Marquis Judith K, Dagher Rafif, Baker Brian A, Jones Michael R
Genzyme Drug Discovery and Development, 153 Second Avenue, Waltham, MA 05451, USA.
Reprod Toxicol. 2006 Feb;21(2):197-207. doi: 10.1016/j.reprotox.2005.07.014. Epub 2005 Sep 23.
WelChol (colesevelam hydrochloride), a bile acid sequestrant for the treatment of hypercholesterolemia, was evaluated for adverse effects on reproduction and fetal development using standard preclinical tests. During gestation, Sprague-Dawley rats used in the developmental toxicity study received feed, feed/control article or feed plus 300, 1,000 or 3,000 mg/kg/day colesevelam whereas rats in the pre- and postnatal toxicity study received vehicle or 100, 300 or 1,000 mg/kg/day colesevelam via gavage. New Zealand white rabbits received control or 100, 500 or 1,000 mg/kg/day colesevelam via gavage. No deaths, premature deliveries or gross pathologic lesions were observed up to gestation day (GD) 20 for rats and GD 28 for rabbits. No significant differences in the number of pregnant animals, average litter size, percentage of viable fetuses, fetal body weights, number of corpora lutea, fetal viability, or gross malformations were observed versus controls. Pre- and postnatal effects were assessed in pregnant rats receiving 100, 300 or 1,000 mg/kg/day colesevelam from GD 6 to postpartum day 22. Gestation, parturition and lactation in F(0) generation dams were similar between treatment and control groups. Colesevelam did not affect physical or neurological development or induce gross pathological changes in F(1) generation rats. Colesevelam does not produce developmental toxicity in rats or rabbits, nor does it exhibit pre- or postnatal toxicity in rats at the tested doses.
考来维仑（盐酸考来维仑）是一种用于治疗高胆固醇血症的胆汁酸螯合剂，通过标准的临床前试验对其对生殖和胎儿发育的不良影响进行了评估。在妊娠期，发育毒性研究中使用的斯普拉格-道利大鼠接受饲料、饲料/对照品或添加300、1000或3000mg/kg/天考来维仑的饲料，而产前和产后毒性研究中的大鼠通过灌胃接受赋形剂或100、300或1000mg/kg/天考来维仑。新西兰白兔通过灌胃接受对照品或100、500或1000mg/kg/天考来维仑。在大鼠妊娠第20天和兔子妊娠第28天之前，未观察到死亡、早产或明显的病理损伤。与对照组相比，在妊娠动物数量、平均窝仔数、活胎百分比、胎儿体重、黄体数量、胎儿活力或明显畸形方面未观察到显著差异。对从妊娠第6天至产后第22天接受100、300或1000mg/kg/天考来维仑的妊娠大鼠进行了产前和产后影响评估。F(0)代母鼠的妊娠、分娩和哺乳在治疗组和对照组之间相似。考来维仑不影响F(1)代大鼠的身体或神经发育，也未诱导明显的病理变化。考来维仑在大鼠或兔子中不产生发育毒性，在所测试的剂量下对大鼠也未表现出产前或产后毒性。
