GABA A receptors exerted by TGB and THIP might increase sleep consolidation and promote deep sleep. However, LEV has no effects on GABA transmission (6), and an increase in SWS and SE is induced also by other drugs such as gabapentin (16) and pregabalin (17), inactive on GABA A and GABA B receptors, but that potently bind to the α2‐δ subunit of P/Q‐type voltage‐regulated calcium channel (18). The synaptic vesicle protein SV2A is the brain binding site of LEV (19), but intriguingly, recent studies show that LEV moderately inhibits another high‐voltage calcium channel, the N‐type, and also may inhibit the release of calcium from cellular stores (6).…”

Section: Discussionmentioning

confidence: 99%

Effects of Levetiracetam on Nocturnal Sleep and Daytime Vigilance in Healthy Volunteers

et al. 2006

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Summary:Purpose: Individuals with epilepsy commonly report daytime sleepiness, attributed to sleep disruption (frequent arousals, awakenings, and stage shifts) induced by ictal and interictal activity or antiepileptic drugs (AEDs) or both. To study the effect of levetiracetam (LEV) on sleep, at full doses but without the interference of epilepsy, we investigated the sleep architecture and daytime vigilance in healthy adults after 3 weeks of treatment.Methods: The study was of a double-blind crossover design with random allocation of multiple doses of two different treatments (randomly first LEV ≤2,000 mg/day or placebo for 3 weeks, washout for 4 weeks, and then the alternative treatment for another 3 weeks). Fourteen healthy volunteers were studied with polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). Epworth Sleepiness Scale (ESS) and sleep log also were evaluated.Results: After treatment with LEV, statistically significant increases were observed in total sleep time, sleep efficiency, and time spent in non-rapid eye movement (NREM) sleep stages 2 and 4. Stage shifts and wake after sleep onset were significantly decreased. Sleep latency was normal at PSG and MSLT in all subjects and did not statistically differ between placebo and LEV. No changes were found in the ESS.Conclusions: Our findings show that in healthy volunteers, LEV consolidates sleep and does not modify vigilance, two appreciated qualities in epilepsy patients with sleep disturbance and daytime sleepiness. Key Words: LevetiracetamSleep architecture-Daytime sleepiness-Antiepileptic drugsPolysomnography.Frequently patients with epilepsy complain of sleep disruption and report daytime sleepiness. Even if, in these patients, sleep may be disrupted also in the absence of seizures and antiepileptic drugs (AEDs), usually these symptoms are related to the effects of ictal and interictal activity or AEDs or both (1). Sleep and epilepsy have reciprocal effects, because sleep is a strong modulator of epileptic activity, which, in turn, can alter the sleep-wake cycle and sleep architecture. The resulting sleep deprivation may provoke further seizures (2). AEDs are able to modify the epileptic phenomena and the sleep architecture by acting at both levels (3). Older AEDs usually reduce the percentage of rapid eye movement (REM) sleep and slow wave sleep (SWS), increase fragmentation, and induce daytime sleepiness (4). The main difference between older and newer AEDs concerns mainly daytime sleepiness, more frequently associated with traditional AEDs (2), although newer AEDs are reported to be less disruptive to sleep (5).In mono-and polytherapy trials, levetiracetam (LEV) has been reported to cause somnolence in 4-15% of the patients, leading to drug discontinuation in 10% of patients (6). Bell et al. (7) evaluated the effects of LEV (1,000 mg in a single dose) on sleep in healthy volunteers and patients with epilepsy receiving carbamazepine (CBZ) monotherapy. LEV produced an increase in non-REM (NREM) sleep stage 2 both in volunteers and pati...

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“…Tiagabine is a potent and selective competitive inhibitor of GAT1 that prevents the reuptake of GABA and increases the availability of this inhibitory neurotransmitter [66]. GABA B receptors are expressed both pre-and postsynaptically [67,68], and their role in facilitation and inhibition of epileptic activity is complex [42]. Mice lacking functional GABA B receptors exhibit spontaneous seizures [69], indicating the pathophysiological importance of this receptor subtype in suppressing epilepsy.…”

Section: Gaba Receptors and Metabolismmentioning

confidence: 99%

“…The latter includes aamino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate sensitive receptors. NMDA receptors can produce channels permeable to calcium and sodium ions, while non-NMDA receptors can build sodium channels [42]. From a pathophysiological point of view, ionotropic glutamate receptors would be ideal molecular candidates for substances administered as part of anticonvulsant, antiepileptogenic, and antiictogenic pharmacostrategies.…”

Section: Glutamate Receptorsmentioning

confidence: 99%

Anticonvulsant, antiepileptogenic, and antiictogenic pharmacostrategies

Holtkamp

Meierkord

2007

Cell. Mol. Life Sci.

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Pharmacological concepts tailored to status epilepticus, to epileptogenesis following acquired brain insults, and to ictogenesis in established epilepsy vary considerably and should ideally be directed at those pathophysiological mechanisms that presumably underly these conditions. Currently known important molecular targets include voltage-gated sodium and calcium channels, the gamma-aminobutyric acid (GABA) system and ionotropic glutamate receptors. Metabotropic glutamate receptors, potassium channels, and neurotransmitters such as acetylcholine, glycine, and monoamines are beyond the scope of this review. In status epilepticus, immediate failure of GABAergic inhibition occurs, and administration of benzodiazepines and barbiturates displays the pharmacostrategic mainstay. In epileptogenesis within limbic structures, the most important underlying pathophysiological mechanisms currently discussed are transient loss of inhibition and aberrant mossy fiber sprouting. Both processes may be facilitated by N-methy-D: -aspartat (NMDA) receptor regulation. NMDA antagonists may exhibit antiepileptogenic properties in experimental animals, but reliable data in humans are lacking. In established epilepsy, voltage-gated ion channels and impairment of GABAergic functions contribute to mechanisms facilitating ictogenesis. Blockade of sodium and calcium channels and enhancement of GABAergic inhibition are currently the most important tools to prevent the occurrence of seizures.

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Mechanisms of Antiepileptic Drug Action

Cited by 13 publications

References 297 publications

Efficacy and safety of eslicarbazepine acetate as add‐on treatment in patients with focal‐onset seizures: Integrated analysis of pooled data from double‐blind phase III clinical studies

Efficacy and safety of eslicarbazepine acetate as add‐on treatment in patients with focal‐onset seizures: Integrated analysis of pooled data from double‐blind phase III clinical studies

Effects of Levetiracetam on Nocturnal Sleep and Daytime Vigilance in Healthy Volunteers

Anticonvulsant, antiepileptogenic, and antiictogenic pharmacostrategies

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