Delving into the Latest Updates on Ethosuximide with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(±)-2-ethyl-2-methylsuccinimide, 2-ethyl-2-methylsuccinimide, 2-methyl-2-ethylsuccinimide

+ [17]

Target

VDCCs

Mechanism

VDCCs blockers(Voltage-gated calcium channel blockers)

Therapeutic Areas

Nervous System Diseases

Active Indication

SeizuresEpilepsy, Absence

Inactive Indication-

Originator Organization

Parke-Davis & Co. Ltd.

Active Organization

Eisai Co., Ltd.

Parke, Davis & Co. LLC

Pfizer Japan, Inc.

+ [1]

Inactive Organization-

Drug Highest PhaseApproved

First Approval Date

US (02 Nov 1960),

Epilepsy, Absence

Regulation-

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Structure

Molecular FormulaC7H11NO2

InChIKeyHAPOVYFOVVWLRS-UHFFFAOYSA-N

CAS Registry77-67-8

PURPOSEIn developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), the thalamocortical network is suggested to play an important role in the pathophysiology of the progression from focal epilepsy to DEE-SWAS. Ethosuximide (ESM) exerts effects by blocking T-type calcium channels in thalamic neurons. With the thalamocortical network in mind, we studied the prediction of ESM effectiveness in DEE-SWAS treatment using phase-amplitude coupling (PAC) analysis.METHODSWe retrospectively enrolled children with DEE-SWAS who had an electroencephalogram (EEG) recorded between January 2009 and September 2022 and were prescribed ESM at Okayama University Hospital. Only patients whose EEG showed continuous spike-and-wave during sleep were included. We extracted 5-min non-rapid eye movement sleep stage N2 segments from EEG recorded before starting ESM. We calculated the modulation index (MI) as the measure of PAC in pair combination comprising one of two fast oscillation types (gamma, 40-80 Hz; ripples, 80-150 Hz) and one of five slow-wave bands (delta, 0.5-1, 1-2, 2-3, and 3-4 Hz; theta, 4-8 Hz), and compared it between ESM responders and non-responders.RESULTSWe identified 20 children with a diagnosis of DEE-SWAS who took ESM. Fifteen were ESM responders. Regarding gamma oscillations, significant differences were seen only in MI with 0.5-1 Hz slow waves in the frontal pole and occipital regions. Regarding ripples, ESM responders had significantly higher MI in coupling with all slow waves in the frontal pole region, 0.5-1, 3-4, and 4-8 Hz slow waves in the frontal region, 3-4 Hz slow waves in the parietal region, 0.5-1, 2-3, 3-4, and 4-8 Hz slow waves in the occipital region, and 3-4 Hz slow waves in the anterior-temporal region.SIGNIFICANCEHigh MI in a wider area of the brain may represent the epileptic network mediated by the thalamus in DEE-SWAS and may be a predictor of ESM effectiveness.

23 Apr 2024·Neurology

A Systematic Review

Review

Author: Vajda, Frank J ; Cockle, Emily ; Malpas, Charles B ; Rayner, Genevieve ; O'Brien, Terence J ; Perucca, Piero ; Honybun, Eliza

BACKGROUND AND OBJECTIVESTo undertake a systematic review of the available literature to examine the relationship between prenatal antiseizure medication (ASM) exposure and adverse postnatal neurodevelopmental outcomes, focusing on social, emotional, behavioral, and adaptive domains of human function, and the frequency of neurodevelopmental and psychiatric disorders in ASM-exposed offspring.METHODSElectronic searches of MEDLINE, PsychINFO, and EMBASE were conducted and limited to studies published between 1990 and 2023 in English. Studies were eligible if they prospectively or retrospectively reported neurodevelopmental outcomes of ASM-exposed offspring. The Newcastle-Ottawa scale was used to conduct methodologic quality assessments of included studies, and a narrative synthesis integrated the review findings.RESULTSForty-three studies were included. Valproate has been consistently associated with a 2- to 4-fold increased risk of autism spectrum disorder (ASD), 2- to 5-fold increased risk of intellectual disability (ID), and poor adaptive functioning. Growing evidence indicates that topiramate is associated with a 2-fold increased risk of ASD and 3- to 4-fold increased risk of ID. The risks of adverse neurodevelopmental outcomes for valproate and topiramate seem to be dose dependent. Phenobarbital has been suggested to be associated with deleterious neurodevelopmental effects, but data are limited. Levetiracetam has recently been linked with an increased risk of attention deficit hyperactivity disorder and anxiety disorders in a single study. Carbamazepine has been associated with variable neurodevelopmental outcomes. Lamotrigine seems to be "safe" in terms of postnatal neurodevelopment. Data for oxcarbazepine, phenytoin, and clonazepam are limited but seem to have little-to-no risk of adverse outcomes. Evidence for the remaining ASMs, including gabapentin, pregabalin, lacosamide, zonisamide, clobazam, perampanel, ethosuximide, or brivaracetam, is lacking. Several methodologic limitations impeded data synthesis, including heterogeneity in outcome measures and small samples of monotherapy exposures.DISCUSSIONThe findings of this review support the conclusion that valproate and topiramate use during pregnancy is associated with a significantly increased risk of neurodevelopmental effects on the fetus. Apart from lamotrigine, which seems to be free of adverse neurodevelopmental effects, data for the other ASMs are mixed or inadequate to draw definite conclusions. Further research into the neurodevelopmental effects of prenatal exposure to ASMs, including most newer agents, is much needed.

01 Apr 2024·Epilepsia Open

Alpha‐2a adrenergic receptor activation in genetic absence epilepsy: An absence status model?

Article

Author: Akkol, Serdar ; Onat, Filiz ; Yavuz, Melis

AbstractObjectiveThe objective of the study was to propose a candidate animal model of absence status epilepticus induced by specific alpha‐2a adrenergic receptor (α2AR) activation. We also aim to investigate the responsiveness of this model to classical anti‐status or anti‐absence medications.MethodsAn α2AR agonist, dexmedetomidine (DEX), was injected intracerebroventricularly into adult rats with genetic absence epilepsy, and their electroencephalography (EEG) was recorded. The total duration, number, and mean duration of each spike‐and‐wave discharges (SWDs) were evaluated. The blocks of absence status events were classified as the initial and second sets of absence statuses. Ethosuximide (ETX) was administered as a pretreatment to another group of rats and later injected with 2.5 μg DEX. In addition, ETX, valproic acid (VPA), diazepam (DIAZ), and atipamezole (ATI) were administered after induced status‐like events following DEX administration. Power spectral characteristics and coherence analysis were performed on the EEG to assess the absence status events and sleep.ResultsThe 2.5 μg dose of DEX increased the total SWD duration and induced continuous SWDs up to 26 min. Following the initial absence status event, sleep was induced; then, the second period of absence status‐like activities were initiated. ETX pretreatment blocked the occurrence of absence status‐like activities. Power spectral density analyses revealed that DEX‐induced post‐sleep activities had higher power in delta frequency band (1–4 Hz) and attenuated power of 7 Hz harmonics (14 and 21 Hz) than the pre‐injection seizure. The mean duration of SWDs were decreased in all the groups, but occasional prolonged activities were seen in ETX or VPA‐injected rats but not with DIAZ or ATI.SignificanceThis study presents an absence status epilepticus animal model that is activated by α2AR activation to investigate the pathophysiological role of absence status. Unlike other agents ATI switched off the second set of absence statuses to normal SWDs, without sedation or lethargy, can show it may preferentially block absence status‐like activity.The Plain Language SummaryThis study proposes a rat model for prolonged seizures, resembling absence status epilepticus. Activating the brain’s alpha‐2a adrenergic receptor with dexmedetomidine induced seizures lasting up to 26 minutes. Ethosuximide pretreatment and post‐treatment with valproic acid, diazepam, and atipamezole decreased induced seizures. The findings suggest this model is valuable for studying absence status epilepticus. In addition, atipamezole normalized abnormal seizures without sedation, hinting at its potential for targeted treatment and further research.

100 Deals associated with Ethosuximide

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External Link

KEGG	Wiki	ATC	Drug Bank
D00539	Ethosuximide	N03AD01	DB00593

R&D Status

10 top approved records.

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Indication	Country/Location	Organization	Date
Seizures	JP	Pfizer Japan, Inc.	04 Sep 1964
Epilepsy, Absence	US	Parke, Davis & Co. LLC	02 Nov 1960
Epilepsy, Absence	US	Parke Davis Pharmaceutical Research Div Warner Lambert Co	02 Nov 1960

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00088452 (Pubmed \| Br Dent J)	Phase 3	Epilepsy, Absence	453	Ethosuximide	(hlqcbcafaq) = anifsevwjr cdhhdmmzoh (zxzkiyarfw )	-	04 Mar 2010
				Valproic acid	(hlqcbcafaq) = ynafbmjdax cdhhdmmzoh (zxzkiyarfw ) View more
NCT00088452 (CTgov)	Phase 3	Epilepsy, Absence \| Seizures	453	Ethosuximide (Ethosuximide)	zzrevmkimj(bktevszhrb) = cbwtteqoon iyspmuqhhk (yrudxdsizt, lcjxcrricx - xqqzzdvhoq) View more	-	14 Oct 2020
				Lamotrigine (Lamotrigine)	zzrevmkimj(bktevszhrb) = ggyvvapvmb iyspmuqhhk (yrudxdsizt, lzvfpckyjo - jjxmdahzdm) View more
NCT00088452 (Pubmed \| Turk J Pediatr)	Phase 3	Epilepsy, Absence	453	Ethosuximide	nymniqxiar(nwcngpeqkd) = calrxbzmlq dcqrqqlnhn (nvvxvbwppz )	-	01 Jan 2013
				Valproic acid	nymniqxiar(nwcngpeqkd) = nqfgvhfouo dcqrqqlnhn (nvvxvbwppz )
ANA2017	Not Applicable	Epilepsy	-	Ethosuximide	cgangrvyki(zfrdkclfhy) = lfcyvoarut xyfgvqptii (lhpkqnenag )	-	15 Oct 2017
AAIC2008	Not Applicable	-	-	γ-secretase-inhibitor with hydrophilic long linker and a cleavable biotin group (GCB)	gqvtxhvbad(pclvwtxogn) = kqqjdxohqt cgekhfgkfm (fhpwujyuvv )	-	01 Jul 2008