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- Depakene, Depakote, Epival
- 関
- Valproic acid
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Wikipedia preview
出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/04/20 08:48:32」(JST)
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| Systematic (IUPAC) name | |
|---|---|
| 2-Propylpentanoic acid | |
| Clinical data | |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682412 |
| Licence data | US FDA:link |
| Pregnancy cat. | D—teratogenic |
| Legal status | POM (UK) ℞-only (US) |
| Routes | Oral, intravenous |
| Pharmacokinetic data | |
| Bioavailability | Rapid absorption |
| Protein binding | Concentration-dependent, from 90% at 40 µg/mL to 81.5% at 130 µg/mL |
| Metabolism | Hepatic—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40% |
| Half-life | 9–16 h |
| Excretion | Less than 3% excreted unchanged in urine. |
| Identifiers | |
| CAS number | 99-66-1 Y |
| ATC code | N03AG01 |
| PubChem | CID 3121 |
| DrugBank | DB00313 |
| 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 |
| Mol. mass | 144.211 g/mol |
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| Y (what is this?) (verify) |
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Valproic acid (VPA), 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 and schizophrenia. 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]
Contents
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Uses
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]
Investigational
HIV
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.[5] 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.[6]
Other diseases
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.[7]
Stem cells
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.[8] This function has also been investigated as an epigenetic therapy for treatment of lupus.[9][dead link]
History
Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian.[10]. 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.[11] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[12] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[13]
Mechanism of action
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.[14]
Valproic acid also blocks the 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.
Contraindications
Safety in pregnancy
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".[15] 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.[16]
Women who intend to become pregnant should switch to a different drug if possible. Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although 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.[17]
Valproate is a folate antagonist[18], 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.[19][20]
Risk of autism
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.[21]
One study found 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.[22]
Risk of low IQ
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.[23][24][25][26]
Adverse effects
Adverse effects is 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.[27]
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 or 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.[28] Valproate levels within the normal range are capable of causing hyperammonemia and ensuing encephalopathy. Taking lactulose may alleviate the hyperammonemia. There have been reports of the development of brain encephalopathy without hyperammonemia or elevated valproate levels.[29]
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.[30][31]
Cognitive dysfunction, Parkinsonian symptoms,[32] and even (reversible) pseudoatrophic brain changes have been reported[33] 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.
Dosing
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 Depakine up to 3000 mg a day. For acute treatment of bipolar type 1 the minimum dose would be 1000 mg a day.
Overdosage
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. In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[34][35][36]
Interactions
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.[37] 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.[38]
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.[38]
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
Branded products include:
- Convulex (Pfizer in the UK and Byk Madaus in South Africa)
- Depakene (Abbott Laboratories in U.S. & Canada)
- Depakine (Sanofi Aventis France)
- Depakine (Sanofi Synthelabo Romania)
- Deprakine (Sanofi Aventis Finland)
- Encorate (Sun Pharmaceuticals India)
- Epival (Abbott Laboratories U.S. & Canada)
- Epilim (Sanofi Synthelabo Australia)
- Stavzor (Noven Pharmaceuticals Inc.)
- Valcote (Abbott Laboratories Argentina)
Chemistry
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.[39][40][41][42]
References
- ^ Alvarez-Breckinridge C.A.; Yu, J; Price, R; Wei, M; Wang, Y; Nowicki, MO; Ha, YP; Bergin, S et al. (2012). "The HDAC inhibitor valproic acid lessens NK cell action against oncolytic virus-infected glioblastoma cells with inhibition of STAT5/T-BET signaling and IFNγ generation". J. Virology 86 (7): 4566–77. doi:10.1128/JVI.05545-11. PMC 3318659. PMID 22318143.
|displayauthors=suggested (help) - ^ Posner E, Lorenzo N (October 11, 2006). "Posttraumatic epilepsy". Emedicine.com. Retrieved on 2008-07-30.
- ^ "FDA Issues Approvable Letter For Stavzor Delayed Release Valproic Acid Capsules". 2007 MediLexicon International Ltd. 2007-10-25. Retrieved 2007-10-29.
- ^ 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.
- ^ Lehrman G, Hogue I, Palmer S, Jennings C, Spina C, Wiegand A, Landay A, Coombs R, Richman D, Mellors J, Coffin J, Bosch R, Margolis D (2005). "Depletion of latent HIV-1 infection in vivo: a proof-of-concept study". Lancet 366 (9485): 549–55. doi:10.1016/S0140-6736(05)67098-5. PMC 1894952. PMID 16099290.
- ^ Sagot-Lerolle N, Lamine A, Chaix ML, Boufassa F, Aboulker JP, Costagliola D, Goujard C, Paller C, Delfraissy JF, Lambotte O; ANRS EP39 study (2008). "Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir". AIDS 22 (10): 1125–29. doi:10.1097/QAD.0b013e3282fd6ddc. PMID 18525257.
- ^ "Annual Report 2007" (PDF). TopoTarget. 14 March 2008. Retrieved 2008-11-23.
- ^ 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.
- ^ http://sexualhealth.e-healthsource.com/index.php?p=news1&id=529147
- ^ Burton B.S. (1882). "On the propyl derivatives and decomposition products of ethylacetoacetate". Am Chem J. 3: 385–395.
- ^ Meunier H, Carraz G, Meunier Y, Eymard P, Aimard M (1963). "Propriétés pharmacodynamiques de l'acide n-dipropylacetique". Therapie 18: 435–438. PMID 13935231.
- ^ Perucca E (2002). "Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience". CNS Drugs 16 (10): 695–714. doi:10.2165/00023210-200216100-00004. PMID 12269862.
- ^ Henry T.R. (2003). "The History of Valproate in Clinical Neuroscience". Psychopharmacology bulletin 37 (Suppl 2): 5–16. PMID 14624229.
- ^ 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): 2090–103. doi:10.1007/s00018-007-7079-x. PMID 17514356.
- ^ 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 (October 2006). "Fetal valproate syndrome". Indian J Pediatr 73 (10): 937–9. doi:10.1007/BF02859291. PMID 17090909.
- ^ British National Formulary (March 2003) 45
- ^ 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
- ^ 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, et al. (2006). "In utero antiepileptic drug exposure: Fetal death and malformations". Neurology 67 (3): 407–12. doi:10.1212/01.wnl.0000227919.81208.b2. PMC 1986655. PMID 16894099.
- ^ Arndt TL, Stodgell CJ, Rodier PM (2005). "The teratology of autism". Int J Dev Neurosci 23 (2–3): 189–99. doi:10.1016/j.ijdevneu.2004.11.001. PMID 15749245.
- ^ Rinaldi T, Silberberg G, Markram H (2007). "Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid". Cereb Cortex 18 (4): 763–70. 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
- ^ Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs, Kimford J. Meador et al. for the NEAD Study Group, N Engl J Med 360:1597 April 16, 2009
- ^ Meador KJ, Baker GA, Browning N et al. (2009). "Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs". New England Journal of Medicine 360 (16): 1597–605. 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
- ^ "Highlights of Prescribing Information".
- ^ 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.
- ^ Gerstner T, Büsing D, Longin E et al. (2007). "Valproic Acid associated encephalopathy -19 new cases in Germany from 1994 to 2003- a side effect associated to VPA-therapy not only in young children". Neuropediatrics 37 (6). doi:10.1055/s-2006-973995.
- ^ Williams DC Jr, Massey GV, Russell EC, Riley RS, Ben-Ezra J. (Mar 2007). "Translocation positive acute myeloid leukemia associated with valproic acid therapy". Pediatric Blood and Cancer 50 (3): 641–3. doi:10.1002/pbc.21149. PMID 17262798.
- ^ Coyle TE, Bair AK, Stein C, Vajpayee N, Mehdi S, Wright J. (2005). "Acute leukemia associated with valproic acid treatment: a novel mechanism for leukemogenesis?". Pediatric Blood and Cancer Apr (78): 256–60. doi:10.1002/ajh.20273. PMID 15795916.
- ^ Ricard C, Martin K, Tournier M, Bégaud B, Verdoux H (2005). "[A case of Parkinsonian syndrome, cognitive impairment and hyperammonemia induced by divalproate sodium prescribed for bipolar disorder]". L'Encéphale (in French) 31 (1 Pt 1): 98–101. doi:10.1016/S0013-7006(05)82378-4. PMID 15971646.
- ^ McLachlan RS (1987). "Pseudoatrophy of the brain with valproic acid monotherapy". The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 14 (3): 294–6. PMID 3117347.
- ^ Sztajnkrycer MD. Valproic acid toxicity: overview and management. Clin. Toxicol. 40: 789-801, 2002.
- ^ Thanacoody RH. Extracorporeal elimination in acute valproic acid poisoning. Clin. Toxicol. 47: 609-616, 2009.
- ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622-1626.
- ^ Gonzalez, Frank J.; Robert H. Tukey (2006). "Drug Metabolism". In Laurence Brunton, John Lazo, Keith Parker (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. p. 79. ISBN 978-0-07-142280-2.
- ^ a b "Depakene side effects (Valproic Acid) and drug interactions". RxList.com. 2007. Retrieved 2007-06-07.
- ^ M. Chignac, C. Grain, U.S. Patent 4,155,929 (1979)
- ^ H.E.J.-M. Meunier, GB 980279 (1963)
- ^ H.E.J.-M. Meunier, U.S. Patent 3,325,361 (1967)
- ^ M. Chignac, C. Grain, Ch. Pigerol, GB 1522450 (1977)
Further reading
- T.R. Henry, "The History of Valproate in Clinical Neuroscience." Psychopharmacology bulletin (2003) 37 (Suppl 2):5-16 (More details on history)
External links
- The Lundbeck Institute Guide to Psychotropics - Valproic acid
- http://www.psycheducation.org/depression/meds/moodstabilizers.htm
- http://www.psycheducation.org/depression/meds/valproate.htm
- 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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English Journal
- Outcome of lamotrigine treatment in juvenile myoclonic epilepsy.
- Bodenstein-Sachar H, Gandelman-Marton R, Ben-Zeev B, Chapman J, Blatt I.SourceDepartment of Neurology, Sheba Medical Center, Tel-Hashomer Tel-Aviv University Sackler School of Medicine, Tel-Aviv Department of Neurology, Assaf Harofe Medical Center, Zerifin Pediatric Neurology Unit, Sheba Medical Center, Tel-Hashomer, Israel.
- Acta neurologica Scandinavica.Acta Neurol Scand.2011 Jul;124(1):22-7. doi: 10.1111/j.1600-0404.2010.01472.x. Epub 2011 Jan 6.
- Bodenstein-Sachar H, Gandelman-Marton R, Ben-Zeev B, Chapman J, Blatt I. Outcome of lamotrigine treatment in juvenile myoclonic epilepsy. Acta Neurol Scand: 2011: 124: 22-27. c 2011 John Wiley & Sons A/S. Objectives?-? To determine the response rate of patients with juvenile myoclonic epile
- PMID 21208196
- The Mental Retardation Associated Protein, srGAP3 Negatively Regulates VPA-Induced Neuronal Differentiation of Neuro2A Cells.
- Chen K, Mi YJ, Ma Y, Fu HL, Jin WL.SourceInstitute of Neurosciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
- Cellular and molecular neurobiology.Cell Mol Neurobiol.2011 Jul;31(5):675-86. Epub 2011 Feb 25.
- The Slit-Robo GTPase-activating proteins (srGAPs) are important multifunctional adaptor proteins involved in various aspects of neuronal development, including axon guidance, neuronal migration, neurite outgrowth, dendritic morphology and synaptic plasticity. Among them, srGAP3, also named MEGAP (Me
- PMID 21350945
Japanese Journal
- Depakote adjunctive therapy in the treatment of partial seizures
- WILLMORE JL.
- Epilepsia 36(suppl 3), 66, 1995
- NAID 10009184814
- Positive response to oral divalproex sodium (Depakote) in patients with spasticity and pain
- ZACHARIAH GH.
- Am J Med Sci 308, 38-40, 173-187, 1994
- NAID 30009097115
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