Absorption, Distribution and Excretion
Messuximide is absorbed from the gastrointestinal tract, reaching peak plasma concentrations within 1-3 hours. One study showed that after a single dose of 600 mg messuximide, the average peak serum concentration was 3 μg/mL; after a single dose of 1.2 g messuximide, the average peak serum concentration was 6-7 μg/mL. Messuximide is rapidly absorbed and metabolized. It has a very low binding rate to plasma proteins. Following oral administration, messuximide is rapidly distributed in rats and can freely cross the blood-brain barrier. Succinimide anticonvulsants can freely distribute to all body tissues except adipose tissue. For more complete data on the absorption, distribution, and excretion of messuximide (7 types), please visit the HSDB records page. Limited studies in patients taking very high doses of mesuccinimide, and one study involving a small number of patients receiving mesuccinimide for epilepsy, indicate that the drug is metabolized to N-demethylmesuccinimide (NDM) via N-demethylation. Severe central nervous system depression following mesuccinimide overdose is thought to be associated with this metabolite, and the drug's anticonvulsant effect may derive from NDM. Mesuccinimide overdose can be a biphasic process; patients may awaken within 24 hours and then relapse into a coma. In a study of patients on long-term mesuccinimide use, plasma NDM concentrations were 700 times higher than those concurrently taking mesuccinimide. Based on this study, a provisional therapeutic plasma concentration of NDM of 10–40 μg/mL has been proposed. Plasma NDM concentrations exceeding 40 μg/mL are associated with toxicity, and coma has been reported at plasma NDM concentrations of 150 μg/mL. This study investigated the pharmacokinetics of mesuximide and its major metabolite, 2-methyl-2-phenylsuccinimide, following a single intravenous injection in dogs. A two-compartment open model was used to describe plasma mesuximide concentration, and a one-compartment open model was used to describe metabolite concentration. An expression was derived to describe the plasma concentrations of mesuximide and its metabolites after mesuximide administration. Observed data showed good agreement with model predictions. The metabolite 2-methyl-2-phenylsuccinimide accounted for 40% of the total elimination of mesuximide, and its half-life (15 hours) was significantly longer than that of the parent drug (1–3.5 hours). These results suggest that the pharmacological effects of mesuximide after administration may be primarily attributed to its metabolites, which may accumulate in vivo during repeated administrations. In dogs, mesuximide is metabolized by hepatic microsomal enzymes to produce N-demethylated and p-hydroxyphenyl derivatives and their glucuronides. ...
After oral administration of 1-2 g of mesuximide to dogs, α-(p-hydroxyphenyl)-α-methylsuccinimide and N-methyl-α-(p-hydroxyphenyl)-α-methylsuccinimide were isolated from urine after 48 hours as the major metabolites, and α-methyl-α-phenylsuccinimide was a minor metabolite. The parent drug was not detected.
Compared to the mesuximide treatment group, the level of the metabolite N-demethylmesuximide was higher in patients in the phensuximide treatment group. Plasma elimination time was 32 hours and 1-2 hours, respectively.
Half-life: Mesuximide is 1.4-2.6 hours, and the active metabolite is 28-38 hours.
Biological half-life
Mesuximide is 1.4-2.6 hours, and the active metabolite is 28-38 hours.
The plasma half-life of mesuximide is slightly less than 3 hours. The relationship between plasma concentrations of mesylate and its demethylated metabolite and clinical efficacy was investigated. Single-dose and long-term dosing studies of mesylate were conducted in 5 patients with refractory epilepsy. Patients were assessed before and after treatment using 6 hours of synchronized video and telemetry EEG recordings to determine seizure type, and plasma antiepileptic drug concentrations were measured daily. Mesylate has a short half-life, averaging 1.4 hours, but its demethylated metabolite has an average half-life of 38 hours, thus its plasma concentration can accumulate to over 40 μg/mL. …In 26 patients with complex partial epilepsy unresponsive to phenytoin sodium, carbamazepine, phenobarbital, or primidone, mesylate was administered for 8 weeks. Eight of these patients experienced a 50% or greater reduction in the frequency of complex partial seizures. …N-Demethylmesylate is the major metabolite detected in plasma, with the following pharmacokinetic parameters: cumulative half-life of 49.7 hours; time to steady state of 10.4 days; elimination half-life of 72.2 hours. ...

Toxicity Summary
Messuximide inhibits paroxysmal spike-and-wave activity (SVEV) with 3 cycles per second associated with loss of consciousness, commonly seen in absence seizures (petit mal seizures). The frequency of epileptic-like seizures is reduced, apparently by inhibiting the motor cortex and raising the central nervous system's threshold for seizure stimuli. Hepatotoxicity
Prospective studies have shown that long-term use of messuximide does not lead to a significant increase in serum transaminase levels, although animal studies have indicated hepatotoxicity. There are no reports of clinically significant hepatotoxicity caused by messuximide, but hypersensitivity reactions such as fever and rash are not uncommon (1% to 5%). Messuximide product information warns of potential liver dysfunction and recommends regular liver function tests. However, even if clinically significant liver injury occurs, it is extremely rare. Probability Score: E (Unproven but suspected rare cause of clinically significant liver injury).

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Drug Interactions
Concomitant use with alcohol, central nervous system depressants, tricyclic antidepressants, loxapine, maprotiline, morindaline, monoamine oxidase inhibitors, phenothiazines, pimozide, and thioxanol 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 Antiepileptics
Concomitant use with carbamazepine, phenobarbital, phenytoin sodium, primidone, etc., may induce hepatic microsomal enzyme activity, leading to increased metabolism of succinimide antiepileptics and/or these drugs, shortened serum concentrations, and elimination half-lives; monitoring serum concentrations is recommended to guide dose adjustments, especially when adding or discontinuing any antiepileptic drug in an existing treatment regimen. Succinimide antiepileptic drugs
Concomitant use with haloperidol may alter the pattern and/or frequency of epileptic-like seizures; dosage adjustment of the antiepileptic drug may be necessary; serum concentrations of haloperidol may be significantly reduced. /Succinimide anticonvulsants/
For more complete data on interactions of methylsuccinimide (9 drugs in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in mice: 900 mg/kg

Therapeutic Uses

Anticonvulsive Drug
Mesuximide is indicated for the treatment of absence seizures unresponsive to other medications. /Included in US product label/
Mesuximide can be used to treat complex partial seizures (epilepsy). /Not included in US product label/
This study investigated the use of mesuximide in 25 children with treatment-resistant epilepsy (mean age 10.2 years) who received an average dose of 20.4 mg/kg/day in addition to their standard antiepileptic medication regimen. Results showed that 15 patients tolerated the drug well, with a 50% or greater reduction in seizure frequency. No serious or irreversible adverse reactions were observed. Mesuximide is often overlooked, but it may be an effective adjunctive antiepileptic drug for children with treatment-resistant epilepsy.
One study treated 26 children with complex partial epilepsy (CPS) unresponsive to phenytoin, carbamazepine, phenobarbital, or primidone with mesuximide for 8 weeks. Eight of the children experienced a 50% or greater reduction in CPS seizure frequency. These eight children continued long-term mesuximide treatment, and five of them maintained a 50% or greater reduction in CPS seizure frequency after 3 to 34 months of follow-up. ...

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Drug Warnings
Succinimide anticonvulsants may cause blood abnormalities, leading to an increased incidence of microbial infections, delayed wound healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental treatment should be postponed until blood cell counts return to normal. Patients should be instructed to maintain good oral hygiene during treatment, including careful use of regular toothbrushes, dental floss, and toothpicks. /Succinimide Anticonvulsants/
Gastrointestinal adverse reactions are common during mesuximide treatment, including nausea or vomiting, weight loss, anorexia, upper abdominal or abdominal pain, diarrhea, and constipation.
Neurological adverse reactions of mesuximide include drowsiness, ataxia, dizziness, irritability and nervousness, headache, photophobia, blurred vision, hiccups, and insomnia. The most common neurological adverse reactions are somnolence, ataxia, and dizziness. Psychological adverse reactions include mood instability, hypochondria, aggression, confusion, depression, and slowed reaction. Rarely, psychosis, suicidal behavior, and auditory hallucinations have been reported. Hematologic adverse reactions associated with mesuximide include eosinophilia, leukopenia, monocytosis, and pancytopenia. Skin adverse reactions may include urticaria, pruritic erythema, and Stevens-Johnson syndrome. Genitourinary adverse reactions associated with mesuximide include proteinuria and microscopic hematuria. Periorbital edema and congestion have also been reported. Systemic lupus erythematosus has been associated with the use of succinimide. For more complete data on drug warnings for mesuximide (9 in total), please visit the HSDB record page.

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Pharmacodynamics
Used for the treatment of epilepsy.
Methosuximide can suppress paroxysmal three-cycle-per-second spike-and-wave activity associated with loss of consciousness, which is common in absence seizures (petit mal seizures). The frequency of epileptiform seizures is reduced, which is apparently achieved by inhibiting the motor cortex and raising the central nervous system's threshold for seizure stimuli.

C12H13NO2

203.24

203.095

77-41-8

6476

Crystals from dilute alcohol
White to grayish white, crystalline powder

1.59g/cm3

489.2ºC at 760 mmHg

52-53°

191.7ºC

1.692

1.27

0

2

1

15

294

0

CC1(CC(=O)N(C)C1=O)C2=CC=CC=C2

AJXPJJZHWIXJCJ-UHFFFAOYSA-N

InChI=1S/C12H13NO2/c1-12(9-6-4-3-5-7-9)8-10(14)13(2)11(12)15/h3-7H,8H2,1-2H3

1,3-dimethyl-3-phenylpyrrolidine-2,5-dione

Celontin; Mesuximide; Methsuximide

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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