Valproate

File:Depakote 500mg ER.jpg

Valproate or valproic acid is used primarily to treat epilepsy and bipolar disorder and to prevent migraine headaches.

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.{{cite journal | vauthors = Löscher W | title = Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy | journal = CNS Drugs | volume = 16 | issue = 10 | pages = 669–694 | year = 2002 | pmid = 12269861 | doi = 10.2165/00023210-200216100-00003 | s2cid = 67999301 }} It has also been successfully given intravenously to treat status epilepticus.{{cite journal | vauthors = Olsen KB, Taubøll E, Gjerstad L | title = Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults | journal = Acta Neurologica Scandinavica. Supplementum | volume = 187 | pages = 51–54 | year = 2007 | pmid = 17419829 | doi = 10.1111/j.1600-0404.2007.00847.x | s2cid = 11159645 }}{{cite journal | vauthors = Kwan SY | title = The role of intravenous valproate in convulsive status epilepticus in the future | journal = Acta Neurologica Taiwanica | volume = 19 | issue = 2 | pages = 78–81 | date = June 2010 | pmid = 20830628 | url = http://www.ant-tnsjournal.com/Mag_Files/19-2/N201072314227_192edi.pdf | department = Editorial | access-date = 19 February 2024 | archive-date = 19 February 2024 | archive-url = https://web.archive.org/web/20240219233048/http://www.ant-tnsjournal.com/Mag_Files/19-2/N201072314227_192edi.pdf | url-status = live }}

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.{{cite web | title=Depakote ER- divalproex sodium tablet, extended release | website=DailyMed | date=24 February 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dc024ce-efc8-4690-7cb5-639c728fccac | access-date=19 February 2024 | archive-date=28 January 2023 | archive-url=https://web.archive.org/web/20230128143053/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dc024ce-efc8-4690-7cb5-639c728fccac | url-status=live }}

Valproate products are used to treat manic or mixed episodes of bipolar disorder.{{cite web |url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/valproate-information |title=Valproate Information |publisher=U.S. Food and Drug Administration (FDA) |access-date=24 April 2015 |url-status=dead |archive-url=https://web.archive.org/web/20150503091048/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm192645.htm |archive-date=3 May 2015 }}{{cite journal | vauthors = Jochim J, Rifkin-Zybutz RP, Geddes J, Cipriani A | title = Valproate for acute mania | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 10 | pages = CD004052 | date = October 2019 | pmid = 31621892 | pmc = 6797024 | doi = 10.1002/14651858.CD004052.pub2 }}

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:{{cite journal | vauthors = Wang Y, Xia J, Helfer B, Li C, Leucht S | title = Valproate for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 11 | pages = CD004028 | date = November 2016 | pmid = 27884042 | pmc = 6734130 | doi = 10.1002/14651858.CD004028.pub4 | url = http://www.cochrane.org/CD004028/SCHIZ_valproate-schizophrenia | url-status = dead | access-date = 27 July 2017 | archive-url = https://web.archive.org/web/20170729002449/http://www.cochrane.org/CD004028/SCHIZ_valproate-schizophrenia | archive-date = 29 July 2017 }}

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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.{{cite journal | vauthors = Pirritano D, Plastino M, Bosco D, Gallelli L, Siniscalchi A, De Sarro G | title = Gambling disorder during dopamine replacement treatment in Parkinson's disease: a comprehensive review | journal = BioMed Research International | volume = 2014 | pages = 728038 | year = 2014 | pmid = 25114917 | pmc = 4119624 | doi = 10.1155/2014/728038 | doi-access = free }}{{cite journal | vauthors = Connolly B, Fox SH | title = Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson's disease | journal = Neurotherapeutics | volume = 11 | issue = 1 | pages = 78–91 | date = January 2014 | pmid = 24288035 | pmc = 3899484 | doi = 10.1007/s13311-013-0238-x }}{{cite journal | vauthors = Averbeck BB, O'Sullivan SS, Djamshidian A | title = Impulsive and compulsive behaviors in Parkinson's disease | journal = Annual Review of Clinical Psychology | volume = 10 | pages = 553–580 | year = 2014 | pmid = 24313567 | pmc = 4197852 | doi = 10.1146/annurev-clinpsy-032813-153705 }}

Valproate is not commonly used to prevent or treat migraine headaches, but it may be prescribed if other medications are not effective.{{Cite web |date=2018-09-27 |title=Valproic acid: medicine used for bipolar disorder, epilepsy and migraine |url=https://www.nhs.uk/medicines/valproic-acid/#:~:text=Valproic%20acid%20is%20not%20used,cannot%20take%20other%20migraine%20medicines. |access-date=2024-11-20 |website=nhs.uk |language=en}}

The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects.{{Citation needed|date=November 2024}} It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.{{cite journal | vauthors = Singh D, Gupta S, Verma I, Morsy MA, Nair AB, Ahmed AF | title = Hidden pharmacological activities of valproic acid: A new insight | journal = Biomedicine & Pharmacotherapy | volume = 142 | pages = 112021 | date = October 2021 | pmid = 34463268 | doi = 10.1016/j.biopha.2021.112021 | doi-access = free }}

Contraindications include:

• Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.{{cite web|title=Valpro sodium valproate|website=TGA eBusiness Services|publisher=Alphapharm Pty Limited|date=16 December 2013|access-date=14 February 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04603-3|format=PDF|archive-date=27 August 2021|archive-url=https://web.archive.org/web/20210827175359/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent=&id=CP-2010-PI-04603-3|url-status=live}}
• Pregnancy 11% risk of birth defects and 30-40% risk of neuro-developmental disabilities which can be permanent{{cite web|title=Update on MHRA review into safe use of valproate|website=gov.uk/ Compendium|date=12 December 2022|url=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}}
• Known hypersensitivity to valproate or any of the ingredients used in the preparation
• Urea cycle disorders
• Hepatic porphyria
• Hepatotoxicity
• Mitochondrial disease
• Pancreatitis
• Porphyria{{cite web|title=Depakote 250mg Tablets - Summary of Product Characteristics|website=electronic Medicines Compendium|publisher=Sanofi|date=28 November 2013|access-date=18 January 2014|url=http://www.medicines.org.uk/emc/medicine/25929/SPC/Depakote+250mg+Tablets/|url-status=live|archive-url=https://web.archive.org/web/20140201115858/http://www.medicines.org.uk/emc/medicine/25929/SPC/Depakote+250mg+Tablets/|archive-date=1 February 2014}}

{{See also|List of adverse effects of valproate|List of adverse effects of valproate semisodium}}

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Most common adverse effects include:{{cite web|title=Depakote- divalproex sodium tablet, delayed release|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08a65cf4-7749-4ceb-6895-8f4805e2b01f |access-date=10 November 2015|url-status=live|archive-url=https://web.archive.org/web/20160305202922/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08a65cf4-7749-4ceb-6895-8f4805e2b01f|archive-date=5 March 2016}}

• Nausea (22%)
• Drowsiness (19%)
• Dizziness (12%)
• Vomiting (12%)
• Weakness (10%)

Serious adverse effects include:

• Bleeding
• Low blood platelets
• Encephalopathy
• Suicidal behavior and thoughts
• Low body temperature

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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.{{cite journal | vauthors = Wu S, Legido A, De Luca F | title = Effects of valproic acid on longitudinal bone growth | journal = Journal of Child Neurology | volume = 19 | issue = 1 | pages = 26–30 | date = January 2004 | pmid = 15032379 | doi = 10.1177/088307380401900105011 | s2cid = 19827846 }}{{cite journal | vauthors = Robinson PB, Harvey W, Belal MS | title = Inhibition of cartilage growth by the anticonvulsant drugs diphenylhydantoin and sodium valproate | journal = British Journal of Experimental Pathology | volume = 69 | issue = 1 | pages = 17–22 | date = February 1988 | pmid = 3126792 | pmc = 2013195 }}{{cite journal | vauthors = Guo CY, Ronen GM, Atkinson SA | title = Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy | journal = Epilepsia | volume = 42 | issue = 9 | pages = 1141–1147 | date = September 2001 | pmid = 11580761 | doi = 10.1046/j.1528-1157.2001.416800.x | s2cid = 25499280 }} Valproic acid can also cause mydriasis, a dilation of the pupils.{{cite web |url=http://www.ehealthme.com/ds/depakote/mydriasis |title=Could Depakote cause Mydriasis |publisher=eHealthMe.com |date=18 November 2014 |access-date=24 April 2015 |url-status=dead |archive-url=https://web.archive.org/web/20141205082551/http://www.ehealthme.com/ds/depakote/mydriasis |archive-date=5 December 2014 }} 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.{{cite journal | vauthors = Bilo L, Meo R | title = Polycystic ovary syndrome in women using valproate: a review | journal = Gynecological Endocrinology | volume = 24 | issue = 10 | pages = 562–570 | date = October 2008 | pmid = 19012099 | doi = 10.1080/09513590802288259 | s2cid = 36426338 }} Weight gain is also possible.{{cite journal | vauthors = Chukwu J, Delanty N, Webb D, Cavalleri GL | title = Weight change, genetics and antiepileptic drugs | journal = Expert Review of Clinical Pharmacology | volume = 7 | issue = 1 | pages = 43–51 | date = January 2014 | pmid = 24308788 | doi = 10.1586/17512433.2014.857599 | s2cid = 33444886 }}

{{excerpt|Fetal valproate spectrum disorder}}

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.

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.{{cite journal | vauthors = Sztajnkrycer MD | title = Valproic acid toxicity: overview and management | journal = Journal of Toxicology. Clinical Toxicology | volume = 40 | issue = 6 | pages = 789–801 | year = 2002 | pmid = 12475192 | doi = 10.1081/CLT-120014645 | s2cid = 23031095 }}

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).{{cite journal | vauthors = Patsalos PN, Berry DJ | title = Therapeutic drug monitoring of antiepileptic drugs by use of saliva | journal = Therapeutic Drug Monitoring | volume = 35 | issue = 1 | pages = 4–29 | date = February 2013 | pmid = 23288091 | doi = 10.1097/FTD.0b013e31827c11e7 | s2cid = 15338188 }}

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.{{cite journal | vauthors = Thanacoody RH | title = Extracorporeal elimination in acute valproic acid poisoning | journal = Clinical Toxicology | volume = 47 | issue = 7 | pages = 609–616 | date = August 2009 | pmid = 19656009 | doi = 10.1080/15563650903167772 | s2cid = 13592043 }}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 overdose{{cite journal | vauthors = Lheureux PE, Penaloza A, Zahir S, Gris M | title = Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? | journal = Critical Care | volume = 9 | issue = 5 | pages = 431–440 | date = October 2005 | pmid = 16277730 | pmc = 1297603 | doi = 10.1186/cc3742 | doi-access = free }}{{cite journal | vauthors = Mock CM, Schwetschenau KH | title = Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy | journal = American Journal of Health-System Pharmacy | volume = 69 | issue = 1 | pages = 35–39 | date = January 2012 | pmid = 22180549 | doi = 10.2146/ajhp110049 }} and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly{{cite journal | vauthors = Matsuoka M, Igisu H | title = Comparison of the effects of L-carnitine, D-carnitine and acetyl-L-carnitine on the neurotoxicity of ammonia | journal = Biochemical Pharmacology | volume = 46 | issue = 1 | pages = 159–164 | date = July 1993 | pmid = 8347126 | doi = 10.1016/0006-2952(93)90360-9 }} than L-carnitine.

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:{{cite journal | vauthors = Herzog AG, Farina EL, Blum AS | title = Serum valproate levels with oral contraceptive use | journal = Epilepsia | volume = 46 | issue = 6 | pages = 970–971 | date = June 2005 | pmid = 15946343 | doi = 10.1111/j.1528-1167.2005.00605.x | s2cid = 7696039 | doi-access = free }}

• 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.

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 the inhibitory synaptic neurotransmitter 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 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.{{cite journal | vauthors = Kay HY, Greene DL, Kang S, Kosenko A, Hoshi N | title = M-current preservation contributes to anticonvulsant effects of valproic acid | journal = The Journal of Clinical Investigation | volume = 125 | issue = 10 | pages = 3904–3914 | date = October 2015 | pmid = 26348896 | pmc = 4607138 | doi = 10.1172/JCI79727 }} Valproate has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.{{cite journal | vauthors = Chang P, Walker MC, Williams RS | title = Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid | journal = Neurobiology of Disease | volume = 62 | pages = 296–306 | date = February 2014 | pmid = 24148856 | pmc = 3898270 | doi = 10.1016/j.nbd.2013.10.017 }}

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.{{cite journal | vauthors = Sakai K, Hara K, Tanemura K | title = Testicular histone hyperacetylation in mice by valproic acid administration affects the next generation by changes in sperm DNA methylation | journal = PLOS ONE | volume = 18 | issue = 3 | pages = e0282898 | date = 3 September 2023 | pmid = 36893188 | pmc = 9997898 | doi = 10.1371/journal.pone.0282898 | doi-access = free | bibcode = 2023PLoSO..1882898S }} Intermediate molecules include VEGF, BDNF, and GDNF.{{cite journal | vauthors = Kostrouchová M, Kostrouch Z, Kostrouchová M | title = Valproic acid, a molecular lead to multiple regulatory pathways | journal = Folia Biologica | volume = 53 | issue = 2 | pages = 37–49 | year = 2007 | doi = 10.14712/fb2007053020037 | pmid = 17448293 | url = http://fb.cuni.cz/Data/files/folia_biologica/volume_53_2007_2/FB2007A0007.pdf | url-status = dead | access-date = 13 February 2014 | archive-url = https://web.archive.org/web/20140221230758/http://fb.cuni.cz/Data/files/folia_biologica/volume_53_2007_2/FB2007A0007.pdf | archive-date = 21 February 2014 }}{{cite journal | vauthors = Chiu CT, Wang Z, Hunsberger JG, Chuang DM | title = Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder | journal = Pharmacological Reviews | volume = 65 | issue = 1 | pages = 105–142 | date = January 2013 | pmid = 23300133 | pmc = 3565922 | doi = 10.1124/pr.111.005512 | author4-link = De-Maw Chuang }}

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.{{cite journal | vauthors = Death AK, McGrath KC, Handelsman DJ | title = Valproate is an anti-androgen and anti-progestin | journal = Steroids | volume = 70 | issue = 14 | pages = 946–953 | date = December 2005 | pmid = 16165177 | doi = 10.1016/j.steroids.2005.07.003 | s2cid = 25958985 | hdl = 10453/16875 | hdl-access = free }} In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.{{cite book|vauthors=Wyllie E, Cascino GD, Gidal BE, Goodkin HP|title=Wyllie's Treatment of Epilepsy: Principles and Practice|url=https://books.google.com/books?id=j9t6Qg0kkuUC&pg=PA288-IA37|date=17 February 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-5348-4|pages=288–|url-status=live|archive-url=https://web.archive.org/web/20140606200832/http://books.google.com/books?id=j9t6Qg0kkuUC|archive-date=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.{{cite journal | vauthors = Uchida H, Maruyama T, Arase T, Ono M, Nagashima T, Masuda H, Asada H, Yoshimura Y | title = Histone acetylation in reproductive organs: Significance of histone deacetylase inhibitors in gene transcription | journal = Reproductive Medicine and Biology | volume = 4 | issue = 2 | pages = 115–122 | date = June 2005 | pmid = 29662388 | pmc = 5891791 | doi = 10.1111/j.1447-0578.2005.00101.x }}{{cite journal | vauthors = Isojärvi JI, Taubøll E, Herzog AG | title = Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy | journal = CNS Drugs | volume = 19 | issue = 3 | pages = 207–223 | year = 2005 | pmid = 15740176 | doi = 10.2165/00023210-200519030-00003 | s2cid = 9893959 }} High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.

File:Valproic acid metabolism.svg of valproic acid. Glucuronidation and β-oxidation are the main metabolic pathways; ω-oxidation metabolites are considered hepatotoxic.{{cite book|title=Austria-Codex|veditors = Haberfeld H|at=Depakine chrono retard 300 mg Filmtabletten|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2021|language=German}}{{cite journal | vauthors = Kumar S, Wong H, Yeung SA, Riggs KW, Abbott FS, Rurak DW | title = Disposition of valproic acid in maternal, fetal, and newborn sheep. II: metabolism and renal elimination | journal = Drug Metabolism and Disposition | volume = 28 | issue = 7 | pages = 857–864 | date = July 2000 | doi = 10.1016/S0090-9556(24)15356-1 | pmid = 10859160 }} Details see text.]]

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut. 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.{{cite book|title=Angewandte Arzneimitteltherapie | veditors = Schneemann H, Young L, Koda-Kimble MA |publisher=Springer |language=de |year=2001 |isbn=3-540-41356-1 |pages=28–29}}Valproate {{Drugs.com|pro|valproate}}. Accessed 6 August 2021. Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.

The vast majority of valproate metabolism occurs in the liver. 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 (see image):

• 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.

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the 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.{{cite web | title=Valproic Acid | url=https://www.drugbank.ca/drugs/DB00313#pharmacology | work=DrugBank | publisher=University of Alberta | date=31 August 2017 | access-date=1 September 2017 | archive-date=31 July 2017 | archive-url=https://web.archive.org/web/20170731023353/https://www.drugbank.ca/drugs/DB00313#pharmacology | url-status=live }} 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.

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

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.{{cite journal | vauthors = Burton BS | year = 1882 | title = On the propyl derivatives and decomposition products of ethylacetoacetate | journal = Am. Chem. J. | volume = 3 | pages = 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.{{cite journal | vauthors = Meunier H, Carraz G, Neunier Y, Eymard P, Aimard M | title = [Pharmacodynamic properties of N-dipropylacetic acid] | language = fr | journal = Therapie | volume = 18 | pages = 435–438 | year = 1963 | pmid = 13935231 | trans-title = 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.{{cite journal | vauthors = Perucca E | title = Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience | journal = CNS Drugs | volume = 16 | issue = 10 | pages = 695–714 | year = 2002 | pmid = 12269862 | doi = 10.2165/00023210-200216100-00004 | s2cid = 803106 }} Valproic acid has also been used for migraine prophylaxis and bipolar disorder.{{cite journal | vauthors = Henry TR | title = The history of valproate in clinical neuroscience | journal = Psychopharmacology Bulletin | volume = 37 | issue = Suppl 2 | pages = 5–16 | year = 2003 | pmid = 14624229 }}

Valproate is available as a generic medication.

{{update section|date=February 2024}}

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.{{cite news|url=https://www.washingtonpost.com/national/health-science/abbott-laboratories-agrees-to-16-billion-settlement-over-marketing-of-depakote/2012/05/07/gIQAh5098T_story.html|newspaper=Washington Post|access-date=27 June 2018|title=Abbott Laboratories to pay $1.6 billion over illegal marketing of Depakote|date=7 May 2012|vauthors=Aizenman NC|archive-date=28 June 2018|archive-url=https://web.archive.org/web/20180628100610/https://www.washingtonpost.com/national/health-science/abbott-laboratories-agrees-to-16-billion-settlement-over-marketing-of-depakote/2012/05/07/gIQAh5098T_story.html|url-status=live}}{{cite news|url=https://www.nytimes.com/2012/05/08/business/abbott-to-pay-1-6-billion-over-illegal-marketing.html|website=New York Times|access-date=27 June 2018|date=8 May 2012|title=Abbott settles marketing lawsuit|vauthors=Schmidt M, Thomas K|archive-date=28 June 2018|archive-url=https://web.archive.org/web/20180628075612/https://www.nytimes.com/2012/05/08/business/abbott-to-pay-1-6-billion-over-illegal-marketing.html|url-status=live}}

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.{{cite journal | vauthors = Gervain J, Vines BW, Chen LM, Seo RJ, Hensch TK, Werker JF, Young AH | title = Valproate reopens critical-period learning of absolute pitch | journal = Frontiers in Systems Neuroscience | volume = 7 | pages = 102 | date = 2013 | pmid = 24348349 | pmc = 3848041 | doi = 10.3389/fnsys.2013.00102 | doi-access = free }}{{cite web |vauthors=Thomson H |title=Learning drugs reawaken grown-up brain's inner child |url=https://www.newscientist.com/article/dn24831-learning-drugs-reawaken-grown-up-brains-inner-child/ |website=New Scientist |publisher=New Scientist Ltd. |access-date=8 May 2021 |archive-date=8 May 2021 |archive-url=https://web.archive.org/web/20210508154258/https://www.newscientist.com/article/dn24831-learning-drugs-reawaken-grown-up-brains-inner-child/ |url-status=live }}

{{Infobox drug

| drug_name = Sodium valproate

| verifiedrevid = 464404696

| image = Sodium-valproate-2D-skeletal.png

| image_class = skin-invert-image

| width = 250

| alt =

| image2 = Valproato Sódico.png

| alt2 =

| USAN = valproate sodium

| tradename =

| DailyMedID = Valproate sodium

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 1069-66-5

| PubChem = 16760703

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DBSALT001257

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 13428

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 5VOM6GYJ0D

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00710

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 9925

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 433

| legal_US = Rx-only

| legal_US_comment = {{cite web | title=Valproate sodium injection | website=DailyMed | date=1 January 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bcf57b31-4811-4104-82b3-46fb91a53ee0 | access-date=7 October 2022 | archive-date=8 October 2022 | archive-url=https://web.archive.org/web/20221008050729/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bcf57b31-4811-4104-82b3-46fb91a53ee0 | url-status=live }}{{cite web | title=Valproate sodium injection, solution | website=DailyMed | date=29 April 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c572ece7-03d3-4c2a-aeb5-61f2023b28ea | access-date=7 October 2022 | archive-date=9 October 2022 | archive-url=https://web.archive.org/web/20221009184059/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c572ece7-03d3-4c2a-aeb5-61f2023b28ea | url-status=live }}

| IUPAC_name = sodium 2-propylpentanoate

| C=8 | H=15 | Na=1 | O=2

| SMILES = CCCC(CCC)C(=O)[O-].[Na+]

| StdInChI_Ref = {{stdinchicite|correct|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-1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = AEQFSUDEHCCHBT-UHFFFAOYSA-M

}}

{{Infobox drug

| drug_name = Valproate semisodium

| imageL = Sodium valproate.svg

| image_classL = skin-invert-image

| widthL = 250

| altL =

| imageR = 2-propylpentanoic acid 200.svg

| image_classR = skin-invert-image

| widthR = 250

| altR =

| captionLR =

| USAN = divalproex sodium

| tradename = Depakote, others

| DailyMedID = Divalproex sodium

| legal_US = Rx-only

| legal_US_comment =

| CAS_number = 76584-70-8

| PubChem = 23663956

| DrugBank = DBSALT000185

| ChemSpiderID = 48337

| UNII = 644VL95AO6

| KEGG = D00304

| ChEBI = 4667

| ChEMBL = 2105613

| synonyms = semisodium valproate

| IUPAC_name = sodium 2-propylpentanoate;2-propylpentanoic acid

| C=16 | H=31 | Na=1 | O=4

| SMILES = CCCC(CCC)C(=O)O.CCCC(CCC)C(=O)[O-].[Na+]

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/2C8H16O2.Na/c2*1-3-5-7(6-4-2)8(9)10;/h2*7H,3-6H2,1-2H3,(H,9,10);/q;;+1/p-1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = MSRILKIQRXUYCT-UHFFFAOYSA-M

}}

File:Magnesium Valproate China.jpg 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.{{cite book |title=The Maudsley Prescribing Guidelines |edition=Tenth |vauthors=Taylor D, Paton C, Kapur S |publisher=CRC Press |year=2009 |isbn=978-0-203-09283-5 |url=https://books.google.com/books?id=pbvLBQAAQBAJ&pg=PA124 |page=124 |access-date=17 September 2017 |archive-date=14 January 2023 |archive-url=https://web.archive.org/web/20230114092530/https://books.google.com/books?id=pbvLBQAAQBAJ&pg=PA124 |url-status=live }} In USA, Europe and many countrie the three variantes 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.{{cite journal | vauthors = Zhang CQ, Li HY, Wan Y, Bai XY, Gan L, Wang J, Sun HB | title = Efficacy, Safety, and Retention Rate of Extended-Release Divalproex Versus Conventional Delayed-Release Divalproex: A Meta-Analysis of Controlled Clinical Trials | language = English | journal = Frontiers in Pharmacology | volume = 13 | pages = 811017 | date = 2022-04-05 | pmid = 35479307 | doi = 10.3389/fphar.2022.811017 | doi-access = free | pmc = 9037144 }} 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.{{Cite web|title=丙戊酸镁片（湖南湘中）|url=https://drugs.dxy.cn/pc/drug/DkKGkIFX1S864petr70Ykg==|work=丁香园·用药助手|access-date=2025-03-23}}{{Cite web|title=丙戊酸镁缓释片（神泰）|url=https://drugs.dxy.cn/pc/drug/5R1pjNO2rmYyYvMYYmjGuA==|work=丁香园·用药助手|access-date=2025-03-23}}

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.{{Cite book|url=https://www.medicinescomplete.com/mc/martindale/current/ms-10447-z.htm|title=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|veditors=Brayfield A|location=London|access-date=3 March 2018|archive-date=27 August 2021|archive-url=https://web.archive.org/web/20210827175406/https://about.medicinescomplete.com/wp-content/themes/mc-marketing/assets/images/favicons-tiles/favicon.ico|url-status=live}}

Branded products include:

{{Div col|colwidth=30em}}

• Absenor (Orion Corporation Finland)
• Convulex (G.L. Pharma GmbH Austria)
• Depakene (Abbott Laboratories in US and Canada){{cite web | title=Depakene- valproic acid capsule, liquid filled | website=DailyMed | date=19 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a0288919-75bf-4752-975f-40579572c0f7 | access-date=14 April 2020 | archive-date=11 July 2020 | archive-url=https://web.archive.org/web/20200711130306/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a0288919-75bf-4752-975f-40579572c0f7 | url-status=live }}
• Depakin (Sanofi S.R.L. Italy){{Cite web |url=https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/farmaco?farmaco=022483 |title=Depakin - Banca Dati Farmaci dell'AIFA |date=6 June 2023 |access-date=6 June 2023 |website=farmaci.agenziafarmaco.gov.it |archive-url=https://web.archive.org/web/20230606001333/https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/farmaco?farmaco=022483 |archive-date=6 June 2023 |url-status=live |publisher=Italian Medicines Agency |language=it |trans-title=Depakin - The AIFA Medicines Database}}
• 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)

{{div col end}}

• Tablets{{snd}} Diplexil-R by Bial.

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

• Epilim Crushable Tablets Sanofi{{cite web | title=Australian product information epilim (sodium valproate) crushable tablets, enteric-coated tablets, syrup, liquid | website=TGA eBS | date=15 April 2020 | url=http://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05620-3 | format=PDF | access-date=15 April 2020 | archive-date=15 March 2020 | archive-url=https://web.archive.org/web/20200315112531/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05620-3 | url-status=live }}
• 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

• Epilim by Sanofi-Aventis

All the above formulations are Pharmac-subsidised.{{cite web |url= http://www.pharmac.govt.nz/Schedule?osq=Sodium%20valproate |title= Sodium valproate -- Pharmaceutical Schedule |publisher= Pharmaceutical Management Agency |access-date= 22 June 2014 |url-status= dead |archive-url= https://web.archive.org/web/20160304081454/http://www.pharmac.govt.nz/Schedule?osq=Sodium%20valproate |archive-date= 4 March 2016 }}

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

• Capsules{{snd}} Episenta prolonged release by Beacon
• Sachets{{snd}} Episenta prolonged release by Beacon
• Intravenous solution for injection{{snd}} Episenta solution for injection by Beacon

• Tablets{{snd}} Orfiril by Desitin Pharmaceuticals
• Intravenous injection{{snd}} Orfiril IV by Desitin Pharmaceuticals

• Syrup{{snd}} Convulex by Byk Madaus{{Cite web |url=http://home.intekom.com/pharm/byk/convulex.html |title=South African Electronic Package Inserts: Convulex |access-date=2 January 2006 |archive-date=12 August 2010 |archive-url=https://web.archive.org/web/20100812052527/http://home.intekom.com/pharm/byk/convulex.html |url-status=dead }}
• Tablets{{snd}} Epilim by Sanofi-synthelabo

• Tablets{{snd}} Epilim (200 ENTERIC COATED) by Sanofi-Aventis
• Controlled release tablets{{snd}} Epilim Chrono (500 CONTROLLED RELEASE) by Sanofi-Aventis{{cite web |title=Malaysian Package Inserts: Epilim |url=https://www.sanofi.com.my/en/products/epilim |access-date=5 June 2023 |archive-date=5 June 2023 |archive-url=https://web.archive.org/web/20230605142828/https://www.sanofi.com.my/en/products/epilim |url-status=live }}

• 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

• Intravenous injection{{snd}} Epival or Epiject by Abbott Laboratories.
• Syrup{{snd}} Depakene by Abbott Laboratories its generic formulations include [https://web.archive.org/web/20070928082043/http://www.apotex.ca/Products/EN/Detail.asp?MaterialNumber=000000000000042290 Apo-Valproic] and [https://web.archive.org/web/20080115210712/http://www.ratiopharm.ca/e/Products/productSearch.asp?Cap=V ratio-Valproic].

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

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

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

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

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

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

• Tablets{{snd}} DI DPA by Megalabs

• Brazil{{snd}} Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil
• Canada{{snd}} Epival by Abbott Laboratories
• Mexico{{snd}} Epival and Epival ER (extended release) by Abbott Laboratories
• United Kingdom{{snd}} Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics
• United States{{snd}} Depakote and Depakote ER (extended release) by Abbott Laboratories and generics
• India{{snd}} 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{{snd}} Ergenyl Chrono by Sanofi-Aventis and generics
• Chile{{snd}} Valcote and Valcote ER by Abbott Laboratories
• France and other European countries{{snd}} Depakote
• Peru{{snd}} Divalprax by AC Farma Laboratories
• China{{snd}} Diprate OD

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.{{Cite report |vauthors=Treadwell JR, Wu M, Tsou AY |date=October 2022 |title=Management of Infantile Epilepsies |url=https://effectivehealthcare.ahrq.gov/products/management-infantile-epilepsy/research |access-date=12 July 2023 |website=effectivehealthcare.ahrq.gov |language=en |doi=10.23970/ahrqepccer252 |pmid=36383706 |location=Rockville (MD) |publisher=Agency for Healthcare Research and Quality (US) |id=Report No.: 22(23)-EHC004 Report No.: 2021-SR-01 |archive-date=5 July 2023 |archive-url=https://web.archive.org/web/20230705073433/https://effectivehealthcare.ahrq.gov/products/management-infantile-epilepsy/research |url-status=live |url-access=subscription }}

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