Fertility and Perinatal/Postnatal Studies in Rats with the Antiarrhythmic Agent Pirmenol

Abstract

Fertility and perinatal/postnatal studies were conducted in Sprague-Dawley rats with the Class Ia antiarrhythmic agent pirmenol. Doses of 25, 50 or 100 mg/kg/day were administered in the diet for both studies; untreated control groups received basal diet. Male rats in the fertility study were treated for 75 days prior to mating, while F0 female rats were treated for 15 days prior to mating, and also during mating, gestation and lactation. F0 female rats in the perinatal/postnatal study were treated from gestation day (GD) 15 to lactation day 21. Caesarean section was performed on half the fertility study females per group on GD 20, while the remaining half of the fertility study females and all perinatal/postnatal study females were allowed to deliver and raise the F1 offspring. The F1 generation was evaluated for survival, growth, development, behaviour and reproductive performance. Although bodyweight and food consumption of fertility study F0 parents were reduced at pirmenol 100 mg/kg/day, no treatment-related effects were observed on reproductive parameters, or on maternal and fetal parameters evaluated at caesarean section. Reduction in bodyweight occurred for fertility study F1 offspring of all treatment groups during the neonatal period, but not during maturation. Offspring were unaffected with regard to survival, development, behaviour or reproductive performance. Treatment-related effects observed in perinatal/postnatal study F1 females at pirmenol 50 and/or 100 mg/kg/day included clinical signs of toxicity, reduction of bodyweight gain and food consumption, and stomach lesions. Food spillage, indicative of a possible palatability problem, also occurred at 100 mg/kg. Viability of F1 offspring was decreased at 100 mg/kg/day, while the incidence of dilated renal pelvis was increased; treatment-related reduction of bodyweight and open field activity occurred at pirmenol 50 and 100 mg/kg/day. Results of these studies indicate that the nature, magnitude and duration of pirmenol-related effects differed according to treatment regimen.