# POLYTHERAPY MECHANISMS IN PREGNANCY

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 1993 · $458,262

## Abstract

Teratogenicity is a considerable problem for women with epilepsy.
Under most circumstances it would be detrimental to their health to have
the antiepileptic medication withdrawn during pregnancy.  At the same
time, there is risk to the fetus exposed to certain anticonvulsants.  The
problem is compounded if the epileptic woman has multiple seizure types
or seizures refractory to monotherapy.  Under these circumstances,
polytherapy is required to control seizures and the rate of
teratogenicity is two to threefold higher with multiple drugs.
     In rodent systems, growth and other physical anomalies apparent in
the embryo or at birth, resulting from phenytoin (PHT) exposure during
gestation, have been linked to reactive metabolite exposure.  However, no
studies have sought to identify the cause of learning and behavioral
deficits which become apparent after birth.  Carbamazepine (CBZ)
apparently forms at least one reactive arene oxide metabolite, but no
studies have been conducted to link any form of carbamazepine-induced
teratogenicity to reactive metabolite exposure, although the likelihood
of this mechanism has been recognized.
     The proposed research will test the hypothesis that teratogenicity
in the form of growth problems at birth and (more importantly)
developmental delays after birth, first in PHT therapy, and second in CBZ
therapy, is due to reactive metabolite exposure.  We propose to conduct
in vivo inhibition, pharmacokinetic, and teratogenicity studies using a
pregnancy monkey model.  These studies will be accomplished by utilizing
a nonteratogenic second drug stiripentol (STP), which in polytherapy with
PHT (or CBZ) inhibits cytochrome P-450 and thus decreases reactive
metabolite exposure while maintaining the plasma concentration of the
parent compound.

## Key facts

- **NIH application ID:** 2199987
- **Project number:** 5R01HD026556-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **SAM.gov UEI:** HD1WMN6945W6
- **Principal Investigator:** JOAN S LOCKARD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $458,262
- **Award type:** 5
- **Project period:** 1991-08-01 → 1995-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2199987

## Citation

> US National Institutes of Health, RePORTER application 2199987, POLYTHERAPY MECHANISMS IN PREGNANCY (5R01HD026556-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2199987. Licensed CC0.

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