Prenatal Prediction of Risk of the Fetal Hydantoin Syndrome

Buehler, Bruce A.; Delimont, Duane; Waes, Michael Van; Finnell, Richard H.

doi:10.1097/00006254-199103000-00012

Cited by 30 publications

(27 citation statements)

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“…A systematic application of pharmacogenetics could provide insight in this regard. However, there are practical, methodological, and theoretical hurdles to overcome [90,91].…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Meador

Baker

Cohen

et al. 2007

Epilepsy & Behavior

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The majority of children of mothers with epilepsy are normal, but they are at increased risk for developmental delay. Antiepileptic drugs (AEDs) appear to play a role. Our current knowledge is reviewed, including research design issues and recommendations for future research. In animals, exposure of the immature brain to some AEDs can produce widespread neuronal apoptosis and behavioral deficits. The risks of AEDs in humans are less clear, but recent studies raise concerns, especially for valproate. There is a critical need for well-designed systematic research to improve our understanding of AED effects on the fetal brain. KeywordsAntiepileptic drugs; Anticonvulsant drugs; Pregnancy; Teratogenesis; Development; Cognition; Behavior Animal studies on behavioral effects of in utero AED exposureAnimal studies have demonstrated that in utero antiepileptic drug (AED) exposure can produce behavioral as well as anatomical defects, which can occur at dosages lower than those required to produce somatic malformations [1,2]. Gestational or neonatal exposure to benzodiazepines can affect brain chemistry and behavior causing hyperactivity or learning deficits [3,4]. Despite the common use of carbamazepine in humans, very few neurobehavioral studies in animals have been conducted with this AED. In utero carbamazepine exposure did not produce hyperexcitability in primates [5]. Perinatal phenobarbital exposure in rats reduces brain weight [6]. Mice exposed prenatally to phenobarbital have neuronal deficits, reduced brain weight, and impaired development of reflexes, open-field activity, schedule-controlled behavior, spatial learning, and cate-cholamine brain levels [7][8][9][10][11][12]. Gestational or neonatal exposure to phenytoin reduces brain weight [13,14], alters neuronal membranes in the hippocampus [15], delays neurodevelopment [16], and impairs spatial learning and motor coordination [17][18][19][20][21][22][23][24][25]. Hyperactivity has been observed in rats and primates following prenatal exposure to phenytoin [5,23,25]. Gestational primidone in rats produces learning deficits and reduces open-field activity [26]. In utero valproate exposure can alter neuronal membranes [27], decrease brain weight in mice [28], and result in adverse neurobehavioral effects [29,30].

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“…A systematic application of pharmacogenetics could provide insight in this regard. However, there are practical, methodological, and theoretical hurdles to overcome [90,91].…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Meador

Baker

Cohen

et al. 2007

Epilepsy & Behavior

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“…Therefore, establishing whether metabolism is qualitatively and quantitatively similar among different species is important when making interspecies extrapolations. For example, differing susceptibilities of various inbred mouse strains, and possibly human individuals, to the developmental effects of phenytoin may involve genetically determined differences in phenytoin biotransformation (16,17), and different sensitivities to retinoid developmental toxicity among species can be attributed partly to differences in metabolism (18).…”

Section: Factors That Modify In Utero Exposure Of the Developing Nervmentioning

confidence: 99%

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

DORMAN

Allen

Byczkowski

et al. 2001

Environ Health Perspect

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We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring. In addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood--brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation). Measurement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure. Physiologically based pharmacokinetic and pharmacodynamic models that incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose--response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic.

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“…A single gene for this enzyme displays two allelic forms, resulting in a trimodal distribution for enzyme activity-high, intermediate, or low. Fetuses homozygous for the recessive allele have low enzyme activity and appear to be at greater risk to develop malformations associated with the fetal anticonvulsant syndrome (95)(96)(97). Polytherapy may promote epoxide production and inhibit epoxide metabolism.…”

Section: Mechanisms Of Aed Mediated Teratogenesismentioning

confidence: 99%

Maximizing the Health of Women with Epilepsy: Science and Ethics in New Drug Development

Morrell

1997

Epilepsia

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Summary:Issues of unique concern to women with epilepsy largely arise from gender-based physiological differences. Female sex steroid hormones may alter the expression of epilepsy and the efficacy of antiepileptic drugs (AEDs). Seizures and AEDs in turn affect the hypothalamic-pituitary axis and can adversely impact reproductive function and bone health. Maternal seizures and exposure to AEDs may compromise fetal development. At this time, women with epilepsy and their medical caretakers do not have access to all the information necessary to formulate a treatment plan that will have the least impact on reproductive and general health. In part, this is because reproductive aged women are excluded from the earliest phases of drug testing and pregnant and lactating women are excluded from all aspects of new drug development. Therefore, as new AEDs enter the marketplace, women with epilepsy must decide whether a new AED is appropriate for therapy based on very limited information. Postmarketing surveillance of gender-specific adverse effects, as with all adverse effects, depends on voluntary reporting. Only a small percentage of significant adverse events are believed to be captured by the present system. Consumers, ethicists, and some physician groups are now arguing that women should be included in all aspects of the development of drugs they will ultimately use-even pregnant and lactating women. Some of the issues of concern for women with epilepsy regarding epilepsy treatment, reproductive function and general health will be reviewed, followed by a discussion of the drug development process and how it does, and could better, address the concerns of women. Key Words: Epilepsy-Women-Anticonvulsant drugs-HormonesDrug therapy-Drug toxicity-Reproduction-Clinical drug evaluation-Clinical trials-Fertility-Teratogens. EFFECT OF HORMONES ON SEIZURES AND ON AED EFFICACYSteroid hormones are active in the central nervous system (CNS) and may alter the seizure threshold to a clinically significant extent (1). The ovarian sex steroid hormones, estrogen and progesterone, appear to act in an opposing fashion to modulate excitability of neurons of the cerebral cortex ( 2 ) . Estrogen has a seizure activating effect in experimental models of epilepsy such as the electroshock seizure threshold and after creation of a new seizure focus. Progesterone has an inhibitory effect in these same models. In human females, estrogen appears to activate interictal epileptiform activity whereas progesterone and its reduced metabolites reduce epileptiform activity.Both estrogen and progesterone exert their opposing effects, at least in part, at the GABA-A receptor complex (3). A recognition site for these neuroactive steroids has been identified on the GABA-A receptor complex (43). When k strogen occupies the receptor site, chloride conductance through the receptor is reduced, whereas progesterone has the opposite effect. Estrogen and progesterone also alter RNA encoding the synthesis of the GABA-A receptor complex and of GABA itselfprobably thr...

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Prenatal Prediction of Risk of the Fetal Hydantoin Syndrome

Cited by 30 publications

References 0 publications

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

Maximizing the Health of Women with Epilepsy: Science and Ethics in New Drug Development

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