Valproic acid chemical structure
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Valproic acid

Valproic acid or 2-Propylpentanoic 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; but 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, and the seizures associated with Lennox-Gastaut syndrome. more...

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Related drugs include the sodium salt – Sodium valproate, and a combined formulation – Valproate semisodium.

Valproate is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain.This principle was used by Ashoka Jahnavi-Prasad when he suggested that sodium valproate could be a safer alternative to lithium salts in treatment of bipolar illness.

Valproic acid has also been shown to be an inhibitor of an enzyme called 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 75% reduction in latent HIV infection. This may one day lead to a cure for HIV and AIDS.

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, preleminary results are encouraging.

Side effects

Common side effects are dyspepsia and/or weight-gain. Less common are dizziness, drowsiness, hair-loss, headaches, nausea, sedation and tremors,

Valproic acid can also rarely cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation times. In ~5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies. Some users have reported growth of curly hair during long-term medication of Sodium Valproate. Note that due to these side effects most doctors will ask for blood test to be worked initially as much as once a week then once every 2 months. Temporary liver enzymes increase has been reported in 20 per cent of cases during the first few months of taking the drug. Inflammation of the liver (hepatitis) is found in rare cases. Your doctor should educate you about hepatitis and how to spot it as the major symptom is jaundice.

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

Contraindications

Valproate is contraindicated in overweight patients because it causes weight gain as outlined above, and in pregnant women because it is teratogenic. Preexisting liver damage, bone marrow depression and coagulation disorders are additional contraindication.

Formulations

US

  • Capsules – Depakene® by Abbott Laboratories.

UK

  • Capsules – Convulex® by Pfizer.

South Africa

  • Capsules – Convulex® by Byk Madaus.

Read more at Wikipedia.org


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Greater risk of birth defects with valproic acid: defect rate is 2-3.5 times higher with valproic acid than with newer AEDs
From OB/GYN News, 10/15/04 by Kate Johnson

Physicians seeing young girls and women with epilepsy now have strong reason to ensure the prescription of newer anti-epileptic drugs whenever possible.

New data suggest that older anti-epileptic drugs (AEDs) particularly valproic acid, when taken during pregnancy, are associated with a high risk of birth defects, said Dr. Diego Wyszynski, who presented his findings at the meeting of the European Federation of Neurological Societies.

"This is the first time that we have data from large pregnancy registries on old anti-epileptic drugs as well as some of the new drugs. So this is a new message alerting clinicians to think, even when they see a young patient, about the risks of the drug during pregnancy." Dr. Wyszynski, assistant professor of medicine and of epidemiology at Boston University, said in an interview.

Published studies suggest that approximately half of all patients with epilepsy tend to stick with the first drug they are prescribed, so starting girls on or switching them to drugs with low teratogenic risk makes sense, he said.

His recommendations are based on new data from three large AED pregnancy registries, which show that the rate of birth defects associated with valproic acid use during pregnancy is between two and three-and-a-half times higher than the rate associated with newer AEDs. Malformations associated with valproic acid include heart defects, spina bifida, multicystic dysplastic kidney, postaxial polydactyly type B, inguinal hernia, and penile hypospadias.

The North American Antiepileptic Drug Pregnancy Registry, for which Dr. Wyszynski is the senior epidemiologist, included 3,400 women from the United States and Canada. The United Kingdom Epilepsy and Pregnancy Register included 2,637 women from Great Britain, and the Australian Independent Prospective Pregnancy Registry included 630 women.

All three registries showed that the risks of serious birth defects associated with carbamazepine and lamotrigine (Lamictal)--both newer AEDs--are between 2% and 3%, which is in line with the baseline risk in women not taking AEDs.

The registries also showed a significantly increased risk associated with valproic acid: 6% in the U.K. registry, almost 11% in the North American registry, and more than 6% in the Australian registry.

In addition, Dr. Wyszynski's group has published data from the North American registry showing that 5 of 77 pregnancies (6.5%) with exposure to phenobarbital were associated with major malformations, which suggests a risk 2-3 times higher for the offspring of exposed women than that in the general population (Arch. Neurol. 61[5]:673-678, 2004).

"The major surprise was not the results per se but that coming from different pregnancy registries, all with different collection protocols and definitions of malformations, the results are remarkably similar." said Dr. Wyszynski. "Now we know that valproic acid substantially increases the risk of birth defects, whereas lamotrigine and carbamazepine do not."

But valproic acid remains a popular AED, because it is well tested and very efficacious, he said. Some patients might not get optimal seizure control on a newer drug.

Additionally, the choice of poorer seizure control in favor of less teratogenicity may not necessarily be safer for the fetus in all cases.

"Having seizures during pregnancy could be so serious that it could endanger the life of both the mother and the fetus, so all these things need to be taken into account," he said.

Although the risks of birth defects associated with lamotrigine and carbamazepine appear no greater than the baseline risk, they should not be viewed as risk-free. Children of women who take lamotrigine and carbamazepine in pregnancy "have the same rate of malformations that you find in the general population, which is not zero," he said.

Additionally, these drugs have other risks associated with them. Carbamazepine, like valproic acid, has been linked to an increased rate of neurodevelopmental and low IQ problems, and long-term lamotrigine use has been tied to the development of polycystic ovary syndrome and osteoporosis.

Both the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics recommend an increased dose of folic acid (4 g/day) preconceptually for women taking AEDs. But 50% of pregnancies in the United States are unplanned, underscoring the need to tackle the issue as early as possible, he said

Switching to a safer AED in pregnancy could potentially do more harm than good. "Because most of the malformations occur between the first and second month of gestation, by the time most women realize they are pregnant it will be too late to prevent them. So not only will switching the drug at this point be ineffective in reducing the risk of malformations, but it may also increase her risk of seizures," he said.

BY KATE JOHNSON

Montreal Bureau

COPYRIGHT 2004 International Medical News Group
COPYRIGHT 2004 Gale Group

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