Fetal edema from benzhydrylpiperazines as a possible cause of oral-facial malformations in rats

Abstract

The following findings may help to explain the production of oral-facial malformations, in rats, after the maternal administration of benzhydrylpiperazine compounds: (1) A delay in the process of palate formation occurs when chlorcyclizine is administered, orally, at a dose that yields a 50% incidence of cleft palate (50 mg/kg). (2) At this dose edema, manifested partly as thoracic enlargement, can be demonstrated during the delay. (3) A similar increase in thoracic size, due to the edema, occurs after the administration of four additional benzhydrylpiperazine compounds that produce the oral-facial malformations, when administered at appropriate doses, but not after three other antihistamines that do not yield the cleft palate. (4) Edema formation is dose-dependent at the intermediate doses for cleft palate formation. (5) Finally, edema production is not dependent upon cleft palate production, but cleft palate production may be dependent upon the edema. From these findings and reference to the literature, a mechanism is suggested that relates the production of the cleft palate, micrognathia (receded mandible), microstomia (small mouth), and glossopalatine fusion (fusion of the tongue to the palatine processes) to pressures from fluidenlarged tissue, perhaps partly from the enlarged thorax. The mechanism is discussed.