VALPROIC ACID

'Valproic acid' ('VPA') 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. However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.^[1]
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.^[2]
According to the U.S. National Institutes of Health and others, valproic acid appears to have wide implications in the treatment of various cancers,^[3] including multiple myeloma (bone marrow cancer),^[4] glioma (an aggressive type of brain tumor),^[5] and melanoma.^[6] 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.

Contents

History

Contraindications

Side effects

Interactions

Formulations

References

External links

History

Valproic acid (by its official name ''2-propylvaleric acid'') was first synthesized in 1882 by Burton as an analogue of valeric acid, found naturally in Valerian.^[7] 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.^[8] Since then it has also been used for migraine and bipolar disorder.^[9]
For more details see T.R. Henry, "The History of Valproate in Clinical Neuroscience." ''Psychopharmacology bulletin'' (2003) 37 (Suppl 2):5-16

Contraindications

Valproate is relatively contraindicated in pregnancy due to its teratogenicity; women who become pregnant while 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).^[10] It is a known folate antagonist, which can cause neural tube defects. Thus, folic acid supplements may alleviate the teratogenic problems. A recent study showed that children of mothers taking valproate during pregnancy are at risk for significantly lower IQs.^[11][12] Exposure of the human embryo to valproic acid is also 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. The teratology of autism, Arndt TL, Stodgell CJ, Rodier PM, , , Int J Dev Neurosci, One study found that 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.^[13]
Valproate is contraindicated in overweight patients because it causes weight gain as outlined above.
Preexisting liver damage, bone marrow depression, urea cycle disorders, and coagulation disorders are additional contraindications.

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.^[14][15]
There have also been rare reports of cognitive dysfunction, Parkinson's disease, and even pseudoatrophic brain changes in long-term treatment with valproic acid.

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.^[16] 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.^[17]

Formulations

Branded products include 'Depakene' (Abbott Laboratories in U.S. & Canada) and 'Convulex' (Pfizer in the UK and Byk Madaus in South Africa).

References

1. The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees?, Rosenberg G, , , Cellular and Molecular Life Sciences, 2007
2. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study, 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, , , Lancet,
3. Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid., 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, , , British Journal of Pharmacology, 2007
4. Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines., Schwartz C, Palissot V, Aouali N, Wack S, Brons NH, Leners B, Bosseler M, Berchem G, , , International Journal of Oncology, 2007
5. Valproic Acid is toxic to malignant glioma cells and increases sensitivity to irradiation and chemotherapy, 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, , , Abstracts for the Seventh Congress of the European Association for Neuro-Oncology (EANO), 2006
6. Valproic Acid Induces Apoptosis, p(16INK4A) Upregulation and Sensitization to Chemotherapy in Human Melanoma Cells, Valentini A, Gravina P, Federici G, Bernardini S., , , Cancer Biology & Therapy, 2007
7. Burton BS (1882). On the propyl derivatives and decomposition products of ethylacetoacetate. ''Am Chem J.'' 3:385-395.
8. Meunier H, Carraz G, Meunier Y, Eymard P, Aimard M. (1963). Propriétés pharmacodynamiques de l’acide n-dipropylacetique. ''Therapie'' 18:435-438.
9. Henry T.R. (2003). The History of Valproate in Clinical Neuroscience. ''Psychopharmacology bulletin'' 37 (Suppl 2):5-16
10. British National Formulary (March 2003) '45'
11. NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids
12. In utero antiepileptic drug exposure: fetal death and malformations, Meador KJ, Baker GA, Finnell RH, ''et al'', , , Neurology, 2006
13. Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid, Rinaldi T, Silberberg G, Markram H, , , Cereb Cortex,
14. Translocation positive acute myeloid leukemia associated with valproic acid therapy, Williams DC Jr, Massey GV, Russell EC, Riley RS, Ben-Ezra J., , , Pediatric Blood and Cancer, 2007
15. Acute leukemia associated with valproic acid treatment: a novel mechanism for leukemogenesis?, Coyle TE, Bair AK, Stein C, Vajpayee N, Mehdi S, Wright J., , , Pediatric Blood and Cancer, 2005
16. Goodman & Gilman's The Pharmacological Basis of Therapeutics, , Frank J., Gonzalez, McGraw-Hill, 2006,
17. Depakene side effects (Valproic Acid) and drug interactions

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)