Reproductive and developmental toxicity studies of landiolol hydrochloride (ONO-1101) (2) teratogenicity study in rats

Abstract

A teratogenicity study of landiolol hydrochloride (ONO-1101), a novel ultra short acting β-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously at a dose level of 0 (control), 25, 50 or 100 mg/kg/day to pregnant rats from day 7 to 17 of gestation, and effects of ONO-1101 on dams, fetuses and their offspring, were examined. In the 100 mg/kg/day group, hypoactivity, bradypnea, reddish lacrimation, clonic convulsion and loss of righting reflex were observed and 2 animals died. Food consumption in the 100 mg/kg/day group decreased during the treatment period. No drug-related changes were observed in dams for their body weights, necropsy findings or organ weights. Decrease in placental weight was seen in the 100 mg/kg/day group, but no effect was found in fetal weight. ONO-1101 had no effects on delivery and lactation. On day 4 after birth, viability of offspring were decrease in the 50 or 100 mg/kg/day group, and body weight of males were decreased in the 100 mg/kg/day group, but no change caused by the treatment was observed in growth of offspring thereafter. On skeletal examination in offsprings culled on day 4 after birth, increase in the incidence of unossificated talus were seen in the 50 or 100 mg/kg/day group. But no drug-related anomalies were observed in external, skeletal or visceral findings in fetuses. It was not also found any influence of ONO-1101 on external differentiations, functional, behavioral or learning abilities or reproductive performance in offspring. From the above results, it is estimated that the no-toxic dose level of ONO-1101 under these experimental conditions is 50 mg/kg/day for dams, and 25 mg/kg/day for their offspring.