Valproic acid, which has been used for the treatment of seizure for more than 30 years, has long been recognized as a teratogen. The investigators administered these drugs intraperitoneally on days 8, 9, and 10 of gestation. The firstpass effect after oral application is often more pronounced in animals than man e. Sodium valproateinduced congenital cardiac abnormalities. Report of the quality standards subcommittee and therapeutics and technology subcommittee of the american academy of neurology and the. Hyperammonemia associated with valproic acid concentrations. The antiepileptic drug valproic acid vpa is a potent inducer of neural tube. In late 2009, the food and drug administration released a warning indicating that there is an increased risk for major birth defects, including craniofacial, neural, cardiac and cognitive. Association of valproateinduced teratogenesis with. June 9, 2010 women with epilepsy who take valproic acid during the first trimester of pregnancy are more likely to have children with birth defects than women who took other epilepsy. Valproic acid and its analogs are excreted in human milk. Teratogenic effects mediated by inhibition of histone.
Valproic acidassociated gene expression changes in mouse embryos to study the gene expression response to vpa during the susceptible stages, that is, when vpa exerts most of its. Abstract teratogenic effects of the anticonvulsant drugs valproic acid vpa and diphenylhydantion dph on the development of mouse embryos during early. Valproic acid vpa is used worldwide to treat epilepsy, migraine headaches, and bipolar disorder. It is known to induce teratogenicity in the form of neural tube. Teratogenesis of calcium valproate in rats toxicological. Interestingly, thalidomide 300% dose given to rabbits treatment in mice, a. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as valproate. Molecular and therapeutic potential and toxicity of. These authors analyzed data from a longstanding prospective cohort to study changes in prescribing habits and pregnancy outcomes following restriction on the use of valproic acid in women. Valpromide is rapidly hydrolyzed to valproic acid after oral administration in man, probablyalready in the stomach and intestinal mucosaas well as in the liverduringabsorption 39. However, vpa is teratogenic and in utero exposure can lead to congenital malformations. Valproic acid pharmacokinetics absorption bioavailability.
Valproic acid, a branched shortchain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as. Division of birth defects and developmental disabilities, center for. Valproic acid vpa is one of the most commonly prescribed drugs to control epileptic seizures and regulate the mania associated with bipolar disorder. Request pdf epigenetic modifications in valproic acidinduced teratogenesis exposure to the anticonvulsant drug valproic acid vpa in utero is associated with a 12% increase in neural tube.
The calcium salt of valproic acid valontin has been proposed for use in the treatment of absence, myoclonic, and tonic clonic seizures of the primarily generalized type. Valproic acid therapy causes subclinical hypothyroidism. Valproic acid vpa is an antiepileptic drug aed which is currently being investigated for its potential application in the treatment of several types of cancers, including solid and nonsolid tumor. Teratogenicity and developmental toxicity of valproic acid. Valproic acid therapy causes subclinical hypothyroidism in children with seizure disorders valproic acid levels were also measured. Valproic acid american society for clinical pharmacology and. Studies were conducted to determine the teratogenic potential of the calcium salt of valproic acid in rats when given orally at doses of 600, 150, and 50 mgkg on days 615 of gestation. Valproic acid vpa is a simple eight carbon branchedchain carboxylic acid figure 1. Vpa is teratogenic in most animal species tested, but the human embryo seems to be the most. A proapoptotic effect of valproic acid on progenitors of.
Antiteratogenic potential and curtailing toxicity of. Valproic acid vpa is a monocarboxylic acid with unclear mechanism of action and this is widely prescribed for epilepsy, bipolar disorder, migraine, alzheimers. Predicting the human teratogenic potential of the anticonvulsant. Rapidly and almost completely absorbed from the gi tract. Valproic acid is a synthetic derivative of propylpentanoic acid with antiepileptic properties and potential antineoplastic and antiangiogenesis activities. Epigenetic modifications in valproic acidinduced teratogenesis toxicology and applied pharmacology, vol. The antiepileptic drug valproic acid is a putative human teratogen as suggested by retrospective studies robert and rosa 1983. Valproic acid is rapidly absorbed from the gastrointestinal tract, peak concentrations being attained 1 to 2 hours after administration of the conventional tablet, but later with the enteric. The use of valproic acid vpa as a single drug monotherapy in the first trimester of pregnancy was associated with significantly increased risks of major and minor malformations, including a 20fold.
The anticonvulsant drug valproic acid 2propylpentanoic acid is teratogenic in laboratory species kao et al. Valproic acid teratogenesis and embryonic lipid metabolism. Valproic acidinduced teratogenesis via oxidative stress oxidative stress responsible for causing damage in the building material of cellular macromolecules such as dna, lipids, and proteins, along with. Clinical pharmacokinetics of valproic acid springerlink. It is predominantly used in the treatment of epilepsy due to the broad activity against both generalized and partial.
Vpa is a branchedchain carboxylic acid introduced as an antiepileptic drug in 1978 in the united states. Since first being approved in 1967, valproic acid vpa in its acidic form, salt form sodium valproate or semisalt form valproate semi sodium houghton and. Exposure to the anticonvulsant drug valproic acid vpa in utero is associated with a 12% increase in neural tube defects ntds, however the molecular mechanisms by which vpa induces teratogenesis. Valproic acidassociated gene expression changes in p19 embryocarcinoma cells genes that respond transcriptionally to vpa in embryos supplemental material, tables 1 and 2 may.
Identical ex perimental conditions were used for all of these anticonvulsants. Teratology is the study of the causes and underlying mechanisms leading to birth defects or malformations. Teratogenesis of calcium valproate in rabbits petrere. The widely used antiepileptic drug valproic acid vpa, which is also used in migraine prophylaxis and the treatment of bipolar disorders, is also under trial as an anticancer agent. It is used to treat partial and generalized seizures and acute. Valproic acid, a widely used anticonvulsant drug, is a potent teratogen resulting in various congenital abnormalities. Teratogenesis is a process that causes birth defects or malformations in an embryo or foetus.
Valproic acid vpa is a shortchain fatty acid that acts as an epigenetic modifier by inhibiting histone deacetylases hdacs with ic values ranging from 0. However, the mechanisms underlying valproic acid induced teratogenesis. This study, employing the rhesus monkey as an animal model, demonstrates that vpa. Teratogenicity of valproic acid and related substances in the. Dosedependent teratogenicity of valproate in mono utrecht. Teratogenic effects of valproic acid and diphenylhydantoin on. Valproic acid clinical trials, side effects aidsinfo. Depakene and depakote er is a drug that has been approved by the u. Antiepileptic properties have been attributed to inhibition of gamma amino butyrate gaba. No definitive adverse reactions have been reported in breastfed infants.
Drug concentrations in milk have been reported to be 1% to 10% of maternal. Maternal exposure to valproic acid monotherapy during the first. Valproic acid associated gene expression changes in mouse embryos to study the gene expression response to vpa during the susceptible stages, that is, when vpa exerts most of its teratogenic effect on the developing neural tube, we extracted total rna from pools of whole embryos removed from control and vpatreated 8. Since first being approved in 1967, valproic acid vpa in its acidic form, salt form sodium valproate or semisalt form valproate semi sodium houghton and bowers, 2003 has for decades been used, worldwide, for anticonvulsant and moodstabilizing therapies. Dawley cd rats at doses of 0, 150, 200, 300, 400, and 600 mgkg administered by gavage on days 718 of. Novel mechanism for valproateinduced teratogenicity. Using inbred c57bl6j b6 and dba2j d2 mice, we asked whether genetic variation could play a role in susceptibility to vpa teratogenesis. Valproic acid vpa is a commonly prescribed drug for those affected by epilepsy and bipolar disorders. Valproic acid vpa is a branchedchain saturated fatty acid with a long history of clinical use as an antiepileptic drug aed. In epilepsy, valproic acid appears to act by increasing. Fetal valproate syndrome nord national organization for.
Maternal absorption, as well as distribution, of the drugs does not usually show great species differences. Pdf species differences in pharmacokinetics and drug. Valproic acid downregulates rbp4 and elicits hypervitaminosis ateratogenesisa kinetic analysis on retinolretinoic acid homeostatic system chaoming chuang1, chihuang chang2, huier wang3. Topiramate 100200 mg daily and valproic acid 5001,000 mg daily are firstline drugs in migraine prevention, while older antiepileptics have no use in this setting. Novel mechanism for valproateinduced teratogenicity ncbi nih. Valproic acid vpa is used worldwide to treat epilepsy, migraine headaches and bipolar disorder. Request pdf epigenetic modifications in valproic acid induced teratogenesis exposure to the anticonvulsant drug valproic acid vpa in utero is associated with a 12% increase in neural tube. The teratogenicity and developmental toxicity of valproic acid vpa was investigated in sprague.
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