Biology:Valproate

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Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and as a mood stabilizer in the treatment of bipolar disorder.[1] They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.[1] They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.[1]

Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth.[1] Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.[1] Other serious risks include pancreatitis and an increased suicide risk.[1]

Valproate is known to cause serious abnormalities or birth defects in the fetus if taken during pregnancy,[1][2] and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition and the person is also prescribed a contraceptive.[1][3][4] Reproductive warnings have also been issued for men using the drug.[5]

Valproate is restricted in the United Kingdom for both women and men under age 55 due to teratogenicity in pregnant women and fertility problems in men.[6] It is also restricted in the European Union.[7][8] The United States Food and Drug Administration has indicated a black box warning given the frequency and severity of the side effects and teratogenicity.[4] Additionally, there is also a black box warning due to risk of hepatotoxicity and pancreatitis.[9]

Valproate has been in use in Japan for the prophylaxis of migraine since 2011.[10] It is approved as an antimanic and antiseizure in Japan as well.[11] In UK, valproate is approved for bipolar mania and epilepsy, and both valproate and divalproex are approved, although divalproex sodium[12] is known as valproate semisodium.[13]

Valproate's precise mechanism of action is unclear.[1][14] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, inhibiting histone deacetylases, and increasing LEF1.[15][16][17] Valproic acid is a branched short-chain fatty acid (SCFA), a derivative of valeric acid.[15]

Valproate was originally synthesized in 1881 and came into medical use in 1962.[18] It is on the World Health Organization's List of Essential Medicines.[19] It is available as a generic medication.[1] In 2023, it was the 160th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[20][21]

Medical uses

500mg tablets of Depakote extended-release

Valproate or valproic acid is used primarily to treat epilepsy and bipolar disorder.[22]

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.[22][23] It has also been successfully given intravenously to treat status epilepticus.[24][25]

In the US, valproic acid is also prescribed as an anti-epileptic drug indicated for the treatment of manic episodes associated with bipolar disorder; monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in people with multiple seizure types that include absence seizures.[4][26]

Psychiatric disorders

Valproate products are used to treat manic or mixed episodes of bipolar disorder.[27][28]

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:[29]

There is limited evidence that adding valproate to antipsychotics may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Valproate was associated with a number of adverse events among which sedation and dizziness appeared more frequently than in the control groups.[29]

Other uses

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.[30][31][32]

Valproate is not commonly used to prevent or treat migraine headaches, but it may be prescribed if other medications are not effective.[33]

The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects. It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.[34]

Contraindications

Contraindications include:

Adverse effects

Most common adverse effects include:[4]

Serious adverse effects include:[4]

Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.[4]

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[38][39][40] Valproic acid can also cause mydriasis, a dilation of the pupils.[41] 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.[42] Weight gain is also possible.[43] Valproic acid may decrease platelets in proportion to its dosage, particularly in women and the elderly.[44]

Pregnancy

This section is an excerpt from Fetal valproate spectrum disorder[ edit ]

Valproate is a teratogen.[45] Teratogens can cause birth defects. Valproate is restricted for all women under age 55 in the United Kingdom and European Union.[6] It has a black box warning for pregnancy in the United States.[46]

There are also restrictions for men. Children fathered by men taking valproate have a higher risk of neurodevelopmental disorders.[6] Valproate is restricted for men under age 55 in the United Kingdom and European Union. The restrictions require two specialists to agree that there is no other effective or tolerated treatment for the patient.[47]

Elderly

Valproate may cause increased somnolence in the elderly. In a trial of valproate in elderly patients with dementia, a significantly higher portion of valproate patients had somnolence compared to placebo. In approximately one-half of such patients, there was associated reduced nutritional intake and weight loss.[4]

Overdose and toxicity

Therapeutic range of valproic acid
Form Lower limit Upper limit Unit
Total (including
protein bound) 		50[48] 125[48] μg/mL or mg/L
350[49] 700[49] μmol/L
Free 6[48] 22[48] μg/mL or mg/L
35[49] 70[49] μmol/L

Excessive amounts of valproic acid can result in somnolence, 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.[50] 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).[51]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[52][53] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[4] Supplemental L-carnitine is indicated in patients having an acute overdose[54][55] and also prophylactically[54] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[56] than L-carnitine.

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.[35] It may also potentiate the CNS depressant effects of alcohol.[35] 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.[35] It may also interact with:[4][35][57]

  • 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: reduce 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: valproate 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.
  • Rifampicin: increases the clearance of valproate, leading to decreased valproate concentrations.
  • Warfarin: valproate may increase free warfarin concentration and prolong bleeding time.
  • Zidovudine: valproate may increase zidovudine serum concentration and lead to toxicity.

Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood,[35] traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of the inhibitory synaptic neurotransmitter gamma-aminobutyric acid (GABA).[35] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[35] In animals, sodium valproate raises cerebral and cerebellar levels of 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.[35] Prevention of neurotransmitter-induced hyperexcitability of nerve cells via Kv7.2 channel and AKAP5 may also contribute to its mechanism.[58] Valproate has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[59]

Valproate is a histone deacetylase inhibitor. By inhibition of histone deacetylase, it promotes more transcriptionally active chromatin structures, that is it exerts an epigenetic effect. This has been proven in mice: Valproic acid induced histone hyperacetylation had brain function effects on the next generation of mice through changes in sperm DNA methylation.[60] Intermediate molecules include VEGF, BDNF, and GDNF.[61][62]

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.[63] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[64] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[63][64]

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.[65][66] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.[66]

Pharmacokinetics

Some metabolites of valproic acid. Glucuronidation and β-oxidation are the main metabolic pathways; ω-oxidation metabolites are considered hepatotoxic.[67][68] Details see text.

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.[67] When in the bloodstream, 80–90% of the substance are bound to plasma proteins, mainly albumin. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patient's age, additional use of other drugs such as aspirin, as well as liver and kidney impairment.[69][70] Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.[67]

The vast majority of valproate metabolism occurs in the liver.[71] Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5.[71] It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.[71] Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):[71]

  • via glucuronidation (30–50%): valproic acid β-O-glucuronide
  • via beta oxidation (>40%): 2E-ene-valproic acid, 2Z-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
  • via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid
  • some others: 3E-ene-valproic acid, 3Z-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid

All in all, over 20 metabolites are known.[67]

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate.[71] The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose.[71] Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.[71] Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.[71] Only a small amount is excreted via the faeces.[67] Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.[67][70]

Chemistry

Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.[15]

History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[72] 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.[73] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[74] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[75]

Society and culture

Valproate is available as a generic medication.[1]

Restrictions

In 2024, for those under age 55, additional restrictions for valproate prescription have been imposed in the United Kingdom.[76] Patients under 55 can still receive valproate, but need to obtain the permission of two specialists. The restrictions are, in women, due to the potential for birth defects in children born of women of childbearing age. In men, the restrictions are due to the potential for reversible male infertility, testicular problems, and the risks of neurodevelopmental conditions in children born to men taking valproate in the 3 months before conception.[6][77] Similar restrictions have been imposed in the European Union for both women and men.[7][8][78] In February 2026, a French man, Jean-Marc Laurent, filed what has been described as the first legal complaint related to paternal exposure to valproate, alleging that his child developed neurodevelopmental disorders after he had been treated with the drug prior to conception.[79][80]

Approval status

Indications United States
FDA-labelled indication?[81] 		Australia
TGA-labelled indication?[22] 		United Kingdom
MHRA-labelled indication?[82] 		Literature support
Epilepsy Yes Yes Yes Limited (depends on the seizure type; it can help with certain kinds of seizures: drug-resistant epilepsy, partial and absence seizures, can be used against glioblastoma and other tumors both to improve survival and treat seizures, and against tonic–clonic seizures and status epilepticus).[83][84][85][86]
Bipolar mania Yes Yes Yes - Bipolar depression No No No Moderate.[88]
Bipolar maintenance No No No Limited.[89]
Migraine prophylaxis Yes Yes (accepted) No Limited.
Acute migraine management No No No Only negative results.[90]
Schizophrenia No No No Weak evidence.[91]
Agitation in dementia No No No Weak evidence. Not recommended for agitation in people with dementia.[92] Increased rate of adverse effects, including a risk of serious adverse effects.[92]
Fragile X syndrome Yes (orphan) No No Limited.[62]
Familial adenomatous polyposis Yes (orphan) No No Limited.
Chronic pain & fibromyalgia No No No Limited.[93]
Alcohol hallucinosis No No No One randomised double-blind placebo-controlled trial.[94]
Intractable hiccups No No No Limited, five case reports support its efficacy, however.[95]
Non-epileptic myoclonus No No No Limited, three case reports support its efficacy, however.[96]
Cluster headaches No No No Limited, two case reports support its efficacy.[97]
West syndrome No No No A prospective clinical trial supported its efficacy in treating infantile spasms.[98]
HIV infection eradication No No No Double-blind placebo-controlled trials have been negative.[99][100][101]
Myelodysplastic syndrome No No No Several clinical trials have confirmed its efficacy as a monotherapy,[102] as an adjunct to tretinoin[102] and as an adjunct to hydralazine.[103]
Acute myeloid leukaemia No No No Two clinical trials have confirmed its efficacy in this indication as both a monotherapy and as an adjunct to tretinoin.[104][105][106]
Cervical cancer No No No One clinical trial supports its use here.[107]
Melanoma No No No One phase II study has seemed to discount its efficacy.[108]
Breast cancer No No No A phase II study has supported its efficacy.[109]
Impulse control disorder No No No Limited.[110][111]

Off-label uses

In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.[112][113]

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.[114][115]

Formulations

Sodium valproate
Clinical data
Other namesvalproate sodium (USAN US)
License data
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC8H15NaO2
Molar mass166.196 g·mol−1
3D model (JSmol)
  (verify)
Valproate semisodium
Clinical data
Trade namesDepakote, others
Other namessemisodium valproate, divalproex sodium (USAN US)
License data
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC16H31NaO4
Molar mass310.410 g·mol−1
3D model (JSmol)
Magnesium valproate extended release and common release tablets manufactured in China

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 mass of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.[118] In Europe, the US, and many other countries three variants of valproate are sold: valproic acid, sodium valproate and valproate semisodium also known as divalproex sodium, the latter is believed to have fewer gastrointestinal side-effects.[13][119] Divalproex sodium tablets are a formulation comprising valproate sodium and valproic acid in a 1:1 molar relationship.

Magnesium valproate is also available in China.[120][121]

Terminology

Valproate is a negative ion. The conjugate acid of valproate is valproic acid (VPA). Valproic acid is fully ionized into valproate at the physiologic pH of the human body, and valproate is the active form of the drug. Sodium valproate is the sodium salt of valproic acid. Divalproex sodium is a coordination complex composed of equal parts of valproic acid and sodium valproate.[122]

Brand names of valproic acid

Branded products include:

  • Absenor (Orion Corporation Finland)
  • Convulex (G.L. Pharma GmbH Austria)
  • Depakene (Abbott Laboratories in US and Canada)[123]
  • Depakin (Sanofi S.R.L. Italy)[124]
  • Depakine (Sanofi Aventis France)
  • Depakine (Sanofi Synthelabo Romania)
  • Depalept (Sanofi Aventis Israel)
  • Deprakine (Sanofi Aventis Finland)
  • Encorate (Sun Pharmaceuticals India)
  • Epilim (Sanofi Synthelabo Australia and South Africa)
  • Stavzor (Noven Pharmaceuticals Inc.)
  • Valcote (Abbott Laboratories Argentina)
  • Valpakine (Sanofi Aventis Brazil)
  • Orfiril (Desitin Arzneimittel GmbH Norway)

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[125]
  • Epilim Sugar Free Liquid Sanofi[125]
  • Epilim Syrup Sanofi[125]
  • Epilim Tablets Sanofi[125]
  • 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.[126]

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[127]
  • Tablets – Epilim by Sanofi-synthelabo
Malaysia
  • Tablets – Epilim (200 ENTERIC COATED) by Sanofi-Aventis
  • Controlled release tablets – Epilim Chrono (500 CONTROLLED RELEASE) by Sanofi-Aventis[128]
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 (Chinese: 帝拔癲; pinyin: 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
  • Valprol CR by Intas Pharmaceutical (India)
  • Encorate Chrono by Sun Pharmaceutical (India)
  • Serven Chrono by Leeven APL Biotech (India)
Uruguay
  • Tablets – DI DPA by Megalabs

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[4]
  • 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

Research

A 2023 systematic review of the literature identified only one study in which valproate was evaluated in the treatment of seizures in infants aged 1 to 36 months. In a randomized control trial, valproate alone was found to show poorer outcomes for infants than valproate plus levetiracetam in terms of reduction of seizures, freedom from seizures, daily living ability, quality of life, and cognitive abilities.[129]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 "Valproic Acid". The American Society of Health-System Pharmacists. 24 November 2020. https://www.drugs.com/monograph/valproic-acid.html. 
  2. ↑ "Valproate banned without the pregnancy prevention programme". https://www.gov.uk/government/news/valproate-banned-without-the-pregnancy-prevention-programme. 
  3. ↑ "Drug Safety Update - Valproate medicines (Epilim, Depakote): contraindicated in women and girls of childbearing potential unless conditions of Pregnancy Prevention Programme are met". GOV.UK - Medicines and Healthcare products Regulatory Agency. 24 April 2018. https://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-contraindicated-in-women-and-girls-of-childbearing-potential-unless-conditions-of-pregnancy-prevention-programme-are-met. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 "Depakote- divalproex sodium tablet, delayed release". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08a65cf4-7749-4ceb-6895-8f4805e2b01f. 
  5. ↑ "Men on sodium valproate told to use contraception". BBC. https://www.bbc.com/news/articles/czjy8zne34xo. 
  6. ↑ 6.0 6.1 6.2 6.3 "Sodium valproate" (in en). Epilepsy Society. 2024-10-01. https://epilepsysociety.org.uk/about-epilepsy/sodium-valproate. 
  7. ↑ 7.0 7.1 "Valproate and related substances - referral" (in en). European Medicines Agency (EMA). 2013-10-11. https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances. 
  8. ↑ 8.0 8.1 "Potential risk of neurodevelopmental disorders in children born to men treated with valproate medicines: PRAC recommends precautionary measures" (in en). European Medicines Agency (EMA). 2024-01-12. https://www.ema.europa.eu/en/news/potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicines-prac-recommends-precautionary-measures. 
  9. ↑ "FDA Information on Valproate". https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018723s039lbl.pdf. 
  10. ↑ "Appendix-II". https://www.neurology-jp.org/guidelinem/ch/appendix-II.html. 
  11. ↑ "Kusuri-no-Shiori(Drug Information Sheet)" (in en). https://www.rad-ar.or.jp/siori/english/search/result?n=36129. 
  12. ↑ "Depakote® (divalproex sodium): bipolar mania & epilepsy". https://www.depakote.com/prescribing-information. 
  13. ↑ 13.0 13.1 "Sodium valproate or valproate semisodium: is there a difference in the treatment of bipolar disorder?" (in en). Psychiatric Bulletin 27 (12): 446–448. December 2003. doi:10.1192/pb.27.12.446. ISSN 0955-6036. 
  14. ↑ "Pharmacology of valproate". Psychopharmacology Bulletin 37 (Suppl 2): 17–24. 2003. PMID 14624230. 
  15. ↑ 15.0 15.1 15.2 "Valproic acid pathway: pharmacokinetics and pharmacodynamics". Pharmacogenetics and Genomics 23 (4): 236–241. April 2013. doi:10.1097/FPC.0b013e32835ea0b2. PMID 23407051. 
  16. ↑ "Valproic acid". University of Alberta. 29 July 2017. https://www.drugbank.ca/drugs/DB00313. 
  17. ↑ "Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients". Molecular Psychiatry 26 (6): 2440–2456. June 2021. doi:10.1038/s41380-020-00981-3. PMID 33398088. 
  18. ↑ The history of epileptic therapy: an account of how medication was developed (1st ed.). Carnforth u.a.: Parthenon Publ. Group. 1993. p. 131. ISBN 978-1-85070-391-4. https://books.google.com/books?id=8DlOOps7D4oC&pg=PA131. Retrieved 17 September 2017. 
  19. ↑ The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. WHO/MHP/HPS/EML/2023.02. 
  20. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  21. ↑ "Valproate Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Valproate. 
  22. ↑ 22.0 22.1 22.2 Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 978-0-9805790-9-3. 
  23. ↑ "Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy". CNS Drugs 16 (10): 669–694. 2002. doi:10.2165/00023210-200216100-00003. PMID 12269861. 
  24. ↑ "Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults". Acta Neurologica Scandinavica. Supplementum 187: 51–54. 2007. doi:10.1111/j.1600-0404.2007.00847.x. PMID 17419829. 
  25. ↑ "The role of intravenous valproate in convulsive status epilepticus in the future". Acta Neurologica Taiwanica 19 (2): 78–81. June 2010. PMID 20830628. http://www.ant-tnsjournal.com/Mag_Files/19-2/N201072314227_192edi.pdf. Retrieved 19 February 2024. 
  26. ↑ 26.0 26.1 26.2 "Depakote ER- divalproex sodium tablet, extended release". 24 February 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dc024ce-efc8-4690-7cb5-639c728fccac. 
  27. ↑ "Valproate Information". U.S. Food and Drug Administration (FDA). https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/valproate-information. 
  28. ↑ "Valproate for acute mania". The Cochrane Database of Systematic Reviews 2019 (10). October 2019. doi:10.1002/14651858.CD004052.pub2. PMID 31621892. 
  29. ↑ 29.0 29.1 "Valproate for schizophrenia". The Cochrane Database of Systematic Reviews 2016 (11). November 2016. doi:10.1002/14651858.CD004028.pub4. PMID 27884042. PMC 6734130. http://www.cochrane.org/CD004028/SCHIZ_valproate-schizophrenia. Retrieved 27 July 2017. 
  30. ↑ "Gambling disorder during dopamine replacement treatment in Parkinson's disease: a comprehensive review". BioMed Research International 2014. 2014. doi:10.1155/2014/728038. PMID 25114917. 
  31. ↑ "Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson's disease". Neurotherapeutics 11 (1): 78–91. January 2014. doi:10.1007/s13311-013-0238-x. PMID 24288035. 
  32. ↑ "Impulsive and compulsive behaviors in Parkinson's disease". Annual Review of Clinical Psychology 10: 553–580. 2014. doi:10.1146/annurev-clinpsy-032813-153705. PMID 24313567. 
  33. ↑ "Valproic acid: medicine used for bipolar disorder, epilepsy and migraine" (in en). 2018-09-27. https://www.nhs.uk/medicines/valproic-acid/#:~:text=Valproic%20acid%20is%20not%20used,cannot%20take%20other%20migraine%20medicines.. 
  34. ↑ "Hidden pharmacological activities of valproic acid: A new insight". Biomedicine & Pharmacotherapy 142. October 2021. doi:10.1016/j.biopha.2021.112021. PMID 34463268. 
  35. ↑ 35.00 35.01 35.02 35.03 35.04 35.05 35.06 35.07 35.08 35.09 35.10 35.11 35.12 35.13 35.14 "Valpro sodium valproate" (PDF). Alphapharm Pty Limited. 16 December 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04603-3. 
  36. ↑ "Update on MHRA review into safe use of valproate". 12 December 2022. https://www.gov.uk/government/news/update-on-mhra-review-into-safe-use-of-valproate?fbclid=IwY2xjawF6F3lleHRuA2FlbQIxMAABHSvvOkoGJkhJcVc7C93-lU9ObahoqP1-B6adTob8Whm-4Y3-gTRmSj7R_w_aem_DgIac_yDNVfiatTQ6ckgaQ. 
  37. ↑ "Depakote 250mg Tablets - Summary of Product Characteristics". Sanofi. 28 November 2013. http://www.medicines.org.uk/emc/medicine/25929/SPC/Depakote+250mg+Tablets/. 
  38. ↑ "Effects of valproic acid on longitudinal bone growth". Journal of Child Neurology 19 (1): 26–30. January 2004. doi:10.1177/088307380401900105011. PMID 15032379. 
  39. ↑ "Inhibition of cartilage growth by the anticonvulsant drugs diphenylhydantoin and sodium valproate". British Journal of Experimental Pathology 69 (1): 17–22. February 1988. PMID 3126792. 
  40. ↑ "Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy". Epilepsia 42 (9): 1141–1147. September 2001. doi:10.1046/j.1528-1157.2001.416800.x. PMID 11580761. 
  41. ↑ "Could Depakote cause Mydriasis". eHealthMe.com. 18 November 2014. http://www.ehealthme.com/ds/depakote/mydriasis. 
  42. ↑ "Polycystic ovary syndrome in women using valproate: a review". Gynecological Endocrinology 24 (10): 562–570. October 2008. doi:10.1080/09513590802288259. PMID 19012099. 
  43. ↑ "Weight change, genetics and antiepileptic drugs". Expert Review of Clinical Pharmacology 7 (1): 43–51. January 2014. doi:10.1586/17512433.2014.857599. PMID 24308788. 
  44. ↑ "The Risk of Thrombocytopenia During Valproic Acid Therapy: A Critical Summary of Available Clinical Data". Drugs in R&D 18 (1): 1–5. March 2018. doi:10.1007/s40268-017-0224-6. PMID 29260458. 
  45. ↑ "Valproate Teratogenicity: A Moving Target". Obstetrics and Gynecology 140 (3): 408–411. September 2022. doi:10.1097/AOG.0000000000004893. PMID 35926210. 
  46. ↑ "Prenatal Exposure to Valproic Acid Across Various Indications for Use". JAMA Network Open 7 (5): e2412680. May 2024. doi:10.1001/jamanetworkopen.2024.12680. PMID 38776082. 
  47. ↑ "Valproate (Belvo, Convulex, Depakote, Dyzantil, Epilim, Epilim Chrono or Chronosphere, Episenta, Epival, and Syonell▼): review by two specialists is required for initiating valproate but not for male patients already taking valproate" (in en). https://www.gov.uk/drug-safety-update/valproate-belvo-convulex-depakote-dyzantil-epilim-epilim-chrono-or-chronosphere-episenta-epival-and-syonellv-review-by-two-specialists-is-required-for-initiating-valproate-but-not-for-male-patients-already-taking-valproate. 
  48. ↑ 48.0 48.1 48.2 48.3 "Valproic Acid Level". Medscape. 11 December 2013. http://emedicine.medscape.com/article/2090462-overview. 
  49. ↑ 49.0 49.1 49.2 49.3 "Free Valproic Acid Assay (Reference – 2013.03.006) Notice of Assessment". Canadian Agency for Drugs and Technologies in Health (CADTH) with INESSS's permission. April 2014. https://www.cadth.ca/media/pdf/lab-tests/06_Free_Valproic_Acid_Assay_e.pdf. 
  50. ↑ "Valproic acid toxicity: overview and management". Journal of Toxicology. Clinical Toxicology 40 (6): 789–801. 2002. doi:10.1081/CLT-120014645. PMID 12475192. 
  51. ↑ "Therapeutic drug monitoring of antiepileptic drugs by use of saliva". Therapeutic Drug Monitoring 35 (1): 4–29. February 2013. doi:10.1097/FTD.0b013e31827c11e7. PMID 23288091. 
  52. ↑ "Extracorporeal elimination in acute valproic acid poisoning". Clinical Toxicology 47 (7): 609–616. August 2009. doi:10.1080/15563650903167772. PMID 19656009. 
  53. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622–1626.
  54. ↑ 54.0 54.1 "Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?". Critical Care 9 (5): 431–440. October 2005. doi:10.1186/cc3742. PMID 16277730. 
  55. ↑ "Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy". American Journal of Health-System Pharmacy 69 (1): 35–39. January 2012. doi:10.2146/ajhp110049. PMID 22180549. 
  56. ↑ "Comparison of the effects of L-carnitine, D-carnitine and acetyl-L-carnitine on the neurotoxicity of ammonia". Biochemical Pharmacology 46 (1): 159–164. July 1993. doi:10.1016/0006-2952(93)90360-9. PMID 8347126. 
  57. ↑ "Serum valproate levels with oral contraceptive use". Epilepsia 46 (6): 970–971. June 2005. doi:10.1111/j.1528-1167.2005.00605.x. PMID 15946343. 
  58. ↑ "M-current preservation contributes to anticonvulsant effects of valproic acid". The Journal of Clinical Investigation 125 (10): 3904–3914. October 2015. doi:10.1172/JCI79727. PMID 26348896. 
  59. ↑ "Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid". Neurobiology of Disease 62: 296–306. February 2014. doi:10.1016/j.nbd.2013.10.017. PMID 24148856. 
  60. ↑ "Testicular histone hyperacetylation in mice by valproic acid administration affects the next generation by changes in sperm DNA methylation". PLOS ONE 18 (3). 3 September 2023. doi:10.1371/journal.pone.0282898. PMID 36893188. Bibcode: 2023PLoSO..1882898S. 
  61. ↑ "Valproic acid, a molecular lead to multiple regulatory pathways". Folia Biologica 53 (2): 37–49. 2007. doi:10.14712/fb2007053020037. PMID 17448293. http://fb.cuni.cz/Data/files/folia_biologica/volume_53_2007_2/FB2007A0007.pdf. Retrieved 13 February 2014. 
  62. ↑ 62.0 62.1 "Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder". Pharmacological Reviews 65 (1): 105–142. January 2013. doi:10.1124/pr.111.005512. PMID 23300133. 
  63. ↑ 63.0 63.1 "Valproate is an anti-androgen and anti-progestin". Steroids 70 (14): 946–953. December 2005. doi:10.1016/j.steroids.2005.07.003. PMID 16165177. 
  64. ↑ 64.0 64.1 Wyllie's Treatment of Epilepsy: Principles and Practice. Lippincott Williams & Wilkins. 17 February 2012. pp. 288–. ISBN 978-1-4511-5348-4. https://books.google.com/books?id=j9t6Qg0kkuUC&pg=PA288-IA37. 
  65. ↑ "Histone acetylation in reproductive organs: Significance of histone deacetylase inhibitors in gene transcription". Reproductive Medicine and Biology 4 (2): 115–122. June 2005. doi:10.1111/j.1447-0578.2005.00101.x. PMID 29662388. 
  66. ↑ 66.0 66.1 "Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy". CNS Drugs 19 (3): 207–223. 2005. doi:10.2165/00023210-200519030-00003. PMID 15740176. 
  67. ↑ 67.0 67.1 67.2 67.3 67.4 67.5 (in German) Austria-Codex. Vienna: Österreichischer Apothekerverlag. 2021. Depakine chrono retard 300 mg Filmtabletten. 
  68. ↑ "Disposition of valproic acid in maternal, fetal, and newborn sheep. II: metabolism and renal elimination". Drug Metabolism and Disposition 28 (7): 857–864. July 2000. doi:10.1016/S0090-9556(24)15356-1. PMID 10859160. 
  69. ↑ (in de) Angewandte Arzneimitteltherapie. Springer. 2001. pp. 28–29. ISBN 3-540-41356-1. 
  70. ↑ 70.0 70.1 Valproate FDA Professional Drug Information. Accessed 6 August 2021.
  71. ↑ 71.0 71.1 71.2 71.3 71.4 71.5 71.6 71.7 "Valproic Acid". DrugBank. University of Alberta. 31 August 2017. https://www.drugbank.ca/drugs/DB00313#pharmacology. 
  72. ↑ "On the propyl derivatives and decomposition products of ethylacetoacetate". Am. Chem. J. 3: 385–395. 1882. 
  73. ↑ "[Pharmacodynamic properties of N-dipropylacetic acid]" (in fr). Therapie 18: 435–438. 1963. PMID 13935231. 
  74. ↑ "Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience". CNS Drugs 16 (10): 695–714. 2002. doi:10.2165/00023210-200216100-00004. PMID 12269862. 
  75. ↑ "The history of valproate in clinical neuroscience". Psychopharmacology Bulletin 37 (Suppl 2): 5–16. 2003. doi:10.64719/pb.7071. PMID 14624229. 
  76. ↑ "New valproate regulations, informed choice and seizure risk". Journal of Neurology 271 (8): 5671–5686. August 2024. doi:10.1007/s00415-024-12436-8. PMID 38896265. 
  77. ↑ "Valproate – reproductive risks" (in en). GOV.UK. 2025-09-23. https://www.gov.uk/guidance/valproate-reproductive-risks. 
  78. ↑ "Secular Trends in the Use of Valproate-Containing Medicines in Women of Childbearing Age in Europe: A Multinational DARWIN EU Network Study". Pharmacoepidemiology and Drug Safety 34 (10). October 2025. doi:10.1002/pds.70232. PMID 41099219. 
  79. ↑ "Jean-Marc Laurent, premier « papa Dépakine » à porter plainte" (in fr). Le Monde. 18 March 2026. https://www.lemonde.fr/planete/article/2026/03/18/la-culpabilite-doit-changer-de-camp-jean-marc-laurent-pere-d-une-adolescente-malade-est-le-premier-papa-depakine-a-saisir-la-justice_6672016_3244.html. 
  80. ↑ "Un premier « papa Dépakine » saisit la justice pour « mise en danger » de sa fille" (in fr). Le Quotidien du Médecin. 18 March 2026. https://www.lequotidiendumedecin.fr/actu-medicale/sante-publique/un-premier-papa-depakine-saisit-la-justice-pour-mise-en-danger-de-sa-fille. 
  81. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named MSR
  82. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. https://archive.org/details/bnf65britishnati0000unse. 
  83. ↑ "An update on sodium valproate". Pharmacotherapy 5 (3): 171–184. May–June 1985. doi:10.1002/j.1875-9114.1985.tb03413.x. PMID 3927267. 
  84. ↑ "Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy". The New England Journal of Medicine 362 (9): 790–799. March 2010. doi:10.1056/NEJMoa0902014. PMID 20200383. 
  85. ↑ "Co-Administration of Valproic Acid and Lamotrigine in the Treatment of Refractory Epilepsy (P1.238)". Neurology 84 (14 Supplement). 6 April 2015. doi:10.1212/WNL.84.14_supplement.P1.238. http://www.neurology.org/content/84/14_Supplement/P1.238. Retrieved 4 May 2015. 
  86. ↑ "O9.06 * Prognostic Relevance and Oncogenic Correlates of Epilepsy in Glioblastoma Patients". Neuro-Oncology 16 (suppl_2): ii21. 1 September 2014. doi:10.1093/neuonc/nou174.77. 
  87. ↑ "Valproate in acute mania: is our practice evidence based?". International Journal of Health Care Quality Assurance 25 (1): 41–52. 2012. doi:10.1108/09526861211192395. PMID 22455007. 
  88. ↑ "Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis". Journal of Affective Disorders 124 (3): 228–234. August 2010. doi:10.1016/j.jad.2009.11.008. PMID 20044142. 
  89. ↑ "A review of valproate in psychiatric practice". Expert Opinion on Drug Metabolism & Toxicology 5 (5): 539–551. May 2009. doi:10.1517/17425250902911455. PMID 19409030. 
  90. ↑ "Use of intravenous valproic acid for acute migraine". The Annals of Pharmacotherapy 42 (3): 403–407. March 2008. doi:10.1345/aph.1K531. PMID 18303140. 
  91. ↑ "Valproate for schizophrenia". The Cochrane Database of Systematic Reviews 2016 (11). November 2016. doi:10.1002/14651858.CD004028.pub4. PMID 27884042. 
  92. ↑ 92.0 92.1 "Valproate preparations for agitation in dementia". The Cochrane Database of Systematic Reviews 2018 (10). October 2018. doi:10.1002/14651858.CD003945.pub4. PMID 30293233. 
  93. ↑ "Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults". The Cochrane Database of Systematic Reviews 2011 (10). October 2011. doi:10.1002/14651858.CD009183.pub2. PMID 21975791. 
  94. ↑ "Valproate treatment of acute alcohol hallucinosis: a double-blind, placebo-controlled study". Alcohol and Alcoholism 43 (4): 456–459. July–August 2008. doi:10.1093/alcalc/agn043. PMID 18495806. 
  95. ↑ "Treatment of intractable hiccups with valproic acid". Neurology 31 (11): 1458–1460. November 1981. doi:10.1212/WNL.31.11.1458. PMID 6796902. 
  96. ↑ "Valproic acid in the treatment of nonepileptic myoclonus". Archives of Neurology 39 (7): 448–449. July 1982. doi:10.1001/archneur.1982.00510190066025. PMID 6808975. 
  97. ↑ "Significance of migrainous features in cluster headache: divalproex responsiveness". Headache 38 (7): 547–551. July–August 1998. doi:10.1046/j.1526-4610.1998.3807547.x. PMID 15613172. 
  98. ↑ "Therapy of infantile spasms with valproate: results of a prospective study". Epilepsia 29 (5): 553–560. September–October 1988. doi:10.1111/j.1528-1157.1988.tb03760.x. PMID 2842127. 
  99. ↑ "Valproic acid and HIV-1 latency: beyond the sound bite". Retrovirology 2 (1). September 2005. doi:10.1186/1742-4690-2-56. PMID 16168066. 
  100. ↑ "Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study". HIV Medicine 13 (5): 291–296. May 2012. doi:10.1111/j.1468-1293.2011.00975.x. PMID 22276680. 
  101. ↑ "Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection". PLOS ONE 5 (2). February 2010. doi:10.1371/journal.pone.0009390. PMID 20186346. Bibcode: 2010PLoSO...5.9390A. 
  102. ↑ 102.0 102.1 "A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain". Journal of Pain and Symptom Management 21 (3): 204–209. March 2001. doi:10.1016/S0885-3924(00)00266-9. PMID 11239739. 
  103. ↑ "Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial". Annals of Hematology 90 (4): 379–387. April 2011. doi:10.1007/s00277-010-1090-2. PMID 20922525. 
  104. ↑ "Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia". Cancer 104 (12): 2717–2725. December 2005. doi:10.1002/cncr.21589. PMID 16294345. 
  105. ↑ "The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia". Cancer 106 (1): 112–119. January 2006. doi:10.1002/cncr.21552. PMID 16323176. 
  106. ↑ "Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents". Clinical Epigenetics 5 (1). July 2013. doi:10.1186/1868-7083-5-12. PMID 23898968. 
  107. ↑ "A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results". Medical Oncology 28 (Suppl 1): S540–S546. December 2011. doi:10.1007/s12032-010-9700-3. PMID 20931299. 
  108. ↑ "A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma". British Journal of Cancer 100 (1): 28–36. January 2009. doi:10.1038/sj.bjc.6604817. PMID 19127265. 
  109. ↑ "Clinical and biological effects of valproic acid as a histone deacetylase inhibitor on tumor and surrogate tissues: phase I/II trial of valproic acid and epirubicin/FEC". Clinical Cancer Research 15 (7): 2488–2496. April 2009. doi:10.1158/1078-0432.CCR-08-1930. PMID 19318486. 
  110. ↑ "Valproate for the treatment of medication-induced impulse-control disorders in three patients with Parkinson's disease". Parkinsonism & Related Disorders 17 (5): 379–381. June 2011. doi:10.1016/j.parkreldis.2011.03.003. PMID 21459656. 
  111. ↑ "Valproate as a treatment for dopamine dysregulation syndrome (DDS) in Parkinson's disease". Journal of Neurology 260 (2): 521–527. February 2013. doi:10.1007/s00415-012-6669-1. PMID 23007193. 
  112. ↑ "Abbott Laboratories to pay $1.6 billion over illegal marketing of Depakote". Washington Post. 7 May 2012. https://www.washingtonpost.com/national/health-science/abbott-laboratories-agrees-to-16-billion-settlement-over-marketing-of-depakote/2012/05/07/gIQAh5098T_story.html. 
  113. ↑ "Abbott settles marketing lawsuit". 8 May 2012. https://www.nytimes.com/2012/05/08/business/abbott-to-pay-1-6-billion-over-illegal-marketing.html. 
  114. ↑ "Valproate reopens critical-period learning of absolute pitch". Frontiers in Systems Neuroscience 7: 102. 2013. doi:10.3389/fnsys.2013.00102. PMID 24348349. 
  115. ↑ "Learning drugs reawaken grown-up brain's inner child". New Scientist Ltd.. https://www.newscientist.com/article/dn24831-learning-drugs-reawaken-grown-up-brains-inner-child/. 
  116. ↑ "Valproate sodium injection". 1 January 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bcf57b31-4811-4104-82b3-46fb91a53ee0. 
  117. ↑ "Valproate sodium injection, solution". 29 April 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c572ece7-03d3-4c2a-aeb5-61f2023b28ea. 
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  119. ↑ "Efficacy, Safety, and Retention Rate of Extended-Release Divalproex Versus Conventional Delayed-Release Divalproex: A Meta-Analysis of Controlled Clinical Trials" (in English). Frontiers in Pharmacology 13. 2022-04-05. doi:10.3389/fphar.2022.811017. PMID 35479307. 
  120. ↑ "丙戊酸镁片（湖南湘中）". 丁香园·用药助手. https://drugs.dxy.cn/pc/drug/DkKGkIFX1S864petr70Ykg==. 
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  122. ↑ Martindale: The Complete Drug Reference. London: Pharmaceutical Press. https://www.medicinescomplete.com/mc/martindale/current/ms-10447-z.htm. Retrieved 3 March 2018. 
  123. ↑ "Depakene- valproic acid capsule, liquid filled". 19 September 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a0288919-75bf-4752-975f-40579572c0f7. 
  124. ↑ "Depakin - Banca Dati Farmaci dell'AIFA" (in it). Italian Medicines Agency. 6 June 2023. https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/farmaco?farmaco=022483. 
  125. ↑ 125.0 125.1 125.2 125.3 "Australian product information epilim (sodium valproate) crushable tablets, enteric-coated tablets, syrup, liquid" (PDF). 15 April 2020. http://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05620-3. 
  126. ↑ "Sodium valproate -- Pharmaceutical Schedule". Pharmaceutical Management Agency. http://www.pharmac.govt.nz/Schedule?osq=Sodium%20valproate. 
  127. ↑ "South African Electronic Package Inserts: Convulex". http://home.intekom.com/pharm/byk/convulex.html. 
  128. ↑ "Malaysian Package Inserts: Epilim". https://www.sanofi.com.my/en/products/epilim. 
  129. ↑ (in en) Management of Infantile Epilepsies (Report). Rockville (MD): Agency for Healthcare Research and Quality (US). October 2022. doi:10.23970/ahrqepccer252. Report No.: 22(23)-EHC004 Report No.: 2021-SR-01. PMID 36383706. https://effectivehealthcare.ahrq.gov/products/management-infantile-epilepsy/research. Retrieved 12 July 2023. 



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