| Project/Area Number |
11470510
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | The University of Tokyo |
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Principal Investigator |
IGA Tatsuji Faculty of Mecicin, The University of Tokyo, Professor, 医学部・附属病院, 教授 (60012663)
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| Co-Investigator(Kenkyū-buntansha) |
大橋 聖子 東京大学, 医学部・附属病院, 助手 (10292939)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥8,300,000 (Direct Cost: ¥8,300,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥6,500,000 (Direct Cost: ¥6,500,000)
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| Keywords | PREDICTION OF DRUG-EFFECT / DYNAMIC MODEL / RECEPTOR OCCUPANCIES / PARKINSONISM / DOPAMINE RECEPTOR / MUSCARINIC RECEPTOR / PHARMACODYNAMIC / CATALEPSY / 薬剤性パーキンソニズム / P-糖タンパク質 / シクロスポリン / ドンペリドン / L-dopa / パーキンソン病モデルラット / PK / PDモデル |
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| Research Abstract |
In this study, the relationship between in vivo dopamine Dl and D2 receptor occupancies and catalepsy was investigated to predict the intensity of catalepsy induced by drugs which bound to Dl and D2 receptors nonselectively. Intensities of catalepsy predicted by using this pharmacodynamic model considering the interaction between Dl and D2 receptors overestimated the observed values, suggesting that these drugs had catalepsy-reducing properties as well. Since muscarinic acetylcholine (mACh) receptor antagonists inhibited the induction of catalepsy, the anticholinergic activities of the drugs were investigated. Relationship between mACh receptor occupancy and change in catalepsy was used as the measure of catalepsy-reducing effects of the drugs.
After coadministration of domperidone and cyclosporin A, intensity of catalepsy was stronger than that predicted after administration of each drug. It is suggested that changes in permeability of the blood-brain barrier (BBB) to domperidone following exposure to cyclosporin A.
In conclusion, the pharmacodynamic model considering Dl , D2, and mACh receptor occupancies and synergism between Dl and D2 receptors may be useful for quantitative prediction of drug-induced catalepsy.
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