Karlsson Miriam, Danielsson Bengt R, Nilsson Mats F, Danielsson Christian, Webster William S
Department of Pharmaceutical Biosciences, Division of Toxicology, S-751 24, Uppsala University, Uppsala, Sweden.
Curr Pharm Des. 2007;13(29):2979-88. doi: 10.2174/138161207782110471.
Drugs blocking the potassium current IKr, either as an intended pharmacologic effect (eg antiarrhythmics dofetilide and almokalant) or as an unwanted side-effect (eg antihistamine astemizole, propulsive drug cisapride, antidepressive drugs and macrolide antibiotics) are potential human teratogens. It is the contention of this paper that the existing repeat dose regimen used in teratology studies to fulfil regulatory requirements, does not properly identify the teratogenic risk of these drugs. Results from conventional studies for dofetilide and almokalant showed high rates of postimplantation embryonic death with few malformed fetuses. For astemizole and cisapride only embryonic death was seen. These latter results were not considered important because they occurred either in the presence of maternal toxicity and/or at high doses. Subsequent studies have shown that IKr-blockers are highly teratogenic when administered on single gestational days (GD) during a sensitive period of rat pregnancy (GD 10-14) when they induce a high incidence of stage-specific malformations. This teratogenic activity of astemizole and cisapride was missed in the original teratology studies. Mechanistically IKr-blockers cause bradycardia and arrhythmia of the embryonic heart and while an embryo may be able to survive a single day exposure to a teratogenic dose, repeat dosing often leads to death of the embryo. With this review we suggest that new drugs identified at the preclinical stage of development as having IKr-blocking properties, should undergo more comprehensive teratology testing including single GD dosing and studies using embryo culture. This would further help identify and characterise their teratogenic potential.
阻断钾电流IKr的药物，无论是作为预期的药理作用（如抗心律失常药多非利特和阿尔莫卡兰特）还是作为不良副作用（如抗组胺药阿司咪唑、促动力药西沙必利、抗抑郁药和大环内酯类抗生素），都是潜在的人类致畸剂。本文的观点是，目前用于致畸学研究以满足监管要求的重复给药方案，不能正确识别这些药物的致畸风险。多非利特和阿尔莫卡兰特的传统研究结果显示，植入后胚胎死亡率高，畸形胎儿少。对于阿司咪唑和西沙必利，仅观察到胚胎死亡。后一种结果不被认为重要，因为它们要么发生在母体毒性存在时和/或高剂量时。随后的研究表明，当在大鼠妊娠敏感期（妊娠第10 - 14天）的单个妊娠日（GD）给药时，IKr阻滞剂具有高度致畸性，会诱导高发生率的阶段特异性畸形。阿司咪唑和西沙必利的这种致畸活性在最初的致畸学研究中未被发现。从机制上讲，IKr阻滞剂会导致胚胎心脏心动过缓和心律失常，虽然胚胎可能能够在一天内耐受致畸剂量的暴露，但重复给药通常会导致胚胎死亡。通过本综述，我们建议在临床前开发阶段被鉴定具有IKr阻断特性的新药，应进行更全面的致畸学测试，包括单个GD给药和使用胚胎培养的研究。这将进一步有助于识别和表征它们的致畸潜力。
