Development of the strategy for the quantitative prediction and avoidance of drug-induced Parkinsonism based on pharmacokinetics and pharmacodynamics

基于药代动力学和药效学定量预测和避免药物性帕金森病的策略的制定

• 批准号: 11470513
• 负责人: SAWADA Yasufumi
• 金额: $ 8.7万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470513/
• 关键词: Parkinsonism; dopamine receptor; catalepsy; Prescription; prediction of adverse reactions

i) The intensity of catalepsy and in vivo receptor occupancies for domapine D1, D2 and muscarinic acetylcholine receptors were investigated for 25 drugs in mice. The intensity of catalepsy was found to be predictable from these receptor occupancies.ii) The relationship between structure and drug-induced parkinsonism was investigated. The diethylaminomethyl moiety was found to play an important role in the induction of parkinsonism.iii) A case of propiverine-induced parkinsonism was found. The mechanisms underlying the induction of parkinsonism by propiverine was investigated in mice.iv) In vitro experiments were carried out to estimate the affinities of 25 drugs for dopamine D1, D2 and muscarinic acetylcholine receptors, which were indispensable for quantitative prediction of drug-induced parkinsonism.v) Developed was the strategy for the quantitative prediction of drug-induced parkinsonism in humans using the above results of i) and iv).vi) The above(iv) strategy was applied to develop a computer-aided drug information system for rational prescription.

i）研究了25种小鼠的药物，研究了Domapine D1，D2和毒蕈碱乙酰胆碱受体的活体内受体占用的强度。从这些受体占用物中发现了细胞蛋白的强度。发现二乙酰氨基甲基部分在帕金森氏症的诱导中起着重要作用。在小鼠中研究了帕金森氏症诱导型帕金森氏症的机制。IV）进行了体外实验，以估计25种药物对多巴胺D1，D2和毒蕈碱乙酰胆碱受体的亲和力，对于量定的量定量预测了parkinsoniston的策略。使用上述i）和iv）的帕金森氏症。

项目成果

R.Nasu, H.Matsuo, H.Takanaga, H.Ohtani and Y.Sawada: "Quantitative prediction of catalepsy induced by amoxapine, cinnarizine and cyclophosphamide in mice."Biopharm.Drug Dispos. 21. 129-138 (2000)

R.Nasu、H.Matsuo、H.Takanaga、H.Ohtani 和 Y.Sawada：“定量预测阿莫沙平、桂利嗪和环磷酰胺诱发的小鼠僵直症。”Biopharm.Drug Dispos。

H.Ohtani and Y.Sawada: "Development and application of the strategy for the quantitative prediction of drug-induced parkinsonisms"Xenobio.Metabol.Dispos.. 16(1). 27-37 (2001)

H.Ohtani 和 Y.Sawada：“药物诱发帕金森病定量预测策略的开发和应用”Xenobio.Metabol.Dispos.. 16(1)。

松井晶子,那須理佐,松尾浩民,高長ひとみ,澤田康文: "In vivoレセプター結合占有率を用いた薬剤性パーキンソニズムの定量的予測"TDM研究. 16. 115-116 (1999)

Akiko Matsui、Risa Nasu、Hirotami Matsuo、Hitomi Takanaga、Yasufumi Sawada：“利用体内受体结合占用定量预测药物诱发的帕金森病”TDM Research 16. 115-116 (1999)。

Nasu R., Matsuo H., Takanaga H., Ohtani H., and Sawada Y.: "Quantitative prediction of catalepsy induced by amoxapine, cinnarizine and cyclophosphamide in mice"Biopharmaceutics and Drug Disposition. 21. 129-138 (2000)

Nasu R.、Matsuo H.、Takanaga H.、Ohtani H. 和 Sawada Y.：“阿莫沙平、桂利嗪和环磷酰胺诱发小鼠僵直症的定量预测”生物药剂学和药物处置。

Y.Sawada, R..Nasu, H.Matsuo and H.Ohtani: "Relationship between structure and drug-induced parkinsonism."Ann.Pharmacother. 34. 668 (2000)

Y.Sawada、R..Nasu、H.Matsuo 和 H.Ohtani：“结构与药物诱发的帕金森病之间的关系。”Ann.Pharmacother。