TERATOGENIC EFFECTS OF VIGABATRIN IN TO MOUSE FETUSES

Vigabatrin (VGB) is a relatively recently introduced antiepileptic dru g that enhances the brain levels of gamma aminobutyric acid (GABA). Fe w data on its teratogenic effects appear to have been reported. Our ob jective was to determine if VGB was teratogenic in the TO mouse. Singl e doses of 300-600 mg/kg of VGB dissolved in saline were administered intraperitoneally (IF) to groups of TO mice an one of gestation days ( GD) 7-12. The controls were saline treated or untreated. No maternal t oxic effects were observed in the 300 or 450 mg/kg groups, and the 600 mg/kg dose was totally lethal to the mothers. Fetuses were collected on GD 18. Both 300 and 450 mg/kg doses induced a consistently signific ant intrauterine growth retardation irrespective of the developmental stage at administration. VGB did not augment the spontaneous incidence of neural tube defects characteristic of this strain, but accelerated destruction of the brain in spontaneous exencephalic embryos. Mandibu lar and maxillary hypoplasia, arched palate, cleft palate (two cases), limb defects (one case), and exomphalos were observed in the malforme d fetuses. The high incidence of exomphalos appears to be a unique res ult of VGB treatment. Alizarin red-S/alcian blue-stained skeletons rev ealed hypoplasia of mid facial bones, stage-dependent increase in the frequency of cervical and lumbar ribs, rib fusion, and sternal and ver tebral malformations in the drug-treated fetuses. Middle and distal ph alanges of the forepaw and mid phalanges and tarsals of the hindpaw fa iled to ossify in a significant number of experimental fetuses. Homeot ic shift in terms of presacral vertebral number and a high incidence o f lumbar and cervical ribs in the treated group are suggestive of trea tment-related alterations in gene expression. in view of the paucity o f human and animal data on the reproductive toxicologic effects of VGB , the results of the present study assume particular importance and su ggest that VGB should be used in pregnancy with extreme caution. (C) 1 997 Wiley-Liss, Inc.