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

+ [21]

Target

VDCCs

Mechanism

VDCCs blockers(Voltage-gated calcium channel blockers)

Therapeutic Areas

Nervous System DiseasesOther 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.

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

ContextIn normal physiological conditions, calcium ions (Ca2+) have an important effect in terms of the regulation of hair cell (HC) functions, and T-type calcium antagonists may be protective against hearing loss. However, no studies have occurred related to a T-type calcium-channel antagonist with regard to otoprotection in a Cdh23 mouse model.ObjectiveThe study intended to examine the protective efficacy of ethosuximide-a T-type calcium-channel antagonist-against age-related hearing loss in a Cadherin 23 (Cdh23) erl/erl mouse model, to potentially offer an insight and foundation for therapy in the near future for patients in clinical practice who suffer from age-related hearing loss.DesignThe research team conducted an animal study.AnimalsThe animals were 12 male and 12 female, Cdh23 erl/erl mice.InterventionThe research team randomly divided the mice into two groups, with 12 mice in each group: (1) the control group, the saline group, which received saline at 10 mL/kg of body weight, and (2) the intervention group, the ethosuximide group, which received ethosuximide at 10 mL/kg of body weight. Both groups received the treatments intraperitoneally every other day, beginning postnatally at 7 days until the mice were 8 weeks old.Outcome MeasuresFor both groups, the research team: (1) measured auditory brainstem response (ABR); (2) measured distortion product otoacoustic emission (DPOAE) at 4, 6, and 8 weeks of age; (3) separated the basilar membrane from the modiolus and lateral tissues and determined the percentage of inner-and-outer hair-cell (IHC and OHC) loss; (4) investigated relative levels of apoptosis-related gene mRNA using reverse transcription polymerase chain reaction (PCR); and (5) examined relative levels of apoptosis-related protein, using immunofluorescent (IF) staining.ResultsCompared to the saline group, the ethosuximide group: (1) had significantly lower ABR thresholds for click at 8 weeks, for 8 KHz at 6 and 8 weeks, and for 16 KHz and 32 KHz (all P < .01); (2) had significantly higher DPOAE amplitudes at 4 weeks at 15.4 KHz and 17.7 KHz (both P < .01); at 6 weeks at 8.8 KHz (P < .05), 10.1 KHz (P < .01), 11.7 KHz (P < .01), 13.4 KHz (P < .01), 15.4 KHz (P < .01), and 17.7 KHz (P < .01); and at 8 weeks at 6.7 KHz (P < .05), 7.7 KHz (P < .05), 10.1 KHz (P < .01), 11.7 KHz (P < .01), 13.4 KHz (P < .01), 15.4 KHz (P < .01), and 17.7 KHz (P < .01); (3) had significantly lower OHC loss in the middle and basal turns of the cochlea's surface (both P < .05); (4) at the age of 2 months, had significantly lower mRNA relative levels of apoptosis-related genes, including caspase-3, caspase-9, caspase-12, m-calpain and u-calpain, as found using a polymerase chain reaction (PCR); and (5) had weaker protein levels of caspase-3 and caspase-9 in the inner ears, as found using immunofluorescent (IF) staining.ConclusionsT-type calcium-channel antagonists can exert protective efficacy in terms of the hearing function among cdh23 erl/erl mouse.

22 Oct 2024·Central Nervous System Agents in Medicinal Chemistry

Thiazolidine-4-one Analogues: Synthesis, In-Silico Molecular Modeling, and In-vivo Estimation for Anticonvulsant Potential

Article

Author: Shah, Kamal ; Mittal, Payal ; Dewangan, Hitesh Kumar ; Ghanghas, Deepak ; Arya, Girish Chandra ; Chaudhary, Aarti ; Sharma, Diksha

Background:Epilepsy is a critically deep-rooted CNS disorder affecting above 50 million people all over the world. Thus, a safe and effective treatment that proves its worth in this ailment is urgently needed. Thiazolidine-4-ones possess the molecules to be used as anticonvulsants. The thiazolidinedione is a cyclic analogue of thiosemicarbazides and thioureas as well as a (bio)isostere of hydantoin (imidazolidine-2,4-dione), which are recognized as novel anticonvulsant designs.Aim:This study aimed to develop and evaluate a novel thiazolidine-4-one derivative by three-component condensation in one pot reaction method.Methods:A novel thiazolidine-4-one derivative was formulated by three-component condensation. The selected OH (Alcohol) derivatives were found to be more potent; hence, a molecular docking study against a selected target LGI1 LRR domain was performed. Various analytical tests like FTIR and H1 NMR were accomplished. The FTIR was used to validate the existence of multiple functional moieties like C-S, O-H, C=O, C-N, N=O, C-NH, C-O in the wave region from 3075 cm-1 – 1236 cm-1 and H1 NMR was employed to ascertain if the synthesized analogues had the complete set of protons. Then, the anti-seizure activity of the selected compound was examined using PTZ models in mice at three successive doses, i.e., 25, 50, and 100mg/kg, and compared with standard ethosuximide.Results:The docking simulations were initiated using PyMOL after the binding site was determined and the receptor and ligand were suitably prepared. It showed higher binding frequency in comparison to the standard marketed drug Ethosuximide. FTIR and H1 NMR spectroscopy were used to characterize the chemical components. Numerous functional groups, including O-H (alcohol), C=O (ketones), N=O, C-NH, C-N, C-S, and C-O bending stretching, were visible in the synthesized molecule accordingly. The synthesized compound was effective in inhibiting the convulsions at the concentration of 100 mg/kg.Conclusion:The novel thiazolidine-4-one derivative showed promising activity and could be considered for further investigation and dosage form preparation.

01 Oct 2024·Epilepsia Open

Huperzine A suppresses absence seizures in the genetic absence epilepsy rat from Strasbourg (GAERS) model of genetic generalized epilepsy with absence seizures

Article

Author: Li, Crystal ; Yu, Chungping ; Garcia‐Olivares, Jennie ; O'Brien, Terence J. ; Li, Rui ; Formella, Andrea E. ; Casillas‐Espinosa, Pablo M.

AbstractObjectiveWe evaluated huperzine A treatment in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model of genetic generalized epilepsy (GGE) with absence seizures.MethodsAdult male GAERS (N = 15) were implanted with EEG recording electrodes 10 days before receiving study drug. Each animal received the following six treatments as a single, intraperitoneal dose, 7 days apart (in random order): huperzine A (0.3, 1.0, or 3.0 mg/kg), two periods of vehicle (0.9% NaCl), or ethosuximide (100 mg/kg) as a positive control. Electroencephalograms (EEGs) were acquired for 24 h before and after each treatment and analyzed for seizure activity during the 90‐min period immediately post‐treatment, including 30‐min intervals at 30, 60, and 90 min. Additional analyses evaluated seizure activity over the 24‐h post‐treatment period using 60‐min intervals at 6, 12, and 24 h. The cumulative 24‐h periods before and after each administered treatment were also compared.ResultsTwo‐way ANOVA showed a treatment difference [F(91,182) = 3.592, p < 0.0001] on the number of seizures over the first 90‐min post‐treatment (primary outcome); Tukey's post hoc analyses showed that, compared to vehicle, huperzine A (3.0 mg/kg) significantly reduced seizures in the 30‐min (p = 0.02) and 60‐min (p = 0.001) intervals, and ethosuximide significantly reduced seizures at all measured time intervals except the 1‐h blocks at 12 and 24 h. Huperzine A 3.0 mg/kg and ethosuximide significantly reduced seizures during the cumulative 24‐h post‐treatment period relative to pretreatment baseline. While huperzine A 3.0 mg/kg did not differ significantly from ethosuximide at any time point, the study was not designed to evaluate non‐inferiority. The only adverse event after huperzine A or ethosuximide was mild, dose‐dependent sedation.SignificanceHuperzine A potently suppressed absence‐like seizures in GAERS, albeit with a shorter duration of action relative to ethosuximide, showing promise for clinical efficacy in GGE.Plain Language SummaryThis study looked at how huperzine A affects seizures in rats with similar abnormal brain activity as seen in humans with absence epilepsy. Rats received different treatments, placebo (i.e., saline solution), huperzine A, and ethosuximide. Ethosuximide is considered a gold standard treatment for absence epilepsy. We recorded brain activity to measure seizures before and after each treatment. We found that huperzine A (3.0 mg/kg) reduced seizures soon after treatment, like ethosuximide. Both treatments appeared safe, causing only mild sleepiness. The study shows that huperzine A could be a good new treatment for a type of absence epilepsy.

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

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00088452 (CTgov)	Phase 3	Seizures \| Epilepsy, Absence	453	Ethosuximide (Ethosuximide)	xzabtvmolm(unilrnonap) = eqtqcyizfz fipfiiewcz (yxqzkxebvs, ldlohbxdip - wiywzuycvy) View more	-	14 Oct 2020
				Lamotrigine (Lamotrigine)	xzabtvmolm(unilrnonap) = clffeucvbq fipfiiewcz (yxqzkxebvs, avwibsebvc - xpiuiwwwia) View more
NCT00088452 (Pubmed \| Turk J Pediatr)	Phase 3	Epilepsy, Absence	453	Ethosuximide	praczcvfux(jaoaepphof) = glonpritgm uehznsgagq (aldvdoziap )	-	01 Jan 2013
				Valproic acid	praczcvfux(jaoaepphof) = vjaqqcubwr uehznsgagq (aldvdoziap )
IEC2011	Not Applicable	Seizures	1	Valproic Acid	xuhknnlnms(gmypuuoavd) = prolonged dissociative state secondary to seizures fohsxsblwd (uertlxtkrv )	Positive	31 Aug 2011
				Ethosuximide
NCT00088452 (Pubmed \| Br Dent J)	Phase 3	Epilepsy, Absence	453	Ethosuximide	(vaayherohw) = jasvnyzhzp gpsmplwjtv (qdpchjpsqr )	-	04 Mar 2010
				Valproic acid	(vaayherohw) = mffneswfsh gpsmplwjtv (qdpchjpsqr ) View more