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valproate
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{{Drugbox| Watchedfields = changed| verifiedrevid = 477003327| IUPAC_name = 2-propylpentanoic acid| image = Valproic acid.svg| width = 200px| image2 = Valproic acid-optimized-ball-and-stick-model.png| width2 = 200px| There is limited evidence that the augmentation of antipsychotics with valproate may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Evidence was entirely based on open randomized controlled trials. Valproate was associated with a number of adverse events among which sedation and dizziness appeared significantly more frequently than in the control groups.! scope="col" style="text-align: left;"| Outcome! scope="col" style="text-align: left;"| Findings in words! scope="col" style="text-align: left;"| Findings in numbers! scope="col" style="text-align: left;"| Quality of evidence! colspan="4" style="text-align: left;"| Global outcome ! colspan="4" style="text-align: left;"| Mental state! colspan="4" style="text-align: left;"| Adverse events! colspan="4" style="text-align: left;"| Missing outcomes and notes
#Formulations>othersmonograph|valproic_acid}}| MedlinePlus = a682412| licence_US = | pregnancy_AU = D| pregnancy_US = X| pregnancy_US_comment = - only for epilepsy or bipolar if other options are not possible| legal_AU = S4| legal_CA = Rx-only| legal_UK = POM| legal_US = Rx-onlyOral administration>By mouth, intravenous| bioavailability = Rapid absorptionPUBLISHER=WEBMDURL=HTTP://REFERENCE.MEDSCAPE.COM/DRUG/DEPAKENE-STAVZOR-VALPROIC-ACID-343024#SHOWALLARCHIVEURL=HTTPS://WEB.ARCHIVE.ORG/WEB/20140221222153/HTTP://REFERENCE.MEDSCAPE.COM/DRUG/DEPAKENE-STAVZOR-VALPROIC-ACID-343024#SHOWALL, 21 February 2014, Liver>Hepatic—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%| elimination_half-life = 9–16 hours| excretion = Urine (30–50%)correct|??}}| CAS_number = 99-66-1| ATC_prefix = N03| ATC_suffix = AG01correct|EBI}}| ChEBI = 39867| PubChem = 3121| IUPHAR_ligand = 7009correct|drugbank}}| DrugBank = DB00313correct|chemspider}}| ChemSpiderID = 3009correct|FDA}}| UNII = 614OI1Z5WIcorrect|kegg}}| KEGG = D00399correct|EBI}}| ChEMBL = 109| NIAID_ChemDB = 057177| synonyms = Valproic acid; Sodium valproate (sodium); Valproate semisodium (semisodium); 2-Propylvaleric acid H=16 | O=2| molecular_weight = 144.211 | SMILES = O=C(O)C(CCC)CCCcorrect|chemspider}}| StdInChI = 1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)correct|chemspider}}| StdInChIKey = NIJJYAXOARWZEE-UHFFFAOYSA-N}}Valproate (VPA), and its valproic acid, sodium valproate, and valproate semisodium forms, are medications primarily used to treat epilepsy and bipolar disorder and to prevent migraine headaches.WEB, Valproic Acid,weblink The American Society of Health-System Pharmacists, Oct 23, 2015, live,weblink 2017-07-31, They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. They can be given intravenously or by mouth. Long and short acting formulations of tablets exist.Common side effects include nausea, vomiting, sleepiness, and dry mouth. Serious side effects can include liver problems and regular monitoring of liver function tests is therefore recommended. Other serious risks include pancreatitis and an increased suicide risk. The drug is known to cause serious abnormalities in babies if taken during pregnancy.WEB, Valproate banned without the pregnancy prevention programme,weblink GOV.UK, 26 April 2018, en, Because of this it is not typically recommended in women of childbearing age who have migraines.It is unclear exactly how valproate works.JOURNAL, Owens MJ, Nemeroff CB, Pharmacology of valproate, Psychopharmacol Bull, 37 Suppl 2, 17–24, 2003, 14624230, Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases.JOURNAL, Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB, Klein TE, Valproic acid pathway: pharmacokinetics and pharmacodynamics, Pharmacogenet. Genomics, 23, 4, 236–241, April 2013, 23407051, 3696515, 10.1097/FPC.0b013e32835ea0b2, WEB, Valproic acid,weblink DrugBank, University of Alberta, 30 July 2017, 29 July 2017, live,weblink 31 July 2017, Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.Valproate was first made in 1881 and came into medical use in 1962.BOOK, Scott, D.F., The history of epileptic therapy : an account of how medication was developed, 1993, Parthenon Publ. Group, Carnforth u.a., 9781850703914, 131, 1. publ.,weblink Valproate is included in 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, It is available as a generic medication. The wholesale cost in the developing world is between {{US$|link=yes}}0.14 and {{US$}}0.52 per day.WEB, Sodium Valproate,weblinkweblink" title="web.archive.org/web/20180122073005weblink">weblink dead, 2018-01-22, International Drug Price Indicator Guide, In the United States, it costs roughly {{US$}}0.90 per day. It is marketed under the brand names Depakote and Epilim, among others.WEB, PRODUCT INFORMATION EPILIM®, sanofi-aventis australia pty ltd, 23 August 2017, TGA eBusiness Services, 7 December 2016,weblink Macquarie Park, Australia, live,weblink 23 August 2017, In 2016 it was the 129th most prescribed medication in the United States with more than 5 million prescriptions.WEB, The Top 300 of 2019,weblink clincalc.com, 22 December 2018, {{TOC limit}}

Terminology

Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as valproate semisodium.BOOK,weblink Martindale: The Complete Drug Reference, Pharmaceutical Press, Brayfield, Alison, London, March 3, 2018,

Medical uses

It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.

Epilepsy

Valproate has a broad spectrum of anticonvulsant activity, although it is primarily used as a first-line treatment for tonic-clonic seizures, absence seizures and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms.JOURNAL, Löscher W, Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy, CNS Drugs, 16, 10, 669–694, 2002, 12269861, 10.2165/00023210-200216100-00003, It has also been successfully given intravenously to treat status epilepticus.JOURNAL, Olsen KB, Taubøll E, Gjerstad L, Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults, Acta Neurol. Scand. Suppl., 187, 51–4, 2007, 17419829, 10.1111/j.1600-0404.2007.00847.x, JOURNAL, Kwan SY, The role of intravenous valproate in convulsive status epilepticus in the future, Acta Neurol Taiwan, 19, 2, 78–81, 2010, 20830628,weblink {{Dead link|date=September 2019 |bot=InternetArchiveBot |fix-attempted=yes }}

Mental illness

Bipolar disorder

Valproate products are also used to treat manic or mixed episodes of bipolar disorder.WEB,weblink Valproate Information, Fda.gov, 2015-04-24, live,weblink" title="web.archive.org/web/20150503091048weblink">weblink 2015-05-03, JOURNAL, Jochim, Janina, Rifkin-Zybutz, Raphael, Geddes, John, Cipriani, Andrea, Valproate for acute mania, Cochrane Database of Systematic Reviews, 7 October 2019, 10.1002/14651858.CD004052.pub2,

Schizophrenia

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:JOURNAL, Wang, Y, Xia, J, B, Helfer, Valproate for schizophrenia, Cochrane Database of Systematic Reviews, 2016, 11,weblink CD004028.pub4, 10.1002/14651858.CD004028.pub4, 27884042, 6734130, live,weblink" title="web.archive.org/web/20170729002449weblink">weblink 2017-07-29, {| class="wikitable"! Summary
{| class="wikitable collapsible collapsed" style="width:100%;"
|When added to antipsychotic drugs valproate probably increases the chance of improvement. Data are based on moderate quality evidence.
|| RR 1.31 (1.16 to 1.47) || Moderate
| Valproate in combination with antipsychotics may slightly reduce the chance of leaving the study early, but the difference between the two treatments is not clear. Data supporting this finding are based on moderate quality evidence.
|| RR 0.76 (0.47 to 1.24) || Moderate
| The combination of valproate and antipsychotic drugs may increase the chance of being given additional sedating medication, but, at present it is not possible to be confident about the difference between the two treatments and data supporting this finding are very limited.
|| RR 3.65 (0.11 to 122.31) || Very low
Positive and Negative Syndrome Scale>PANSS total, high = poor) On average, people receiving the valproate combination scored lower (better) than people treated with antipsychotics in combination with placebo or antipsychotic drugs alone. There was a clear difference between the groups, but the meaning of this in day-to-day care is unclear. Mean absolute difference 5.85 lower (7.8 lower to 3.91 lower) >The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach>Moderate
| Adding valproate to antipsychotic drug treatment does not clearly cause liver problems. Data supporting this finding are based on moderate quality evidence.
|| RR 1.26 (0.72 to 2.22) || Moderate
| Adding valproate to antipsychotic drugs probably causes little or no increase to the chance of feeling sick, but the difference between the two treatments is not clear. Data supporting this finding are based on moderate quality evidence.
|| RR 1.22 (0.80 to 1.86) || Moderate
Quality of life outcomes were not reported in the included studies. *Increase in alanine transaminase/gamma-glutamyl transpeptidase >|

Dopamine dysregulation syndrome

Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinson's disease with levodopa.JOURNAL, Pirritano D, Plastino M, Bosco D, Gallelli L, Siniscalchi A, De Sarro G, Gambling disorder during dopamine replacement treatment in Parkinson's disease: a comprehensive review, Biomed Res Int, 2014, 1–9, 2014, 25114917, 4119624, 10.1155/2014/728038, JOURNAL, Connolly B, Fox SH, Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson's disease, Neurotherapeutics, 11, 1, 78–91, 2014, 24288035, 3899484, 10.1007/s13311-013-0238-x, JOURNAL, Averbeck BB, O'Sullivan SS, Djamshidian A, Impulsive and compulsive behaviors in Parkinson's disease, Annu Rev Clin Psychol, 10, 553–80, 2014, 24313567, 4197852, 10.1146/annurev-clinpsy-032813-153705,

Migraines

Valproate is also used to prevent migraine headaches. Because this medication can be potentially harmful to the fetus, valproate should be considered for those able to become pregnant only after the risks have been discussed.

Other

The medication has been tested in the treatment of AIDS and cancer, owing to its histone deacetylase-inhibiting effects.JOURNAL, Činčárová L, Zdráhal Z, Fajkus J, New perspectives of valproic acid in clinical practice, Expert Opin Investig Drugs, 22, 12, 1535–1547, 2013, 24160174, 10.1517/13543784.2013.853037,

Adverse effects

{{See also|List of adverse effects of valproic acid|List of adverse effects of valproate semisodium}}{{Div col|colwidth=30em}}Most common adverse effects include:WEB, DEPAKOTE- divalproex sodium tablet, delayed release,weblink 10 November 2015, live,weblink" title="web.archive.org/web/20160305202922weblink">weblink 5 March 2016, Serious adverse effects include: {{colend}}Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.JOURNAL, 15032379, 19, 1, Effects of valproic acid on longitudinal bone growth, Wu S, Legido A, De Luca F, J Child Neurol, 26–30, 2004, 10.1177/088307380401900105011, JOURNAL, 2013195, 3126792, 69, 1, Inhibition of cartilage growth by the anticonvulsant drugs diphenylhydantoin and sodium valproate, Robinson PB, Harvey W, Belal MS, Br J Exp Pathol, 17–22, 1988, JOURNAL, 10.1046/j.1528-1157.2001.416800.x, 11580761, 42, 9, Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy, Guo CY, Ronen GM, Atkinson SA, Epilepsia, 1141–7, 2002, JOURNAL, 11580761, 42, 9, Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy, Guo CY, Ronen GM, Atkinson SA, Epilepsia, 1141–7, 10.1046/j.1528-1157.2001.416800.x, 2002, Valproic acid can also cause mydriasis, a dilation of the pupils.WEB,weblink Could Depakote cause Mydriasis, eHealthMe.com, 2014-11-18, 2015-04-24, live,weblink" title="web.archive.org/web/20141205082551weblink">weblink 2014-12-05, There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder.JOURNAL, Polycystic ovary syndrome in women using valproate: a review, Bilo, Leonilda, October 2008, Gynecological Endocrinology, 10.1080/09513590802288259, 19012099, Meo, Roberta, 24, 10, 562–70, Weight gain is also possible.JOURNAL, Chukwu, J, Delanty, N, Webb, D, Cavalleri, GL, Weight change, genetics and antiepileptic drugs, Expert Review of Clinical Pharmacology, January 2014, 7, 1, 43–51, 10.1586/17512433.2014.857599, 24308788,

Pregnancy

Valproate causes birth defects;New evidence in France of harm from epilepsy drug valproate {{webarchive|url=https://web.archive.org/web/20170421023357weblink |date=2017-04-21 }} BBC, 2017 exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug.JOURNAL, Koch S, Göpfert-Geyer I, Jäger-Roman E, etal, [Anti-epileptic agents during pregnancy. A prospective study on the course of pregnancy, malformations and child development], German, Dtsch. Med. Wochenschr., 108, 7, 250–7, February 1983, 6402356, 10.1055/s-2008-1069536, JOURNAL, Moore SJ, Turnpenny P, Quinn A, etal, A clinical study of 57 children with fetal anticonvulsant syndromes, J. Med. Genet., 37, 7, 489–97, July 2000, 10882750, 10.1136/jmg.37.7.489, 1734633, More rarely, with several other defects, including a "valproate syndrome".JOURNAL, Ornoy A, Valproic acid in pregnancy: how much are we endangering the embryo and fetus?, Reprod. Toxicol., 28, 1, 1–10, 2009, 19490988, 10.1016/j.reprotox.2009.02.014, Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.JOURNAL, Kulkarni ML, Zaheeruddin M, Shenoy N, Vani HN, Fetal valproate syndrome, Indian J Pediatr, 73, 10, 937–939, 2006, 17090909, 10.1007/bf02859291, While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.JOURNAL, Adab N, Kini U, Vinten J, etal, The longer term outcome of children born to mothers with epilepsy, J. Neurol. Neurosurg. Psychiatry, 75, 11, 1575–83, November 2004, 15491979, 10.1136/jnnp.2003.029132,weblink This argues that the fetal valproate syndrome constitutes a real clinical entity that includes developmental delay and cognitive impairments, but that some children might exhibit some developmental delay without marked dysmorphism., 1738809, live,weblink" title="web.archive.org/web/20080906184429weblink">weblink 2008-09-06, Children of mothers taking valproate during pregnancy are at risk for lower IQs.JOURNAL, Umur AS, Selcuki M, Bursali A, Umur N, Kara B, Vatansever HS, Duransoy YK, Simultaneous folate intake may prevent adverse effect of valproic acid on neurulating nervous system, Childs Nerv Syst, 28, 5, 729–737, 2012, 22246336, 10.1007/s00381-011-1673-9, WEB,weblink NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids, Cassels, Caroline, December 8, 2006, Medscape, 2007-05-23, live,weblink" title="web.archive.org/web/20110731160315weblink">weblink July 31, 2011, JOURNAL, Meador KJ, Baker GA, Finnell RH, Kalayjian LA, Liporace JD, Loring DW, Mawer G, Pennell PB, Smith JC, Wolff MC, In utero antiepileptic drug exposure: fetal death and malformations, Neurology, 67, 3, 407–412, 2006, 16894099, 1986655, 10.1212/01.wnl.0000227919.81208.b2, Maternal valproate use during pregnancy has been associated with a significantly higher probability of autism in the offspring.JOURNAL, Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M, Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism, JAMA, 309, 16, 1696–1703, 2013, 23613074, 4511955, 10.1001/jama.2013.2270, A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.JOURNAL, Rasalam AD, Hailey H, Williams JH, etal, Characteristics of fetal anticonvulsant syndrome associated autistic disorder, Dev Med Child Neurol, 47, 8, 551–5, August 2005, 16108456, 10.1017/S0012162205001076,weblink {{Dead link|date=October 2019 |bot=InternetArchiveBot |fix-attempted=yes }} The normal incidence for autism in the general population is estimated at less than one percent.Autism Society of America: About Autism {{webarchive|url=https://web.archive.org/web/20110110092133weblink |date=2011-01-10 }} A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.I.Q. Harmed by Epilepsy Drug in Utero {{webarchive|url=https://web.archive.org/web/20151229233954weblink |date=2015-12-29 }} By RONI CARYN RABIN, New York Times, April 15, 2009JOURNAL, Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW, Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs, N. Engl. J. Med., 360, 16, 1597–1605, 2009, 19369666, 2737185, 10.1056/NEJMoa0803531, Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy) {{webarchive|url=https://web.archive.org/web/20110902085932weblink |date=2011-09-02 }}. FDA. June 2011Sodium valproate has been associated with the rare condition paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.JOURNAL, 17884759, Paroxysmal tonic upgaze of childhood with co-existent absence epilepsy, Luat, AF, 20 September 2007, Epileptic Disorders, 10.1684/epd.2007.0119, 9, 3, 332–6, 2019-09-18, JOURNAL, 3209843, Benign paroxysmal tonic upgaze of childhood, Ouvrier, RA, July 1988, Journal of Child Neurology, 10.1177/088307388800300305, 3, 3, 177–80, Women who intend to become pregnant should switch to a different medication if possible, or decrease their dose of valproate.Valproate Not To Be Used for Migraine During Pregnancy, FDA Warns {{webarchive|url=https://web.archive.org/web/20130709080004weblink |date=2013-07-09 }} Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have even worse consequences). Studies have shown that taking folic acid can reduce the risk of congenital neural tube defects. The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the EU, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.WEB,weblink New measures to avoid valproate exposure in pregnancy endorsed, 31 May 2018, European Medicines Agency, live,

Elderly

Valproate in elderly people with dementia caused increased sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake was also associated in one half of people who become sleepy.

Contraindications

Contraindications include:WEB, Valpro sodium valproate, TGA eBusiness Services, Alphapharm Pty Limited, 16 December 2013, 14 February 2014,weblink PDF,

Interactions

Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves. It may also potentiate the CNS depressant effects of alcohol. It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself. It may also interact with:JOURNAL, Serum Valproate Levels with Oral Contraceptive Use, Herzog, Andrew, June 9, 2005, Epilepsia, 10.1111/j.1528-1167.2005.00605.x, 15946343, Farina, Erin, 46, 6, 970–971,
  • Aspirin: may increase valproate concentrations. May also interfere with valproate's metabolism.
  • Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
  • Carbapenem antibiotics: reduces valproate levels, potentially leading to seizures.
  • Cimetidine: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
  • Erythromycin: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
  • Ethosuximide: may increase ethosuximide concentrations and lead to toxicity.
  • Felbamate: may increase plasma concentrations of valproate.
  • Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
  • Oral contraceptives: may reduce plasma concentrations of valproate.
  • Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure.
  • Rifampin: increases the clearance of valproate, leading to decreased valproate concentrations
  • Warfarin: may increase warfarin concentration and prolong bleeding time.
  • Zidovudine: may increase zidovudine serum concentration and lead to toxicity.
|Form|Lower limit|Upper limit|Unit Total (including protein bound)">

Overdose and toxicity{| class"wikitable" align"right"|+ Therapeutic range of valproic acid|Form|Lower limit|Upper limit|Unit Total (including protein bound)

FIRST=SUZANNEDATE=DEC 11, 2013PUBLISHER=MEDSCAPEARCHIVEURL=HTTPS://WEB.ARCHIVE.ORG/WEB/20150504030450/HTTP://EMEDICINE.MEDSCAPE.COM/ARTICLE/2090462-OVERVIEW| µg/mL or mg/lDATE=APRIL 2014ACCESSDATE=2015-06-05ARCHIVEURL=HTTPS://WEB.ARCHIVE.ORG/WEB/20160303232944/HTTPS://WWW.CADTH.CA/MEDIA/PDF/LAB-TESTS/06_FREE_VALPROIC_ACID_ASSAY_E.PDF| μmol/L Free| µg/mL or mg/l| μmol/LExcessive amounts of valproic acid can result in sleepiness, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/l during controlled therapy, but may reach 150–1500 mg/l following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.JOURNAL, Sztajnkrycer MD, Valproic acid toxicity: overview and management, J. Toxicol. Clin. Toxicol., 40, 6, 789–801, 2002, 12475192, 10.1081/CLT-120014645, In contrast to other antiepileptic drugs, at present there is little favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproate's weak acid property (pKa of 4.9).JOURNAL, Patsalos PN, Berry DJ, Therapeutic drug monitoring of antiepileptic drugs by use of saliva, Ther Drug Monit, 35, 1, 4–29, 2013, 23288091, 10.1097/FTD.0b013e31827c11e7, In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.JOURNAL, Thanacoody RH, Extracorporeal elimination in acute valproic acid poisoning, Clin Toxicol, 47, 7, 609–616, 2009, 19656009, 10.1080/15563650903167772, R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622-1626. Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored. Supplemental L-carnitine is indicated in patients having an acute overdoseJOURNAL, Lheureux PE, Penaloza A, Zahir S, Gris M, Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?, Crit Care, 9, 5, 431–440, 2005, 16277730, 1297603, 10.1186/cc3742, JOURNAL, Mock CM, Schwetschenau KH, Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy, Am J Health Syst Pharm, 69, 1, 35–39, 2012, 22180549, 10.2146/ajhp110049, and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedlyJOURNAL, Matsuoka M, Igisu H, Comparison of the effects of L-carnitine, D-carnitine and acetyl-L-carnitine on the neurotoxicity of ammonia, Biochem. Pharmacol., 46, 1, 159–164, 1993, 8347126, 10.1016/0006-2952(93)90360-9, than L-carnitine.

Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA). The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism.JOURNAL, Kay, Hee Yeon, Greene, Derek L., Kang, Seungwoo, Kosenko, Anastasia, Hoshi, Naoto, 2015-10-01, M-current preservation contributes to anticonvulsant effects of valproic acid, The Journal of Clinical Investigation, 125, 10, 3904–3914, 10.1172/JCI79727, 0021-9738, 4607138, 26348896, Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.JOURNAL, Chang P, Walker MC, Williams RS, Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid, Neurobiol. Dis., 62, 296–306, 2014, 24148856, 3898270, 10.1016/j.nbd.2013.10.017, It also has histone deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.JOURNAL, Kostrouchová M, Kostrouch Z, Kostrouchová M, Valproic acid, a molecular lead to multiple regulatory pathways, Folia Biol. (Praha), 53, 2, 37–49, 2007, 17448293,weblink live,weblink" title="web.archive.org/web/20140221230758weblink">weblink 2014-02-21, JOURNAL, Chiu CT, Wang Z, Hunsberger JG, Chuang DM, Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder, Pharmacol. Rev., 65, 1, 105–142, 2013, 23300133, 3565922, 10.1124/pr.111.005512,

Endocrine actions

Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.JOURNAL, Death AK, McGrath KC, Handelsman DJ, Valproate is an anti-androgen and anti-progestin, Steroids, 70, 14, 946–53, 2005, 16165177, 10.1016/j.steroids.2005.07.003,weblink 10453/16875, In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.BOOK, Wyllie E, Cascino GD, Gidal BE, Goodkin HP, Wyllie's Treatment of Epilepsy: Principles and Practice,weblink 17 February 2012, Lippincott Williams & Wilkins, 978-1-4511-5348-4, 288–, live,weblink" title="web.archive.org/web/20140606200832weblink">weblink 6 June 2014, These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men.JOURNAL, Uchida, Hiroshi, Maruyama, Tetsuo, Arase, Toru, Ono, Masanori, Nagashima, Takashi, Masuda, Hirotaka, Asada, Hironori, Yoshimura, Yasunori, Histone acetylation in reproductive organs: Significance of histone deacetylase inhibitors in gene transcription, Reproductive Medicine and Biology, 4, 2, 2005, 115–122, 1445-5781, 10.1111/j.1447-0578.2005.00101.x, 29662388, 5891791, JOURNAL, Isojärvi, Jouko I T, Taubøll, Erik, Herzog, Andrew G, Effect of Antiepileptic Drugs on Reproductive Endocrine Function in Individuals with Epilepsy, CNS Drugs, 19, 3, 2005, 207–223, 1172-7047, 10.2165/00023210-200519030-00003, 15740176, High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.

Pharmacokinetics

{{expand section|date=August 2017}}

Metabolism

The vast majority of valproate metabolism occurs in the liver. In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as a glucuronide conjugate. The other major pathway in the metabolism of valproate is mitochondrial beta-oxidation, which typically accounts for over 40% of an administered dose. Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.ENCYCLOPEDIA, Valproic Acid,weblink DrugBank, University of Alberta, 31 August 2017, Pharmacology, Valproate is known to be metabolized by the Cytochrome P450 enzymes: CYP2A6, CYP2B6, CYP2C9, and CYP3A5. It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes: UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15. Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include: 2-ene-valproic acid, 3Z-ene-valproic acid, 3E-ene-valproic acid, 4-ene-valproic acid, valproic acid β-O-glucuronide, 3-oxovalproic acid, 3-hydroxyvalproic acid, 4-hydroxyvalproic acid, 5-hydroxyvalproic acid, and valproyl-CoA, among others.

Chemistry

Valproic acid is a branched short-chain fatty acid and a derivative of valeric acid.

History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.JOURNAL, Burton BS, 1882, On the propyl derivatives and decomposition products of ethylacetoacetate, Am. Chem. J., 3, 385–395, Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats.JOURNAL, Meunier H, Carraz G, Neunier Y, Eymard P, Aimard M, [Pharmacodynamic properties of N-dipropylacetic acid], French, Thérapie, 18, 435–438, 1963, 13935231, Pharmacodynamic properties of N-dipropylacetic acid, It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.JOURNAL, Perucca E, Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience, CNS Drugs, 16, 10, 695–714, 2002, 12269862, 10.2165/00023210-200216100-00004, Valproic acid has also been used for migraine prophylaxis and bipolar disorder.JOURNAL, Henry TR, The history of valproate in clinical neuroscience, Psychopharmacol Bull, 37 Suppl 2, 5–16, 2003, 14624229,

Society and culture

Cost

It is available as a generic medication. The wholesale cost in the developing world is between $0.14 and $0.52 USD per day. In the European Union, end-user costs are less than 0.60 EUR for an average daily dose in Germany.Regular pharmacy price, including all taxes, et cetera: less than 34,43 EUR for 200 controlled release pills with 500mg each; date: 2016-11-30{{citation needed|date=November 2016}} In the United States, it costs about $0.90 USD per day.

Approval status{| class wikitable

! Indications! {{flagicon|USA}}FDA-labelled indication?! {{flagicon|AUS}}TGA-labelled indication?BOOK, Australian Medicines Handbook, 2013, The Australian Medicines Handbook Unit Trust, 978-0-9805790-9-3, 2013, Adelaide, Rossi, S, ! scope="col" |{{flagicon|GBR}}MHRA-labelled indication?BOOK, Joint Formulary Committee, British National Formulary (BNF), 978-0-85711-084-8, 65, London, UK, Pharmaceutical Press, 2013, ! Literature supportglioblastoma and other tumors both to improve survival and treat seizures, and against tonic-clonic seizures and status epilepticus).RIMMER EM, RICHENS A JOURNAL = PHARMACOTHERAPY ISSUE = 3 DATE = MAY–JUNE 1985 DOI = 10.1002/J.1875-9114.1985.TB03413.X, ETHOSUXIMIDE, VALPROIC ACID, AND LAMOTRIGINE IN CHILDHOOD ABSENCE EPILEPSY >JOURNAL=NEW ENGLAND JOURNAL OF MEDICINE ISSUE=9 DOI=10.1056/NEJMOA0902014 PMC = 2924476LAST1=GLAUSER LAST2=CNAAN LAST3=SHINNAR LAST4=HIRTZ LAST5=DLUGOS LAST6=MASUR LAST7=CLARK LAST8=CAPPARELLI LAST9=ADAMSON FIRST=MEIDATE=6 APRIL 2015VOLUME=84PAGES=P1.238LAST1=BERENDSENLAST2=KROONENLAST3=SEUTELAST4=SNIJDERSLAST5=BROEKMANLAST6=SPLIETLAST7=WILLEMSLAST8=ARTESILAST9=BOURSLAST10=ROBEJOURNAL=NEURO-ONCOLOGYISSUE=SUPPL_2DOI=10.1093/NEUONC/NOU174.77, 4185847, JOURNAL = INT J HEALTH CARE QUAL ASSUR ISSUE = 1 YEAR = 2012 DOI = 10.1108/09526861211192395, JOURNAL = J AFFECT DISORD ISSUE = 3 YEAR = 2010 DOI = 10.1016/J.JAD.2009.11.008, JOURNAL = EXPERT OPIN DRUG METAB TOXICOL ISSUE = 5 YEAR = 2009 DOI = 10.1517/17425250902911455, | Limited. JOURNAL = ANN PHARMACOTHER ISSUE = 3 YEAR = 2008 DOI = 10.1345/APH.1K531, LAST2=XIALAST3=HELFERLAST4=LILAST5=LEUCHTDATE=2016URL=VOLUME=11DOI=10.1002/14651858.CD004028.PUB4PMID=27884042, LAST2=NARAYANALAST3=LUXENBERGLAST4=CLIFTONDATE=2018-10-05JOURNAL=THE COCHRANE DATABASE OF SYSTEMATIC REVIEWSPAGES=CD003945ISSN=1469-493XPMC=6516950, Increased rate of adverse effects, including a risk of serious adverse effects.Fragile X syndrome > JOURNAL = PHARMACOL. REV. ISSUE = 1 YEAR = 2013 PMC = 3565922, 10.1124/pr.111.005512, Familial adenomatous polyposis >| Limited. JOURNAL = COCHRANE DATABASE SYST REV PAGES = CD009183 PMID = 21975791 DOI = 10.1002/14651858.CD009183.PUB2, JOURNAL = ALCOHOL ALCOHOL. ISSUE = 4 DATE = JULY–AUGUST 2008 DOI = 10.1093/ALCALC/AGN043,weblink JOURNAL = NEUROLOGY ISSUE = 11 YEAR = 1981 DOI = 10.1212/WNL.31.11.1458, JOURNAL = ARCH. NEUROL. ISSUE = 7 YEAR = 1982 DOI = 10.1001/ARCHNEUR.1982.00510190066025, JOURNAL = HEADACHE ISSUE = 7 DATE = JULY–AUGUST 1998 DOI = 10.1046/J.1526-4610.1998.3807547.X, West syndrome > JOURNAL = EPILEPSIA ISSUE = 5 DATE = SEPTEMBER–OCTOBER 1988 DOI = 10.1111/J.1528-1157.1988.TB03760.X, JOURNAL = RETROVIROLOGY ISSUE = 1 YEAR = 2005 PMC = 1242254 URL = HTTP://WWW.RETROVIROLOGY.COM/CONTENT/PDF/1742-4690-2-56.PDF ARCHIVEURL = HTTPS://WEB.ARCHIVE.ORG/WEB/20150924090435/HTTP://WWW.RETROVIROLOGY.COM/CONTENT/PDF/1742-4690-2-56.PDF JOURNAL = HIV MED. ISSUE = 5 YEAR = 2012 DOI = 10.1111/J.1468-1293.2011.00975.X, ARCHIN NM, CHEEMA M, PARKER D, WIEGAND A, BOSCH RJ, COFFIN JM, ERON J, COHEN M, MARGOLIS DM > TITLE = ANTIRETROVIRAL INTENSIFICATION AND VALPROIC ACID LACK SUSTAINED EFFECT ON RESIDUAL HIV-1 VIREMIA OR RESTING CD4+ CELL INFECTION VOLUME = 5 PAGES = E9390 PMID = 20186346 DOI = 10.1371/JOURNAL.PONE.0009390, 2010PLoSO...5.9390A, Myelodysplastic syndrome > JOURNAL = J PAIN SYMPTOM MANAGE ISSUE = 3 YEAR = 2001 DOI = 10.1016/S0885-3924(00)00266-9 date=October 2019 fix-attempted=yes }} as an adjunct to tretinoin and as an adjunct to hydralazine.CANDELARIA M, HERRERA A, LABARDINI J, GONZáLEZ-FIERRO A, TREJO-BECERRIL C, TAJA-CHAYEB L, PéREZ-CáRDENAS E, DE LA CRUZ-HERNáNDEZ E, ARIAS-BOFILL D, VIDAL S, CERVERA E, DUEñAS-GONZALEZ A > TITLE = HYDRALAZINE AND MAGNESIUM VALPROATE AS EPIGENETIC TREATMENT FOR MYELODYSPLASTIC SYNDROME. PRELIMINARY RESULTS OF A PHASE-II TRIAL VOLUME = 90 PAGES = 379–387 PMID = 20922525, 10.1007/s00277-010-1090-2, Acute myeloid leukaemia >tretinoin.BUG G, RITTER M, WASSMANN B, SCHOCH C, HEINZEL T, SCHWARZ K, ROMANSKI A, KRAMER OH, KAMPFMANN M, HOELZER D, NEUBAUER A, RUTHARDT M, OTTMANN OG JOURNAL = CANCER ISSUE = 12 YEAR = 2005 DOI = 10.1002/CNCR.21589, KUENDGEN A, SCHMID M, SCHLENK R, KNIPP S, HILDEBRANDT B, STEIDL C, GERMING U, HAAS R, DOHNER H, GATTERMANN N > TITLE = THE HISTONE DEACETYLASE (HDAC) INHIBITOR VALPROIC ACID AS MONOTHERAPY OR IN COMBINATION WITH ALL-TRANS RETINOIC ACID IN PATIENTS WITH ACUTE MYELOID LEUKEMIA VOLUME = 106 PAGES = 112–119 PMID = 16323176 JOURNAL = CLIN EPIGENETICS ISSUE = 1 YEAR = 2013 PMC = 3733883 URL = HTTP://WWW.CLINICALEPIGENETICSJOURNAL.COM/CONTENT/PDF/1868-7083-5-12.PDF ARCHIVEURL = HTTPS://WEB.ARCHIVE.ORG/WEB/20140221155251/HTTP://WWW.CLINICALEPIGENETICSJOURNAL.COM/CONTENT/PDF/1868-7083-5-12.PDF, 2014-02-21, Cervical cancer > JOURNAL = MED. ONCOL. PAGES = S540–6 PMID = 20931299, 10.1007/s12032-010-9700-3, Malignant melanoma > JOURNAL = BR. J. CANCER ISSUE = 1 YEAR = 2009 PMC = 2634690, 10.1038/sj.bjc.6604817, Breast cancer > JOURNAL = CLIN. CANCER RES. ISSUE = 7 YEAR = 2009 DOI = 10.1158/1078-0432.CCR-08-1930,weblink Impulse control disorder > JOURNAL = PARKINSONISM RELAT. DISORD. ISSUE = 5 YEAR = 2011 PMID = 21459656, SRIRAM A, WARD HE, HASSAN A, IYER S, FOOTE KD, RODRIGUEZ RL, MCFARLAND NR, OKUN MS > TITLE = VALPROATE AS A TREATMENT FOR DOPAMINE DYSREGULATION SYNDROME (DDS) IN PARKINSON'S DISEASE VOLUME = 260 PAGES = 521–7 DOI = 10.1007/S00415-012-6669-1, 23007193,

Off-label uses

In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.NEWS,weblink Washington Post, 27 June 2018, Abbott Laboratories to pay $1.6 billion over illegal marketing of Depakote, 7 May 2012, N. C., Aizenman, NEWS,weblink New York Times, 27 June 2018, 8 May 2012, Abbott settles marketing lawsuit, Michael, Schmidt, Katie, Thomas,

Formulations

{{Drugbox| drug_name = Sodium valproate| verifiedrevid = 464404696| IUPAC_name = sodium 2-propylpentanoate| image = Sodium-valproate-2D-skeletal.png| image2 = Valproato Sódico.png| width = 180correct|??}}| CAS_number = 1069-66-5correct|drugbank}}| DrugBank = correct|chemspider}}| ChemSpiderID = 13428correct|FDA}}| UNII = 5VOM6GYJ0Dcorrect|kegg}}| KEGG = D00710correct|EBI}}| ChEBI = 9925correct|EBI}}| ChEMBL = 433 H=15 O=2| smiles = [Na+].[O-]C(=O)C(CCC)CCCcorrect|chemspider}}| StdInChI = 1S/C8H16O2.Na/c1-3-5-7(6-4-2)8(9)10;/h7H,3-6H2,1-2H3,(H,9,10);/q;+1/p-1correct|chemspider}}| StdInChIKey = AEQFSUDEHCCHBT-UHFFFAOYSA-M}}Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.BOOK, The Maudsley Prescribing Guidelines, Tenth Edition, David Taylor, Carol Paton, Shitij Kapur, 10, revised, CRC Press, 2009, 9780203092835,weblink 124,

Brand names of valproic acid

Branded products include:{{Div col|colwidth=30em}} {{colend}}

Brand names of sodium valproate

Portugal

  • Tablets – Diplexil-R by Bial.

United States

  • Intravenous injection – Depacon by Abbott Laboratories.
  • Syrup – Depakene by Abbott Laboratories. (Note Depakene capsules are valproic acid).
  • Depakote tablets are a mixture of sodium valproate and valproic acid.
  • Tablets – Eliaxim by Bial.

Australia

  • Epilim Crushable Tablets Sanofi
  • Epilim Sugar Free Liquid Sanofi
  • Epilim Syrup Sanofi
  • Epilim Tablets Sanofi
  • Sodium Valproate Sandoz Tablets Sanofi
  • Valpro Tablets Alphapharm
  • Valproate Winthrop Tablets Sanofi
  • Valprease tablets Sigma

New Zealand

  • Epilim by Sanofi-Aventis
All the above formulations are Pharmac-subsidised.WEB,weblink Sodium valproate -- Pharmaceutical Schedule, Pharmaceutical Management Agency, 22 June 2014, live,weblink" title="web.archive.org/web/20160304081454weblink">weblink 4 March 2016,

UK

  • Depakote Tablets (as in USA)
  • Tablets – Orlept by Wockhardt and Epilim by Sanofi
  • Oral solution – Orlept Sugar Free by Wockhardt and Epilim by Sanofi
  • Syrup – Epilim by Sanofi-Aventis
  • Intravenous injection – Epilim Intravenous by Sanofi
  • Extended release tablets – Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
  • Enteric-coated tablets – Epilim EC200 by Sanofi is a 200-mg sodium valproate enteric-coated tablet.

UK only

  • Capsules – Episenta prolonged release by Beacon
  • Sachets – Episenta prolonged release by Beacon
  • Intravenous solution for injection – Episenta solution for injection by Beacon

Germany, Switzerland, Norway, Finland, Sweden

  • Tablets – Orfiril by Desitin Pharmaceuticals
  • Intravenous injection – Orfiril IV by Desitin Pharmaceuticals

South Africa

  • Syrup – Convulex by Byk Madaus
  • Tablets – Epilim by Sanofi-synthelabo

Malaysia

  • Tablets – Epilim by Sanofi-Aventis

Romania

  • Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH
  • Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets

Canada

Japan

  • Tablets – Depakene by Kyowa Hakko Kirin
  • Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa
  • Syrup – Depakene by Kyowa Hakko Kogyo

Europe

In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.

Taiwan

  • Tablets (white round tablet) – Depakine ({{zh-cp|c=帝拔癲|p=di-ba-dian}}) by Sanofi Winthrop Industrie (France)

Iran

  • Tablets –Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo
  • Slow release tablets: Depakine Chrono by Sanofi Winthrop Industrie (France)

Israel

Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.

India, Russia and CIS countries

  • Valparin Chrono by Sanofi India limited
  • Valprol CR by Intas Pharmaceutical (India)
  • Encorate Chrono by Sun Pharmaceutical (India)
  • Serven Chrono by Leeven APL Biotech (India)

Brand names of valproate semisodium

  • Brazil – Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil
  • Canada – Epival by Abbott Laboratories
  • Mexico – Epival and Epival ER (extended release) by Abbott Laboratories
  • United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics
  • United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics
  • India – Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma
  • Germany – Ergenyl Chrono by Sanofi-Aventis and generics
  • Chile – Valcote and Valcote ER by Abbott Laboratories
  • France and other European countries — Depakote
  • Peru – Divalprax by AC Farma Laboratories
  • China – Diprate OD

References

{{Reflist}}

Further reading

  • JOURNAL, Chateauvieux S, Morceau F, Dicato M, Diederich M, Molecular and therapeutic potential and toxicity of valproic acid, J. Biomed. Biotechnol., 2010, 1–18, 2010, 20798865, 2926634, 10.1155/2010/479364,
  • JOURNAL, Monti B, Polazzi E, Contestabile A, Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection, Curr Mol Pharmacol, 2, 1, 95–109, 2009, 20021450, 10.2174/1874467210902010095,weblink 2015-02-07,weblink" title="web.archive.org/web/20130627052338weblink">weblink 2013-06-27, dead,

External links

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