Cleft palate and open eyelids inducing activity of lorazepam and the effect of flumazenil, the benzodiazepine antagonist.

Lorazepam (Ativan, Wyeth) at dosages of 20-36 mg/kg was used to test for developmental toxicity in the mouse embryo/foetus model. Two separate regions were considered: (1) the central nervous system and (2) the roof of the mouth and the eyelids. In the first case a single administration of lorazepam was applied at the very beginning of the 9th gestation day. In the second, it was administered in preliminary tests on two consecutive gestation days between the 11th and 14th days and in later experiments once only on the 13th or 14th gestation day. In the first part of investigations regarding the development of the central nervous system, lorazepam unlike many other neurotropic drugs, was found not to induce any aberrations in the process of the neural tube closure. In the second part, in which palate closure and the temporary closure of eyelids were monitored, it was found that lorazepam does interfere with these processes. In order to test whether lorazepam's neurocristopathic activity can be prevented, suggesting the presence of benzodiazepine receptors in the neural crest cells, we used the benzodiazepine antagonist, flumazenil (Anexate, Roche). The results of these experiments indicated the flumazenil was able to prevent cleft palate and open eyelids cases almost completely if it was administered 3 hr after administration of lorazepam. If the treatments were administered in the reverse order, the frequency of neurocristopathy cases was unaffected, i.e. flumazenil did not influence the teratogenic activity of lorazepam.