Developmental toxicity of the class III antiarrhythmic agent almokalant in mice. Adverse effects mediated via induction of embryonic heart rhythm abnormalities.
Almokalant (ALM, CAS 123955-10-2), a class III antiarrhythmic drug, has been shown to be embryotoxic in rats. In the absence of human pregnancy outcome data, the human relevance of these findings in rats is unknown, and results from other species would indicate if these findings are of more universal interest. Therefore, this study was initiated to evaluate the potential effects in mice. ALM was given to three groups of pregnant mice (approximately 20 mice/group) during gestation days 6-15 at dose levels of 50, 125 and 300 mumol/kg. A fourth group served as a control. In addition, whole embryo culture was performed on gestation day 10 with doses of ALM ranging from 325-5200 nmol/l (approximately 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 intermediate 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 column and among the phalanges. ALM caused bradycardia in a concentration dependent manner (13-42% at 650-5200 nmol/l). Irregular heart rhythm and/or episodes 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 mouse, most likely secondary to adverse effects on the embryonic heart. The results may suggest that class III antiarrhythmics are embryotoxic also in humans.
Department of Pharmaceutical Biosciences, Uppsala University, Sweden. anna-carin.skold@astrazeneca.com
A C
AC
Sköld
B R
BR
Danielsson
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D004435:Eating / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D005318:Fetal Heart / Q000187:drug effects*; D051379:Mice; D011247:Pregnancy; D011412:Propanolamines / Q000097:blood / Q000633:toxicity*; D013723:Teratogens / Q000633:toxicity*; D015430:Weight Gain / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D011412:Propanolamines; D013723:Teratogens; C074334:almokalant