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Infant monkey hyperexcitability after prenatal exposure to antiepileptic compounds
1Department of Psychology, University of Washington, Seattle 98195-1525, USA.
Insights
Prenatal exposure to carbamazepine (CBZ) or CBZ with stiripentol (STP) did not cause infant hyperexcitability in a monkey model. This contrasts with phenytoin (PHT) exposure, which was previously shown to increase hyperexcitability risk.
Area of Science:
- Neuroscience
- Developmental Toxicology
- Pharmacology
Background:
- Prenatal exposure to certain antiepileptic drugs can impact infant neurodevelopment.
- Phenytoin (PHT) and stiripentol (STP) have been previously studied for their effects on infant hyperexcitability.
- Further investigation is needed for other antiepileptic drugs like carbamazepine (CBZ).
Purpose of the Study:
- To assess infant hyperexcitability in a non-human primate model following prenatal exposure to carbamazepine (CBZ) alone or in combination with stiripentol (STP).
- To compare the effects of CBZ and CBZ+STP with previous findings for PHT and STP monotherapy.
Main Methods:
- A Macaca fascicularis monkey model was used, with pregnant females receiving PHT, STP, CBZ, or CBZ+STP.
- Drug plasma levels were maintained within specific therapeutic ranges throughout pregnancy.
- Infant hyperexcitability was assessed using a standardized scale during recognition memory tests from 2 weeks to 3 months of age.
Main Results:
- Infants prenatally exposed to PHT (monotherapy or polytherapy with STP) showed increased risk for hyperexcitability.
- Infants exposed to STP monotherapy did not exhibit increased hyperexcitability.
- Infants exposed to CBZ or CBZ+STP demonstrated no increased hyperexcitability, similar to control infants.
Conclusions:
- Prenatal exposure to CBZ, whether as monotherapy or in polytherapy with STP, does not lead to infant hyperexcitability in this primate model.
- These findings confirm previous observations regarding PHT-induced hyperexcitability and highlight the differential effects of various antiepileptic drugs.
- The study suggests CBZ may be a safer option regarding this specific neurodevelopmental outcome compared to PHT.
Purpose:
A monkey (Macaca fascicularis) model was previously used to assess infant hyperexcitability after prenatal exposure to phenytoin (PHT), stiripentol (STP) or PHT+STP. To explore this issue further, we studied additional monkey infants in those groups, as well as groups prenatally exposed to carbamazepine (CBZ) in monotherapy (n = 5) or CBZ+STP polytherapy (n = 10).
Methods:
The drug-exposed groups were compared with a group of control infants (n = 10) for whom procedures were matched except that there was no prenatal drug exposure. All adult female monkeys were equipped with tether systems and stomach catheters so that drug administration (or water for controls) could be initiated before they were mated and continued throughout pregnancy. During pregnancy, PHT, STP, and CBZ plasma levels were maintained between 4-12, 4-10, and 1-6 micrograms/ ml, respectively (for both monotherapy and polytherapy). At birth, infants were separated from mothers and transferred to the University of Washington's (Seattle, WA, U.S.A.) Infant Primate Research Laboratory (IPRL) for postnatal care and follow-up testing. During tests of recognition memory administered between 2 weeks and 3 months of age, infants were rated on a hyperexcitability scale.
Results:
Previously reported data indicated that infants prenatally exposed to PHT, in monotherapy or polytherapy with STP, were at increased risk for hyperexcitability (screeching, refusing to attend to stimuli, lack of visual orientation). This was not the case for infants prenatally exposed to STP monotherapy.
Conclusions:
Our results confirm previous findings and also demonstrate that infants prenatally exposed to CBZ or CBZ+STP, like controls, are not hyperexcitable during testing.
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