Valproic acid

Valproic acid
Systematic (IUPAC) name
2-propylpentanoic acid
Identifiers
CAS number 99-66-1
ATC code N03AG01
PubChem CID 3121
DrugBank DB00313
ChemSpider 3009
Chemical data
Formula C8H16O2 
Mol. mass 144.211 g/mol
SMILES 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 h
Excretion Less than 3% excreted unchanged in urine.
Therapeutic considerations
Licence data US FDA:link
Pregnancy cat. D—teratogenic
Legal status POM (UK) ℞-only (US)
Routes Oral, intravenous
 YesY(what is this?)  (verify)

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, bipolar disorder, and less commonly major depression. It is also used to treat migraine headaches and schizophrenia. It is marketed under the brand names Depakote, Depakote ER, Depakene, Depacon, Depakine, Stavzor.

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 the U.S. also as an anticonvulsant.

VPA is a histone deacetylase inhibitor and is under investigation for treatment of HIV and various cancers.

Contents

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.[1] 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 the anticonvulsant properties of valproic acid 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.[2] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[3] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[4]

Pharmacology

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 principal mechanism of action is believed to be the inhibition of the transamination of GABA (by inhibiting GABA transaminase). Valproate is also believed to reverse the transamination process to form more GABA. Hence, Valproate indirectly acts as a GABA agonist. However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.[5]

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.

Indications

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.[6]

Valproic acid is also FDA approved for the treatment of manic episodes associated with bipolar disorder, adjunctive therapy in multiple seizure types (including epilepsy), and prophylaxis of migraine headaches.[7] It is more recently being used to treat neuropathic pain, as a second line agent, particularly lancinating pain from A* fibres.

Investigational

HIV

Histone deacetylase HDAC1 is needed for HIV to remain latent in infected cells. 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.[8] The idea was that valproic acid, by inhibiting HDAC1, allowed HIV to reactivate and replicate. 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 patients of HIV. Subsequent trials, however, found no long term benefits of valproic acid in HIV infection.[9]

Cancers

According to the U.S. National Institutes of Health and others, valproic acid appears to have wide implications in the treatment of various cancers,[10] including multiple myeloma (bone marrow cancer),[11] glioma (an aggressive type of brain tumor),[12] and melanoma.[13] Valproic acid is cytotoxic to many different cancer types through its action as a histone deacetylase inhibitor. A phase I trial showed the maximum tolerated dose was 60 mg/kg.[14]

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.

Valproic acid has given encouraging results for breast cancer when used alongside a standard chemotherapy in a phase I/II trial (44+10 patients).[15]

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.[16]

In October, 2008 a research team at the University of British Columbia in Vancouver, Canada announced that in a study doses of valproic acid reversed the early stages of Alzheimer's disease in mice. Human trials are underway.

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. This function has also been investigated as an epigenetic therapy for treatment of lupus.[17]

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".[18] 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, antiverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.[19]

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 would 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 don't find all birth defects.[20]

Valproate 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.[21][22]

Risk of autism

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.[23]

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.[24]

A 2009 study demonstrated that children of pregnant women taking valproate had an I.Q. nine points lower than a well-matched control group.[25][26][27]

Adverse effects

Valproate is contraindicated in overweight patients because it might cause weight gain.

Preexisting hepatic (liver) and/or renal (kidney) damage or cancer, hepatitis, pancreatitis, end-stage AIDS HIV infection, bone marrow depression, urea cycle disorders, and coagulation hematological disorders are absolute contraindications.

Common side effects are dyspepsia and/or weight gain. Less common are fatigue, peripheral edema, acne, dizziness, drowsiness, hair loss, headaches, nausea, sedation and tremors. Valproic acid also causes hyperammonemia, which can lead to brain damage.[28] Valproate levels within the normal range are capable of causing hyperammonemia and ensuing encephalopathy. There have been reports of brain encephalopathy developing without hyperammonemia or elevated valproate levels.[29]

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.[30][31]

There have also been reports of cognitive dysfunction, Parkinsonian symptoms,[32] and even (reversible) pseudoatrophic brain changes[33] 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.[34] 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.[35]

Also, Valproic acid should not be used with the benzodiazepine clonazepam and aspirin to avoid adverse effects.

Valproic acid (and Sodium Valproate) reduces 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:

References

  1. ↑ Burton BS (1882). On the propyl derivatives and decomposition products of ethylacetoacetate. Am Chem J. 3:385-395.
  2. ↑ Meunier H, Carraz G, Meunier Y, Eymard P, Aimard M. (1963). Propriétés pharmacodynamiques de l'acide n-dipropylacetique. Therapie 18:435-438.
  3. ↑ Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002; 16:695–714.
  4. ↑ Henry T.R. (2003). The History of Valproate in Clinical Neuroscience. Psychopharmacology bulletin 37 (Suppl 2):5-16
  5. ↑ 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. doi:10.1007/s00018-007-7079-x. PMID 17514356. 
  6. ↑ Posner E, Lorenzo N (October 11, 2006). "Posttraumatic epilepsy". Emedicine.com. Retrieved on 2008-07-30.
  7. ↑ "FDA Issues Approvable Letter For Stavzor Delayed Release Valproic Acid Capsules". 2007 MediLexicon International Ltd. 2007-10-25. http://www.medicalnewstoday.com/articles/86674.php. Retrieved 2007-10-29. 
  8. ↑ 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. PMID 16099290. 
  9. ↑ 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. 
  10. ↑ 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 (3): 573–82. PMID 17273758. 
  11. ↑ 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. 
  12. ↑ 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. doi:10.1186/1476-4598-5-71. PMID 17156483. 
  13. ↑ 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): 185–91. PMID 17218782. 
  14. ↑ http://meeting.ascopubs.org/cgi/content/abstract/22/14_suppl/3169
  15. ↑ "Phase I/II trial combining the HDAC inhibitor, valproic acid (VPA) and FEC100 (5-fluorouracil, epirubicin and cyclophosphamide) in locally advanced/metastatic breast cancer.". http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=32900. 
  16. ↑ "Annual Report 2007" (PDF). TopoTarget. 14 March 2008. http://www.topotarget.com/multimedia/Topotarget_rapport_web_2007_UK_final.pdf. Retrieved 2008-11-23. 
  17. ↑ http://sexualhealth.e-healthsource.com/index.php?p=news1&id=529147
  18. ↑ 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. 
  19. ↑ Kulkarni ML, Zaheeruddin M, Shenoy N, Vani HN (October 2006). "Fetal valproate syndrome". Indian J Pediatr 73 (10): 937–9. PMID 17090909. http://medind.nic.in/icb/t06/i10/icbt06i10p937.pdf. 
  20. ↑ British National Formulary (March 2003) 45
  21. ↑ Cassels, Caroline (December 8, 2006). "NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids". Medscape. http://www.medscape.com/viewarticle/549073. Retrieved 2007-05-23. 
  22. ↑ 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. PMID 16894099. 
  23. ↑ 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. 
  24. ↑ Rinaldi T, Silberberg G, Markram H (2007). "Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid". Cereb Cortex 18 (4): 763. doi:10.1093/cercor/bhm117. PMID 17638926. 
  25. ↑ I.Q. Harmed by Epilepsy Drug in Utero By RONI CARYN RABIN, New York Times, April 15, 2009
  26. ↑ 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
  27. ↑ Which drug for the pregnant woman with epilepsy? Torbjorn Tomson, N Engl J Med 360:1597 April 16, 2009
  28. ↑ Valproate-associated Hyperammonemic Encephalopathy - Wadzinski et al. 20 (5): 499 - The Journal of the American Board of Family Medicine
  29. ↑ Thieme-connect - Abstract
  30. ↑ 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 (3): 641. doi:10.1002/pbc.21149. PMID 17262798. 
  31. ↑ 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. 
  32. ↑ 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]" (in French). L'Encéphale 31 (1 Pt 1): 98–101. doi:10.1016/S0013-7006(05)82378-4. PMID 15971646. 
  33. ↑ 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. 
  34. ↑ 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. pp. 79. ISBN 978-0071422802. 
  35. ↑ "Depakene side effects (Valproic Acid) and drug interactions". RxList.com. 2007. http://www.rxlist.com/cgi/generic/depakene_ad.htm. Retrieved 2007-06-07. 

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