- 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）』「2016/08/24 13:41:37」(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 |
| License data |
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| Pregnancy category |
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| Routes of administration |
By mouth, intravenous |
| Legal status | |
| Legal status |
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| 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 Number | 99-66-1 Y |
| ATC code | N03AG01 (WHO) |
| 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 |
| Molar mass | 144.211 g/mol |
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SMILES
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InChI
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Valproate (VPA), and its valproic acid, sodium valproate, and divalproex sodium forms, are medications primarily used to treat epilepsy and bipolar disorder and to prevent migraine headaches.[2] It is useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. It can be given intravenously or by mouth. Long acting formulations exist.[2]
Common side effects include nausea, vomiting, sleepiness, and a dry mouth. Serious side effects can include liver problems and regular monitoring of liver function tests is therefore recommended. Other serious risks include pancreatitis and an increased suicide risk. It is known to cause serious abnormalities in the baby if taken during pregnancy. Because of this it is not typically recommended in women of childbearing age who have migraines. It is unclear how valproate works.[2]
Valproate was first made in 1881 and came into medical use in 1962.[3] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[4] It is available as a generic medication.[2] The wholesale cost in the developing world is between 0.14 and 0.52 USD per day.[5] In the United States it costs about 0.90 USD per day. It is marketed under the brand name Depakote among others.[2]
Contents
- 1 Terminology
- 2 Medical uses
- 2.1 Epilepsy
- 2.2 Psychiatric disorders
- 2.3 Migraines
- 2.4 Other
- 3 Adverse effects
- 3.1 Other possible side effects
- 3.2 Pregnancy
- 3.3 Elderly
- 3.4 Contraindications
- 3.5 Interactions
- 3.6 Overdose and toxicity
- 4 Mechanism of action
- 5 History
- 6 Approval status
- 7 Formulations
- 7.1 Brand names of valproic acid
- 7.2 Brand names of sodium valproate
- 7.2.1 Portugal
- 7.2.2 United States
- 7.2.3 Australia
- 7.2.4 New Zealand
- 7.2.5 UK
- 7.2.5.1 UK only
- 7.2.6 Germany, Switzerland, Norway, Finland, Sweden
- 7.2.7 South Africa
- 7.2.8 Malaysia
- 7.2.9 Romania
- 7.2.10 Canada
- 7.2.11 Japan
- 7.2.12 Europe
- 7.2.13 Taiwan
- 7.2.14 Israel
- 7.2.15 India, Russia and CIS countries
- 7.3 Brand names of valproate semisodium
- 8 Research
- 9 References
- 10 Further reading
- 11 External links
Terminology
Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as divalproex sodium.
Medical uses
It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.[6]
Epilepsy
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.[6][7] It has also been successfully given intravenously to treat status epilepticus.[8][9]
Psychiatric disorders
Valproate products are also used to treat manic or mixed episodes of bipolar disorder.[10]
Off-label uses include impulse control disorders, suggested by recent evidence of efficacy in controlling this adverse effect of Parkinson's disease medical therapy.[11]
Migraines
Valproate is also used to prevent migraine headaches. Because this medication can be potentially harmful to the fetus, valproate should be considered for women of childbearing potential only after the risks have been discussed.[12]
Other
The medication has been tested in the treatment of AIDS and cancer, owing to its histone deacetylase-inhibiting effects.[13]
Adverse effects
See also: List of adverse effects of valproic acid and List of adverse effects of valproate semisodium
Most common adverse effects include:[12]
- Nausea (22%)
- Drowsiness (19%)
- Dizziness (12%)
- Vomiting (12%)
- Weakness (10%)
Serious adverse effects include:[12]
- Bleeding
- Low blood platelets
- Encephalopathy
- Suicidal behavior and thoughts
- Low body temperature
Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.[12]
Other possible side effects
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[14][15][16][17] Valproic acid can also cause mydriasis, a dilation of the pupils.[18] There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder.[19]
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.[20][21] 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 a triangle-shaped forehead, 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] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[24]
Children of mothers taking valproate during pregnancy are at risk for lower IQs.[25][26][27] Maternal valproate use during pregnancy has been associated with a significantly higher probability of autism in the offspring.[28] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[29] The normal incidence for autism in the general population is estimated at less than one percent.[30] 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.[31][32][33]
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.[34][35]
Women who intend to become pregnant should switch to a different medication if possible, or decrease their dose of valproate.[36] 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.) Studies have shown that taking folic acid can reduce the risk of congenital neural tube defects.[12]
Elderly
Valproate in elderly people with dementia caused increased sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake was also associated in one-half of people who become sleepy.[12]
Contraindications
Contraindications include:[37]
- 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 ingredients used in the preparation
- Urea cycle disorders
- Hepatic porphyria
- Hepatotoxicity[37]
- Mitochondrial disease[37]
- Pancreatitis[37]
- Porphyria[38]
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.[37] It may also potentiate the CNS depressant effects of alcohol.[37] 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.[37] It may also interact with:[12][37][39]
- Aspirin: may increase valproate concentrations. May also interfere with valproate's metabolism.
- Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
- Carbapenem antibiotics: reduces valproate levels, potentially leading to seizures.
- Cimetidine: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
- Erythromycin: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
- Ethosuximide: may increase ethosuximide concentrations and lead to toxicity.
- Felbamate: may increase plasma concentrations of valproate.
- Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
- Oral contraceptives: may reduce plasma concentrations of valproate.
- Primidone: may decrease pyrimidone clearance leading to toxicity.
- Rifampin: increases the clearance of valproate, leading to decreased valproate concentrations
- Warfarin: may increase warfarin concentration and prolong bleeding time.
- Zidovudine: may increase zidovudine serum concentration and lead to toxicity.
Overdose and toxicity
| Form | Lower limit | Upper limit | Unit |
| Total (including protein bound) |
50[40] | 125[40] | µg/mL or mg/l |
| 350[41] | 700[41] | μmol/L | |
| Free | 6[40] | 22[40] | µg/mL or mg/l |
| 35[41] | 70[41] | μmol/L |
Excessive amounts of valproic acid can result in sleepiness, 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.[42] 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).[43]
In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[44][45] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[12] Supplemental L-carnitine is indicated in patients having an acute overdose[46][47] and also prophylactically[46] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[48] than L-carnitine.
Mechanism of action
Although the mechanism of action of valproate is not fully understood,[37] it has recently been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[49] 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).[37] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[37] 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.[37]
It also has 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.[50][51]
Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a non-steroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.[52] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[53] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[52][53]
History
Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[54] 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.[55] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[56] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[57]
Approval status
| Indications | FDA-labelled indication?[1] |
TGA-labelled indication?[6] |
MHRA-labelled indication?[58] |
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).[59][60][61][62] |
| Bipolar mania | Yes | Yes | Yes | Limited.[63] |
| Bipolar depression | No | No | No | Moderate.[64] |
| Bipolar maintenance | No | No | No | Limited.[65] |
| Migraine prophylaxis | Yes | Yes (accepted) | No | Limited. |
| Acute migraine management | No | No | No | Only negative results.[66] |
| Schizophrenia | No | No | No | Weak and mostly negative evidence.[67] |
| Agitation in dementia | No | No | No | Weak and mostly negative evidence.[68] |
| Fragile X syndrome | Yes (orphan) | No | No | Limited.[69] |
| Familial adenomatous polyposis | Yes (orphan) | No | No | Limited. |
| Chronic pain & fibromyalgia | No | No | No | Limited.[70] |
| Alcohol hallucinosis | No | No | No | One randomised double-blind placebo-controlled trial.[71] |
| Intractable hiccups | No | No | No | Limited, five case reports support its efficacy, however.[72] |
| Non-epileptic myoclonus | No | No | No | Limited, three case reports support its efficacy, however.[73] |
| Cluster headaches | No | No | No | Limited, two case reports support its efficacy.[74] |
| West syndrome | No | No | No | A prospective clinical trial supported its efficacy in treating infantile spasms.[75] |
| HIV infection eradication | No | No | No | Double-blind placebo-controlled trials have been negative.[76][77][78] |
| Myelodysplastic syndrome | No | No | No | Several clinical trials have confirmed its efficacy as a monotherapy,[79] as an adjunct to tretinoin[79] and as an adjunct to hydralazine.[80] |
| 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.[81][82][83] |
| Cervical cancer | No | No | No | One clinical trial supports its use here.[84] |
| Malignant melanoma | No | No | No | One phase II study has seemed to discount its efficacy.[85] |
| Breast cancer | No | No | No | A phase II study has supported its efficacy.[86] |
| Impulse control disorder | No | No | No | Limited.[11][87] |
Formulations
| Systematic (IUPAC) name | |
|---|---|
|
sodium 2-propylpentanoate
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|
| Identifiers | |
| CAS 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 |
| Molar mass | 166.20 g·mol−1 |
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Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more of sodium vaproate is needed than valproic acid without sodium to compensate for the sodium itself.[88]
Brand names of valproic acid
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.[89]
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
Research
As of 2016[update] it is also registered for 45 phase II clinical trials (some completed) for various cancers.[90]
References
- ^ a b c d "Depakene, Stavzor (valproic acid) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 13 February 2014.
- ^ a b c d e "Valproic Acid". The American Society of Health-System Pharmacists. Retrieved Oct 23, 2015.
- ^ Scott, D.F. (1993). The history of epileptic therapy : an account of how medication was developed (1. publ. ed.). Carnforth u.a.: Parthenon Publ. Group. p. 131. ISBN 9781850703914.
- ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ "Sodium Valproate". International Drug Price Indicator Guide.
- ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- ^ 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.
- ^ "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.
- ^ a b c d e f g h "DEPAKOTE- divalproex sodium tablet, delayed release". 09/15. Retrieved 10 November 2015. Check date values in:
|date=(help) - ^ 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.
- ^ 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.
- ^ Bilo, Leonilda; Meo, Roberta (October 2008). "Polycystic ovary syndrome in women using valproate: a review.". Gynecological Endocrinology. doi:10.1080/09513590802288259. PMID 19012099.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Autism Society of America: About Autism
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- ^ 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.
- ^ 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. doi:10.1111/j.1528-1157.1988.tb03760.x. PMID 2842127.
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- ^ Phase II cancer trials of valproic acid
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. 抗てんかん剤：作用機序、薬理学、および有害事象 antiepileptic drugs mechanism of action pharmacology and adverse effects
- 3. 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
- 4. てんかんおよび妊娠に関連するリスク risks associated with epilepsy and pregnancy
- 5. 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
English Journal
- Delayed toxicity following ingestion of enteric-coated divalproex sodium (Epival).
- Brubacher JR, Dahghani P, McKnight D.Author information Department of Emergency Medicine, Vancouver Hospital and Health Sciences Centre, British Columbia, Canada.AbstractToxicity occurs rapidly after overdose with regular-release valproic acid, but there is less experience with enteric-coated formulations. We report a case of delayed onset of toxicity and time to peak levels after ingestion of enteric-coated divalproex sodium (Epival). The patient was a 24-year-old female who ingested an unknown amount of Epival together with ibuprofen, dimenhydrinate, and ethanol. Ninety minutes after ingestion, the patient had only mild toxicity, and valproic acid was undetectable in her blood. By 13 h post-ingestion, valproate levels were 7450 micromol/L (1,075 mg/L), and the patient was comatose and required endotracheal intubation and mechanical ventilation. The toxicity and pharmacokinetics of valproic acid are discussed in the context of this case, and management guidelines are proposed.
- The Journal of emergency medicine.J Emerg Med.1999 May-Jun;17(3):463-7.
- Toxicity occurs rapidly after overdose with regular-release valproic acid, but there is less experience with enteric-coated formulations. We report a case of delayed onset of toxicity and time to peak levels after ingestion of enteric-coated divalproex sodium (Epival). The patient was a 24-year-old
- PMID 10338240
- Single-dose kinetics and bioavailability of sodium-hydrogen divalproate.
- Anderson P, Elwin CE.AbstractSodium-hydrogen divalproate (SHD) is a new chemical entity that quickly dissociates into valproic acid (VPA) and sodium valproate in water and is absorbed as VPA from the gastrointestinal tract. SHD is formulated as an enteric-coated tablet and may also result in less gastrointestinal irritation than other preparations of VPA. The bioavailability of valproate from SHD enteric-coated tablets (Epival, Abbott-50711) and from sodium valproate enteric-coated tablets (Ergenyl) was compared in a single-dose, double-blind, crossover study. Fourteen healthy volunteers (mean age 28.7 years) participated. A single oral dose of 250 mg SHD (assayed potency 249.3 mg VPA) or 300 mg sodium valproate (assayed potency 251.1 mg VPA) was given to each volunteer. Blood samples were collected intermittently up to 48 h and VPA in serum was assayed by gas chromatography. The areas under the serum concentration-time curves (AUC0----infinity) did not show any statistically significant difference (2,925.0 +/- 189.1 versus 2,816.2 +/- 162.2 h X mumol/L) between SHD and sodium valproate. The elimination parameters for SHD were t1/2 = 12.6 +/- 0.7 h and CLs = 0.008 +/- 0.0005 L/kg/h. Vd,area was 0.146 +/- 0.004 L/kg. Data for sodium valproate were not significantly different. Thus, the extent of bioavailability and the single-dose kinetics of SHD and sodium valproate are similar with the exception of a more rapid absorption (Tmax 2.37 versus 3.23 h) and a higher concentration (Cmax 192 versus 176 mumol/L) for SHD. Both of these differences were statistically significant (p less than 0.01).
- Clinical neuropharmacology.Clin Neuropharmacol.1985;8(2):156-64.
- Sodium-hydrogen divalproate (SHD) is a new chemical entity that quickly dissociates into valproic acid (VPA) and sodium valproate in water and is absorbed as VPA from the gastrointestinal tract. SHD is formulated as an enteric-coated tablet and may also result in less gastrointestinal irritation tha
- PMID 3924399
Related Links
- What are the side effects of Epival? Are patients happy when taking Epival? Compare patients positive and negative experiences with Epival and alternative drugs. ... Discussed topics: Lamictal Keppra Epival Seizures Pregnancy and ...
- Divalproex belongs to the family of medications called anticonvulsants. It is used to manage and control of certain types of seizures. It can be used alone or in combination with other seizure control medications. It is also used for ...
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