A novel detoxification treatment for organophosphorus poisoning by using BBB penetrative oximes
| Project/Area Number |
25462845
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Emergency medicine
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| Research Institution | National Research Institute of Police Science |
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Principal Investigator |
Ohta Hikoto 科学警察研究所, 法科学第三部, 室長 (40392261)
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| Co-Investigator(Kenkyū-buntansha) |
櫻田 宏一 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10334228)
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| Co-Investigator(Renkei-kenkyūsha) |
YAMAMURO Tadashi 科学警察研究所, 法科学第三部, 室長 (80646555)
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| Project Period (FY) |
2013-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2013: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
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| Keywords | アセチルコリンエステラーゼ / 脳内活性回復 / 4-PAO / 2-PAM / サリン類似体 / サリン阻害ラット / AChE活性測定 / MATP+ / 救急蘇生学 / 有機リン中毒 / 神経剤 / 解毒剤 / 血液脳関門 / オキシム |
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| Outline of Final Research Achievements |
In Tokyo subway sarin attack in 1995 in Japan, 2-PAM was used for remedy of victims; however, it was insufficient for reactivation of inhibited AChE in CNS of victims since it does not penetrate BBB. In order to develop more effective antidote, we studied the direct reactivation of sarin-inhibited AChE in rat brain by BBB-penetrative oxime. Among the N-alkyl 4-pyridinealdoximes, only 4-PAO (side chain length: n-C8) showed enough BBB permeability and AChE reactivation activity. Sarin-inhibited rats (brain AChE inhibited to 12.5%) was prepared by safe sarin analogue INMP, and then administered 4-PAO by continuous infusion at 0 (negative control), 1, 3, or 8 mg/kg with 0.4 mg/kg of atropine. After 4 hours and 20 min, the inhibited rat brain AChE was quantitatively recovered by 4-PAO. At 8 mg/kg of 4-PAO, the inhibited brain AChE activity was recovered from 12.5% to 79.3% ± 12.3%. This study suggests that 4-PAO has both adequate delivery across BBB and in vivo AChE reactivating capacity.
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Report
(5 results)
Research Products
(4 results)
