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种药物对小鼠的猝厥强度和体内多巴胺D1、D2和毒蕈碱乙酰胆碱受体的占用率。猝倒的强度可以从这些受体占位中预测出来。ii)探讨结构与药物性帕金森病的关系。发现二乙胺甲基在帕金森病的诱导中起重要作用。iii)发现丙酸所致帕金森病1例。在小鼠实验中研究了丙酸诱导帕金森病的机制。iv)通过体外实验，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，这是定量预测药物性帕金森病不可缺少的。v)开发了利用上述i)和iv)结果定量预测人类药物性帕金森病的策略。vi)将上述（iv）策略应用于开发用于合理处方的计算机辅助药物信息系统。

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。

H.Matsuo, A.Matsui, R.Nasu, H.Takanaga, N.Inoue, F.Hattori, H.Ohtani and Y.Sawada: "Propiverine-induced Parkinsonism : A case report and a pharmacokinetic/pharmacody namic study in mace."Pharm.Res.. 17. 565-571 (2000)

H.Matsuo、A.Matsui、R.Nasu、H.Takanaga、N.Inoue、F.Hattori、H.Ohtani 和 Y.Sawada：“丙哌维林诱发的帕金森病：病例报告和肉豆蔻药代动力学/药理学研究