Developmental toxicity of the class III antiarrhythmic agent almokalant inmice - Adverse effects mediated via induction of embryonic heart rhythm abnormalities

Almokalant (ALM, CAS 123955-10-2), a class III antiarrhythmic drug, has bee n shown to be embryotoxic in rats. In the absence of human pregnancy outcom e data, the human relevance of these findings in rats is unknown, and resul ts from other species would indicate if these findings are of more universa l interest. Therefore, this study was initiated to evaluate the potential e ffects in mice. ALM was given to three groups of pregnant mice (similar to 20 mice/group) during gestation days 6-15 at dose levels of 50, 125 and 300 mu mol/kg. A fourth group served as a control. In addition, whole embryo c ulture was performed on gestation day 10 with doses of ALM ranging from 325 -5200 nmol/l (similar to 17 embryos/group) in order to study if ALM had the potential to induce dysrhythmia in the embryonic mouse heart. ALM induced total embryonic death in the high dose group, and in the interm ediate group the level of embryonic death was elevated and the mean foetal weights decreased. A slight increase in minor skeletal defects was observed , mainly consisting of reduced calcification of elements in the vertebral c olumn and among the phalanges. ALM caused bradycardia in a concentration de pendent manner (13-42% at 650-5200 nmol/l). Irregular heart rhythm and/or e pisodes of cardiac arrest were observed in one embryo at 2600 and in seven embryos at 5200 nmol/l. In conclusion, ALM caused embryotoxicity in the mou se, most likely secondary to adverse effects on the embryonic heart. The re sults may suggest that class III antiarrhythmics are embryotoxic also in hu mans.