Evidence for Ras-Dependent Signal Transduction in Phenytoin Teratogenicity

Winn, Louise M.; Wells, Peter G.

doi:10.1006/taap.2002.9504

“…One study suggested that PHT can act through Ras-dependent signal transduction. In the whole embryo culture experiment with mouse embryos, it was demonstrated that inhibition of the K-ras oncogene protected the embryos from PHT-induced structural defects [Winn and Wells, 2002]. Lastly, it has been suggested that the oxidative intermediate of interest is one that is not sufficiently detoxified by enzymatic conjugation with reduced glutathione [Diepold et al, 1982, Moldeus and Jemstrom, 1983].…”

Section: Antiepileptic Drugsmentioning

confidence: 99%

Antiepileptic drugs and pregnancy outcomes

Wlodarczyk

¹

,

Palacios

²

,

George

³

et al. 2012

American J of Med Genetics Pt A

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The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer and neuropathic pain. Despite the fact that the majority of pregnancies of women with epilepsy who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when antiepileptic drugs (AEDs) are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of women with epilepsy, and to provide information on the latest experimental and human epidemiological studies of the effects of antiepileptic drugs in the exposed embryos.

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“…In experiments on mouse embryos cultured in vitro , it was demonstrated that inhibition of the K-ras oncogene protected the embryos from PHT-induced structural defects [116]. Finally, it is possible that the oxidative intermediate of interest is one that is not sufficiently detoxified by enzymatic conjugation with reduced glutathione [117,118].…”

Section: Mechanisms Of Aed Teratogenicitymentioning

confidence: 99%

Teratogenic effects of antiepileptic drugs

Hill

¹

,

Wlodarczyk

²

,

Palacios

³

et al. 2010

Expert Review of Neurotherapeutics

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Many antiepileptic drugs (AEDs) have therapeutic applications that extend beyond epilepsy to include neuropathic pain, migraine headaches and psychiatric disorders. The risk of some AEDs has been clearly established, but for newer drugs, small sample sizes and polytherapy exposures preclude a conclusive determination of their teratogenic potential. Most women with epilepsy will require AED therapy throughout their entire pregnancy to control seizures; the vast majority of pregnancies in women with epilepsy have positive outcomes. A conservative estimate suggests that AED monotherapy doubles, and polytherapy triples, the risk for major congenital malformations. Furthermore, while evidence is still accruing, recent investigations suggest that exposure to select AEDs results in altered cognitive function later in development. There is no evidence to suggest that additional folic acid supplementation ameliorates the increased risk of congenital malformations conferred by in utero AED exposure.

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“…One study suggested that PHT can act through Ras-dependent signal transduction. In the whole embryo culture experiment with mouse embryos, it was demonstrated that inhibition of the K-ras oncogene protected the embryos from PHT-induced structural defects [Winn and Wells, 2002]. Lastly, it has been suggested that the oxidative intermediate of interest is one that is not sufficiently detoxified by enzymatic conjugation with reduced glutathione [Diepold et al, 1982, Moldeus andJemstrom, 1983].…”

Section: Antiepileptic Drugsmentioning

confidence: 99%

Antiepileptic Drugs and Pregnancy Outcomes

Wlodarczyk

¹

,

Palacios

²

,

George³

et al. 2012

Obstetrical &Amp; Gynecological Survey

View full text Add to dashboard Cite

The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer and neuropathic pain. Despite the fact that the majority of pregnancies of women with epilepsy who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when antiepileptic drugs (AEDs) are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of women with epilepsy, and to provide information on the latest experimental and human epidemiological studies of the effects of antiepileptic drugs in the exposed embryos.

show abstract

Evidence for Ras-Dependent Signal Transduction in Phenytoin Teratogenicity

Cited by 24 publications

References 36 publications

Antiepileptic drugs and pregnancy outcomes

Antiepileptic drugs and pregnancy outcomes

Teratogenic effects of antiepileptic drugs

Antiepileptic Drugs and Pregnancy Outcomes

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