Tissue and plasma levels of a teratogenic dose of dopamine in the chick embryo following pretreatment with metoprolol or phosphate buffered saline.

Metoprolol pretreatment has been shown to reduce the cardiovascular malformation rate produced by topical doses of dopamine in the stage 24 chick embryo. We report on the tissue and plasma levels and teratogenic effect of dopamine hydrochloride following topical application of a teratogenic dose in stage 24 chick embryos pretreated with either metoprolol tartrate or phosphate buffered saline (PBS). Pretreatment with either metoprolol or PBS resulted in similar patterns of dopamine distribution in the head, body, and heart, with peak levels occurring at 12 hours after dopamine treatment. Plasma concentrations of dopamine were similar for both PBS and metoprolol pretreated embryos, with plasma levels exceeding tissue concentrations, but also peaking at 12 hours after dopamine treatment. Pretreatment with PBS followed by a teratogenic dose of dopamine resulted in a decrease in the teratogenic effect of dopamine similar to that found in previous work in our lab with pretreatment with metoprolol. The developing chick cardiovascular system experiences peak susceptibility to the teratogenic effects of dopamine at stage 24 during development, which represents a time frame of about 12 hours. A delay in the peak levels of dopamine to 12 hours after dopamine treatment as compared to previous work in our lab reporting peak levels of dopamine at 1 hour, suggests that the previously reported antiteratogenic effects of metoprolol may be due, at least in part, to a delayed absorption of dopamine past the time of peak susceptibility of the embryo to the teratogen.

Strain differences in phenobarbital-induced teratogenesis in mice.

Anticonvulsant drugs are widely prescribed medications known to complicate more than 11,500 pregnancies each year in the United States. Although there is no clear consensus as to the teratogenicity of all of the clinically available compounds, it appears that most anticonvulsant drugs can induce congenital abnormalities in susceptible individuals. In a study designed to examine the role of the genotype on sensitivity to phenobarbital-induced malformations, three highly inbred mouse strains (SWV, C57BL/6J, and LM/Bc) received the drug via chronic oral administration. Phenobarbital was found to have a significant teratogenic potential in mice, resulting in skeletal, cardiac, renal, neural, and urogenital defects in a dose-related fashion. The LM/Bc strain was most sensitive to phenobarbital, with 46.7% of the fetuses exposed to the highest maternal plasma concentrations having malformations. C57BL/6J fetuses were the most resistant strain, with only 28.6% abnormalities.

Variable patterns in anticonvulsant drug-induced malformations in mice: comparisons of phenytoin and phenobarbital.

Anticonvulsant drugs are known to induce a varied pattern of malformation in both humans and in experimental rodent models. Often the clinical overlap between the pattern of defects induced by different anticonvulsant drugs is so striking that many clinicians question the role these compounds play relative to the existing maternal seizure disorder in the etiology of the observed malformations. In three inbred mouse strains exposed to phenytoin or phenobarbital in utero, the pattern of malformation differed markedly. From the types of anomalies observed, it is apparent that phenobarbital induced more malformations, while phenytoin produced a higher frequency of anomalies related to incomplete development. Thus, while there exists a certain degree of similarity between some of the minor features characteristic of each drug-induced syndrome, there are distinct differences in pregnancy outcome in experimental animals exposed to these drugs. Given the fact that phenobarbital induces more malformations that can be traced to exposure during early organogenesis, it may be wise to consider a therapeutic strategy in which phenytoin is utilized only during organogenesis, and is then replaced with phenobarbital for the remainder of the pregnancy.