Valproic acid

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Valproic acid
Systematic (IUPAC) name
2-Propylpentanoic acid
Clinical data
AHFS/Drugs.commonograph
MedlinePlusa682412
Licence dataUS FDA:link
Pregnancy cat.D—teratogenic
Legal statusPOM (UK) -only (US)
RoutesOral, intravenous
Pharmacokinetic data
BioavailabilityRapid absorption
Protein bindingConcentration-dependent, from 90% at 40 µg/mL to 81.5% at 130 µg/mL
MetabolismHepaticglucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Half-life9–16 h
ExcretionLess than 3% excreted unchanged in urine.
Identifiers
CAS number99-66-1 YesY
ATC codeN03AG01
PubChemCID 3121
DrugBankDB00313
ChemSpider3009 YesY
UNII614OI1Z5WI YesY
KEGGD00399 YesY
ChEBICHEBI:39867 YesY
ChEMBLCHEMBL109 YesY
NIAID ChemDB057177
Synonyms2-Propylvaleric acid
Chemical data
FormulaC8H16O2 
Mol. mass144.211 g/mol
 YesY (what is this?)  (verify)
 
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Valproic acid
Systematic (IUPAC) name
2-Propylpentanoic acid
Clinical data
AHFS/Drugs.commonograph
MedlinePlusa682412
Licence dataUS FDA:link
Pregnancy cat.D—teratogenic
Legal statusPOM (UK) -only (US)
RoutesOral, intravenous
Pharmacokinetic data
BioavailabilityRapid absorption
Protein bindingConcentration-dependent, from 90% at 40 µg/mL to 81.5% at 130 µg/mL
MetabolismHepaticglucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Half-life9–16 h
ExcretionLess than 3% excreted unchanged in urine.
Identifiers
CAS number99-66-1 YesY
ATC codeN03AG01
PubChemCID 3121
DrugBankDB00313
ChemSpider3009 YesY
UNII614OI1Z5WI YesY
KEGGD00399 YesY
ChEBICHEBI:39867 YesY
ChEMBLCHEMBL109 YesY
NIAID ChemDB057177
Synonyms2-Propylvaleric acid
Chemical data
FormulaC8H16O2 
Mol. mass144.211 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, less commonly, major depression. It is also used to treat 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 the various brand names Depakote, Depakote ER, Depakene, Depakene Crono (extended release in Spain), Depacon, Depakine, Valparin, and Stavzor.

Approved uses of the various formulations vary by country; e.g., valproate semisodium is used as a mood stabilizer and also in the US as an anticonvulsant.

VPA is a histone deacetylase inhibitor and is under investigation for treatment of HIV and various cancers.[1]

Uses[edit]

As an anticonvulsant, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, juvenile myoclonic epilepsy, and the seizures associated with Lennox-Gastaut syndrome. It is also used in treatment of myoclonus. In some countries, parenteral preparations of valproate are used also as second-line treatment of status epilepticus, as an alternative to phenytoin. Valproate is one of the most common drugs used to treat post-traumatic epilepsy.[2] It is more recently being used to treat neuropathic pain, as a second-line agent, particularly lancinating pain from A delta fibers.

In the United States, valproic acid is approved by the Food and Drug Administration only for the treatment of manic episodes associated with bipolar disorder, adjunctive therapy in multiple seizure types (including epilepsy), and prophylaxis of migraine headaches.[3][4]

Valproic acid is also used off-label for controlling behavioral disturbances in dementia patients.[4]

Some randomized controlled studies have repeatedly indicated that sodium valproate and valproic acid, in borderline personality disorder and antisocial personality disorder, may have some slight to moderate mood-stabilizing advantage over no drug treatment or placebo. This is because it is believed to help reduce impulsive aggressive behavioral episodes and improving interpersonal sensitivity. These improvements would likely be somewhat better when used along with the standard psychotherapeutic regimen for these disorders- which often incorporates, among other elements, individual intensive one-on-one cognitive behavioral therapy, perhaps in a secure setting. However, these two personality disorders are widely known to still normally be lifelong and quite treatment-resistant, with a significant recidivism rate.[5]

Investigational[edit]

HIV[edit]

The enzyme histone deacetylase 1 (HDAC1) is needed for HIV to remain latent, or dormant, in infected cells. When the virus is latent, it cannot be destroyed by anti-HIV drugs. A study published in August 2005 found that three of four patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a mean 75% reduction in latent HIV infection.[6] The idea was that valproic acid, by inhibiting HDAC1, forced HIV out of latency (reactivation) and into its replicative cycle. The highly active antiretroviral drugs could then stop the virus, whilst the immune system could destroy the infected cell. Flushing out all latent virus in this manner would potentially cure HIV patients. Subsequent trials, however, found no long-term benefits of valproic acid in HIV infection.[7]

Other diseases[edit]

Three distinct formulations of valproic acid have been investigated in clinical trials for the treatment of colorectal polyps in familial adenomatous polyposis patients; treatment of hyperproliferative skin diseases (e.g., basal cell carcinoma); and treatment of inflammatory skin diseases (e.g., acne) by TopoTarget. The current names for these therapeutics are Savicol, Baceca and Avugane, respectively.[8]

Stem cells[edit]

Valproic acid's function as an HDAC inhibitor has also led to its use in direct reprogramming in generation of induced pluripotent stem (iPS) cells, where it has been shown that addition of VPA allows for reprogramming of human fibroblasts to iPS cells without addition of genetic factors Klf4 and c-myc.[9] This function has also been investigated as an epigenetic therapy for treatment of lupus.[10]

Learning[edit]

In a single small study, adult men who took valproate learned to identify pitch better than those taking placebo. It is believed that the drug effects the "plasticity" of the human brain, though the mechanisms of how are not fully understood.[11]

History[edit]

Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian.[12] It has two propyl groups, hence the name "val.pro~ic". 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.[13] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[14] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[15]

Mechanism of action[edit]

Valproate is believed to affect the function of the neurotransmitter GABA in the human brain, making it an alternative to lithium salts in treatment of bipolar disorder. Its mechanism of action includes enhanced neurotransmission of GABA (by inhibiting GABA transaminase, which breaks down GABA). However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.[16]

Valproic acid also blocks voltage-gated sodium channels and T-type calcium channels. These mechanisms make valproic acid a broad-spectrum anticonvulsant drug.

Valproic acid is an inhibitor of the enzyme histone deacetylase 1 (HDAC1), hence it is a histone deacetylase inhibitor.

Dosing[edit]

Dosing depends on which disease is being treated and whether valproic acid is being treated for maintenance or acute application. For maintenance of bipolar disorder type 1 the dose range can be tested through blood serum testing or by mg per kilogram of weight: minimum of 250 mg a day of Depakote up to 3000 mg a day. For acute treatment of bipolar type 1 the minimum dose would be 1000 mg a day.

Combination therapy[edit]

Valproic acid[17][18] or valproate[19][20] are synergistic with lithium, with combination therapy proving more efficacious than monotherapy with valproic acid or valproate alone. This is true at least for glutamate excitotoxicity,[17] amyotrophic lateral sclerosis,[18] Huntington's disease,[19] and bipolar disorder.[20][21]

Safety[edit]

Contraindications[edit]

Safety in 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".[22] 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.[23]

Women who intend to become pregnant should switch to a different drug if possible.[24] 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.[25]

Valproate is a folate antagonist,[26] which can cause neural tube defects. Thus, folic acid supplements may alleviate the teratogenic problems. A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower IQs.[27][28]

Risk of autism[edit]

Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring.[29] 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.[30] 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.[31]

Risk of low IQ[edit]

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.[32][33][34]

Adverse effects[edit]

Adverse effects are dosage-related.

The foremost and most severe concern for anyone taking valproic acid is its potential for sudden and severe, possibly fatal, fulminating impairments in liver and impairments of hematopoietic or pancreatic function, especially in those just starting the medication. This particular warning is the first one listed on any drug adverse effect listing when one receives the drug at the pharmacy.

In rare reports, individuals having used valproic acid for a long time (chronic users) have suffered renal impairment, usually as a result of having been injured or ill or on a drug regimen already and, so, having been overwhelmed.

Valproate is also cautioned against in many patients because it can cause weight gain.[35]

Absolute contraindications are pre-existing severe hepatic (liver) or renal (kidney) damage and certain cases of metastatic cancer, severe hepatitis or pancreatitis, end-stage AIDS HIV infection, marked bone marrow depression, urea cycle disorders, and coagulation hematological disorders that have caused impairment. Some patients with symptomatic but manageable AIDS, cancer, and hepatic or renal disease are kept on the medication (usually at a reduced dose with more frequent blood tests) to avoid having to manipulate the drug regimen for as long as possible.

Common side effects are dyspepsia or weight gain. Less common are fatigue, peripheral edema, acne, feelings of feeling cold or chills, blurred vision, burning of the eyes, dizziness, drowsiness, hair loss, headaches, nausea, sedation, and tremors. Valproic acid also causes hyperammonemia, an increase of ammonia levels in the blood, which can lead to vomiting and sluggishness, and ultimately to mental changes and brain damage.[36] Valproate levels within the normal range are capable of causing hyperammonemia and ensuing encephalopathy. Lactulose has been used on a temporary basis to alleviate the hyperammonemia caused by valproic acid.[37] L-Carnitine is used for hyperammonemia caused by valproic acid toxicity. There have been reports of the development of brain encephalopathy without hyperammonemia or elevated valproate levels.[38]

In rare circumstances, valproic acid can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation (clotting) times due to a lack of blood cells. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies that resemble fetal alcohol syndrome, with a possibility of cognitive impairment. Due to these side effects, most doctors will try to continue the medication, but will ask for blood tests, initially as often as once a week and then once every two months (those taking it for a long period may go six months before being retested; if a pregnant woman and her doctor decide to keep using the drug and to keep the pregnancy, then frequent blood testing, and possibly a higher frequency of diagnostic ultrasounds to identify fetal problems, is a must). Temporary liver enzyme increase has been reported in 20% of cases during the first few months of taking the drug. Inflammation of the liver (hepatitis), the first symptom of which is jaundice, is found in rare cases.

Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome.[39][40]

Valproate use in women with epilepsy[41][42] or bipolar disorder[42] is associated with an increased prevalence of polycystic ovary syndrome.

Cognitive dysfunction, Parkinsonian symptoms,[43] and even reversible pseudoatrophic brain changes have been reported[44] in long-term treatment with valproic acid.

According to the information provided with a prescription of this drug, some individuals have become depressed or had a suicidal ideation while on the drug; those taking it should be monitored for this side effect.

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.[45]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[46][47] Supplemental L-carnitine is indicated in patients having an acute overdose[48][49] and also prophylactically[49] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[50] than L-carnitine.

Interactions[edit]

Valproic acid may interact with carbamazepine, as valproates inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide (the main active metabolite of carbamazepine) into inactive metabolites.[51] By inhibiting mEH, valproic acid causes a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.

Valproic acid also decreases the clearance of amitriptyline and nortriptyline.[52]

Aspirin may decrease the clearance of valproic acid, leading to higher-than-intended serum levels of the anticonvulsant. Also, combining valproic acid with the benzodiazepine clonazepam can lead to profound sedation and increases the risk of absence seizures in patients susceptible to them.[52]

Valproic acid and sodium valproate reduce the apparent clearance of lamotrigine (Lamictal). In most patients, the lamotrigine dosage for coadministration with valproate must be reduced to half the monotherapy dosage.

Valproic acid is contraindicated in pregnancy, as it decreases the intestinal reabsorption of folate (folic acid), which leads to neural tube defects. Because of a decrease in folate, megaloblastic anemia may also result. Phenytoin also decreases folate absorption, which may lead to the same adverse effects as valproic acid.

Formulations[edit]

Branded products include:

Chemistry[edit]

Valproic acid, 2-propylvaleric acid, is synthesized by the alkylation of cyanoacetic ester with two moles of propylbromide, to give dipropylcyanoacetic ester. Hydrolysis and decarboxylation of the carboethoxy group gives dipropylacetonitrile, which is hydrolyzed into valproic acid.[53][54][55][56]

Valproic acid synthesis.svg

See also[edit]

References[edit]

Notes

  1. ^ Alvarez-Breckenridge, C. A.; Yu, J.; Price, R.; Wei, M.; Wang, Y.; Nowicki, M. O.; Ha, Y. P.; Bergin, S.; Hwang, C.; Fernandez, S. A.; Kaur, B.; Caligiuri, M. A.; Chiocca, E. A. (2012). "The Histone Deacetylase Inhibitor Valproic Acid Lessens NK Cell Action against Oncolytic Virus-Infected Glioblastoma Cells by Inhibition of STAT5/T-BET Signaling and Generation of Gamma Interferon". Journal of Virology 86 (8): 4566–4577. doi:10.1128/JVI.05545-11. PMC 3318659. PMID 22318143.  edit
  2. ^ Posner E, Lorenzo N (October 11, 2006). "Posttraumatic epilepsy". Emedicine.com. Retrieved on 2008-07-30.
  3. ^ "FDA Issues Approvable Letter For Stavzor Delayed Release Valproic Acid Capsules". 2007 MediLexicon International Ltd. 2007-10-25. Retrieved 2007-10-29. 
  4. ^ a b "Abbott Labs to Pay $1.5 Billion to Resolve Criminal & Civil Investigations of Off-label Promotion of Depakote". Justice News, U.S. Department of Justice. Retrieved 2012-09-04. 
  5. ^ http://apt.rcpsych.org/content/10/5/389.full.pdf
  6. ^ Lehrman, G.; Hogue, I. B.; Palmer, S.; Jennings, C.; Spina, C. A.; Wiegand, A.; Landay, A. L.; Coombs, R. W.; Richman, D. D.; Mellors, J. W.; Coffin, J. M.; Bosch, R. J.; Margolis, D. M. (2005). "Depletion of latent HIV-1 infection in vivo: A proof-of-concept study". The Lancet 366 (9485): 549–555. doi:10.1016/S0140-6736(05)67098-5. PMC 1894952. PMID 16099290.  edit
  7. ^ Sagot-Lerolle, N.; Lamine, A.; Chaix, M. L.; Boufassa, F.; Aboulker, J. P.; Costagliola, D.; Goujard, C. C.; Pallier, C.; Delfraissy, J. F. O.; Lambotte, O.; Anrs Ep39, S. (2008). "Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir". AIDS 22 (10): 1125–1129. doi:10.1097/QAD.0b013e3282fd6ddc. PMID 18525257.  edit
  8. ^ "Annual Report 2007" (PDF). TopoTarget. 14 March 2008. Retrieved 2008-11-23. 
  9. ^ Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, Melton DA (2008). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology, 26, 1269 - 1275.
  10. ^ http://news.e-healthsource.com/index.php?p=news1&id=529147
  11. ^ Gervain, J.; Vines, B. W.; Chen, L. M.; Seo, R. J.; Hensch, T. K.; Werker, J. F.; Young, A. H. (2013). "Valproate reopens critical-period learning of absolute pitch". Frontiers in Systems Neuroscience 7: 102. doi:10.3389/fnsys.2013.00102. PMC 3848041. PMID 24348349.  edit
  12. ^ Burton B.S. (1882). "On the propyl derivatives and decomposition products of ethylacetoacetate". Am Chem J. 3: 385–395. 
  13. ^ Meunier, H.; Carraz, G.; Neunier, Y.; Eymard, P.; Aimard, M. (1963). "Pharmacodynamic properties of N-dipropylacetic acid". Therapie 18: 435–438. PMID 13935231.  edit
  14. ^ 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
  15. ^ Henry, T. R. (2003). "The history of valproate in clinical neuroscience". Psychopharmacology bulletin. 37 Suppl 2: 5–16. PMID 14624229.  edit
  16. ^ Rosenberg, G. (2007). "The mechanisms of action of valproate in neuropsychiatric disorders: Can we see the forest for the trees?". Cellular and Molecular Life Sciences 64 (16): 2090–2103. doi:10.1007/s00018-007-7079-x. PMID 17514356.  edit
  17. ^ a b Leng, Y.; Liang, M. -H.; Ren, M.; Marinova, Z.; Leeds, P.; Chuang, D. -M. (2008). "Synergistic Neuroprotective Effects of Lithium and Valproic Acid or Other Histone Deacetylase Inhibitors in Neurons: Roles of Glycogen Synthase Kinase-3 Inhibition". Journal of Neuroscience 28 (10): 2576–2588. doi:10.1523/JNEUROSCI.5467-07.2008. PMID 18322101.  edit
  18. ^ a b Feng, H. -L.; Leng, Y.; Ma, C. -H.; Zhang, J.; Ren, M.; Chuang, D. -M. (2008). "Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model". Neuroscience 155 (3): 567–572. doi:10.1016/j.neuroscience.2008.06.040. PMC 2709275. PMID 18640245.  edit
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  20. ^ a b BALANCE investigators and collaborators; Geddes, J. R.; Goodwin, G. M.; Rendell, J.; Azorin, J. M.; Cipriani, A.; Ostacher, M. J.; Morriss, R.; Alder, N.; Juszczak, E. (2010). "Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): A randomised open-label trial". The Lancet 375 (9712): 385–395. doi:10.1016/S0140-6736(09)61828-6. PMID 20092882.  edit
  21. ^ Mitchell, P.; Withers, K.; Jacobs, G.; Hickie, I. (1994). "Combining lithium and sodium valproate for bipolar disorder". The Australian and New Zealand journal of psychiatry 28 (1): 141–143. doi:10.3109/00048679409075856. PMID 8067959.  edit
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  23. ^ 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
  24. ^ http://www.lawyersandsettlements.com/lawsuit/valproate-not-to-be-used-migraine-during-pregnancy.html#.UZPulit35cI
  25. ^ British National Formulary (March 2003) 45
  26. ^ 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
  27. ^ Cassels, Caroline (December 8, 2006). "NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids". Medscape. Retrieved 2007-05-23. 
  28. ^ 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
  29. ^ 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
  30. ^ 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
  31. ^ 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
  32. ^ I.Q. Harmed by Epilepsy Drug in Utero By RONI CARYN RABIN, New York Times, April 15, 2009
  33. ^ 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
  34. ^ Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy). FDA. June 2011
  35. ^ "Highlights of Prescribing Information". 
  36. ^ Wadzinski, J.; Franks, R.; Roane, D.; Bayard, M. (2007). "Valproate-associated Hyperammonemic Encephalopathy". The Journal of the American Board of Family Medicine 20 (5): 499–502. doi:10.3122/jabfm.2007.05.070062. PMID 17823470.  edit
  37. ^ Chopra, A.; Kolla, B. P.; Mansukhani, M. P.; Netzel, P.; Frye, M. A. (2012). "Valproate-induced hyperammonemic encephalopathy: An update on risk factors, clinical correlates and management". General Hospital Psychiatry 34 (3): 290–298. doi:10.1016/j.genhosppsych.2011.12.009. PMID 22305367.  edit
  38. ^ Gerstner, T.; Buesing, D.; Longin, E.; Bendl, C.; Wenzel, D.; Scheid, B.; Goetze, G.; Macke, A.; Lippert, G.; Klostermann, W.; Mayer, G.; Augspach-Hofmann, R.; Fitzek, S.; Haensch, C. A.; Reuland, M.; Koenig, S. A. (2006). "Valproic acid induced encephalopathy – 19 new cases in Germany from 1994 to 2003 – A side effect associated to VPA-therapy not only in young children". Seizure 15 (6): 443–448. doi:10.1016/j.seizure.2006.05.007. PMID 16787750.  edit
  39. ^ Williams, D. C.; Massey, G. V.; Russell, E. C.; Riley, R. S.; Ben-Ezra, J. (2008). "Translocation positive acute myeloid leukemia associated with valproic acid therapy". Pediatric Blood & Cancer 50 (3): 641–643. doi:10.1002/pbc.21149. PMID 17262798.  edit
  40. ^ Coyle, T. E.; Bair, A. K.; Stein, C.; Vajpayee, N.; Mehdi, S.; Wright, J. (2005). "Acute leukemia associated with valproic acid treatment: A novel mechanism for leukemogenesis?". American Journal of Hematology 78 (4): 256–260. doi:10.1002/ajh.20273. PMID 15795916.  edit
  41. ^ Hu, X.; Wang, J.; Dong, W.; Fang, Q.; Hu, L.; Liu, C. (2011). "A meta-analysis of polycystic ovary syndrome in women taking valproate for epilepsy". Epilepsy Research 97 (1–2): 73–82. doi:10.1016/j.eplepsyres.2011.07.006. PMID 21820873.  edit
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