Interactions between teratogens and genetic factors in the mechanismsof malformations in the offspring of epileptic mothers.

致畸剂和遗传因素在癫痫母亲后代畸形机制中的相互作用。

• 批准号: 05454309
• 负责人: KANEKO Sunao
• 金额: $ 4.35万
• 依托单位: Hirosaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454309/
• 关键词: Malformation; Antiepileptic drug; Glutathione S-transferase; Epoxide hydrolase; Epilepsy; Genetice; Pregnancy; Prevention of malformation; 抗かんてん薬; glutatione S-transferase; epoxide hydrolase; 奇形発現機序; 抗てんかん薬・活性代謝産物

The purpose of this project is to assess the relative contributions of antiepileptic drugs (AED) and genetic factors of mothers and their offspring to occurrence of congenital malformations, and the following results were obtained :1.The predominant contribution of AED factors to the occurrence of malformation in the offspring of epileptic mothers has been established. The AED factors include a high drug dose, a high serum drug concentration, the use of AEDs with a high potential for teratogenicity (primidone>valproate>phenytion>carbamazepine>phenobarbital) and AED polytherapy (especially valproate plus carbamazepine).2.The mechanisms of teratogenicity of AED is still being investigated, but it is postulated that epoxide intermediates and other toxic metabolites of AED (ex, 4-en valproate) together with maternal compound itself are invloved. The balance between metabolic activation and detoxification determined by pharmacogenetic variability as well as drug-drug interaction is the relevant to the teratogenic activity. Folate deficiency and impaired folate matabolism caused by AEDs may contribute to the teratogenicity of the drugs.3.For individual predictive testing for safe therapy, the establishment of criteria of the drug withdrawal and markers indicative of the defects in the drug detoxification pathway is needed.

本项目旨在评估抗癫痫药物（AED）与母亲及其后代遗传因素对先天性畸形发生的相对贡献，得到以下结果：1.抗癫痫药物（AED）与母亲及其后代遗传因素对先天性畸形发生的相对贡献。AED因素对癫痫母亲的后代畸形发生的主要贡献已经确立。AED因素包括高药物剂量、高血清药物浓度、使用致畸性高的AED（普米酮b>丙戊酸b>苯化b>卡马西平b>苯巴比妥）和AED综合治疗（尤其是丙戊酸加卡马西平）。AED致畸机制仍在研究中，但假设AED的环氧化物中间体和其他毒性代谢物（例如，4-en丙戊酸酯）与母体化合物本身有关。由药物遗传变异和药物-药物相互作用决定的代谢激活和解毒之间的平衡与致畸活性有关。抗癫痫药引起的叶酸缺乏和叶酸代谢障碍可能导致药物的致畸性。对于安全治疗的个体化预测检测，需要建立停药标准和药物解毒途径缺陷标志物。

项目成果

Kazumaru Wada,et al.: "The recurrence of seizures in epileptic patients who had been free from seizures for 10 years or more" Epilepsia. (in press). (1996)

Kazumaru Wada 等人：“10 年或更长时间没有癫痫发作的癫痫患者的癫痫发作复发”癫痫。

兼子直: "てんかん学の進歩,No.3:妊娠・出産とてんかん,pp.189-201(分担)" 岩崎学術出版社, 490 (1996)

Nao Kaneko：“癫痫学进展，第 3 期：妊娠、分娩和癫痫，第 189-201 页（共享）”岩崎学术出版社，490（1996）

Sunao Kaneko: "Epilepsy and Genetics." Journal of Psychiatry and Allied Neurosciences. (in press). (1995)

金子须直：“癫痫与遗传学。”

Motohiro Okada, Sunao Kaneko, Takayuki Hirano, Kazuhisa Mizuno: "Effects of zonisamide on dopaminergic system." Epilepsy Research. 22(3). 193-205 (1996)

Motohiro Okada、Sunao Kaneko、Takayuki Hirano、Kazuhisa Mizuno：“唑尼沙胺对多巴胺能系统的影响。”

Kazumaru Wada, Yutaka Fukushima, Sunao Kaneko, Fumio Saito, Kazuaki Hashimoto: "The recurrence of seizure in epileptic patients who had been free from seizures for 10 years or more." Epilepsia. (in press). (1996)

Kazumaru Wada、Yutaka Fukushima、Sunao Kaneko、Fumio Saito、Kazuaki Hashimoto：“10 年或更长时间没有癫痫发作的癫痫患者的癫痫发作复发。”