Valproic Acid

Valproic Acid - What is 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, 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, 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.

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. 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. Since then it has also been used for migraine and bipolar disorder.

Branded products include:

  • Depakene (Abbott Laboratories in U.S. & Canada)
  • Convulex (Pfizer in the UK and Byk Madaus in South Africa)
  • Stavzor (Noven Pharmaceuticals Inc.)
  • Depakine (Sanofi Aventis)
  • Deprakine (Sanofi Aventis Finland)
  • Epival (Abbott Laboratories U.S. & Canada)
  • Epilim (Sanofi Synthelabo Australia)
  • Encorate (Sun Pharmaceuticals India)
  • Valcote (Abbott Laboratories Argentina)

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Valproic Acid 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 principle 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.

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.

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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. 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. 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.

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Valproic Acid Issues

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".

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.

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

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.

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Valproic Acid Side Effects

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. 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.

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.

There have also been reports of cognitive dysfunction, Parkinsonian symptoms, and even (reversible) pseudoatrophic brain changes in long-term treatment with valproic acid.

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Valproic Acid 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 (administered intravenously) 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.

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.

It is more recently being used to treat neuropathic pain, as a second line agent, particularly lancinating pain from A* fibres.

Investigational

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. 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.

According to the U.S. National Institutes of Health and others, valproic acid appears to have wide implications in the treatment of various cancers, including multiple myeloma (bone marrow cancer), glioma (an aggressive type of brain tumor), and melanoma. 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.

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.

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.

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.

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.

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