Open Access Articles- Top Results for Valproic acid
Journal of Blood & LymphComparative Study between Valproic Acid Combined with Conventional Chemotherapy Versus Conventional Chemotherapy Alone in Egyptian Acute Myeloid Leu
Modern Chemistry & ApplicationsAnti-Convulsant Drug Valproic Acid in Cancers and in Combination Anti-Cancer Therapeutics
Pharmaceutica Analytica ActaAtypical Kinetics of Valproic Acid Glucuronidation In vitro and In vivo in Humans
|File:Valproic acid 3d structure.png|
|Systematic (IUPAC) name|
|Trade names||Convulex, Depakote, Epilim, Stavzor, Vilapro|
|Licence data||US FDA:|
|Metabolism||Hepatic—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%|
|14px (what is this?)|
Valproic acid (VPA, valproate), an acidic chemical compound, has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder and prevention of migraine headaches. VPA is a liquid at room temperature, but it can be reacted with a base such as sodium hydroxide to form the salt sodium valproate, which is a solid.
The acid, salt, or a mixture of the two (valproate semisodium) are marketed under a number of different brand names, including: Convulex, Depakote, Epilim, Valparin, Valpro, Vilapro and Stavzor. It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.
- 1 Medical uses
- 2 Adverse effects
- 3 Mechanism of action
- 4 History
- 5 Society and culture
- 6 Formulations
- 7 Chemistry
- 8 See also
- 9 References
- 10 Further reading
- 11 External links
Its primary use in medicine is in the treatment of epilepsy, bipolar mania and to protect against the development of migraines. Valproate products are also used to treat manic or mixed episodes associated with bipolar disorder. Off-label uses include impulse control disorders, suggested by recent evidence of efficacy in controlling this adverse effect of Parkinson's disease medical therapy. Recently, it has been trialled in the treatment of HIV and cancer, owing to its histone deacetylase-inhibiting effects. 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. It has also been successfully given intravenously to treat status epilepticus.
The most common adverse effects of valproic acid are digestive complaints like diarrhea, nausea, vomiting and indigestion; vision problems like seeing double or lazy eye; hormonal disturbances (increased testosterone production in females and menstrual irregularities), hair loss, memory problems, weight gain, infections, low platelet count (which can make one bleed more easily), dizziness, drowsiness, tremor and headache. Less common, yet serious side effects include liver damage, brittle bones (becomes far more common with long-term use), polycystic ovaries, movement disorders (which may be irreversible like tardive dyskinesia), psychiatric/neurologic disturbances like hallucinations, anxiety and confusion; pancreatic inflammation, low body temperature and potentially life-threatening blood abnormalities.
Other possible side effects
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height. Valproic acid can also cause mydriasis, a protracted dilation of the pupils.
Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida and, more rarely, with several other defects, possibly including a "valproate syndrome". Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle shaped forehead due to earlier than normal fusion of the metopic suture, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.
Women who intend to become pregnant should switch to a different medication if possible. Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have even worse consequences.) They should take high-dose folic acid and be offered antenatal screening (alpha-fetoprotein and second-trimester ultrasound scans), although screening and scans do not find all birth defects.
Valproate can cause neural tube defects. Folic acid supplements may reduce the risk of birth defects, however. A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower IQs. Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring. Exposure of the human embryo to valproic acid is associated with risk of autism, and it is possible to duplicate features characteristic of autism by exposing rat embryos to valproic acid at the time of neural tube closure. Valproate exposure on embryonic day 11.5 led to significant local recurrent connectivity in the juvenile rat neocortex, consistent with the underconnectivity theory of autism. A 2009 study found that the 3 year old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.
- Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.
- Known hypersensitivity to valproate or any of the excipients used in the preparation
- Urea cycle disorders
- Hepatic porphyria
- Mitochondrial disease
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:
- Anticoagulants, due to its ability to prolong the bleeding time.
- Psychotropic agents; potential pharmacokinetic interactions.
- Benzodiazepines; may potentiate CNS depression and there are possible pharmacokinetic interactions.
- Ethosuximide; potential for ethosuximide toxicity.
- Primidone; may reduce pyrimidone's clearance leading to toxicity.
- Zidovudine; may raise its (zidovudine's) serum concentration and lead to toxicity.
- Aspirin; may displace valproate from plasma proteins, leading to increased plasma concentrations. Also interferes with valproate's metabolism.
- Felbamate; may increase plasma concentrations of valproate.
- Mefloquine; potential for increased valproate metabolism combined with the direct epileptogenic effects of mefloquine.
- Cimetidine; inhibits valproate's metabolism in the liver, hence leading to increased plasma concentrations of valproate.
- Erythromycin; inhibits valproate's metabolism in the liver, hence leading to increased plasma concentrations of valproate.
- Carbapenem antibiotics; reduces valproate levels, potentially leading to seizures.
Overdose and toxicity
Excessive amounts of valproic acid can result in 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. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly than L-carnitine.
Mechanism of action
Although the mechanism of action of valproate is not fully understood, it has recently been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism. In addition, its anticonvulsant effect has been attributed to the blockade of voltage-dependent sodium channels and increased brain levels of gamma-aminobutyric acid (GABA). The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells. It also possesses histone deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.
Valproic acid was first synthesized in 1882 by B.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
|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).|
|Acute migraine management||No||No||No||Only negative results.|
|Schizophrenia||No||No||No||Weak and mostly negative evidence.|
|Agitation in dementia||No||No||No||Weak and mostly negative evidence.|
|Fragile X syndrome||Yes (orphan)||No||No||Limited.|
|Familial adenomatous polyposis||Yes (orphan)||No||No||Limited.|
|Chronic pain & fibromyalgia||No||No||No||Limited.|
|Alcohol hallucinosis||No||No||No||One randomised double-blind placebo-controlled trial.|
|Intractable hiccups||No||No||No||Limited, five case reports support its efficacy, however.|
|Non-epileptic myoclonus||No||No||No||Limited, three case reports support its efficacy, however.|
|Cluster headaches||No||No||No||Limited, two case reports support its efficacy.|
|West syndrome||No||No||No||A prospective clinical trial supported its efficacy in treating infantile spasms.|
|HIV infection eradication||No||No||No||Double-blind placebo-controlled trials have been negative.|
|Myelodysplastic syndrome||No||No||No||Several clinical trials have confirmed its efficacy as a monotherapy, as an adjunct to tretinoin and as an adjunct to hydralazine.|
|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.|
|Cervical cancer||No||No||No||One clinical trial supports its use here.|
|Malignant melanoma||No||No||No||One phase II study has seemed to discount its efficacy.|
|Breast cancer||No||No||No||A phase II study has supported its efficacy.|
|Impulse control disorder||No||No||No||Limited.|
Branded products include:
- Absenor (Orion Corporation Finland)
- Convulex (G.L. Pharma GmbH Austria)
- Depakene (Abbott Laboratories in US and Canada)
- Depakine (Sanofi Aventis France)
- Depakine (Sanofi Synthelabo Romania)
- Depalept (Sanofi Aventis Israel)
- Deprakine (Sanofi Aventis Finland)
- Encorate (Sun Pharmaceuticals India)
- Epival (Abbott Laboratories US and Canada)
- Epilim (Sanofi Synthelabo Australia)
- Stavzor (Noven Pharmaceuticals Inc.)
- Valcote (Abbott Laboratories Argentina)
- Valpakine (Sanofi Aventis Brazil)
Valproic acid, 2-propylvaleric acid, is synthesized by the alkylation of ethyl cyanoacetate with two equivalents of propyl bromide, to give dipropylcyanoacetic ester. Hydrolysis and decarboxylation of the carboethoxy group gives 2-propylpentanenitrile, which is hydrolyzed into valproic acid.
- "Depakene, Stavzor (valproic acid) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 13 February 2014.
- "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- "Valproate Information". Fda.gov. Retrieved 2015-04-24.
- Hicks CW, Pandya MM, Itin I, Fernandez HH (2011). "Valproate for the treatment of medication-induced impulse-control disorders in three patients with Parkinson's disease". Parkinsonism Relat. Disord. 17 (5): 379–81. PMID 21459656. doi:10.1016/j.parkreldis.2011.03.003.
- Činčárová L, Zdráhal Z, Fajkus J (2013). "New perspectives of valproic acid in clinical practice". Expert Opin Investig Drugs 22 (12): 1535–1547. PMID 24160174. doi:10.1517/13543784.2013.853037.
- Löscher W (2002). "Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy". CNS Drugs 16 (10): 669–694. PMID 12269861. doi:10.2165/00023210-200216100-00003.
- Olsen KB, Taubøll E, Gjerstad L (2007). "Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults". Acta Neurol. Scand., Suppl.c 187: 51–4. PMID 17419829. doi:10.1111/j.1600-0404.2007.00847.x.
- Kwan SY (2010). "The role of intravenous valproate in convulsive status epilepticus in the future" (PDF). Acta Neurol Taiwan 19 (2): 78–81. PMID 20830628.
- Tiamkao S, Sawanyawisuth K, Chancharoen A (2013). "The efficacy of intravenous sodium valproate and phenytoin as the first-line treatment in status epilepticus: a comparison study" (PDF). BMC Neurol 13 (1): 98. PMC 3727978. PMID 23889906. doi:10.1186/1471-2377-13-98.
- Joint Formulary Committee. British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
- Effects of valproic acid on longitudinal bone... [J Child Neurol. 2004] - PubMed - NCBI
- Inhibition of cartilage growth by the anticonvulsant drugs diphenylhydantoin and sodium valproate
- Long-Term Valproate and Lamotrigine Treatment May Be a Marker for Reduced Growth and Bone Mass in Children with Epilepsy - Guo - 2002 - Epilepsia - Wiley Online Library
- Long-term valproate and lamotrigine treatment may ... [Epilepsia. 2001] - PubMed - NCBI
- "Could Depakote cause Mydriasis". eHealthMe.com. 2014-11-18. Retrieved 2015-04-24.
- Ornoy A (2009). "Valproic acid in pregnancy: how much are we endangering the embryo and fetus?". Reprod. Toxicol. 28 (1): 1–10. PMID 19490988. doi:10.1016/j.reprotox.2009.02.014.
- Kulkarni ML, Zaheeruddin M, Shenoy N, Vani HN (2006). "Fetal valproate syndrome". Indian J Pediatr 73 (10): 937–939. PMID 17090909. doi:10.1007/bf02859291.
- Valproate Not To Be Used for Migraine During Pregnancy, FDA Warns
- British National Formulary (March 2003) 45
- Umur AS, Selcuki M, Bursali A, Umur N, Kara B, Vatansever HS et al. (2012). "Simultaneous folate intake may prevent adverse effect of valproic acid on neurulating nervous system". Childs Nerv Syst 28 (5): 729–737. PMID 22246336. doi:10.1007/s00381-011-1673-9.
- Cassels, Caroline (December 8, 2006). "NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids". Medscape. Retrieved 2007-05-23.
- Meador KJ, Baker GA, Finnell RH, Kalayjian LA, Liporace JD, Loring DW et al. (2006). "In utero antiepileptic drug exposure: fetal death and malformations". Neurology 67 (3): 407–412. PMC 1986655. PMID 16894099. doi:10.1212/01.wnl.0000227919.81208.b2.
- Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH et al. (2013). "Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism". JAMA 309 (16): 1696–1703. PMID 23613074. doi:10.1001/jama.2013.2270.
- Arndt TL, Stodgell CJ, Rodier PM (2005). "The teratology of autism". Int. J. Dev. Neurosci. 23 (2-3): 189–199. PMID 15749245. doi:10.1016/j.ijdevneu.2004.11.001.
- Rinaldi T, Silberberg G, Markram H (2008). "Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid". Cereb. Cortex 18 (4): 763–770. PMID 17638926. doi:10.1093/cercor/bhm117.
- I.Q. Harmed by Epilepsy Drug in Utero By RONI CARYN RABIN, New York Times, April 15, 2009
- Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M et al. (2009). "Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs". N. Engl. J. Med. 360 (16): 1597–1605. PMC 2737185. PMID 19369666. doi:10.1056/NEJMoa0803531.
- Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy). FDA. June 2011
- "Valpro sodium valproate" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 16 December 2013. Retrieved 14 February 2014.
- Sztajnkrycer MD (2002). "Valproic acid toxicity: overview and management". J. Toxicol. Clin. Toxicol. 40 (6): 789–801. PMID 12475192. doi:10.1081/CLT-120014645.
- Patsalos PN, Berry DJ (2013). "Therapeutic drug monitoring of antiepileptic drugs by use of saliva". Ther Drug Monit 35 (1): 4–29. PMID 23288091. doi:10.1097/FTD.0b013e31827c11e7.
- Thanacoody RH (2009). "Extracorporeal elimination in acute valproic acid poisoning". Clin Toxicol (Phila) 47 (7): 609–616. PMID 19656009. doi:10.1080/15563650903167772.
- R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622-1626.
- Lheureux PE, Penaloza A, Zahir S, Gris M (2005). "Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?". Crit Care 9 (5): 431–440. PMC 1297603. PMID 16277730. doi:10.1186/cc3742.
- Mock CM, Schwetschenau KH (2012). "Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy". Am J Health Syst Pharm 69 (1): 35–39. PMID 22180549. doi:10.2146/ajhp110049.
- Matsuoka M, Igisu H (1993). "Comparison of the effects of L-carnitine, D-carnitine and acetyl-L-carnitine on the neurotoxicity of ammonia". Biochem. Pharmacol. 46 (1): 159–164. PMID 8347126. doi:10.1016/0006-2952(93)90360-9.
- Chang P, Walker MC, Williams RS (2014). "Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid". Neurobiol. Dis. 62: 296–306. PMC 3898270. PMID 24148856. doi:10.1016/j.nbd.2013.10.017.
- Kostrouchová M, Kostrouch Z, Kostrouchová M (2007). "Valproic acid, a molecular lead to multiple regulatory pathways" (PDF). Folia Biol. (Praha) 53 (2): 37–49. PMID 17448293.
- Chiu CT, Wang Z, Hunsberger JG, Chuang DM (2013). "Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder". Pharmacol. Rev. 65 (1): 105–142. PMC 3565922. PMID 23300133. doi:10.1124/pr.111.005512.
- Burton BS (1882). "On the propyl derivatives and decomposition products of ethylacetoacetate". Am Chem J. 3: 385–395.
- Meunier H, Carraz G, Neunier Y, Eymard P, Aimard M (1963). "[Pharmacodynamic properties of N-dipropylacetic acid]" [Pharmacodynamic properties of N-dipropylacetic acid]. Therapie (in French) 18: 435–438. PMID 13935231.
- Perucca E (2002). "Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience". CNS Drugs 16 (10): 695–714. PMID 12269862. doi:10.2165/00023210-200216100-00004.
- Henry TR (2003). "The history of valproate in clinical neuroscience". Psychopharmacol Bull. 37 Suppl 2: 5–16. PMID 14624229.
- Rimmer EM, Richens A (May–June 1985). "An update on sodium valproate". Pharmacotherapy 5 (3): 171–84. PMID 3927267. doi:10.1002/j.1875-9114.1985.tb03413.x.
- Vasudev K, Mead A, Macritchie K, Young AH (2012). "Valproate in acute mania: is our practice evidence based?". Int J Health Care Qual Assur 25 (1): 41–52. PMID 22455007. doi:10.1108/09526861211192395.
- Bond DJ, Lam RW, Yatham LN (2010). "Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis". J Affect Disord 124 (3): 228–334. PMID 20044142. doi:10.1016/j.jad.2009.11.008.
- Haddad PM, Das A, Ashfaq M, Wieck A (2009). "A review of valproate in psychiatric practice". Expert Opin Drug Metab Toxicol 5 (5): 539–51. PMID 19409030. doi:10.1517/17425250902911455.
- Frazee LA, Foraker KC (2008). "Use of intravenous valproic acid for acute migraine". Ann Pharmacother 42 (3): 403–7. PMID 18303140. doi:10.1345/aph.1K531.
- Schwarz C, Volz A, Li C, Leucht S (2008). "Valproate for schizophrenia" (PDF). Cochrane Database Syst Rev (3): CD004028. PMID 18646098. doi:10.1002/14651858.CD004028.pub3.
- Lonergan E, Luxenberg J (2009). "Valproate preparations for agitation in dementia" (PDF). Cochrane Database Syst Rev (3): CD003945. PMID 19588348. doi:10.1002/14651858.CD003945.pub3.
- Chiu CT, Wang Z, Hunsberger JG, Chuang DM (2013). "Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder" (PDF). Pharmacol. Rev. 65 (1): 105–142. PMC 3565922. PMID 23300133. doi:10.1124/pr.111.005512.
- Gill D, Derry S, Wiffen PJ, Moore RA (2011). "Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults" (PDF). Cochrane Database Syst Rev (10): CD009183. PMID 21975791. doi:10.1002/14651858.CD009183.pub2.
- Aliyev ZN, Aliyev NA (July–August 2008). "Valproate treatment of acute alcohol hallucinosis: a double-blind, placebo-controlled study" (PDF). Alcohol Alcohol. 43 (4): 456–459. PMID 18495806. doi:10.1093/alcalc/agn043.
- Jacobson PL, Messenheimer JA, Farmer TW (1981). "Treatment of intractable hiccups with valproic acid". Neurology 31 (11): 1458–1458. PMID 6796902. doi:10.1212/WNL.31.11.1458.
- Sotaniemi K (1982). "Valproic acid in the treatment of nonepileptic myoclonus". Arch. Neurol. 39 (7): 448–9. PMID 6808975. doi:10.1001/archneur.1982.00510190066025.
- Wheeler SD (July–August 1998). "Significance of migrainous features in cluster headache: divalproex responsiveness". Headache 38 (7): 547–51. PMID 15613172. doi:10.1046/j.1526-4610.1998.3807547.x.
- Siemes H, Spohr HL, Michael T, Nau H (September–October 1988). "Therapy of infantile spasms with valproate: results of a prospective study". Epilepsia 29 (5): 553–60. PMID 2842127. doi:10.1111/j.1528-1157.1988.tb03760.x.
- Smith SM (2005). "Valproic acid and HIV-1 latency: beyond the sound bite" (PDF). Retrovirology 2 (1): 56. PMC 1242254. PMID 16168066. doi:10.1186/1742-4690-2-56.
- Routy JP, Tremblay CL, Angel JB, Trottier B, Rouleau D, Baril JG et al. (2012). "Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study". HIV Med. 13 (5): 291–6. PMID 22276680. doi:10.1111/j.1468-1293.2011.00975.x.
- Archin NM, Cheema M, Parker D, Wiegand A, Bosch RJ, Coffin JM et al. (2010). "Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection" (PDF). PLoS ONE 5 (2): e9390. PMC 2826423. PMID 20186346. doi:10.1371/journal.pone.0009390.
- Hardy JR, Rees EA, Gwilliam B, Ling J, Broadley K, A'Hern R (2001). "A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain" (PDF). J Pain Symptom Manage 21 (3): 204–9. PMID 11239739. doi:10.1016/S0885-3924(00)00266-9.
- Candelaria M, Herrera A, Labardini J, González-Fierro A, Trejo-Becerril C, Taja-Chayeb L et al. (2011). "Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial". Ann. Hematol. 90 (4): 379–387. PMID 20922525. doi:10.1007/s00277-010-1090-2.
- Bug G, Ritter M, Wassmann B, Schoch C, Heinzel T, Schwarz K et al. (2005). "Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia" (PDF). Cancer 104 (12): 2717–2725. PMID 16294345. doi:10.1002/cncr.21589.
- Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl C et al. (2006). "The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia" (PDF). Cancer 106 (1): 112–119. PMID 16323176. doi:10.1002/cncr.21552.
- Fredly H, Gjertsen BT, Bruserud O (2013). "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" (PDF). Clin Epigenetics 5 (1): 12. PMC 3733883. PMID 23898968. doi:10.1186/1868-7083-5-12.
- Coronel J, Cetina L, Pacheco I, Trejo-Becerril C, González-Fierro A, de la Cruz-Hernandez E et al. (2011). "A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results". Med. Oncol. 28 Suppl 1: S540–6. PMID 20931299. doi:10.1007/s12032-010-9700-3.
- Rocca A, Minucci S, Tosti G, Croci D, Contegno F, Ballarini M et al. (2009). "A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma" (PDF). Br. J. Cancer 100 (1): 28–36. PMC 2634690. PMID 19127265. doi:10.1038/sj.bjc.6604817.
- Munster P, Marchion D, Bicaku E, Lacevic M, Kim J, Centeno B et al. (2009). "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" (PDF). Clin. Cancer Res. 15 (7): 2488–96. PMID 19318486. doi:10.1158/1078-0432.CCR-08-1930.
- Sriram A, Ward HE, Hassan A, Iyer S, Foote KD, Rodriguez RL et al. (2013). "Valproate as a treatment for dopamine dysregulation syndrome (DDS) in Parkinson's disease". J. Neurol. 260 (2): 521-7. PMID 23007193. doi:10.1007/s00415-012-6669-1.
- M. Chignac, C. Grain, U.S. Patent 4,155,929 (1979)
- H.E.J.-M. Meunier, GB 980279 (1963)
- H.E.J.-M. Meunier, U.S. Patent 3,325,361(1967)
- M. Chignac, C. Grain, Ch. Pigerol, GB 1522450 (1977)
- Chateauvieux S, Morceau F, Dicato M, Diederich M (2010). "Molecular and therapeutic potential and toxicity of valproic acid" (PDF). J. Biomed. Biotechnol. 2010: 1. PMC 2926634. PMID 20798865. doi:10.1155/2010/479364.
- Monti B, Polazzi E, Contestabile A (2009). "Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection" (PDF). Curr Mol Pharmacol 2 (1): 95–109. PMID 20021450. doi:10.2174/1874467210902010095.
- PsychEducation: Valproate/divalproex (divalproex)
- The Comparative Toxicogenomics Database:Valproic Acid
- Chemical Land21: Valproic Acid
- RXList.com: Depakene (Valproic Acid) (U.S.)
- South African Electronic Package Inserts: Convulex
- Med Broadcast.com: Valproic Acid (Canadian)