Padmanabhan R, Abdulrazzaq Y M, Bastaki S M A, Shafiullah M, Chandranath S I
Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
Birth Defects Res B Dev Reprod Toxicol. 2003 Oct;68(5):428-38. doi: 10.1002/bdrb.10042.
Virtually all antiepileptic drugs (AED) tested so far have been found to be teratogenic. The second generation AED possess a number of therapeutic advantages over the older ones. There are, however, very little data on their effects on embryonic development. A recent report suggests that lamotrigine (LTG) can be teratogenic to human fetuses. With only a few cases of prenatal exposure to LTG in the record, however, it has not been possible to establish a recognizable pattern of malformations in the infants of LTG-treated mothers.
The objectives of the present study were to evaluate the reproductive toxic effects of LTG .
Single (50-200 mg/kg) or multiple doses (25, 50, 75 mg/kg) of LTG were administered by intraperitoneal (i.p.) injection (note that the therapeutic administration is oral) to groups of TO mice on gestation day (GD) 7 or 8. Fetuses were collected on GD 18. Maternal toxic effects including a dose-related mortality, a high incidence of abortion, embryo lethality, congenital malformations and intrauterine growth retardation (IUGR) were observed in the LTG-treated group. Administration of LTG in multiple low doses resulted in a better maternal survival and increased incidence of embryonic resorption and malformations with increasing dose; IUGR was significant but not dose-dependent. The malformations characteristic of the LTG multiple low dose group fetuses included maxillary-mandibular hypoplasia, exencephaly, cleft palate, median facial cleft, urogenital anomalies and varying degrees of caudal regression. Skeletal malformations and developmental delay of the skeleton were observed both in single and multiple dose groups.
The results of this study indicate that LTG administered i.p. at high doses can induce intrauterine growth retardation and at low multiple doses causes a dose-dependent increase in embryonic resorption, craniofacial and caudal malformations as well as maternal toxicity in the mouse. Previous studies in other laboratories have used oral route of exposure and concluded that there are no teratogenic effects of LTG at dose levels that are not maternally toxic.
迄今为止，几乎所有已测试的抗癫痫药物（AED）都被发现具有致畸性。第二代AED相对于第一代具有许多治疗优势。然而，关于它们对胚胎发育影响的数据却非常少。最近一份报告表明，拉莫三嗪（LTG）可能对人类胎儿有致畸性。然而，记录中仅有少数几例胎儿在产前接触过LTG的情况，因此尚无法确定LTG治疗的母亲所生婴儿中可识别的畸形模式。
本研究的目的是评估LTG的生殖毒性作用。
在妊娠第7天或第8天，通过腹腔注射（i.p.）（注意治疗给药途径为口服）给多组TO小鼠单次（50 - 200mg/kg）或多次（25、50、75mg/kg）注射LTG。在妊娠第18天收集胎儿。在LTG治疗组中观察到母体毒性作用，包括剂量相关的死亡率、高流产率、胚胎致死率、先天性畸形和宫内生长迟缓（IUGR）。多次低剂量给予LTG可使母体存活率提高，但随着剂量增加，胚胎吸收和畸形的发生率增加；IUGR显著但不依赖剂量。LTG多次低剂量组胎儿的畸形特征包括上颌 - 下颌发育不全、无脑儿、腭裂、面部正中裂、泌尿生殖系统异常以及不同程度的尾部退化。在单次和多次剂量组中均观察到骨骼畸形和骨骼发育延迟。
本研究结果表明，腹腔注射高剂量LTG可导致宫内生长迟缓，多次低剂量给药会导致胚胎吸收剂量依赖性增加、颅面和尾部畸形以及小鼠母体毒性。其他实验室先前的研究采用口服暴露途径，并得出结论，在不产生母体毒性的剂量水平下，LTG没有致畸作用。
