| Project/Area Number |
05454309
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Psychiatric science
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| Research Institution | Hirosaki University |
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Principal Investigator |
KANEKO Sunao Hirosaki University, Neuropsychiatry, Professor, 医学部, 教授 (40106852)
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| Co-Investigator(Kenkyū-buntansha) |
WADA Kazumaru Hirosaki University, Neuropsychiatry, Assistant School of Medicine, 医学部附属病院, 助手 (60241486)
KONDO Tsuyoshi Hirosaki University, Neuropsychiatry, Assistant School of Medicine, 医学部, 助手 (40215455)
OTANI Koichi Hirosaki University, Neuropsychiatry, Lecturer School of Medicine, 医学部附属病院, 講師 (00194192)
佐藤 公彦 弘前大学, 医学部, 助教授 (70003655)
福島 裕 弘前大学, 医学部, 教授 (80003482)
斎藤 文男 弘前大学, 医学部附属病院, 講師 (50133864)
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| Project Period (FY) |
1993 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 1995: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1994: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1993: ¥4,500,000 (Direct Cost: ¥4,500,000)
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| Keywords | 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 |
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| Research Abstract |
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.
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