[Reproductive and developmental toxicity studies of montirelin hydrate (2)--Teratogenicity and postnatal study in rats by intravenous administration].

A study of the effect of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, during the period of organogenesis was conducted in Sprague-Dawley rats. Female rats were given the drug intravenously at dose levels of 0 (control), 0.02, 1 and 50 mg/kg from day 7 to day 17 of pregnancy. Twenty-three or twenty-five female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and the pregnant rats (13-15 per dose levels) were allowed to deliver naturally for postnatal examination of their offspring. In the 1 or 50 mg/kg group, water consumption and the weights of adrenals of the dams increased and the weights of the thymus of the dams decreased. In addition, tremor, disappeared within some minutes, was observed from day 7 to day 16 of pregnancy in all dams given 50 mg/kg. Moreover, food consumption increased and the weights of the submaxillary glands of the dams given 50 mg/kg increased. The drug had no effect on the number of corpora lutea and implantations, on fetal mortality, on fetal body weights, on sex ratio, or on external, visceral and skeletal development of the fetuses. The drug also did not affect delivery. The drug did not have any adverse effects on the newborn such as the number of live newborns, birth index and body weights of live newborn, or on the postnatal development of the first generation offspring (F1) such as differentiation, functional development, emotionality, motor ability, learning ability or reproductive performance. The drug also had no adverse effects of the second generation offspring (F2). These results show that the NOAEL of montirelin hydrate are 0.02 mg/kg for general toxicity in mother animals, 50 mg/kg for pregnancy and delivery of mother animals and 50 mg/kg for development of their offspring.

[Reproductive and developmental toxicity study of mofezolac (N-22) (2)--Study by oral administration of N-22 during the period of fetal organogenesis in rats].

The teratogenicity of mofezolac (N-22), a new developed analgesic and anti-inflammatory agent, was investigated in rats. N-22 was given orally to pregnant rats of the Jcl: Wistar strain (30 rats per group) at dose levels of 10, 50, 100 and 150 mg/kg/day from days 7 to 17 of gestation. Caesarean sections were performed on 20 dams per group on day 20 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. The remaining 10 dams per group were allowed to deliver and their offspring were examined for growth and reproductive performance. Results were as follows. 1. Effects on F0 generation At 150 mg/kg, eleven out of the 30 dams exhibited decreased motor activity, pale eyes, unkempt fur, urine-smeared lower abdomen, weakness and emaciation. At autopsy, twelve dams revealed gastrointestinal ulcers, peritonitic lesions, hypertrophy of the spleen, adrenal and mesenteric lymph node, atrophy of the submaxillary gland, thymus and liver and discoloration of the liver and kidney. Death, sacrificing in extremis, premature or delayed delivery and poor nursing occurred in one to two dams each. Food consumption was significantly decreased and body weight gain was significantly retarded in this dose level group. At 100 mg/kg, urine-smeared lower abdomen, hypertrophy of the spleen and poor nursing were observed in one dam each. 2. Effects on F1 generation At 150 mg/kg, significantly decreased fetal weight, increased number of immature fetuses and significantly retarded ossification of the 5th and 6th sternebrae and coccygeal vertebrae as well as significantly depressed body weight gain of female offspring were observed. No abnormalities were observed in each treated group in terms of development, behavior, learning ability and reproductive performance of offspring. 3. Effects on F2 generation No abnormalities were observed in fetuses and newborn young in each treated group. Based on these results, the maximum non-effective doses of N-22 in this study were considered to be 50 mg/kg/day for dams and offspring and 100 mg/kg/day for fetuses.