- 同
- Depakene, Depakote, Epival
- 関
- Valproic acid
目次
Wikipedia preview
出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/03 07:45:17」(JST)
wiki en
| Systematic (IUPAC) name | |
|---|---|
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2-propylpentanoic acid
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| Clinical data | |
| Trade names | Convulex, Depakote, Epilim, Stavzor, Vilapro |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682412 |
| Licence data | US FDA:link |
| Pregnancy category |
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| Legal status |
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| Routes of administration |
Oral, intravenous |
| Pharmacokinetic data | |
| Bioavailability | Rapid absorption |
| Protein binding | 80-90%[1] |
| Metabolism | Hepatic—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40% |
| Biological half-life | 9–16 hours[1] |
| Excretion | Urine (30-50%)[1] |
| Identifiers | |
| CAS Registry Number | 99-66-1 Y |
| ATC code | N03AG01 |
| PubChem | CID: 3121 |
| DrugBank | DB00313 Y |
| ChemSpider | 3009 Y |
| UNII | 614OI1Z5WI Y |
| KEGG | D00399 Y |
| ChEBI | CHEBI:39867 Y |
| ChEMBL | CHEMBL109 Y |
| NIAID ChemDB | 057177 |
| Synonyms | 2-Propylvaleric acid |
| Chemical data | |
| Formula | C8H16O2 |
| Molecular mass | 144.211 g/mol |
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SMILES
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InChI
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| Y (what is this?) (verify) | |
Valproate (VPA, valproic acid), an acidic organic 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.[2]
Contents
- 1 Medical uses
- 2 Adverse effects
- 2.1 Other possible side effects
- 2.2 Pregnancy
- 2.3 Contraindications
- 2.4 Interactions
- 2.5 Overdose and toxicity
- 3 Mechanism of action
- 4 History
- 5 Society and culture
- 5.1 Approval status
- 6 Formulations
- 6.1 Brand names of valproate
- 6.2 Brand names of sodium valproate
- 6.2.1 Portugal
- 6.2.2 United States
- 6.2.3 Australia
- 6.2.4 New Zealand
- 6.2.5 UK
- 6.2.5.1 UK only
- 6.2.6 Germany, Switzerland, Norway, Finland, Sweden
- 6.2.7 South Africa
- 6.2.8 Malaysia
- 6.2.9 Romania
- 6.2.10 Canada
- 6.2.11 Japan
- 6.2.12 Europe
- 6.2.13 Taiwan
- 6.2.14 Israel
- 6.2.15 India, Russia and CIS countries
- 6.3 Brand names of valproate semisodium
- 7 References
- 8 Further reading
- 9 External links
Medical uses
Its primary use in medicine is in the treatment of epilepsy, bipolar mania and to protect against the development of migraines.[3] Valproate products are also used to treat manic or mixed episodes associated with bipolar disorder.[4] Off-label uses include impulse control disorders, suggested by recent evidence of efficacy in controlling this adverse effect of Parkinson's disease medical therapy.[5] Recently, it has been trialled in the treatment of HIV and cancer, owing to its histone deacetylase-inhibiting effects.[6] 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.[3][7] It has also been successfully given intravenously to treat status epilepticus.[8][9][10]
Adverse effects
See also: List of adverse effects of valproic acid and List of adverse effects of valproate semisodium
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.[3][11] 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.[3]
Other possible side effects
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[12][13][14][15] Valproic acid can also cause mydriasis, a protracted dilation of the pupils.[16]
Pregnancy
Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug.[17][18] More rarely, with several other defects, possibly including a "valproate syndrome".[19] 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.[20] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[21]
A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower IQs.[22][23][24] Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring.[25] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[26] The normal incidence for autism in the general population is estimated at less than one percent.[27] It is possible to duplicate features characteristic of autism in humans by exposing rat embryos to valproic acid at the time of neural tube closure.[28] 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.[29] 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.[30][31][32]
Sodium valproate has been associated with the rare condition paroxysmal tonic upgaze of childhood, also known as Ouvrier-Billson syndrome, from childhood or fetal exposure (this condition resolved after discontinuing valproate therapy.[33][34]
Women who intend to become pregnant should switch to a different medication if possible.[35] Valproate may best be avoided in women with localisation epilepsy, where more effective and less risky alternatives, such as carbamazepine, are available.[21] 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.[36] Women who are already pregnant and taking high doses of valproate should try to lower their doses.[37][38]
Contraindications
Contraindications include:[39]
- Pregnancy
- 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
- Hepatotoxicity[39]
- Mitochondrial disease[39]
- Pancreatitis[39]
- Porphyria[40]
Interactions
Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves.[39] It may also potentiate the CNS depressant effects of alcohol.[39] 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.[39] It may also interact with:[39]
- 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
| Form | Lower limit | Upper limit | Unit |
| Total (including protein bound) |
50[41] | 125[41] | µg/mL or mg/l |
| 350[42] | 700[42] | μmol/L | |
| Free | 6[41] | 22[41] | µg/mL or mg/l |
| 35[42] | 70[42] | μmol/L |
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.[43] 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).[44]
In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[45][46] Supplemental L-carnitine is indicated in patients having an acute overdose[47][48] and also prophylactically[47] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[49] than L-carnitine.
Mechanism of action
Although the mechanism of action of valproate is not fully understood,[39] it has recently been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[50] 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).[39] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[39] 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.[39] 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.[51][52]
History
Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian.[53] 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.[54] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[55] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[56]
Society and culture
Approval status
| Indications | FDA-labelled indication?[1] |
TGA-labelled indication?[3] |
MHRA-labelled indication?[11] |
Literature support |
|---|---|---|---|---|
| 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).[57][58][59][60] |
| Bipolar mania | Yes | Yes | Yes | Limited.[61] |
| Bipolar depression | No | No | No | Moderate.[62] |
| Bipolar maintenance | No | No | No | Limited.[63] |
| Migraine prophylaxis | Yes | No | No | Limited. |
| Acute migraine management | No | No | No | Only negative results.[64] |
| Schizophrenia | No | No | No | Weak and mostly negative evidence.[65] |
| Agitation in dementia | No | No | No | Weak and mostly negative evidence.[66] |
| Fragile X syndrome | Yes (orphan) | No | No | Limited.[67] |
| Familial adenomatous polyposis | Yes (orphan) | No | No | Limited. |
| Chronic pain & fibromyalgia | No | No | No | Limited.[68] |
| Alcohol hallucinosis | No | No | No | One randomised double-blind placebo-controlled trial.[69] |
| Intractable hiccups | No | No | No | Limited, five case reports support its efficacy, however.[70] |
| Non-epileptic myoclonus | No | No | No | Limited, three case reports support its efficacy, however.[71] |
| Cluster headaches | No | No | No | Limited, two case reports support its efficacy.[72] |
| West syndrome | No | No | No | A prospective clinical trial supported its efficacy in treating infantile spasms.[73] |
| HIV infection eradication | No | No | No | Double-blind placebo-controlled trials have been negative.[74][75][76] |
| Myelodysplastic syndrome | No | No | No | Several clinical trials have confirmed its efficacy as a monotherapy,[77] as an adjunct to tretinoin[77] and as an adjunct to hydralazine.[78] |
| 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.[79][80][81] |
| Cervical cancer | No | No | No | One clinical trial supports its use here.[82] |
| Malignant melanoma | No | No | No | One phase II study has seemed to discount its efficacy.[83] |
| Breast cancer | No | No | No | A phase II study has supported its efficacy.[84] |
| Impulse control disorder | No | No | No | Limited.[5][85] |
Formulations
| Systematic (IUPAC) name | |
|---|---|
|
sodium 2-propylpentanoate
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| Identifiers | |
| CAS Registry Number | 1069-66-5 Y |
| ChemSpider | 13428 Y |
| UNII | 5VOM6GYJ0D Y |
| KEGG | D00710 Y |
| ChEBI | CHEBI:9925 Y |
| ChEMBL | CHEMBL433 Y |
| Chemical data | |
| Formula | C8H15NaO2 |
| Molecular mass | 166.20 g·mol−1 |
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SMILES
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InChI
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Valproate exists in two main molecular variants: sodium valproate and valproate 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 of sodium vaproate is needed than valproate without sodium to compensate for the sodium itself.[86]
Brand names of valproate
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)
Brand names of sodium valproate
Portugal
- Tablets – Diplexil-R by Bial.
United States
- Intravenous injection – Depacon by Abbott Laboratories.
- Syrup – Depakene by Abbott Laboratories. (Note Depakene capsules are valproic acid).
- Depakote tablets are a mixture of sodium valproate and valproic acid.
- Tablets – Eliaxim by Bial.
Australia
- Epilim Crushable Tablets Sanofi
- Epilim Sugar Free Liquid Sanofi
- Epilim Syrup Sanofi
- Epilim Tablets Sanofi
- Sodium Valproate Sandoz Tablets Sanofi
- Valpro Tablets Alphapharm
- Valproate Winthrop Tablets Sanofi
- Valprease tablets Sigma
New Zealand
- Epilim by Sanofi-Aventis
All the above formulations are Pharmac-subsidised.[87]
UK
- Depakote Tablets (as in USA)
- Tablets – Orlept by Wockhardt and Epilim by Sanofi
- Oral solution – Orlept Sugar Free by Wockhardt and Epilim by Sanofi
- Syrup – Epilim by Sanofi-Aventis
- Intravenous injection – Epilim Intravenous by Sanofi
- Extended release tablets – Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
- Enteric-coated tablets – Epilim EC200 by Sanofi is a 200-mg sodium valproate enteric-coated tablet.
UK only
- Capsules – Episenta prolonged release by Beacon
- Sachets – Episenta prolonged release by Beacon
- Intravenous solution for injection – Episenta solution for injection by Beacon
Germany, Switzerland, Norway, Finland, Sweden
- Tablets – Orfiril by Desitin Pharmaceuticals
- Intravenous injection – Orfiril IV by Desitin Pharmaceuticals
South Africa
- Syrup – Convulex by Byk Madaus
- Tablets – Epilim by Sanofi-synthelabo
Malaysia
- Tablets – Epilim by Sanofi-Aventis
Romania
- Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH
- Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets
Canada
- Intravenous injection – Epival or Epiject by Abbott Laboratories.
- Syrup – Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.
Japan
- Tablets – Depakene by Kyowa Hakko Kirin
- Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa
- Syrup – Depakene by Kyowa Hakko Kogyo
Europe
In much of Europe, Depakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.
Taiwan
- Tablets (white round tablet) – Depakine (Chinese: 帝拔癲; pinyin: di-ba-dian) by Sanofi Winthrop Industrie (France)
Israel
Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.
India, Russia and CIS countries
- Valprol CR by Intas Pharmaceutical (India)
- Encorate Chrono by Sun Pharmaceutical (India)
- Serven Chrono by Leeven APL Biotech (India)
Brand names of valproate semisodium
- Brazil – Depakote by Abbott Laboratories
- Canada – Epival by Abbott Laboratories
- Mexico – Epival and Epival ER (extended release) by Abbott Laboratories
- United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics
- United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics
- India – Valance and Valance OD by Abbott Healthcare Pvt Ltd,Divalid ER by Linux laboratories Pvt Ltd,Valex ER by Sigmund Promedica, Dicorate by Sun Pharma
- Germany – Ergenyl Chrono by Sanofi-Aventis and generics
- Chile – Valcote and Valcote ER by Abbott Laboratories
- France and other European countries — Depakote
- Peru – Divalprax by AC Farma Laboratories
- China – Diprate OD
References
- ^ a b c d "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.
- ^ 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.
- ^ "Valproate Information". Fda.gov. Retrieved 2015-04-24.
- ^ a b 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. doi:10.1016/j.parkreldis.2011.03.003. PMID 21459656.
- ^ Činčárová L, Zdráhal Z, Fajkus J (2013). "New perspectives of valproic acid in clinical practice". Expert Opin Investig Drugs 22 (12): 1535–1547. doi:10.1517/13543784.2013.853037. PMID 24160174.
- ^ 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.
- ^ 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. doi:10.1111/j.1600-0404.2007.00847.x. PMID 17419829.
- ^ 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. doi:10.1186/1471-2377-13-98. PMC 3727978. PMID 23889906.
- ^ a b 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.
- ^ Koch S, Göpfert-Geyer I, Jäger-Roman E et al. (February 1983). "[Anti-epileptic agents during pregnancy. A prospective study on the course of pregnancy, malformations and child development]". Dtsch. Med. Wochenschr. (in German) 108 (7): 250–7. doi:10.1055/s-2008-1069536. PMID 6402356. CS1 maint: Explicit use of et al. (link)
- ^ Moore SJ, Turnpenny P, Quinn A et al. (July 2000). "A clinical study of 57 children with fetal anticonvulsant syndromes". J. Med. Genet. 37 (7): 489–97. doi:10.1136/jmg.37.7.489. PMC 1734633. PMID 10882750. CS1 maint: Explicit use of et al. (link)
- ^ Ornoy A (2009). "Valproic acid in pregnancy: how much are we endangering the embryo and fetus?". Reprod. Toxicol. 28 (1): 1–10. doi:10.1016/j.reprotox.2009.02.014. PMID 19490988.
- ^ Kulkarni ML, Zaheeruddin M, Shenoy N, Vani HN (2006). "Fetal valproate syndrome". Indian J Pediatr 73 (10): 937–939. doi:10.1007/bf02859291. PMID 17090909.
- ^ a b Adab N, Kini U, Vinten J et al. (November 2004). "The longer term outcome of children born to mothers with epilepsy". J. Neurol. Neurosurg. Psychiatr. 75 (11): 1575–83. doi:10.1136/jnnp.2003.029132. PMC 1738809. PMID 15491979.
This argues that the fetal valproate syndrome constitutes a real clinical entity that includes developmental delay and cognitive impairments, but that some children might exhibit some developmental delay without marked dysmorphism.
CS1 maint: Explicit use of et al. (link) - ^ Umur AS, Selcuki M, Bursali A, Umur N, Kara B, Vatansever HS, Duransoy YK (2012). "Simultaneous folate intake may prevent adverse effect of valproic acid on neurulating nervous system". Childs Nerv Syst 28 (5): 729–737. doi:10.1007/s00381-011-1673-9. PMID 22246336.
- ^ 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, Mawer G, Pennell PB, Smith JC, Wolff MC (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.
- ^ Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, 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.
- ^ Rasalam AD, Hailey H, Williams JH et al. (August 2005). "Characteristics of fetal anticonvulsant syndrome associated autistic disorder". Dev Med Child Neurol 47 (8): 551–5. doi:10.1017/S0012162205001076. PMID 16108456. CS1 maint: Explicit use of et al. (link)
- ^ Autism Society of America: About Autism
- ^ Arndt TL, Stodgell CJ, Rodier PM (2005). "The teratology of autism". Int. J. Dev. Neurosci. 23 (2-3): 189–199. doi:10.1016/j.ijdevneu.2004.11.001. PMID 15749245.
- ^ 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. doi:10.1093/cercor/bhm117. PMID 17638926.
- ^ 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, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW (2009). "Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs". N. Engl. J. Med. 360 (16): 1597–1605. doi:10.1056/NEJMoa0803531. PMC 2737185. PMID 19369666.
- ^ Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy). FDA. June 2011
- ^ Epileptic Disord. 2007 Sep; 9(3):332-6
- ^ J Child Neurol. 1988 Jul;3(3):177-80
- ^ Valproate Not To Be Used for Migraine During Pregnancy, FDA Warns
- ^ British National Formulary (March 2003) 45
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Further reading
- Chateauvieux S, Morceau F, Dicato M, Diederich M (2010). "Molecular and therapeutic potential and toxicity of valproic acid" (PDF). J. Biomed. Biotechnol. 2010: 1. doi:10.1155/2010/479364. PMC 2926634. PMID 20798865.
- Monti B, Polazzi E, Contestabile A (2009). "Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection" (PDF). Curr Mol Pharmacol 2 (1): 95–109. doi:10.2174/1874467210902010095. PMID 20021450.
External links
- 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)
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UpToDate Contents
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- 1. バルプロ酸中毒 valproic acid poisoning
- 2. 小児における痙攣およびてんかん症候群の治療の概要 overview of the treatment of seizures and epileptic syndromes in children
- 3. 抗てんかん剤の薬理学 pharmacology of antiepileptic drugs
- 4. 思春期における多嚢胞性卵巣症候群の診断的評価 diagnostic evaluation of polycystic ovary syndrome in adolescents
- 5. 成人における双極性障害：急性躁病および軽躁に対する薬物療法 bipolar disorder in adults pharmacotherapy for acute mania and hypomania
English Journal
- Ultrasonic emulsification of parenteral valproic acid-loaded nanoemulsion with response surface methodology and evaluation of its stability.
- Tan SF1, Masoumi HR2, Karjiban RA2, Stanslas J3, Kirby BP4, Basri M2, Basri HB5.
- Ultrasonics sonochemistry.Ultrason Sonochem.2016 Mar;29:299-308. doi: 10.1016/j.ultsonch.2015.09.015. Epub 2015 Sep 26.
- Response surface methodology (RSM) was used to optimize the formulation of a nanoemulsion for central delivery following parenteral administration. A mixture of medium-chain triglyceride (MCT) and safflower seed oil (SSO) was determined as a sole phase from the emulsification properties. Similarly,
- PMID 26585010
- The role of antiepileptic drugs in free radicals generation and antioxidant levels in epileptic patients.
- Eldin EE1, Elshebiny HA2, Mostafa Mohamed T3, Abdel-Aziz MA2, El-Readi MZ1,4,5.
- The International journal of neuroscience.Int J Neurosci.2016 Feb;126(2):105-15. doi: 10.3109/00207454.2014.994207. Epub 2015 May 22.
- Many risk factors are encountered during the pathogenesis of epilepsy. In this study, the effect of seizure frequency on free radical generation and antioxidants levels in epileptic patients was evaluated. This study was carried out on 15 healthy controls (GI) and 60 epileptic patients treated with
- PMID 25539180
- A novel combination of oridonin and valproic acid in enhancement of apoptosis induction of HL-60 leukemia cells.
- Shi M1, Ren X1, Wang X2, Wang H1, Liu G3, Yuan X1, Zheng S4, Yu L1, Pan S3, Song G1, Guo Q1, Li L1, Zhang X1, Zhang Z1, Ding H3, Jiang G1.
- International journal of oncology.Int J Oncol.2016 Feb;48(2):734-46. doi: 10.3892/ijo.2015.3294. Epub 2015 Dec 15.
- Oridonin, obtained from the traditional Chinese herbal medicine rabdosia rubescens, exerts potent antitumor activities in cancer cells. Valproic acid (VPA), as a potent histone deacetylase inhibitor (HDACI), also plays an important role in inhibition of proliferation of tumor cells. However, there a
- PMID 26676928
Japanese Journal
- 健常人におけるシロップ剤からのバルプロ酸の吸収に及ぼすエンシュア・リキッド^[○!R]及びマーロックス^[○!R]の影響
- 病院薬学 26(3), 259-263, 2000-06-10
- NAID 110001166976
- Pharmacokinetics of Cytosine Arabinoside, Methotrexate, Nimustine and Valproic Acid in Cerebrospinal Fluid during Cerebrospinal Fluid Perfusion Chemotherapy
- Biological & pharmaceutical bulletin 23(6), 784-787, 2000-06-01
- NAID 110003640068
- 健常人におけるシロップ剤からのバルプロ酸の吸収に及ぼすエンシュア・リキッド及びマーロックスの影響
- 病院薬学 26(3), 259-263, 2000
- NAID 130004299770
Related Links
- （Depakene） HOME 広告 通販 病院ランキング 血液検査 副作用 漢方薬 「テンカン」 「点頭テンカン」 「ケイレン」 「むずむず脚症候群」 「欠伸発作」 「意識障害 」 「痴呆症」 「脳細胞」 「活性酸素」 「鉛中毒」 テンカン ...
- Learn about Depakene (Valproic Acid) may treat, uses, dosage, side effects, drug interactions, warnings, patient labeling, reviews, and related medications. ... Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a ...
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