背景:在这项研究中,在围产期检查了JJH201501的生殖毒性,以支持其作为新型5-羟色胺能药物(5-HT)抗抑郁药的安全性。妊娠Sprague-Dawley大鼠(F0,n=24/组)连续暴露于0(对照组),6、18和60mg/kg体重/天的JJH201501通过从妊娠第15天到泌乳第21天的胃内给药。
方法:在此期间,根据临床症状评估母体毒性,体重,饲料摄入量,交货条件,凋落物参数,尸检,体重,性别比例,畸形发生率,物理,对所有后代大鼠进行神经发育评估。在出生后第4天(PND4)从每个剂量组中的每个大坝中随机选择10只幼崽(雄性:雌性1:1)。PND35后对一对进行行为评估(F1a),10周后对繁殖性能(F1b)进行评估,PND35上的器官重量和畸形(F1c)三个。交配成功后,将F1b雄性大鼠称重并解剖以评估生殖器官重量和精子活力。每周两次对怀孕的F1b大鼠称重并监测食物摄入量,直到GD14进行剖腹手术,记录活/死胎儿,resorptions,植入,卢泰语料库,和子宫重量。在JJH治疗组和对照组的母体体重之间发现了一些统计学差异,食物消费,和F1体重和水迷宫性能。
结果:尸检结果表明,JJH201501在F0中具有低心脏指数作用,未检测到明显的组织病理学变化。在整个实验过程中,高剂量组只有一个F1后代死亡。由于缺乏剂量依赖性效应和这些改变的一致生长模式,研究结果对观察结果没有任何毒理学意义.
结论:结论:JJH201501对围产期大鼠的未观察到的不良反应水平约为60mg/kgb.w./天.
BACKGROUND: In this
study, JJH201501 was examined for reproductive toxicity during the perinatal period to support its safety as a novel serotonergic agent (5-HT) antidepressant. Pregnant Sprague-Dawley rats (F0, n = 24/group) were continuously exposed to 0 (control), 6, 18, and 60 mg/kg body weight/day of JJH201501 by intragastric administration from gestation day 15 to lactation day 21.
METHODS: During this period, maternal toxicity was evaluated based on clinical signs, body weight, feed intake, delivery condition, litter parameters, and necropsy, with body weight, sex ratios, malformation incidence, physical, and neurodevelopmental assessments conducted on all offspring rats. Ten pups (male:female 1:1) from each dam within each dose group on postnatal day 4 (PND4) were randomly selected. One pair was evaluated for behavior evaluations (F1a) after PND35, one for reproduction performance (F1b) after 10 weeks, and three for organ weight and deformities (F1c) on PND35. After successful mating, F1b male rats were weighed and dissected to assess reproductive organ weight and sperm motility. Pregnant F1b rats were weighed and monitored for food intake twice weekly until laparotomy on GD14, which recorded live/dead fetuses, resorptions, implantations, corpora lutea, and uterine weight. Some statistical differences were found between the JJH-treated and control groups in maternal weight, food consumption, and F1 body weight and water maze performance.
RESULTS: Autopsy results showed that JJH201501 had a low cardiac index effect in F0, with no significant histopathological changes detected. Only one F1 offspring died in the high-dose group throughout the experiment. Due to the lack of dose-dependent effects and the consistent growth pattern of these alterations, the
study findings do not suggest any toxicological significance for the observed results.
CONCLUSIONS: In conclusion, the no-observed-adverse-effect level of JJH201501 for perinatal rats is about 60 mg/kg b.w./day.