Ritchie Helen, Oakes Diana, Hung Tzong-tyng, Hegedus Elizabeth, Sood Shreya, Webster William
Discipline of Biomedical Science, University of Sydney, New South Wales, Australia.
Biological Resources Imaging Laboratory, University of New South Wales, New South Wales, Australia.
Birth Defects Res B Dev Reprod Toxicol. 2015 Oct;104(5):196-203. doi: 10.1002/bdrb.21162. Epub 2015 Sep 24.
There are a wide range of drugs including antidepressants, anticonvulsants and antipsychotics that cause embryonic bradycardia in vitro but it is unknown if they have a similar effect in vivo. One way to verify whether these in vitro findings are replicated in vivo is by the use of ultrasound examination of dosed pregnant rats. We tested this by examining the effect of dofetilide on embryonic heart rate (HR) in vivo using ultrasound.
Rats were dosed with dofetilide (4 or 2.5 mg/kg) on GD11 or (5 or 2.5 mg/kg) on GD13 and embryonic HR assessed by ultrasound, 2 and 24 hr later. Fetuses were examined for malformations on GD20.
HR of control rat embryos showed a wide range at each gestational day. Dosing with dofetilide on GD11 caused severe bradycardia (∼ 60% reduction) 2 hours after dosing with recovery after 24 h of >60% of LD but death and slow HR among the HD embryos. At term, 32% of the LD surviving fetuses had hypoplastic upper lip while >90% of HD embryos had died. On GD13, embryonic HR was reduced in a dose-dependent manner with >85% of LD and HD recovered by 24 hr. At term, all LD fetuses were normal while 29% of HD fetuses had limb defects.
Ultrasound is a useful technique to investigate the effect of maternally administered drugs on the embryonic HR in the rat. The results may provide more information about the safety of these drugs in pregnancy leading to better risk assessment for the human.
包括抗抑郁药、抗惊厥药和抗精神病药在内的多种药物在体外会导致胚胎心动过缓，但它们在体内是否有类似作用尚不清楚。验证这些体外研究结果在体内是否能重现的一种方法是对给药的怀孕大鼠进行超声检查。我们通过超声检查多非利特对体内胚胎心率（HR）的影响来对此进行测试。
在妊娠第11天给大鼠注射多非利特（4或2.5毫克/千克），或在妊娠第13天注射（5或2.5毫克/千克），并在2小时和24小时后通过超声评估胚胎心率。在妊娠第20天检查胎儿是否有畸形。
对照大鼠胚胎的心率在每个妊娠日都有很大范围。在妊娠第11天注射多非利特后2小时导致严重心动过缓（约降低60%），24小时后恢复，低剂量组（LD）恢复超过60%，但高剂量组（HD）胚胎中有死亡和心率缓慢的情况。足月时，低剂量组存活胎儿中有32%有上唇发育不全，而高剂量组超过90%的胚胎死亡。在妊娠第13天，胚胎心率呈剂量依赖性降低，低剂量组和高剂量组在24小时内恢复率均超过85%。足月时，所有低剂量组胎儿均正常，而高剂量组29%的胎儿有肢体缺陷。
超声是一种有用的技术，可用于研究母体给药对大鼠胚胎心率的影响。这些结果可能会提供更多关于这些药物在孕期安全性的信息，从而为人提供更好的风险评估。
