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
The oral bioavailability is 93%. Ethosuximide is absorbed via the gastrointestinal tract. Peak plasma concentrations are reached within 4 hours after a single oral dose; however, steady-state plasma concentrations are typically achieved with 4–7 days of conventional doses. The therapeutically required plasma concentration is generally considered to be in the range of 40–100 μg/mL; plasma concentrations below 40 μg/mL are rarely effective. The relationship between plasma ethosuximide concentrations and drug toxicity is not well understood; however, plasma concentrations up to 150 μg/mL have not been associated with toxic symptoms. Ethosuximide appears to be completely absorbed, with peak plasma concentrations reached approximately 3 hours after a single oral dose. Ethosuximide has low protein binding; during long-term treatment, drug concentrations in cerebrospinal fluid are similar to those in plasma. The apparent volume of distribution is 0.7 L/kg on average. In vitro data indicate that ethosuximide has low protein binding. A pediatric study showed that after a single 250 mg dose of ethosuximide, peak drug concentrations in cerebrospinal fluid reached 25-50 μg/mL within 1-2 hours. These concentrations were maintained for 12-24 hours, and the drug remained detectable in cerebrospinal fluid up to 65 hours after administration. Ethosuximide is primarily excreted slowly in the urine. Approximately 20% of the dose is excreted unchanged, while up to 50% may be excreted in the urine as hydroxylated metabolites and/or their glucuronides. Small amounts of the unchanged drug are also excreted in bile and feces. For more complete data on the absorption, distribution, and excretion of ethosuximide (9 types in total), please visit the HSDB record page. Metabolism/Metabolites: Metabolized in the liver via CYP3A4 and CYP2E1. ...Metabolized by hepatic microsomal enzymes. In rats, ethosuximide... is metabolized to monohydroxyethosuximide, 2-ethyl-3-hydroxy-2-methylsuccinimide... stereoisomers 2-(1-hydroxyethyl)-2-methylsuccinimide and... 2-(2-hydroxyethyl)-2-methylsuccinimide... These metabolites are excreted in the urine in free form and as ether glucuronide. Different plasma metabolic profiles were obtained after administration. Ethosuximide... in rats and humans... only unaltered drug and trace metabolites were detected in rat plasma. In human plasma, the diastereomeric form of 2-(1-hydroxyethyl)-2-methylsuccinimide... is the major component. Ethosuximide is a chiral drug primarily used to treat absence seizures. Clinically, it is used in racemic form. The human urinary metabolites of ethosuximide (I) were studied using chiral gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS). The identified metabolites included the previously reported unaltered enantiomers of ethosuximide (I), all four stereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide (II), and four stereoisomers of 2-ethyl-3-hydroxy-2-methylsuccinimide (III). Two enantiomers of 2-ethyl-2-hydroxymethylsuccinimide (VI), a previously unreported metabolite of ethosuximide, were identified by chemical derivatization and GC/MS. It is primarily metabolized in the liver via CYP3A4 and CYP2E1. Half-life: 53 hours. This study included 10 mothers with epilepsy treated with ethosuximide (ES) and their 13 newborns. At birth, the fetal/maternal serum concentration ratio was 0.97 ± 0.02 (n=7), and the ES half-lives of the three newborns were 32, 37, and 38 hours, respectively. The plasma half-life of ethosuximide in adults is approximately 60 hours, and in children it is approximately 30 hours. This study included 10 mothers with epilepsy who received ethosuximide (ES) treatment and their 13 newborns. At birth, the fetal/maternal serum concentration ratio was 0.97 ± 0.02 (n=7), and the ES half-lives of the three newborns were 32, 37, and 38 hours, respectively.

Toxicity Summary
Binding with T-type voltage-gated calcium channels. Voltage-gated calcium channels (VSCCs) mediate calcium ion entry into excitatory cells and participate in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell movement, cell division, and cell death. The α-1G isoform generates T-type calcium currents. T-type calcium channels belong to the "low-voltage activation (LVA)" group and can be strongly blocked by mibepidil. These channels are characterized by opening at a relatively negative potential and exhibiting voltage-dependent inactivation. T-type channels function as pacemakers in central neurons and myocardial tuberous cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in regulating neuronal firing patterns, which are crucial for information processing and cell growth processes. Hepatotoxicity
Prospective studies have shown that long-term ethosuximide treatment does not lead to a significant increase in serum transaminase levels, but it does increase gamma-glutamyl transferase levels. Clinically significant hepatotoxicity caused by ethosuximide is extremely rare. Despite the drug's use for half a century, published case reports are scarce. Furthermore, reported liver injury is usually mild and asymptomatic, part of a systemic hypersensitivity syndrome accompanied by fever, rash, facial edema, lymphadenopathy, and eosinophilia or atypical lymphocytosis. The incubation period for the hypersensitivity syndrome is typically 2 to 8 weeks. Typical serum enzyme elevations present as a mixed cholestasis-hepatocellular pattern, and jaundice has not been present in any of the reported cases. Although the ethosuximide product label warns of potential liver dysfunction and recommends regular monitoring of liver function, clinically significant liver injury (with jaundice) caused by ethosuximide is rare.
Probability score: E (Suspected but not confirmed cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
On average, 50% to 60% of the maternal weight-adjusted dose of ethosuximide is excreted into breast milk, and the concentration of ethosuximide in the infant's plasma is typically 25% to 30% of the maternal concentration. Although there have been no reports of adverse reactions caused solely by ethosuximide in breast milk, infant drowsiness, weight gain, and developmental milestones should still be monitored, especially in younger exclusively breastfed infants and when used in combination with anticonvulsants. If there are concerns about toxicity, measuring the infant's serum drug concentration may help rule out toxicity.
◉ Effects on breastfed infants
An infant whose mother took 250 mg of ethosuximide daily was exclusively breastfed from day 2 postpartum and observed for 4.5 months. During this period, the infant developed normally and showed no signs of adverse reactions.
A breastfed newborn whose mother took ethosuximide experienced sedation, poor sucking, and slow weight gain in the first 4 weeks after birth. This reaction may be caused by ethosuximide in breast milk; however, the mother was concurrently taking primidone and valproic acid. Three exclusively breastfed infants and one primarily formula-fed infant, whose mothers were all taking ethosuximide, did not show any adverse reactions in the first 1.5 to 4.5 months after birth. ◉ Effects on breastfeeding and breast milk As of the revision date, no relevant published information was found. Interactions…Therefore, it is speculated that the possible mechanism of action of ethosuximide is to reduce calcium transport, as calcium transport inhibitors such as sodium nitroprusside and verapamil enhance the blocking effect of ethosuximide on smooth muscle contraction. Concomitant use/with alcohol; central nervous system depressants; tricyclic antidepressants; loxapine; maprotiline; morinda; monoamine oxidase inhibitors; phenothiazines; pimozide; thioxanthates may lower the seizure threshold, enhance central nervous system depression, and reduce the efficacy of anticonvulsants. Succinimide anticonvulsants: Patients receiving anticonvulsant therapy may need to increase their folic acid intake. Succinimide anticonvulsants: Concomitant use of succinimide anticonvulsants and/or drugs such as carbamazepine, phenobarbital, phenytoin sodium, primidone, etc., may induce hepatic microsomal enzyme activity, leading to increased metabolism, shortened serum concentrations, and elimination half-life; monitoring serum concentrations is recommended to guide dose adjustments, especially when adding or discontinuing any anticonvulsant in an existing treatment regimen. /Succinimide anticonvulsants/
For more complete data on interactions of ethosuximide (8 drugs in total), please visit the HSDB record page.

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Non-human toxicity values
Mice intravenous LD50: 780 mg/kg
Mice subcutaneous LD50: 1810 mg/kg
Mice intraperitoneal LD50: 1752 mg/kg
Mice oral LD50: 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

Anticonvulsant
Ethosuximide is the first-line drug, while phenylsuximide is indicated for controlling absence seizures (petit mal) epilepsy. /US product label contains/
Drug Warnings

Because ethosuximide is dialysis-removable, patients undergoing hemodialysis may require supplemental doses or adjustments to their dosing regimen.
The most common dose-related side effects are gastrointestinal discomfort (nausea, vomiting, and anorexia) and central nervous system reactions (drowsiness, stupor, euphoria, dizziness, headache, and hiccups). Patients gradually develop tolerance to these reactions. Additionally, Parkinson's-like symptoms and photophobia have been reported. Restlessness, anxiety, aggression, inattention, and other behavioral abnormalities primarily occur in patients with a history of mental illness. Urticaria and other skin reactions, including Stevens-Johnson syndrome, as well as systemic lupus erythematosus, eosinophilia, leukopenia, thrombocytopenia, pancytopenia, and aplastic anemia have also been associated with this drug. Even with continued use, leukopenia may be temporary, but several deaths have been reported due to bone marrow suppression. No reports of kidney or liver toxicity have been received. The most common adverse reactions to ethosuximide are gastrointestinal symptoms, including anorexia and weight loss, mild stomach upset, cramps, abdominal pain, diarrhea, nausea, vomiting, and upper abdominal discomfort. For more complete data on ethosuximide (13 in total), please visit the HSDB record page.

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Pharmacodynamics
Used to treat epilepsy. Ethosuximide inhibits paroxysmal spike-and-wave activity at 3 cycles per second, which is common in absence seizures (petit mal seizures). The frequency of epileptiform seizures is reduced, apparently by inhibiting the motor cortex and raising the central nervous system's threshold for seizure 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.)