Valproate

Valproate or valproic acid is used primarily to treat epilepsy and bipolar disorder. It has also been successfully given intravenously to treat status epilepticus. 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. Psychiatric disorders Valproate products are used to treat manic or mixed episodes of bipolar disorder. A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia: 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. Valproate is not commonly used to prevent or treat migraine headaches, but it may be prescribed if other medications are not effective. 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. ==Contraindications==

Contraindications include: • Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related. • Pregnancy 11% risk of birth defects and 30-40% risk of neuro-developmental disabilities which can be permanent • Known hypersensitivity to valproate or any of the ingredients used in the preparation ==Adverse effects==

Most common adverse effects include: • Nausea (22%) • Drowsiness (19%) • Dizziness (12%) • Vomiting (12%) • Weakness (10%) Serious adverse effects include: Valproic acid can also cause mydriasis, a dilation of the pupils. 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. Weight gain is also possible. Valproic acid may decrease platelets in proportion to its dosage, particularly in women and the elderly. Pregnancy Valproate is a teratogen. Teratogens can cause birth defects. Valproate is restricted for all women under age 55 in the United Kingdom and European Union. There are also restrictions for men. Children fathered by men taking valproate have a higher risk of neurodevelopmental disorders. 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. ==Overdose and toxicity==

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. 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). In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored. and also prophylactically 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. • 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, Valproate has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism. 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. Intermediate molecules include VEGF, BDNF, and GDNF. 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. In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations. These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment. High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid. Details see text. Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut. Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations. Only a small amount is excreted via the faeces. Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers. ==Chemistry==

Valproic acid is a branched short-chain fatty acid and the 2-n-propyl 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. 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. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder. ==Society and culture==

Valproate is available as a generic medication. 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. Similar restrictions have been imposed in the European Union for both women and men. 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. Approval status 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. Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language. Formulations 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. 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. 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. 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. 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) • Depakin (Sanofi S.R.L. Italy) • 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 • Epilim Sugar Free Liquid Sanofi 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 (200 ENTERIC COATED) by Sanofi-Aventis • Controlled release tablets Epilim Chrono (500 CONTROLLED RELEASE) 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 • Intravenous injection Epival or Epiject by Abbott Laboratories. • Syrup Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic. 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 () 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 • 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. == References ==