Paramethadione Explained

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]

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by Abbott Laboratories[14] Abbott Labbortories continued to hold the patent to paramethadione until the approval was withdrawn in 2004 due to the drug no longer being in use.[15]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

External links

Notes and References

  1. http://articles.chicagotribune.com/2012-12-30/business/ct-biz-1230-bf-abbott-spin-20121230_1_longtime-abbott-executive-abbvie-abbott-laboratories More than splitting pills: Health care giant Abbott Laboratories ready to spin off AbbVie
  2. Web site: Oxazolidinedione Anticonvulsants . drugs.com .
  3. Book: Sittig. Marshall . vanc . Pharmaceutical manufacturing encyclopedia.. 2015. William Andrew Pub.. New York.
  4. Book: Lennox WG . Epilepsy and related disorders. . registration. 1960. Little Brown. Boston.
  5. Shorvon SD . Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959-2009 . Epilepsia . 50 Suppl 3 . s3 . 93–130 . March 2009 . 19298435 . 10.1111/j.1528-1167.2009.02042.x . free .
  6. Web site: Paramethadione . Drug Bank .
  7. von Krosigk M, Bal T, McCormick DA . Cellular mechanisms of a synchronized oscillation in the thalamus . Science . 261 . 5119 . 361–4 . July 1993 . 8392750 . 10.1126/science.8392750 . 2881575 .
  8. Book: Miller RR, Greenblatt DJ . Handbook of Drug Therapy. 1979. Elsevier North Holland. New York. 978-0-444-00329-4.
  9. https://www.nlm.nih.gov/cgi/jablonski/syndrome_cgi?term=paramethadione+syndrome&field=name Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes
  10. Book: Miller RR, Greenblatt DJ . Handbook of Drug Therapy. 1979. Elsevier North Holland. New York. 597.
  11. http://www.reference.md/files/PA/PARADIONE.html Drug information for PARADIONE
  12. Shorvon SD . Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959-2009 . Epilepsia . 50 Suppl 3 . s3 . 93–130 . March 2009 . 19298435 . 10.1111/j.1528-1167.2009.02042.x . free .
  13. https://www.nlm.nih.gov/cgi/jablonski/syndrome_cgi?term=paramethadione+syndrome&field=name Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes
  14. Spielman MA . US . 2575693 . 1951 .
  15. Schering Corp.. etal. 2004. Withdrawal of Approval of 92 New Drug Applications and 49 Abbreviated New Drug Applications. DEPARTMENT OF HEALTH AND HUMAN SERVICES: Food and Drug Administration. 25125 . Docket No. 2004N-0159.
  16. Davis JP, Lennox WG . 1949. A comparison of paradione and tridione in the treatment of epilepsy . The Journal of Pediatrics. 34. 3 . 273–278. 10.1016/S0022-3476(49)80080-1.
  17. Drake FR . The current drug therapy of epilepsy: a review . The American Journal of the Medical Sciences . 230 . 1 . 98–107 . July 1955 . 14388023 . 10.1097/00000441-195507000-00014 .

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