It is believed that ethosimide-induced dilatation of low-voltage activated T calcium channels is the cause of generalized inactivation. When ethosimide-treated tau cell-blasting worms were compared to vehicle controls, total tau levels did not decrease. The quantification of soluble and insoluble (RIPA-cleavable) Tau relative to total Tau levels thus demonstrated the rescue effects of ethosimide and the presence of improperly folded peptides in ethosimide-treated worms as opposed to untreated worms. Soluble Tau increases in proportion to a considerable reduction in insoluble Tau [1]. Not only was ethimide at a dose of 1 μM more efficient than ethymide at 2 μM or higher, but ethymide also caused cytotoxicity. Following ethimide treatment, GABA abruptly increased in neurons at concentrations of 0.1 and 1 μM, respectively, as demonstrated by immunofluorescence of GABA staining. Two to three days after ethimide-induced nuclear proliferation, BrdU staining was seen. After Brdu staining, the high concentration of nuclear solvent was 25.27±0.48, whereas the low concentration nuclear cutter of ethyximide was 15.98±0.41. This value for lithium chloride [2] is 11.05±0.2.

Absorption, Distribution and Excretion
Bioavailability following oral administration is 93%.
Ethosuximide is absorbed from the GI tract. Following oral administration of a single dose, peak blood concentrations are reached within 4 hours; however, about 4-7 days of therapy at usual dosage are required to achieve steady-state plasma concentrations. The plasma concentration required for therapeutic effect is generally considered to range from 40-100 ug/mL; plasma concentrations less than 40 ug/mL are rarely effective. The relationship between plasma ethosuximide concentrations and toxic effects of the drug has not been clearly established; however, plasma concentrations as high as 150 ug/mL have not been associated with signs of toxicity.
Absorption of ethosuximide appears to be complete, and peak concentrations occur in plasma within about 3 hr after a single oral dose. Ethosuximide is not significantly bound to plasma proteins; during long-term therapy, the concentration in the CSF is similar to that in plasma. The apparent volume of distribution averages 0.7 L/kg.
In vitro data suggest that there is no substantial degree of protein binding for ethosuximide. In one study in children, peak CSF concentrations of 25-50 ug/mL were achieved within 1-2 hours following a single 250-mg dose of ethosuximide. These concentrations were maintained for 12-24 hours, and the drug was still detectable in the CSF 65 hours after the drug was given.
Ethosuximide is excreted slowly in urine. Approximately 20% of a dose is excreted unchanged and up to 50% may be excreted in urine as the hydroxylated metabolite and/or its glucuronide. Small amounts of unchanged drug are also excreted in bile and feces.
For more Absorption, Distribution and Excretion (Complete) data for ETHOSUXIMIDE (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic, via CYP3A4 and CYP2E1.
... Metabolized by hepatic microsomal enzymes.
In rats, ethosuximide ... is metabolized into monohydroxyethosuximides, 2-ethyl-3-hydroxy-2-methyl-succinimide ... stereoisomeric 2-(1-hydroxyethyl)-2-methylsuccinimides & ... 2-(2-hydrox yethyl)-2-methylsuccinimide ... which are excreted, in urine, in free form and as ether glucuronides.
Different plasma profiles were obtained following admin of ethosuximide...to rat & man... Unchanged drug & only trace amt of metabolites were detected in rat plasma. In human plasma, diastereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide...were major components.
Ethosuximide is a chiral drug substance primarily indicated for the treatment of absence seizures. This drug is used clinically as the racemate. The human urinary metabolites of ethosuximide (I) have been studied using chiral gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS). The metabolites identified were the previously reported unchanged ethosuximide (I) enantiomers, all four stereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide (II), and the four stereoisomers of 2-ethyl-3-hydroxy-2-methylsuccinimide (III). Through chemical derivatization methodology and GC/MS two enantiomers of a previously unreported metabolite of ethosuximide, 2-ethyl-2-hydroxymethylsuccinimide (VI), have been identified.
Hepatic, via CYP3A4 and CYP2E1.
Half Life: 53 hours

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Biological Half-Life
53 hours
A total of 10 epileptic mothers treated with ethosuximide (ES) as well as their 13 newborns were included in this study. At birth fetal/maternal serum concentration ratios were 0.97 +/- 0.02 (n = 7) and ES half-lives in three neonates were 32, 37 and 38 hr. ...
The plasma half-life of ethosuximide is about 60 hours in adults and about 30 hours in children.
A total of 10 epileptic mothers treated with ethosuximide (ES) as well as their 13 newborns were included in this study. At birth fetal/maternal serum concentration ratios were 0.97 +/- 0.02 (n = 7) and ES half-lives in three neonates were 32, 37 and 38 hr.

Toxicity Summary
Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes.

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Hepatotoxicity
Prospective studies suggest that chronic ethosuximide therapy is not accompanied by significant elevations in serum aminotransferase levels, but can increase gamma glutamyltranspeptidase levels. Clinically apparent hepatotoxicity from ethosuximide is very rare with few case reports published despite use of this agent for half a century. Futhermore, the liver injury in reported cases was usually mild and asymptomatic and a part of a generalized hypersensitivity syndrome with fever, rash, facial edema, lymphadenopathy, and eosinophilia or atypical lymphocytosis. The usual latency to onset of the hypersensitivity syndrome is 2 to 8 weeks. The typical serum enzyme elevations are a mixed-cholestatic-hepatocellular pattern and reported cases have not been jaundiced. While the product labeling for ethosuximide warns of hepatic dysfunction and recommends periodic monitoring of liver tests, clinically apparent liver injury with jaundice from ethosuximide is rare.
Likelihood score: E* (suspected but unproven cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Average ethosuximide dosages of 50 to 60% of the maternal weight-adjusted dosage are excreted in human milk and infant plasma levels of 25 to 30% of maternal levels are common. Although no adverse effects attributable solely to ethosuximide in breastmilk have been reported, monitor the infant for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants and when using combinations of anticonvulsants. Measurement of an infant serum level might help rule out toxicity if there is a concern.
◉ Effects in Breastfed Infants
An infant whose mother was taking ethosuximide 250 mg daily began exclusive breastfeeding on day 2 postpartum and continued through 4.5 months of observation. The infant developed normally during this time and had no signs of an adverse reaction.
Sedation, poor sucking and poor weight gain during the first 4 weeks of life occurred in a breastfed newborn whose mother was taking ethosuximide. The reaction was possibly caused by ethosuximide in breastmilk; however, the mother was also taking primidone and valproic acid.
Three fully breastfed infants and a mostly formula-fed whose mothers were taking ethosuximide had no adverse reactions observed during the first 1.5 to 4.5 months of life.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Interactions
... It is thus assumed that the probable mechanism of action of ethosuximide consists in lowering calcium transport since the inhibitors of calcium transport sodium nitroprusside and verapamil intensify the blocking effect of ethosuximide on smooth muscle contractile activity.
Concurrent use /with alcohol; central nervous system depression-producing medications; tricyclic antidepressants; loxapine; maprotiline; molindone; monoamine oxidase inhibitors; phenothiazines; pimozide; thioxanthenes/ may lower the convulsive threshold, enhance CNS depression, and decrease the effects of the anticonvulsant medication. /Succinimide anticonvulsants/
Requirements for folic acid may be increased in patients receiving anticonvulsant therapy. /Succinimide anticonvulsants/
Induction of hepatic microsomal enzyme activity resulting in increased metabolism and decreased serum concentrations and elimination half-lives of succinimide anticonvulsants and/or these medications /carbamazepine, phenobarbital, phenytoin, primidone/ may occur during concurrent therapy; monitoring of serum concentrations as a guide to dosage is recommended, especially when any anticonvulsant is added to or withdrawn from an existing regimen. /Succinimide anticonvulsants/
For more Interactions (Complete) data for ETHOSUXIMIDE (8 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse iv 780 mg/kg
LD50 Mouse sc 1810 mg/kg
LD50 Mouse ip 1752 mg/kg
LD50 Mouse oral 1530 mg/kg

[1]. Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression. Mol Neurodegener. 2015 Sep 29;10:51.

[2]. Analysis of the antiepileptic, ethosuximide impacts on neurogenesis of rat forebrain stem cells. Fundam Clin Pharmacol. 2014 Oct;28(5):512-8.

Therapeutic Uses
Anticonvulsants
Ethosuximide, the drug of choice, and phensuximide are indicated for the control of seizures in absence (petit mal) epilepsy. /Included in US product labeling/

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Drug Warnings
Hemodialysis patients concurrently receiving ethosuximide may require a supplemental dose or an altered dosing schedule, based on the conclusion that ethosuximide is dialyzable.
The most common dose-related side effects are gastrointestinal complaints (nausea, vomiting, and anorexia) and CNS effects (drowsiness, lethargy, euphoria, dizziness, headache, and hiccough). Some tolerance to these effects develops. Parkinsonlike symptoms and photophobia also have been reported. Restlessness, agitation, anxiety, aggressiveness, inability to concentrate, and other behavioral effects have occurred primarily in patients with a prior history of psychiatric disturbance.
Urticaria and other skin reactions, including Stevens-Johnson syndrome, as well as systemic lupus erythematosus, eosinophilia, leukopenia, thrombocytopenia, pancytopenia, and aplastic anemia also have been attributed to the drug. The leukopenia may be transient, despite continuation of the drug, but several deaths have resulted from bone-marrow depression. Renal or hepatic toxicity has not been reported.
The most common adverse effects of ethosuximide are GI symptoms including anorexia and weight loss, vague gastric upset, cramps, abdominal pain, diarrhea, nausea, vomiting, and epigastric distress.
For more Drug Warnings (Complete) data for ETHOSUXIMIDE (13 total), please visit the HSDB record page.

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Pharmacodynamics
Used in the treatment of epilepsy. Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.

C7H11NO2

141.1677

141.078

77-67-8

Ethosuximide-d3;1189703-33-0;Ethosuximide-d5;1989660-59-4

3291

White to off-white solid powder

1.1±0.1 g/cm3

265.3±9.0 °C at 760 mmHg

51ºC

123.8±18.9 °C

0.0±0.5 mmHg at 25°C

1.451

0.38

1

2

1

10

188

0

HAPOVYFOVVWLRS-UHFFFAOYSA-N

InChI=1S/C7H11NO2/c1-3-7(2)4-5(9)8-6(7)10/h3-4H2,1-2H3,(H,8,9,10)

3-ethyl-3-methylpyrrolidine-2,5-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~708.37 mM)
H2O : ~100 mg/mL (~708.37 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (14.73 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (14.73 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (14.73 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)