著者

杉本 八郎

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学雑誌 (ISSN:00155691)

巻号頁・発行日

vol.124, no.3, pp.163-170, 2004 (Released:2004-08-27)

参考文献数

12

被引用文献数

3 2

---

1970年代にD.M.Bowenらはアルツハイマー病(AD)患者の死後脳でコリン作動性神経の異常を報告した.彼らはAD患者脳の大脳皮質にアセチルコリン合成酵素(ChAT)活性が異常に低下していることを見出した.またE.K.PerryらはChAT活性の低下と記憶力減少とは相関すると報告した.これらの背景からコリン仮説が生まれた.コリン仮説には神経プレ側,ポスト側に作用して記憶を改善する方法があるが臨床研究で成功しているアプローチはアセチルコリンエステラーゼ(AChE)阻害作用に基づく方法が成功している.ドネペジルの成功は従来のAChE阻害薬とは全く化学構造が異なる点にある.4年間の探索研究は1000化合物の中から臨床上もっともバランスの良い化合物を選択できる道を与えてくれた.高い生体利用率に裏打ちされ1日1回投与を可能にした.動物実験ではAChEに対する高い選択性や優れた脳内移行性が副作用を軽減していることが考えられる.また厳密な治験活動がADAS-cogとCIBIC-plusの2つの臨床試験でプラセボと比較して極めて高い有用性を見出すことが出来た.AChE阻害薬はAD以外にレビー小体,脳血管性痴呆,偏頭痛,パーキンソン病による痴呆症などたくさんの可能性を検討している.また抗酸剤,女性ホルモンなどとの併用,そして最近,欧州と米国でAD治療薬として承認されたNMDA拮抗薬メマンチンは作用機序が異なることからドネペジルとの相乗効果などが期待されている.さらにドネペジル単独でも神経保護作用が報告されていて臨床で長期間投与したときのドネペジルの効果にさらなる検討を期待したい.またドネペジルがMCI(Mild Cognitive Impairment)に対して効果が確認されればAD予防薬の可能性がある.今後もAChE阻害薬は基礎実験と臨床試験の両面から可能性が検討されることを期待したい.

著者

杉本 八郎

出版者

広島大学

巻号頁・発行日

1996

---

博士論文

著者

杉本 八郎

出版者

一般社団法人 国立医療学会

雑誌

医療 (ISSN:00211699)

巻号頁・発行日

vol.62, no.3, pp.174-175, 2008-03-20 (Released:2011-10-07)

著者

杉本 八郎 山西 嘉晴 小倉 博雄 飯村 洋一 山津 清實

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.119, no.2, pp.101-113, 1999-02-01 (Released:2008-05-30)

参考文献数

28

被引用文献数

3 9

---

The most consistent change of neurotransmitter in the brain of Alzheimer's patients is the dramatic decrease of cholinergic innervation due to the loss of neurons in the basal forebrain. The most widely studied acetylcholinesterase inhibitors (AChEIs) have been physostigmine and tacrine. Physostigmine has very short duration, and tacrine has liability to hepatotoxicity. These are the defects of the inhibitors. Our objective was to find a new type of AChEIs that would overcome the disadvantages of physostigmine and tacrine. Through a random screening, we incidentally found an N-benzylpiperazine derivative which showed positive cholinergic behavior in rats. We replaced the N-benzylpiperazine moiety with N-benzylpiperidine moiety and found a dramatic increase in anti-AChE activity. Even after the replacement of an amide group with a ketone group the activity was held. Furthermore, the cyclic-amide derivative showed enhanced inhibitory activity. On the basis of these results, an indanone derivative was designed. Among these indanone derivatives, donepazil hydrochloride (E2020), brand name ARICEPT was found to be the most balanced compound. The clinical studies of donepezil hydrochloride demonstrated statistically significant effects on ADAS-cog (Alzheimer's Disease Assessment Scale cognitive sub.) and CIBIC Plus (Clinician's Interview-Based Impression of Change plus).

著者

杉本 八郎

出版者

The Society of Synthetic Organic Chemistry, Japan

雑誌

有機合成化学協会誌 (ISSN:00379980)

巻号頁・発行日

vol.56, no.4, pp.320-327, 1998-04-01 (Released:2009-11-16)

参考文献数

17

被引用文献数

6 4

著者

谷内 信彦 新留 徹広 杉本 八郎

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.135, no.2, pp.323-329, 2015-02-01 (Released:2015-02-01)

参考文献数

36

被引用文献数

1 1

---

In addition to cognitive decline, Alzheimer's disease patients also exhibit non-cognitive symptoms commonly referred to as behavioral and psychological symptoms of dementia, or BPSD. These symptoms have a serious impact on the quality of life of these patients, as well as that of their caregivers, but there are currently no effective therapies. The amyloid β-peptide (Aβ) is suspected to play a central role in the cascade leading to Alzheimer's disease, but the precise mechanisms are still incompletely known. To assess the influence of Aβ pathology on cognitive and non-cognitive behaviors, we examined locomotor activity, motor coordination, and spatial memory in male and female APPswePS1dE9 mice (Alzheimer's disease model, double transgenic mice expressing an amyloid precursor protein with Swedish mutation and a presenilin-1 with deletion of exon 9) at 5 months of age, when the mice had subtle Aβ deposits, and again at 9 months of age, when the mice had numerous Aβ deposits. Compared to wild-type mice, the male and female APPswe/PS1dE9 mice showed normal motor coordination in the rotarod test at both 5 and 9 months. In the Morris water maze test, male and female APPswe/PS1dE9 mice showed impaired spatial memory at 9 months; however, no such deficits were found at 5 months. In a locomotor activity test, male APPswe/PS1dE9 mice exhibited locomotor hyperactivity at 9 months, while females exhibited locomotor hyperactivity at both 5 and 9 months compared to the control mice. Together, these results indicate that APPswe/PS1dE9 mice developed spatial memory impairment and BPSD-like behavioral alterations resulting from Aβ accumulation.

著者

杉本 八郎

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.130, no.4, pp.521-526, 2010 (Released:2010-04-01)

参考文献数

8

被引用文献数

6 6

---

Currently, there are five anti-Alzheimer's disease drugs approved. These are tacrine, donepezil, rivastigmine, galantamine, and memantine. The mechanism of the first four drugs is acetylcholinesterase inhibition, while memantine is an NMDA-receptor antagonist. However, these drugs do not cure Alzheimer's, but are only symptomatic treatments. Therefore, a cure for Alzheimer's disease is truly needed. Alzheimer's disease is a progressive neurodegenerative disease characterized by cognitive deficits. The cause of the disease is not well understood, but research indicates that the aggregation of β-amyloid is the fundamental cause. This theory suggests that β-amyloid aggregation causes neurotoxicity. Therefore, development of the next anti-Alzheimer's disease drug is based on the β-amyloid theory. We are now studying natural products, such as mulberry leaf extracts and curcumin derivatives, as potential cure for Alzheimer's disease. In this report, we describe some data about these natural products and derivatives.