Nishimura T, Nakagawa Y, Sakai M, Sugai S, Chihara N, Shirakawa R, Sakamoto T, Ikeda Y, Itagaki I, Ozeki Y, Shinomiya K, Fujita T
Fukui Institute for Safety Research, ONO Pharmaceutical Co., Ltd., Japan.
J Toxicol Sci. 1998 Jul;23 Suppl 3:531-8. doi: 10.2131/jts.23.supplementiii_531.
Teratogenicity of sodium N[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino]benzoyl] aminoacetate tetrahydrate (ONO-5046.Na), a novel inhibitor of human neutrophil elastase, was studied. ONO-5046.Na was injected intravenously at doses of 0, 7.5, 15 and 30 mg/kg/day to pregnant Kbl: NZW rabbits from day 6 to day 18 of pregnancy. All female rabbits were sacrificed on day 29 of pregnancy and their fetuses were examined. There were no clinical signs or death attributable to ONO-5046.Na. One dam in the control group and 3 dams in the 30 mg/kg/day group aborted. Body weight gain in the 15 and 20 mg/kg/day groups and food intake in the 30 mg/kg/day group were decreased during the administration period. These changes had recovered by the end of the study. Kidney weight was increased in the 30 mg/kg/day group. There were no effects of ONO-5046.Na in necropsy findings at cesarean section in dams at any dose levels. Developmental toxicity of ONO-5046.Na was not found at any dose levels. From these results, it is considered that the NOAEL of ONO-5046.Na is 7.5 mg/kg/day for pregnant animals and 30 mg/kg/day for fetuses.
对新型人中性粒细胞弹性蛋白酶抑制剂N-[2-[4-(2,2-二甲基丙酰氧基)苯磺酰氨基]苯甲酰基]甘氨酸钠四水合物（ONO-5046.Na）的致畸性进行了研究。在妊娠第6天至第18天，对妊娠的Kbl:NZW兔静脉注射ONO-5046.Na，剂量分别为0、7.5、15和30mg/kg/天。所有雌性兔在妊娠第29天处死，并检查其胎儿。未观察到归因于ONO-5046.Na的临床症状或死亡情况。对照组有1只母兔流产，30mg/kg/天组有3只母兔流产。给药期间，15和20mg/kg/天组的体重增加以及30mg/kg/天组的食物摄入量减少。这些变化在研究结束时已恢复。30mg/kg/天组的肾脏重量增加。在任何剂量水平下，剖宫产母兔的尸检结果中均未发现ONO-5046.Na的影响。在任何剂量水平下均未发现ONO-5046.Na的发育毒性。根据这些结果，认为ONO-5046.Na对妊娠动物的无观察到有害作用水平（NOAEL）为7.5mg/kg/天，对胎儿为30mg/kg/天。
