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ethosuximide

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ethosuximide
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{{Drugbox| Watchedfields = changed| verifiedrevid = 461096657| IUPAC_name = (RS)-3-Ethyl-3-methyl-pyrrolidine-2,5-dione| image = (RS)-Ethosuximid Structural Formula V1.svg| width = 140| chirality = Racemic mixture| tradename = Zarontin class="hintergrundfarbe6"! colspan="2"| Enantiomers of ethosuximide
monograph|ethosuximide}}| MedlinePlus = a682327| pregnancy_AU = D| pregnancy_US = C| legal_US = Rx-only| legal_status = ℞-onlyCapsule (pharmacy)>capsules, solution)| bioavailability = 93%| metabolism = liver (CYP3A4, CYP2E1)| elimination_half-life = 53 hours| excretion = kidney (20%)| IUPHAR_ligand = 7182correct|??}}| CAS_number = 77-67-8| ATC_prefix = N03| ATC_suffix = AD01| PubChem = 3291correct|drugbank}}| DrugBank = DB00593correct|chemspider}}| ChemSpiderID = 3175correct|FDA}}| UNII = 5SEH9X1D1Dcorrect|kegg}}| KEGG = D00539correct|EBI}}| ChEBI = 4887correct|EBI}}| ChEMBL = 696 H = 11 O = 2| molecular_weight = 141.168 g/mol| SMILES = O=C1NC(=O)CC1(C)CCcorrect|chemspider}}| StdInChI = 1S/C7H11NO2/c1-3-7(2)4-5(9)8-6(7)10/h3-4H2,1-2H3,(H,8,9,10)correct|chemspider}}| StdInChIKey = HAPOVYFOVVWLRS-UHFFFAOYSA-N| melting_point = 64| melting_high = 65}}Ethosuximide, sold under the brand name Zarontin among others, is a medication used to treat absence seizures. It may be used by itself or with other antiseizure medications such as valproic acid. Ethosuximide is taken by mouth.WEB, Ethosuximide,weblink The American Society of Health-System Pharmacists, 8 December 2016, live,weblink 21 December 2016, Side effects are generally minimal.BOOK, WHO Model Formulary 2008, 2009, World Health Organization, 9789241547659, 69, 74–75,weblink 8 December 2016, live,weblink" title="web.archive.org/web/20161213060118weblink">weblink 13 December 2016, Common side effects include loss of appetite, abdominal pain, diarrhea, and feeling tired. Serious side effects include suicidal thoughts, low blood cell levels, and lupus erythematosus. It is unclear if use during pregnancy or under the age of three is safe for the baby. Ethosuximide is in the succinimide family of medications. How exactly it works is unclear.Ethosuximide was approved for medical use in the United States in 1960. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.WEB, WHO Model List of Essential Medicines (19th List),weblink World Health Organization, 8 December 2016, April 2015, live,weblink" title="web.archive.org/web/20161213052708weblink">weblink 13 December 2016, Ethosuximide is available as a generic medication. The wholesale cost in the developing world is about US$27.77 per month.WEB, Ethosuximide,weblink International Drug Price Indicator Guide, 8 December 2016, In the United States the wholesale cost as of 2016 is about US$41.55 per month for a typical dose.WEB, NADAC as of 2016-12-07 {{!, Data.Medicaid.gov|url=https://data.medicaid.gov/Drug-Prices/NADAC-as-of-2016-12-07/ry9m-tx78|website=Centers for Medicare and Medicaid Services|access-date=13 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221003023weblink|archive-date=21 December 2016}}{{TOC limit|3}}

Medical uses

It is approved for absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug, valproic acid.

Adverse effects

Central nervous system

Common

Rare

Gastrointestinal

Genitourinary

Blood

The following can occur with or without bone marrow loss:

Skin

Eyes

Drug interactions

Valproates can either decrease or increase the levels of ethosuximide; however, combinations of valproates and ethosuximide had a greater protective index than either drug alone.It may elevate serum phenytoin levels.

Mechanism of action

The mechanism by which ethosuximide affects neuronal excitability includes block of T-type calcium channels, and may include effects of the drug on other classes of ion channel. The primary finding that ethosuximide is a T-type calcium channel blocker gained widespread support, but initial attempts to replicate the finding were inconsistent. Subsequent experiments on recombinant T-type channels in cell lines demonstrated conclusively that ethosuximide blocks all T-type calcium channel isoforms.{{citation needed|date=May 2014}} Significant T-type calcium channel density occurs in dendrites of neurons, and recordings from reduced preparations that strip away this dendritic source of T-type calcium channels may have contributed to reports of ethosuximide ineffectiveness.In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+ currents in T-type calcium channels in freshly removed thalamic neurons. In June of that same year, they also found the mechanism of this reduction to be voltage-dependent, using acutely dissociated neurons of rats and guinea pigs; it was also noted that valproic acid, which is also used in absence seizures, did not do that. The next year, they showed that anticonvulsant succinimides did this and that the pro-convulsant ones did not. The first part was supported by Kostyuk et al. in 1992, who reported a substantial reduction in current in dorsal root ganglia at concentrations ranging from 7 µmol/L to 1 mmol/L.That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L.{ The year after, a study conducted on human neocortical cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca2+ currents at the concentrations typically needed for a therapeutic effect.In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mmol/L, far higher than Kostyuk reported. That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na+ current by 60% and the Ca2+-activated K+ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na+ current is responsible for the anti-absence properties.In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the University of Virginia in Charlottesville pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels. Using cloned α1G, α1H, and α1I T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an IC50 of 12 ± 2 mmol/L and that of N-desmethylmethsuximide (the active metabolite of mesuximide) is 1.95 ± 0.19 mmol/L for α1G, 1.82 ± 0.16 mmol/L for α1I, and 3.0 ± 0.3 mmol/L for α1H. It was suggested that the blockade of open channels is facilitated by ethosuximide's physically plugging the channels when current flows inward.

Availability

Ethosuximide is marketed under the trade names Emeside and Zarontin. However, both capsule preparations were discontinued from production, leaving only generic preparations available. Emeside capsules were discontinued by their manufacturer, Laboratories for Applied Biology, in 2005.JOURNAL,weblink Concern over ethosuximide capsule discontinuation, Pharm J, Oct 29, 2005, 275, 539, 2008-08-31, live,weblink" title="web.archive.org/web/20081013220747weblink">weblink 2008-10-13, (paywalled archive) Similarly, Zarontin capsules were discontinued by Pfizer in 2007.WEB,weblink Zarontin capsules discontinued, 2012-10-24, live,weblink" title="web.archive.org/web/20120626002021weblink">weblink 2012-06-26, Syrup preparations of both brands remained available.

Stereochemistry

Ethosuximide is a chiral drug with a stereocenter. Therapeutically, the racemate, the 1: 1 mixture of ( S ) and ( R ) - isomers used.Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, {{ISBN|978-3-946057-10-9}}, S. 182.{| class="wikitable" style="text-align:center"
140 px) CAS-Nummer: 39122-20-8140 px) CAS-Nummer: 39122-19-5

See also

References

External links

{{Anticonvulsants}}

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