[Reproductive and developmental toxicity studies of landiolol hydrochloride (ONO-1101) (1). Fertility study in rats].
A fertility study of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously to males from the 64th day before mating until necropsy, and to females from 15th day before mating until day 7 of gestation, at a dose level of 0 (control), 25, 50 or 100 mg/kg/day. On day 20 of gestation, all dams were sacrificed and their fetuses were examined. In the 100 mg/kg/day group, hypoactivity, clonic convulsion, bradypnea/apnea and redish lacrimation were observed after administration in both sexes, and 3 males and 2 females died. Reddish lacrimation was occasionally seen in males at late stage of the treatment period in 50 mg/kg/day group. In the 100 mg/kg/day group, body weight gain suppressed in females from the premating through the gestation period, and food consumption decreased in females during the premating period, and mean thymus weight decreased in males. ONO-1101 did not affect estrous cycle, copulatory or fertility in both sexes or external, skeletal or visceral features of the fetuses. 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 general toxicity in parents, and 100 mg/kg/day for the reproductive performance in parents and for the development of fetuses.
Nishimura
T
T
Fukui Institute for Safety Research, Ono Pharmaceutical Co., Ltd., Japan.
Chihara
N
N
Oku
H
H
Mori
H
H
Shinomiya
K
K
Ozeki
Y
Y
Fujita
T
T
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D005333:Fetus / Q000187:drug effects; D008431:Maternal-Fetal Exchange; D009025:Morpholines / Q000008:administration & dosage / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity
D000319:Adrenergic beta-Antagonists; D009025:Morpholines; C077049:landiolol; D014508:Urea