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Mesuximide
Clinical data
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa682028
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic (demethylation and glucuronidation)
Elimination half-life1.4–2.6 hours (mesuximide)
28–38 hours (active metabolite)
ExcretionRenal
Identifiers
  • (RS)-1,3-dimethyl-3-phenyl-pyrrolidine-2,5-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC12H13NO2
Molar mass203.237 g/mol g·mol−1
3D model (JSmol)
Melting point52–54 °C (126–129 °F)
Boiling point166–167 °C (331–333 °F)
  • O=C2N(C(=O)CC2(c1ccccc1)C)C
  • 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 checkY
  • Key:AJXPJJZHWIXJCJ-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Mesuximide (or methsuximide, methosuximide) is a succinimide anticonvulsant medication. It is sold as a racemate by Pfizer under the tradenames Petinutin (Switzerland)[1] and Celontin (United States).[2] The therapeutic efficacy of methosuximide is largely due to its pharmacologically active metabolite, N-desmethylmethosuximide, which has a longer half-life and attains much higher plasma levels than its parent.[3]

History of treatments

[edit]

Methsuximide was discovered in the early 1950’s primarily for the treatment of absence seizures (petit mal seizures).[4] Methsuximide is a broader spectrum antiepileptic drug[3] and was considered a last resort drug to treat seizure disorders in patients that are refractory to treatment with other antiepileptic drugs. However, continued clinical trials led to many off label uses for effective treatment of a broad spectrum of seizures; refractory partial complex seizures,[5] psychomotor seizures,[6] myoclonic seizures,[7][8] mixed epilepsy[9] and Lennox-Gastaut syndrome.[10]

Synthesis

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Synthesis of Methsuximide

2-Methyl-2-phenylsuccinic acid is reacted with an excess of methylamine and water to produce methsuximide. The excess methylamine and water are distilled off under reduced pressure to yield the dimethylamine salt of the acid. The dimethylamine salt undergoes pyrolysis at 250 ˚C the product is dissolved in solvent and treated with activated charcoal. Methsuximde is precipitated with the addition of water.[11][12]

Characteristics

[edit]

Methsuximide has a nonpolar lipophilic moiety which allows for rapid tissue distribution.[13] Water solubility at pH 7.0 (25˚C) is 2.8 mg/ml.[14]

Pharmacodynamics

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Mechanism of action

[edit]

Petit mal seizures

[edit]

N-desmethylmethosuximide, the active metabolite of methsuximide, dampens the low threshold calcium currents in thalamic neurons that play a role in the generation of the spike-wave discharges in petit mal epilepsy by blocking voltage-gated t-type calcium channels.[15] N-desmethylmethosuximide and the low threshold calcium current-reducing receptor show a bimolecular interaction, which indicates co-operative binding of more than one molecule of N-desmethylmethosuximide binding to a receptor.[15] The extent of the reduction of the low threshold calcium current is voltage dependent and most effective at the voltage threshold for initiating the current.[15] N-desmethylmethosuximide has a lower potency but a higher efficacy when compared to a similar succinimide, ethosuximide, with a maximal effect of 100% and an Ic50 of 1100 μM compared to ethosuximide maximal effect 40% and an Ic50 of 200 μM.[15]

Other seizure types

[edit]

The structure of N-desmethylmethosuximide is very similar to phenytoin. Therefore, it is predicted that the broad spectrum anticonvulsant effects are due to its effects on sodium currents.[15]

Pharmacokinetics

[edit]

Methsuximide is administered orally and is rapidly absorbed into the small intestine and rapidly distributed throughout the body.[16] Methsuximide crosses the blood brain barrier, which may be due to its nonpolar lipophilic properties.[17] Dose amount and dose frequency differ for adults and children and are generally based on the serum concentration of N-desmethylmethsuximide.[18] The average starting dose is 10 mg/kg to reach a recommended serum range for adults: 20-40 ug/mL and children: 40-50 ug/mL.[19] Methsuximide and N-desmethylmethsuximide follow first order kinetics and there is a linear relationship between dose and steady state serum levels.[20] Once a determined drug regimen has begun, N-desmethylmethsuximide reaches steady state in 8.1-16.8 days.[21] Maximum plasma concentration Tmax values for N-Desmethylmethsuximide in adults is 1-4 hours[22] and children is 2-3 hours.[18]

The serum protein binding of methsuximide is negligible.[21] The serum protein binding for N-desmethylmethsuximide is 45-60%.[5][21] The serum concentration of N-desmethylmethsuximide is approximately 700 times more than methsuximide.[20]

In the liver N-desmethylmethsuximide is rapidly formed by the n-demethylation of methsuximide.[23] The half-life of methsuximide is 1.4[3] to 2.6 hours.[23] The average half-life of N-desmethylmethsuximide in adults is 36-45 hours[21] and in children 16-45 hours.[22] N-desmethylmethsuximide is further metabolized by enzyme cytochrome P450 2C19.[22] Other possible mechanisms of metabolism of N-desmethylmethsuximide are: microsomal enzyme induction, porphyrinogenesis and hydrolysis of the succinimide ring.[23]

Elimination is primarily renal; methsuximide and N-desmethylmethsuximide are detected in urine.[16]

Potential side effects

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Some of the most common side effects are; nausea, abdominal discomfort, anorexia, vomiting, diarrhea, drowsiness, vertigo, diplopia, blurred vision, rash, ataxia, dizziness, hiccups, and irritability. Some of the less common side effects include; inattention, personality change, confusion, nervousness, headaches, lethargy, fearfulness, slurred speech, dysarthria, increased seizures, and photophobia. Some severe and rare side effects include; irreversible cerebellar damage, periorbital edema, porphyria, restless leg syndrome, proteinuria, microscopic hematuria, hyperemia, and death.[24]

Methsuximide interactions with other Antiepileptic Drugs

[edit]

Methsuximide increases the serum concentrations of phenobarbital and phenytoin and decreases the serum concentrations of primidone, valproic acid, levetiracetam, lamotrigine, topiramate, and oxcarbazepine.[21] Phenytoin and phenobarbital increase the metabolism of methsuximide and therefore increase the serum ratio of N-desmethylmethsuximide to methsuximide.[21][22] Serum levels of N-desmethylmethsuximide are increased by the inhibition of methsuximide metabolism by Felbamate.[22]

References

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  1. ^ Pfizer AG (2005). "Petinutin (Mésuximide)". Official Pfizer AG Website (in French). Retrieved August 21, 2006. [dead link]
  2. ^ Pfizer Inc. (2008). "Celontin (methsuximide capsules, USP)". Official Pfizer Inc. Website. Retrieved November 21, 2014.
  3. ^ a b c Porter, RJ; Penry, JK; Lacy, JR; Newmark, ME; Kupferberg, HJ (November 1979). "Plasma concentrations of phensuximide, methsuximide, and their metabolites in relation to clinical efficacy". Neurology. 29 (11): 1509–13. doi:10.1212/wnl.29.11.1509. PMID 116142. S2CID 43643797.
  4. ^ CHEN, G; WESTON, JK; BRATTON AC, Jr (March 1963). "Anticonvulsant activity and toxicity of phensuximide, methsuximide and ethosuximide". Epilepsia. 4 (1–4): 66–76. doi:10.1111/j.1528-1157.1963.tb05209.x. PMID 14020499. S2CID 29675349.
  5. ^ a b Wad, N; Bourgeois, B; Krämer, G (1999). "Serum protein binding of desmethyl-methsuximide". Clinical Neuropharmacology. 22 (4): 239–40. PMID 10442255.
  6. ^ FRENCH, EG; REY-BELLET, J; LENNOX, WG (1 May 1958). "Methsuximide in psychomotor and petit-mal seizures". The New England Journal of Medicine. 258 (18): 892–4. doi:10.1056/NEJM195805012581807. PMID 13541681.
  7. ^ eds), Elaine Wyllie (editor-in-chief ) ; Gregory D. Cascino, Barry E. Gidal, Howard P. Goodkin (associate (2011). Wyllie's treatment of epilepsy : principles and practice (5th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. ISBN 9781582559377. {{cite book}}: |first1= has generic name (help)CS1 maint: multiple names: authors list (link)
  8. ^ Hurst, DL (March 1996). "Methsuximide therapy of juvenile myoclonic epilepsy". Seizure. 5 (1): 47–50. doi:10.1016/s1059-1311(96)80062-8. PMID 8777552. S2CID 7549450.
  9. ^ DOW, RS; MACFARLANE, JP; STEVENS, JR (March 1958). "Celontin in patients with refractory epilepsy". Neurology. 8 (3): 201–4. doi:10.1212/wnl.8.3.201. PMID 13517486. S2CID 38278847.
  10. ^ Sigler, M; Strassburg, HM; Boenigk, HE (March 2001). "Effective and safe but forgotten: methsuximide in intractable epilepsies in childhood". Seizure. 10 (2): 120–4. doi:10.1053/seiz.2000.0467. PMID 11407955. S2CID 11569157.
  11. ^ Kar, Ashutosh (2005). Medicinal chemistry (Revised and expanded third ed.). New Delhi: New Age International Limited, Publishers. ISBN 9788122415650.
  12. ^ Miller, C. A.; Long, Loren M. (October 1951). "Anticonvulsants. I. An Investigation of N-R-α-R-α-Phenylsuccinimides". Journal of the American Chemical Society. 73 (10): 4895–4898. doi:10.1021/ja01154a126.
  13. ^ Nicholls, PJ; Orton, TC (October 1971). "Absorption, distribution and excretion of methsuximide in male rats". British Journal of Pharmacology. 43 (2): 459P–460P. PMC 1665853. PMID 5158235.
  14. ^ Schmidt, Editors: Dixon M. Woodbury, J. Kiffin Penry [and] Richard P. (1972). Antiepileptic drugs. New York: Raven Press. ISBN 0911216294. {{cite book}}: |first1= has generic name (help)CS1 maint: multiple names: authors list (link)
  15. ^ a b c d e Coulter, DA; Huguenard, JR; Prince, DA (August 1990). "Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction". British Journal of Pharmacology. 100 (4): 800–6. doi:10.1111/j.1476-5381.1990.tb14095.x. PMC 1917607. PMID 2169941.
  16. ^ a b Nicholls, PJ; Orton, TC (May 1972). "The physiological disposition of 14 C-methsuximide in the rat". British Journal of Pharmacology. 45 (1): 48–59. doi:10.1111/j.1476-5381.1972.tb09575.x. PMC 1666192. PMID 5041507.
  17. ^ Panayiotopoulos, C.P. (2005). The epilepsies : seizures, syndromes and management. Chipping Norton, England: Bladon Medical Publishing. ISBN 1-904218-34-2.
  18. ^ a b Miles, MV; Tennison, MB; Greenwood, RS (April 1989). "Pharmacokinetics of N-desmethylmethsuximide in pediatric patients". The Journal of Pediatrics. 114 (4 Pt 1): 647–50. doi:10.1016/s0022-3476(89)80714-0. PMID 2926578.
  19. ^ Tennison, MB; Greenwood, RS; Miles, MV (February 1991). "Methsuximide for intractable childhood seizures". Pediatrics. 87 (2): 186–9. PMID 1987529.
  20. ^ a b Strong, JM; Abe, T; Gibbs, EL; Atkinson AJ, Jr (March 1974). "Plasma levels of methsuximide and N-desmethylmethsuximide during methsuximide therapy". Neurology. 24 (3): 250–5. doi:10.1212/wnl.24.3.250. PMID 4855951. S2CID 41450735.
  21. ^ a b c d e f Hoepner, R; May, TW; Rambeck, B; Ottenottebrock, H; Valentin, R; Brandt, C (September 2012). "Symptoms and course of intoxication with mesuximide--a case report". Epilepsy & Behavior : E&B. 25 (1): 129–30. doi:10.1016/j.yebeh.2012.06.011. PMID 22818365. S2CID 205752867.
  22. ^ a b c d e Patsalos, P.N. (2012). Antiepileptic drug interactions : a clinical guide (2nd ed.). London: Springer. ISBN 978-1-4471-2433-7.
  23. ^ a b c Glazko, AJ (June 1975). "Antiepileptic drugs: biotransformation, metabolism, and serum half-life". Epilepsia. 16 (2): 367–91. doi:10.1111/j.1528-1157.1975.tb06064.x. PMID 238831. S2CID 30432063.
  24. ^ .̤, eds. René H. Levy (2002). Antiepileptic drugs (5th ed.). Philadelphia: Lippincott Williams and Wilkins. ISBN 9780781723213. {{cite book}}: |first1= has generic name (help); |last1= has numeric name (help)

Category:Anticonvulsants Category:Succinimides


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