Valproic acid

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Valproic acid
Systematic (IUPAC) name
2-propylpentanoic acid
Identifiers
CAS number	99-66-1
ATC code	N03AG01
PubChem	3121
DrugBank	APRD00256
Chemical data
Formula	C₈H₁₆O₂
Mol. mass	144.211 g/mol
SMILES	search in eMolecules, PubChem
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 hours
Excretion	Less than 3% excreted unchanged in urine.
Therapeutic considerations
Pregnancy cat.	D - teratogenic
Legal status
Routes	Oral, IV

Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy and bipolar disorder. It is also used to treat migraine headaches and schizophrenia. In epileptics, 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 (administered intravenously) preparations of valproate are used also as second-line treatment of status epilepticus, alternatively to phenytoin.

Related drugs include the sodium salts sodium valproate, used as an anticonvulsant, and a combined formulation, valproate semisodium, used as a mood stabilizer and additionally in U.S. also as an anticonvulsant.

Valproate is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain, making it an alternative to lithium salts in treatment of bipolar disorder.

Valproic acid is an inhibitor of the enzyme histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. A study published in August 2005 revealed that patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a median 75% reduction in latent HIV infection.^[1]

According to the U.S. National Institutes of Health and others, valproic acid appears to have wide implications in the treatment of various cancers^[2], including multiple myeloma (bone marrow cancer)^[3], glioma (an aggressive type of brain tumor)^[4], and melanoma.^[5]. Valproic acid is cytotoxic to many different cancer types through its action as a histone-deacetylase inhibitor.

Another potential indication may be leukemia in juvenile patients. Studies conducted by several European centres are ongoing. Although it is too early to make a definitive statement, preliminary results are encouraging.^{[citation needed]}

1 History
2 Side effects
3 Contraindications
4 Formulations
5 References
6 External links

[edit] History

Valproic acid (by its official name 2-propylvaleric acid) was first synthesized in 1882 by Burton.^[6] A clear liquid fatty acid 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 valproic acid's antiseizure activity while using it as a vehicle for a number of other compounds that were being screened for anti-seizure activity. He found that it prevented pentylenetetrazol-induced convulsions in rodents.^[7] Since then it has also been used for migraine and bipolar disorder.^[8]

For more details see T.R. Henry, "The History of Valproate in Clinical Neuroscience." Psychopharmacology bulletin (2003) 37 (Suppl 2):5-16

[edit] Side effects

Common side effects are dyspepsia and/or weight gain. Less common are dysphoria, fatigue, peripheral edema, dizziness, drowsiness, hair loss, headaches, nausea, sedation and tremors. Valproic acid also causes hyperammonemia.

Rarely, valproic acid can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation times. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies. Due to these side effects, most doctors will ask for blood tests, initially as often as once a week and then once every 2 months. 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.^[9]^[10]

There have also been rare reports of cognitive dysfunction, Parkinson's disease, and even pseudoatrophic brain changes in long-term treatment with valproic acid.

[edit] Contraindications

Valproate is relatively contraindicated in pregnancy due to its teratogenicity; women who become pregnant whilst taking valproate should be counselled as to its risks, take high dose folic acid and be offered antenatal screening (alpha-fetoprotein and second trimester ultrasound scans).^[11]. It is a known folate antagonist, which can cause neural tube defects. Thus, folic acid supplements may alleviate the teratogenic problems.

Valproate is contraindicated in overweight patients because it causes weight gain as outlined above.

Preexisting liver damage, bone marrow depression, and coagulation disorders are additional contraindications.

It may be dangerous in combination with antidepressants, specifically venlafaxine (effexor). [confirmation needed]

[edit] Formulations

Branded products include Depakene (Abbott Laboratories in U.S. & Canada),Valpro (Alphapharm in Australia), Epilim (Sanofi-Aventis in the UK), Convulex (Pfizer in the UK and Byk Madaus in South Africa), Depakine and MicropakineLP by Sanofi-Aventis and Orfiril by Desitin Arzneimittel GmbH in Europe.

[edit] References

^ 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. "Depletion of latent HIV-1 infection in vivo: a proof-of-concept study". Lancet 366 (9485): 549–55. PMID 16099290.
^ Isenberg JS, Jia Y, Field L, Ridnour LA, Sparatore A, Del Soldato P, Sowers AL, Yeh GC, Moody TW, Wink DA, Ramchandran R, Roberts DD (2007). "Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid.". British Journal of Pharmacology Mar 12. PMID 17273758.
^ Schwartz C, Palissot V, Aouali N, Wack S, Brons NH, Leners B, Bosseler M, Berchem G (2007). "Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines.". International Journal of Oncology Mar (30): 573-82. PMID 17273758.
^ A.M. Admirant, J. A. Hendricks, P.C. De Witt Hamer, S. Leenstra, W.P. Vandertop, C.J.F. van Noorden, and J.P. Medema (2006). "Valproic Acid is toxic to malignant glioma cells and increases sensitivity to irradiation and chemotherapy". Abstracts for the Seventh Congress of the European Association for Neuro-Oncology (EANO) Sept 14-17: 334.
^ Valentini A, Gravina P, Federici G, Bernardini S. (2007). "Valproic Acid Induces Apoptosis, p(16INK4A) Upregulation and Sensitization to Chemotherapy in Human Melanoma Cells". Cancer Biology & Therapy Feb 5 (6). PMID 17218782.
^ Burton BS (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.
^ Henry T.R. (2003). The History of Valproate in Clinical Neuroscience. Psychopharmacology bulletin 37 (Suppl 2):5-16
^ Williams DC Jr, Massey GV, Russell EC, Riley RS, Ben-Ezra J. (2007). "Translocation positive acute myeloid leukemia associated with valproic acid therapy". Pediatric Blood and Cancer Mar 29. 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. PMID 15795916.
^ British National Formulary (March 2003) 45