Teratogenic Risks of Drug Synergism

Abstract

IT is well known that the effectiveness of teratogens, measured either in incidence or in severity of resulting malformations, is frequently modified, in a plus or minus direction, by unrelated external conditions. The mechanisms by which these modifying agencies operate are largely unknown. A little, if not a great deal more, is known about the role of drug interaction in teratogenesis. There are, for example, the facts of interference with essential metabolites, such as deprivation of available vitamins by competing analogues¹ or by blockage of their utilization in co-enzyme systems². Then there are the potentiating effects of lowering the available sources of utilizable carbohydrates₃ or of uncoupling oxidative phosphorylation⁴. Among the latter sources of synergism we found compounds, for example, 2-deoxy-D-glucose and chlorpromazine, which when administered alone were nonteratogenic and which even in larger (and highly toxic) amounts did not produce malformations. Other compounds of this type, however, are themselves teratogenic, in dosages higher than those required for synergism, but the range of their interference with development may be more restricted than their synergistic activity.