Abdulrazzaq Y M, Bastaki S M, Padmanabhan R
Department of Pediatrics, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
Teratology. 1997 Mar;55(3):165-76. doi: 10.1002/(SICI)1096-9926(199703)55:3<165::AID-TERA1>3.0.CO;2-1.
Vigabatrin (VGB) is a relatively recently introduced antiepileptic drug that enhances the brain levels of gamma aminobutyric acid (GABA). Few data on its teratogenic effects appear to have been reported. Our objective was to determine if VGB was teratogenic in the TO mouse. Single doses of 300-600 mg/kg of VGB dissolved in saline were administered intraperitoneally (IP) to groups of TO mice on one of gestation days (GD) 7-12. The controls were saline treated or untreated. No maternal toxic effects were observed in the 300 or 450 mg/kg groups, and the 600 mg/kg dose was totally lethal to the mothers. Fetuses were collected on GD 18. Both 300 and 450 mg/kg doses induced a consistently significant intrauterine growth retardation irrespective of the developmental stage at administration. VGB did not augment the spontaneous incidence of neural tube defects characteristic of this strain, but accelerated destruction of the brain in spontaneous exencephalic embryos. Mandibular and maxillary hypoplasia, arched palate, cleft palate (two cases), limb defects (one case), and exomphalos were observed in the malformed fetuses. The high incidence of exomphalos appears to be a unique result of VGB treatment. Alizarin red-S/alcian blue-stained, skeletons revealed hypoplasia of mid facial bones, stage-dependent increase in the frequency of cervical and lumbar ribs, rib fusion, and sternal and vertebral malformations in the drug-treated fetuses. Middle and distal phalanges of the forepaw and mid phalanges and tarsals of the hindpaw failed to ossify in a significant number of experimental fetuses. Homeotic shift in terms of presacral vertebral number and a high incidence of lumbar and cervical ribs in the treated group are suggestive of treatment-related alterations in gene expression. In view of the paucity of human and animal data on the reproductive toxicologic effects of VGB, the results of the present study assume particular importance and suggest that VGB should be used in pregnancy with extreme caution.
氨己烯酸（VGB）是一种相对较新引入的抗癫痫药物，可提高大脑中γ-氨基丁酸（GABA）的水平。关于其致畸作用的报道似乎很少。我们的目的是确定VGB在TO小鼠中是否具有致畸性。在妊娠第7 - 12天的某一天，将溶解于生理盐水的300 - 600 mg/kg单剂量VGB经腹腔注射（IP）给予几组TO小鼠。对照组接受生理盐水处理或未处理。在300或450 mg/kg组中未观察到母体毒性作用，而600 mg/kg剂量对母亲具有完全致死性。在妊娠第18天收集胎儿。300和450 mg/kg剂量均导致一致且显著的宫内生长迟缓，无论给药时的发育阶段如何。VGB并未增加该品系特有的神经管缺陷的自发发生率，但加速了自发露脑胚胎中大脑的破坏。在畸形胎儿中观察到下颌和上颌发育不全、腭裂、腭裂（2例）、肢体缺陷（1例）和脐膨出。脐膨出的高发生率似乎是VGB治疗的独特结果。茜素红S/阿尔新蓝染色的骨骼显示，药物处理的胎儿中面部中部骨骼发育不全、颈椎和腰椎肋骨频率的阶段依赖性增加、肋骨融合以及胸骨和脊柱畸形。在大量实验胎儿中，前爪的中节和远节指骨以及后爪的中节趾骨和跗骨未能骨化。治疗组中骶前椎骨数量的同源异型转变以及腰椎和颈椎肋骨的高发生率提示与治疗相关的基因表达改变。鉴于关于VGB生殖毒理学效应的人类和动物数据匮乏，本研究结果具有特别重要的意义，并表明在妊娠期间应极其谨慎地使用VGB。
