Danielsson Christian, Azarbayjani Faranak, Sköld Anna-Carin, Sjögren Niklas, Danielsson Bengt R
Department of Medicine, Karolinska Institute, Karolinska University Hospital, S 14186 Stockholm, Sweden.
Birth Defects Res A Clin Mol Teratol. 2007 Aug;79(8):595-603. doi: 10.1002/bdra.20378.
The antiepileptic drugs (AEDs) phenytoin, phenobarbital, dimethadione, and carbamazepine cause a similar pattern of malformations in humans, with an increased risk after polytherapy. The teratogenicity has been linked to cardiac rhythm disturbances and hypoxic damage as a consequence of their common potential to inhibit a specific potassium ion current (IKr). The IKr is of major importance for embryonic cardiac repolarization and rhythm regulation. This study investigated whether these AEDs cause irregular rhythm and if various combinations of AEDs result in higher arrhythmia risk than exposure to a single AED.
The effects on heart rhythm of a single AED (monotherapy), and of various combinations (polytherapy) of AEDs, in gestational day 10 C57BL mouse embryos in culture were analyzed and graphically illustrated during a 25 s recording with a digitalization technique.
All of the studied AEDs caused increased intervals between heartbeats (resulting in bradycardia) and large variations in the interval between heartbeats (resulting in irregular rhythm) in a concentration-dependent manner in cultured mouse embryos. Dimethadione caused irregular rhythm at concentrations within and phenytoin slightly above the therapeutic ranges. Polytherapy resulted in more substantial prolongation of the mean interval between heartbeats (>60 ms) than monotherapy at clinically relevant concentrations.
The results suggest that polytherapy more than monotherapy causes substantial prolongation of the cardiac repolarization, a marker associated with high risk of developing irregular rhythm during longer exposure periods (days to months). This supports the idea that the increased risk for malformations following polytherapy is linked to an increased risk for cardiac rhythm disturbances.
抗癫痫药物（AEDs）苯妥英、苯巴比妥、二甲双酮和卡马西平在人类中会导致相似的畸形模式，联合治疗后风险增加。致畸性与心律失常和缺氧损伤有关，这是由于它们共同具有抑制特定钾离子电流（IKr）的潜力。IKr对胚胎心脏复极化和节律调节至关重要。本研究调查了这些AEDs是否会导致心律不齐，以及AEDs的各种组合是否会比单一使用一种AEDs导致更高的心律失常风险。
采用数字化技术，在25秒的记录过程中，分析并以图形方式展示了单一AED（单药治疗）以及AEDs的各种组合（联合治疗）对孕10天的C57BL小鼠胚胎心脏节律的影响。
在培养的小鼠胚胎中，所有研究的AEDs均以浓度依赖性方式导致心跳间隔增加（导致心动过缓）以及心跳间隔的大幅变化（导致心律不齐）。二甲双酮在治疗范围内及略高于治疗范围的浓度时会导致心律不齐。苯妥英在略高于治疗范围的浓度时也会导致心律不齐。在临床相关浓度下，联合治疗比单药治疗导致心跳平均间隔延长更显著（>60毫秒）。
结果表明，联合治疗比单药治疗更能显著延长心脏复极化时间，这是一个与在较长暴露期（数天至数月）发生心律不齐高风险相关的指标。这支持了联合治疗后畸形风险增加与心律失常风险增加相关的观点。
