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. 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, 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 additionally in the U.S. as an anticonvulsant.

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

History
Valproic acid (systematic name 2-propylpentanoic acid and historical name 2-propylvaleric acid) was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian. Names are given to organic acids in the following way. Each organic acid containing only one chain with a specific number of carbon atoms was given the name of the natural (organic) substance from which it was first isolated, e.g. caproic acid (goat). The many historical names became too difficult to memorize. So systematic names were given based on Greek numbers starting from 5, pentanoic acid (valeric acid), then 6, hexanoic acid (caproic acid), etc. Each carbon atom in the chain can then have a group of atoms bonded to it. The name of this group and the number of the carbon atom to which it is attached is then prefixed to the root name of the acid, thus 2-propylpentanoic acid. (propyl is the name of a three carbon atom chain.)

As are many organic acids with eight or fewer carbon atoms, valproic acid is a fatty acid that is 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. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder.

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, then GABA would increase in concentration). 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.

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 posttraumatic 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 delta fibers.

HIV
Histone deacetylase 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. 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 HIV patients. Subsequent trials, however, found no long-term benefits of valproic acid in HIV infection.

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, 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 limited by neurotoxicity.

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).

the salt magnesium valproate is in phase III trials for cervical cancer and ovarian cancer.

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.

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.

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". 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.

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 do not 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 children of mothers taking valproate during pregnancy are at risk for significantly lower IQs.

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.

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.

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

Adverse effects
The foremost and most severe concern for anyone taking valproic acid is its potential for sudden and severe, possibly fatal, fulminating impairments in liver, hematopoietic and/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.

There are rare reports of individuals who have used valproic acid for a long time (chronic users) who 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.

Preexisting severe hepatic (liver) and/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 are absolute contraindications. Some patients with symptomatic but manageable AIDS, cancer, 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 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.

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. Serum or plasma valproic acid concentrations are generally 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.

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.

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.

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 French)
 * 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.
 * M. Chignac, C. Grain, (1979).
 * H.E.J.-M. Meunier, (1963).
 * H.E.J.-M. Meunier, (1967).
 * M. Chignac, C. Grain, Ch. Pigerol, (1977).