Valproic acid

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Valproic acid
Valproic acid.svg
Valproic acid3Dan.gif
Systematic (IUPAC) name
2-Propylpentanoic acid
Clinical data
Trade names Depakote, Epilim, Stavzor, Vilapro
AHFS/Drugs.com monograph
MedlinePlus a682412
Licence data US FDA:link
Pregnancy cat. D (AU) X (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes Oral, intravenous
Pharmacokinetic data
Bioavailability Rapid absorption
Protein binding 80-90%[1]
Metabolism Hepaticglucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Half-life 9–16 hours[1]
Excretion Urine (30-50%)[1]
Identifiers
CAS number 99-66-1 YesY
ATC code N03AG01
PubChem CID 3121
DrugBank DB00313
ChemSpider 3009 YesY
UNII 614OI1Z5WI YesY
KEGG D00399 YesY
ChEBI CHEBI:39867 YesY
ChEMBL CHEMBL109 YesY
NIAID ChemDB 057177
Synonyms 2-Propylvaleric acid
Chemical data
Formula C8H16O2 
Mol. mass 144.211 g/mol
 YesY (what is this?)  (verify)

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: Depakote, Epilim, Valparin, Valpro, Vilapro and Stavzor.

Uses[edit]

Its primary use in medicine is in the treatment of epilepsy, bipolar mania and migraine prophylaxis.[2] It is also used off-label for bipolar maintenance.[2] Recently, it has been trialled in the treatment of HIV and cancer, owing to its histone deacetylase-inhibiting effects.[3] 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.[2][4] It has also been successfully given intravenously to treat status epilepticus.[5][6][7] In mice, valproic acid reversed fatty liver disease and lowered blood glucose.[8]

A study conducted on rats concluded that valproic acid's histone deacetylase-inhibiting effects prevented downregulation of the GluA1 and GluA2 AMPA receptors caused by heavy, chronic methamphetamine use. The authors suggested that this may make valproic acid an effective treatment for methamphetamine addiction, but this use has not been studied clinically.[9]


Adverse effects[edit]

By frequency[edit]

Sources:[1][2][10][36]
Very common (>10% frequency):

  • Nausea
  • Vomiting
  • Diarrhea
  • Headache
  • Thrombocytopenia (dose-related)
  • Tremor (dose-related)
  • Hair loss (usually temporary)
  • Drowsiness
  • Dizziness
  • Elevated aminotransferase concentrations (dose-related)
  • Hyperandrogenism in females
  • Diplopia
  • Indigestion
  • Amblyopia
  • Infection
  • Tinnitus

Common (1-10% frequency):

  • Paraesthesia
  • Abdominal pain
  • Tremor
  • Increased appetite
  • Weight gain
  • Ataxia
  • Asymptomatic hyperammonaemia
  • Polycystic ovaries
  • Memory impairment
  • Menstrual irregularities
  • Rash
  • Back pain
  • Mood changes
  • Anxiety
  • Confusion
  • Abnormal gait
  • Hallucinations
  • Catatonia
  • Dysarthria
  • Tardive dyskinesia
  • Vertigo

Uncommon (0.1-1% frequency):

  • Peripheral oedema
  • SIADH

Rare (<0.1% frequency):

  • Liver failure
  • Pancreatitis (these usually occur in first 6 months and can be fatal)
  • Leucopenia
  • Neutropenia
  • Pure red cell aplasia
  • Agranulocytosis
  • Extrapyramidal syndrome (including parkinsonism, may be reversible)
  • Hyperammonaemic encephalopathy
  • Hypothermia
  • Hypersensitivity reactions including multi-organ hypersensitivity syndrome
  • Eosinophilic pleural effusion
  • Bone fractures (reduced BMD with long-term use)

Other possible side effects[edit]

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in short stature. [37] [38] [39] [40]

Pregnancy[edit]

Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major anomalies as usual, mainly spina bifida and, more rarely, with several other defects, possibly including a "valproate syndrome".[41] Characteristics of this valproate syndrome include facial features that tend to evolve with age, including trigonocephaly, 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.[42]

Women who intend to become pregnant should switch to a different drug if possible.[43] 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 vaproate 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.[10]

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.[44][45][46] Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring.[47] 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.[48] 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.[49] 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.[50][51][52]

Contraindications[edit]

Contraindications include:[36]

  • Pregnancy
  • Pre-existing acute or chronic hepatic dysfunction or family history of severe hepatitis, particularly medicine related.
  • Known hypersensitivity to valproate or any of the excipients used in the preparation
  • Urea cycle disorders
  • Hepatic porphyria

Interactions[edit]

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.[36] It may also potentiate the CNS depressant effects of alcohol.[36] 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.[36] It may also interact with:[36]

  • 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.
  • Felbalmate; 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 reduced 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[edit]

Excessive amounts of valproic acid can result in tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. Overdosage in children is usually of an accidental nature, whereas with adults it is more likely to be an intentional act. 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.[53]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[54][55] Supplemental L-carnitine is indicated in patients having an acute overdose[56][57] and also prophylactically[56] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[58] than L-carnitine.

Mechanism of action[edit]

The mechanism of action of valproate is not fully understood.[36] Its anticonvulsant effect is attributed to the blockade of voltage-dependent sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[36] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[36] In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic transmitter, 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.[36] It also possesses histone deacetylase-inhibiting effects.[59]

History[edit]

Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian.[60] 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.[61] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[62] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[63]

Formulations[edit]

Branded products include:

Chemistry[edit]

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.[64][65][66][67]

Valproic acid synthesis.svg

See also[edit]

References[edit]

  1. ^ a b c d e "Depakene, Stavzor (valproic acid) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 13 February 2014. 
  2. ^ a b c d e Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  3. ^ Činčárová, L; Zdráhal, Z; Fajkus, J (December 2013). "New perspectives of valproic acid in clinical practice". Expert Opinion on Investigational Drugs 22 (12): 1535–1547. doi:10.1517/13543784.2013.853037. PMID 24160174. 
  4. ^ 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. doi:10.2165/00023210-200216100-00003. PMID 12269861. 
  5. ^ Olsen, KB; Taubøll, E; Gjerstad, L (2007). "Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults.". Acta Neurologica Scandinavica 187: 51–4. doi:10.1111/j.1600-0404.2007.00847.x. PMID 17419829. 
  6. ^ Kwan, SY (June 2010). "The role of intravenous valproate in convulsive status epilepticus in the future." (PDF). Acta Neurologica Taiwanica 19 (2): 78–81. PMID 20830628. 
  7. ^ Tiamkao, Somsak; Sawanyawisuth, Kittisak; Chancharoen, Alongkorn (2013). "The efficacy of intravenous sodium valproate and phenytoin as the first-line treatment in status epilepticus: a comparison study" (PDF). BMC Neurology 13 (1): 98. doi:10.1186/1471-2377-13-98. PMC 3727978. PMID 23889906. 
  8. ^ Avery, L. B.; Bumpus, N. N. (2014). "Valproic acid is a novel activator of AMP-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice". Molecular Pharmacology 85 (1): 1–10. doi:10.1124/mol.113.089755. PMC 3868906. PMID 24105977.  edit
  9. ^ Lud Cadet, J.; Jayanthi, S. (2013). "Epigenetics of Methamphetamine-Induced Changes in Glutamate Function". Neuropsychopharmacology 38: 248. doi:10.1038/npp.2012.169.  edit
  10. ^ a b c Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.  edit
  11. ^ Rimmer, EM; Richens, A (May-June 1985). "An update on sodium valproate.". Pharmacotherapy 5 (3): 171–84. doi:10.1002/j.1875-9114.1985.tb03413.x. PMID 3927267. 
  12. ^ Vasudev, K; Mead, A; Macritchie, K; Young, AH (2012). "Valproate in acute mania: is our practice evidence based?". International Journal of Health Care Quality Assurance 25 (1): 41–52. doi:10.1108/09526861211192395. PMID 22455007. 
  13. ^ Bond, DJ; Lam, RW; Yatham, LN (August 2010). "Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis.". Journal of Affective Disorders 124 (3): 228–334. doi:10.1016/j.jad.2009.11.008. PMID 20044142. 
  14. ^ Haddad, PM; Das, A; Ashfaq, M; Wieck, A (May 2009). "A review of valproate in psychiatric practice.". Expert Opinion on Drug Metabolism & toxicology 5 (5): 539–51. doi:10.1517/17425250902911455. PMID 19409030. 
  15. ^ Frazee, LA; Foraker, KC (March 2008). "Use of intravenous valproic acid for acute migraine.". The Annals of pharmacotherapy 42 (3): 403–7. doi:10.1345/aph.1K531. PMID 18303140. 
  16. ^ Schwarz, C; Volz, A; Li, C; Leucht, S (16 July 2008). "Valproate for schizophrenia." (PDF). The Cochrane database of systematic reviews (3): CD004028. doi:10.1002/14651858.CD004028.pub3. PMID 18646098. 
  17. ^ Lonergan, E; Luxenberg, J (8 July 2009). "Valproate preparations for agitation in dementia." (PDF). The Cochrane Database of Systematic Reviews (3): CD003945. doi:10.1002/14651858.CD003945.pub3. PMID 19588348. 
  18. ^ Chiu, CT; Wang, Z; Hunsberger, JG; Chuang, DM (January 2013). "Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder." (PDF). Pharmacological reviews 65 (1): 105–142. doi:10.1124/pr.111.005512. PMC 3565922. PMID 23300133. 
  19. ^ Gill, D; Derry, S; Wiffen, PJ; Moore, RA (5 October 2011). "Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults." (PDF). The Cochrane Database of Systematic Reviews (10): CD009183. doi:10.1002/14651858.CD009183.pub2. PMID 21975791. 
  20. ^ Aliyev, ZN; Aliyev, NA (July-August 2008). "Valproate treatment of acute alcohol hallucinosis: a double-blind, placebo-controlled study." (PDF). Alcohol and alcoholism (Oxford, Oxfordshire) 43 (4): 456–459. doi:10.1093/alcalc/agn043. PMID 18495806. 
  21. ^ Jacobson, P. L.; Messenheimer, J. A.; Farmer, T. W. (1 November 1981). "Treatment of intractable hiccups with valproic acid". Neurology 31 (11): 1458–1458. doi:10.1212/WNL.31.11.1458. PMID 6796902. 
  22. ^ Sotaniemi, K (July 1982). "Valproic acid in the treatment of nonepileptic myoclonus.". Archives of Neurology 39 (7): 448–9. doi:10.1001/archneur.1982.00510190066025. PMID 6808975. 
  23. ^ Wheeler, SD (July-August 1998). "Significance of migrainous features in cluster headache: divalproex responsiveness.". Headache 38 (7): 547–51. doi:10.1046/j.1526-4610.1998.3807547.x. PMID 15613172. 
  24. ^ 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. 
  25. ^ Smith, SM (2005). "Valproic acid and HIV-1 latency: beyond the sound bite" (PDF). Retrovirology 2 (1): 56. doi:10.1186/1742-4690-2-56. PMID 16168066. 
  26. ^ Routy, JP; Tremblay, CL; Angel, JB; Trottier, B; Rouleau, D; Baril, JG; Harris, M; Trottier, S; Singer, J; Chomont, N; Sékaly, RP; Boulassel, MR (May 2012). "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): 291–6. doi:10.1111/j.1468-1293.2011.00975.x. PMID 22276680. 
  27. ^ Archin, NM; Cheema, M; Parker, D; Wiegand, A; Bosch, RJ; Coffin, JM; Eron, J; Cohen, M; Margolis, DM (23 February 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. doi:10.1371/journal.pone.0009390. PMC 2826423. PMID 20186346. 
  28. ^ a b Hardy, JR; Rees, EA; Gwilliam, B; Ling, J; Broadley, K; A'Hern, R (March 2001). "A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain." (PDF). Journal of Pain and Symptom Management 21 (3): 204–9. doi:10.1016/S0885-3924(00)00266-9. PMID 11239739. 
  29. ^ Candelaria, M; Herrera, A; Labardini, J; González-Fierro, A; Trejo-Becerril, C; Taja-Chayeb, L; Pérez-Cárdenas, E; Cruz-Hernández, E; Arias-Bofill, D; Vidal, S; Cervera, E; Dueñas-Gonzalez, A (5 October 2010). "Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial". Annals of Hematology 90 (4): 379–387. doi:10.1007/s00277-010-1090-2. PMID 20922525. 
  30. ^ Bug, G; Ritter, M; Wassmann, B; Schoch, C; Heinzel, T; Schwarz, K; Romanski, A; Kramer, OH; Kampfmann, M; Hoelzer, D; Neubauer, A; Ruthardt, M; Ottmann, OG (15 December 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. doi:10.1002/cncr.21589. PMID 16294345. 
  31. ^ Kuendgen, A; Schmid, M; Schlenk, R; Knipp, S; Hildebrandt, B; Steidl, C; Germing, U; Haas, R; Dohner, H; Gattermann, N (1 January 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. doi:10.1002/cncr.21552. PMID 16323176. 
  32. ^ Fredly, H; Gjertsen, BT; Bruserud, O (30 July 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). Clinical Epigenetics 5 (1): 12. doi:10.1186/1868-7083-5-12. PMC 3733883. PMID 23898968. 
  33. ^ Coronel, J; Cetina, L; Pacheco, I; Trejo-Becerril, C; González-Fierro, A; de la Cruz-Hernandez, E; Perez-Cardenas, E; Taja-Chayeb, L; Arias-Bofill, D; Candelaria, M; Vidal, S; Dueñas-González, A (December 2011). "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: S540–6. doi:10.1007/s12032-010-9700-3. PMID 20931299. 
  34. ^ Rocca, A; Minucci, S; Tosti, G; Croci, D; Contegno, F; Ballarini, M; Nolè, F; Munzone, E; Salmaggi, A; Goldhirsch, A; Pelicci, PG; Testori, A (13 January 2009). "A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma." (PDF). British Journal of Cancer 100 (1): 28–36. doi:10.1038/sj.bjc.6604817. PMC 2634690. PMID 19127265. 
  35. ^ Munster, P; Marchion, D; Bicaku, E; Lacevic, M; Kim, J; Centeno, B; Daud, A; Neuger, A; Minton, S; Sullivan, D (1 April 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). Clinical Cancer Research 15 (7): 2488–96. doi:10.1158/1078-0432.CCR-08-1930. PMID 19318486. 
  36. ^ a b c d e f g h i j "Valpro sodium valproate" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 16 December 2013. Retrieved 14 February 2014. 
  37. ^ http://www.ncbi.nlm.nih.gov/pubmed/15032379
  38. ^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2013195/
  39. ^ http://onlinelibrary.wiley.com/doi/10.1046/j.1528-1157.2001.416800.x/pdf
  40. ^ http://www.ncbi.nlm.nih.gov/pubmed/11580761
  41. ^ Ornoy, A. (2009). "Valproic acid in pregnancy: How much are we endangering the embryo and fetus?". Reproductive Toxicology 28 (1): 1–10. doi:10.1016/j.reprotox.2009.02.014. PMID 19490988.  edit
  42. ^ Kulkarni, M. L.; Zaheeruddin, M.; Shenoy, N.; Vani, H. N. (2006). "Fetal valproate syndrome". Indian journal of pediatrics 73 (10): 937–939. PMID 17090909.  edit
  43. ^ http://www.lawyersandsettlements.com/lawsuit/valproate-not-to-be-used-migraine-during-pregnancy.html#.UZPulit35cI
  44. ^ Umur, A. S.; Selcuki, M.; Bursali, A.; Umur, N.; Kara, B.; Vatansever, H. S.; Duransoy, Y. K. (2012). "Simultaneous folate intake may prevent advers effect of valproic acid on neurulating nervous system". Child's Nervous System 28 (5): 729–737. doi:10.1007/s00381-011-1673-9. PMID 22246336.  edit
  45. ^ Cassels, Caroline (December 8, 2006). "NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids". Medscape. Retrieved 2007-05-23. 
  46. ^ Meador, K. J.; Baker, G. A.; Finnell, R. H.; Kalayjian, L. A.; Liporace, J. D.; Loring, D. W.; Mawer, G.; Pennell, P. B.; Smith, J. C.; Wolff, M. C.; Nead Study, G. (2006). "In utero antiepileptic drug exposure: Fetal death and malformations". Neurology 67 (3): 407–412. doi:10.1212/01.wnl.0000227919.81208.b2. PMC 1986655. PMID 16894099.  edit
  47. ^ Christensen, J.; Grønborg, T. K.; Sørensen, M. J.; Schendel, D.; Parner, E. T.; Pedersen, L. H.; Vestergaard, M. (2013). "Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism". JAMA 309 (16): 1696–1703. doi:10.1001/jama.2013.2270. PMID 23613074.  edit
  48. ^ Arndt, T. L.; Stodgell, C. J.; Rodier, P. M. (2005). "The teratology of autism". International Journal of Developmental Neuroscience 23 (2–3): 189–199. doi:10.1016/j.ijdevneu.2004.11.001. PMID 15749245.  edit
  49. ^ Rinaldi, T.; Silberberg, G.; Markram, H. (2007). "Hyperconnectivity of Local Neocortical Microcircuitry Induced by Prenatal Exposure to Valproic Acid". Cerebral Cortex 18 (4): 763–770. doi:10.1093/cercor/bhm117. PMID 17638926.  edit
  50. ^ I.Q. Harmed by Epilepsy Drug in Utero By RONI CARYN RABIN, New York Times, April 15, 2009
  51. ^ Meador, K. J.; Baker, G. A.; Browning, N.; Clayton-Smith, J.; Combs-Cantrell, D. T.; Cohen, M.; Kalayjian, L. A.; Kanner, A.; Liporace, J. D.; Pennell, P. B.; Privitera, M.; Loring, D. W.; Nead Study, G. (2009). "Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs". New England Journal of Medicine 360 (16): 1597–1605. doi:10.1056/NEJMoa0803531. PMC 2737185. PMID 19369666.  edit
  52. ^ Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy). FDA. June 2011
  53. ^ Sztajnkrycer, M. D. (2002). "Valproic acid toxicity: Overview and management". Journal of toxicology. Clinical toxicology 40 (6): 789–801. doi:10.1081/CLT-120014645. PMID 12475192.  edit
  54. ^ Thanacoody, R. H. K. (2009). "Extracorporeal elimination in acute valproic acid poisoning". Clinical Toxicology 47 (7): 609–616. doi:10.1080/15563650903167772. PMID 19656009.  edit
  55. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622-1626.
  56. ^ a b Lheureux, P. E.; Penaloza, A.; Zahir, S.; Gris, M. (2005). "Science review: Carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?". Critical Care 9 (5): 431–440. doi:10.1186/cc3742. PMC 1297603. PMID 16277730.  edit
  57. ^ Mock, C. M.; Schwetschenau, K. H. (2011). "Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy". American Journal of Health-System Pharmacy 69 (1): 35–39. doi:10.2146/ajhp110049. PMID 22180549.  edit
  58. ^ Matsuoka, M.; Igisu, H. (1993). "Comparison of the effects of L-carnitine, D-carnitine and acetyl-L-carnitine on the neurotoxicity of ammonia". Biochemical pharmacology 46 (1): 159–164. doi:10.1016/0006-2952(93)90360-9. PMID 8347126.  edit
  59. ^ Kostrouchová, M; Kostrouch, Z; Kostrouchová, M (2007). "Valproic acid, a molecular lead to multiple regulatory pathways." (PDF). Folia biologica 53 (2): 37–49. PMID 17448293. 
  60. ^ Burton B.S. (1882). "On the propyl derivatives and decomposition products of ethylacetoacetate". Am Chem J. 3: 385–395. 
  61. ^ Meunier, H.; Carraz, G.; Neunier, Y.; Eymard, P.; Aimard, M. (1963). "Pharmacodynamic properties of N-dipropylacetic acid". Therapie 18: 435–438. PMID 13935231.  edit
  62. ^ Perucca, E. (2002). "Pharmacological and therapeutic properties of valproate: A summary after 35 years of clinical experience". CNS drugs 16 (10): 695–714. doi:10.2165/00023210-200216100-00004. PMID 12269862.  edit
  63. ^ Henry, T. R. (2003). "The history of valproate in clinical neuroscience". Psychopharmacology bulletin. 37 Suppl 2: 5–16. PMID 14624229.  edit
  64. ^ M. Chignac, C. Grain, U.S. Patent 4,155,929 (1979)
  65. ^ H.E.J.-M. Meunier, GB 980279  (1963)
  66. ^ H.E.J.-M. Meunier, U.S. Patent 3,325,361(1967)
  67. ^ M. Chignac, C. Grain, Ch. Pigerol, GB 1522450  (1977)

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