Paramethadione

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Paramethadione
Paramethadione.svg
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
ATC code
Pharmacokinetic data
Protein binding Not significant
Identifiers
  • (RS)-5-Ethyl-3,5-dimethyl-oxazolidine-2,4-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.003.726 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C7H11NO3
Molar mass 157.169 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • O=C1N(C(=O)OC1(C)CC)C
  • InChI=1S/C7H11NO3/c1-4-7(2)5(9)8(3)6(10)11-7/h4H2,1-3H3 Yes check.svgY
  • Key:VQASKUSHBVDKGU-UHFFFAOYSA-N Yes check.svgY
   (verify)

Paramethadione (brand name Paradione) is an anticonvulsant drug of the chemical class called oxazolidinediones developed by the Illinois-based pharmaceutical company Abbott Laboratories (known as AbbVie since January 1, 2013 [1] ), and approved by the Food and Drug Administration in 1949 for the treatment of absence seizures, also called partial seizures. [2] [3]

Contents

In 1960, the yearly cost for 900 mg/day paramethadione was approximately $66, [4] which would translate to $462 yearly in 2007 (with CPI inflation) if paramethadione was still sold. [5]

Mechanism of Action

Paramethadione acts to reduce T-type calcium currents in thalamic neurons which has been proposed to underlie the 3-Hz spike-and-wave discharge seen on electroencephalogram (EEG) during absence seizures. [6] [7]

Adverse Effects

Paramethadione is associated with various adverse effects including sedation, increased visual sensitivity to light, GI distress, edema, nephropathy, neutropenia, myasthenia gravis-like syndrome, fatal aplastic anemia, and severe birth defects known as fetal trimethadione syndrome (or paramethadione syndrome). [8] [9]

History, society, and culture

FDA approval

Paramethadione (brand name Paradione) was originally approved by the U.S. Food and Drug Administration (FDA) in 1949, as a second-line treatment for petit mal and absence seizures. [10] Paramethadione was ultimately discontinued in 1994 due to safety and efficacy concerns, [11] [12] such as being associated with fetal trimethadione syndrome, which is also known as paramethadione syndrome. [13]

Patents

Paramethadione was first patented in 1949 by Abbott Laboratories [14] Abbott Labbortories continued to hold the patent to paramethadione until the approval was withdrawn in 2004 due to the drug no longer being in use. [15]

Clinical Trials

In the 1940s trimethadione (brand name Tridione) was the only available treatment for absence seizures. However, while effective, this drug presented with significant adverse effects, which led to the search for an equally effective analog. While limited information is available from the time, a pre-market clinical study found that paramethadione, an analog of trimethadione, was not quite as effective at alleviating seizures as trimethadione, however, it did have a significantly lower side effect profile in 85 patients over the course of 2 years. [16] Notably, 80% of patients still showed a good response to paramethadione. [17]

Chemistry

Paramethadione, 5-ethyl-3,5-dimethyloxazolidine-2,4-dione, differs from trimethadione only in the substitution of one methyl group with an ethyl group. It is synthesized in a completely analogous manner, except that it comes from 2-hydroxy-2-methylbutyric acid instead of 2-hydroxyisobutyric acid. [14]

Related Research Articles

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People with epilepsy may be classified into different syndromes based on specific clinical features. These features include the age at which seizures begin, the seizure types, and EEG findings, among others. Identifying an epilepsy syndrome is useful as it helps determine the underlying causes as well as deciding what anti-seizure medication should be tried. Epilepsy syndromes are more commonly diagnosed in infants and children. Some examples of epilepsy syndromes include benign rolandic epilepsy, childhood absence epilepsy and juvenile myoclonic epilepsy. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance Lennox-Gastaut syndrome and West syndrome.

References

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  11. Drug information for PARADIONE
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