TERATOLOGICAL STUDY OF STOBADIN AFTER SINGLE AND REPEATED ADMINISTRATION IN RATS

The toxic developmental potential of the anti-arrhythmic drug stobadin was assessed after single intravenous or repeated oral doses to pregnant rats. Stobadin was studied in the form of dihydrochloride (DH 1011) at doses of 2 and 6 mg/kg, given in single intravenous injections on days 3, 6, 9, or 12 of gestation. Immediately after injection of the 6-mg/kg dose of DH 1011 to pregnant rats, saccade abdominal respiration, tremor of hindlimbs, and sedative behaviour were observed on each day of medication. No deaths of females occurred in either the control or experimental groups. Slight foetal toxicity was manifested by significantly decreased foetal weight only after treatment on day 3 of gestation at 6 mg/kg and by significantly increased incidence of delayed ossification of the parietal and supraoccipital bone also at 6 mg/kg DH 1011 given on day 12 of gestation. The effect of repeated oral treatment in the form of dipalmitate salt (DP 1031) was studied in doses of 5, 15, and 45 mg/kg from days 2-15 of gestation. Oral exposure to 45 mg/kg DP 1031 resulted in significant reduction of maternal body weight gain and in embryofoetal toxicity, namely, increased preimplantation foetal loss, anomalies of sternebrae, and, after 15 and 45 mg/kg DP 1031, significantly decreased foetal weight and smaller litter size. The relevance of the two routes of stobadin administration for risk extrapolation is discussed.