JPWO2005011736A1 - Preventive and / or therapeutic agent for Alzheimer's disease - Google Patents
Preventive and / or therapeutic agent for Alzheimer's disease Download PDFInfo
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- JPWO2005011736A1 JPWO2005011736A1 JP2005512443A JP2005512443A JPWO2005011736A1 JP WO2005011736 A1 JPWO2005011736 A1 JP WO2005011736A1 JP 2005512443 A JP2005512443 A JP 2005512443A JP 2005512443 A JP2005512443 A JP 2005512443A JP WO2005011736 A1 JPWO2005011736 A1 JP WO2005011736A1
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Abstract
本発明の課題は、新規なアルツハイマー病の予防および／または治療剤を提供することである。そして本発明のアルツハイマー病の予防および／または治療剤は、脳内移行性のアンギオテンシン変換酵素阻害剤を有効成分とすることを特徴とするものである。An object of the present invention is to provide a novel preventive and / or therapeutic agent for Alzheimer's disease. The preventive and / or therapeutic agent for Alzheimer's disease of the present invention is characterized by comprising an angiotensin-converting enzyme inhibitor that migrates into the brain as an active ingredient.
Description
本発明は、新規なアルツハイマー病の予防および／または治療剤に関する。 The present invention relates to a novel preventive and / or therapeutic agent for Alzheimer's disease.
アルツハイマー病（ＡＤ）の治療に関する研究は精力的に行われているが、完全なその予防法および治療法に関する報告はいまだ存在しない。これまでエストローゲンや非ステロイド性抗炎症薬（ＮＳＡＩＤｓ）がＡＤの治療に寄与すると報告されているが、その効果は必ずしも明らかではない（文献１：Ｋｙｏｍｅｎ ＨＨ，Ｈｅｎｎｅｎ Ｊ，Ｇｏｔｔｌｉｅｂ ＧＬ，ｅｔ ａｌ．Ｅｓｔｒｏｇｅｎ ｔｈｅｒａｐｙ ａｎｄ ｎｏｎｃｏｇｎｉｔｉｖｅ ｐｓｙｃｈｉａｔｒｉｃ ｓｉｇｎｓ ａｎｄ ｓｙｍｐｔｏｍｓ ｉｎ ｅｌｄｅｒｌｙ ｐａｔｉｅｎｔｓ ｗｉｔｈ ｄｅｍｅｎｔｉａ．Ａｍ Ｊ Ｐｓｙｃｈｉａｔ ２００２；１５９：１２２５−１２２７．）。ＡＤの病態にアミロイドβ蛋白（Ａβ）の蓄積が関与している事から、これまでのＡＤの治療において、その前駆体であるアミロイドプレカーサー蛋白（ＡＰＰ）の、神経成長因子およびアポ蛋白Ｅ（Ａｐｏ−Ｅ）による修飾によってＡβの蓄積を抑制することが試みられてきたが（文献２：Ａｒａｉ Ｈ．Ｂｉｏｌｏｇｉｃａｌ ｍａｒｋｅｒｓ ｆｏｒ ｔｈｅ ｃｌｉｎｉｃａｌ ｄｉａｇｎｏｓｉｓ ｏｆ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ．Ｔｏｈｏｋｕ Ｊ Ｅｘｐ Ｍｅｄ １９９６；１７９：６５−７９．）、この方法は必ずしも成功しているとは言い難い。またこれまで、ＡＤの発症にアセチルコリン、ノルアドレナリン、セロトニン、グルタミン酸、ソマトスタチンおよびコルチコトロピン放出因子などのたくさんの神経伝達物質や神経ペプチドの低下が関与すると言われており（前述の文献２，文献３：Ｊｉａ ＹＸ，Ｌｉ ＪＱ，Ｍａｔｓｕｉ Ｔ，ｅｔ ａｌ．Ｎｅｕｒｏｃｈｅｍｉｃａｌ ｒｅｇｕｌａｔｉｏｎ ｏｆ ｓｗａｌｌｏｗｉｎｇ ｒｅｆｌｅｘ ｉｎ ｇｕｉｎｅａ ｐｉｇｓ．Ｇｅｒｉａｔｒ Ｇｅｒｏｎｔｏｌ Ｉｎｔｅｒｎａｔ ２００１；１：５６−６１．）、これらの因子の不足を補うことをターゲットにした治療が試みられてきたが、いずれも充分とは言えない。
これらのＡＤの治療の中で、コリン性因子へのアプローチが試みられている。例えば、脳内のコリン作動性神経の機能障害がＡＤの患者に認められるとの報告があり、アセチルコリンエステラーゼ阻害剤のドネペジルは、脳内のアセチルコリン（Ａｃｈ）を増加させることから、ＡＤの治療薬として開発されてきた。そして、ドネペジルは、ＡＤの患者のＭＭＳＥ（Ｍｉｎｉ−Ｍｅｎｔａｌ Ｓｔａｔｅ Ｅｘａｍｉｎａｔｉｏｎ）スコアを容量依存的に改善させると報告されている（文献４：Ｒｏｇｅｒｓ ＳＬ，Ｆａｒｌｏｗ ＭＲ，Ｄｏｏｄｙ ＲＳ，ｅｔ ａｌ．Ａ ２４−ｗｅｅｋ，ｄｏｕｂｌｅ−ｂｌｉｎｄ，ｐｌａｃｅｂｏ−ｃｏｎｔｒｏｌｌｅｄ ｔｒｉａｌ ｏｆ ｄｏｎｅｐｅｚｉｌ ｉｎ ｐａｔｉｅｎｔｓ ｗｉｔｈ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ．Ｎｅｕｒｏｌｏｇｙ １９９８；５０：１３６−１４５．）。ドネペジルは、ＡＤの患者に対し、処方開始後２ないし３ヶ月で３０点中２ないし３点のＭＭＳＥスコアを改善させると言われているが、半年後には非治療群に比べ１点のみの改善にとどまると報告されている（前述の文献４）。以上のように、ドネペジルのＡＤに対する効果は限られている。我々は以前、和漢薬でコリンアセチルトランスフェラーゼ活性を高める加味温胆湯（Ｋａｍｉ−Ｕｎｔａｎ−Ｔｏ：ＫＵＴ）が、軽度から中等度のＡＤの患者でＭＭＳＥスコアの改善効果を示すと報告している（文献５：Ｗａｎｇ Ｑ，Ｉｗａｓａｋｉ Ｋ，Ｓｕｚｕｋｉ Ｔ，ｅｔ ａｌ．Ｐｏｔｅｎｔｉａｔｉｏｎ ｏｆ ｂｒａｉｎ ａｃｅｔｙｌｃｈｏｌｉｎｅ ｎｅｕｒｏｎｓ ｂｙ Ｋａｍｉ−Ｕｎｔａｎ−Ｔｏ（ＫＵＴ）ｉｎ ａｇｅｄ ｍｉｃｅ：ｉｍｐｌｉｃａｔｉｏｎｓ ｆｏｒ ａ ｐｏｓｓｉｂｌｅ ａｎｔｉ−ｄｅｍｅｎｔｉａ ｄｒｕｇ．Ｐｈｙｔｏｍｅｄｉｃｉｎｅ ２０００；７：２５３−２５８．，文献６：Ｓｕｚｕｋｉ Ｔ，Ａｒａｉ Ｈ，Ｉｗａｓａｋｉ Ｋ ｅｔ ａｌ．Ａ Ｊａｐａｎｅｓｅ ｈｅｒｂａｌ ｍｅｄｉｃｉｎｅ（Ｋａｍｉ−Ｕｎｔａｎ−Ｔｏ）ｉｎ ｔｈｅ ｔｒｅａｔｍｅｎｔ ｏｆ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ：ａ ｐｉｌｏｔ ｓｔｕｄｙ．Ａｌｚｈｅｉｍｅｒｓ Ｒｅｐ ２００１；５：１７７−１８２．）。しかし、加味温胆湯の効果は、ドネペジルと同様に限界があると言われている。ドネペジルと加味温胆湯のアセチルコリン増強作用の機序には相違があると言われており、その組み合わせ治療は更に検討される余地がある。
前述の通り、ＡＤの病態に、脳内におけるＡβの蓄積が関与していると言われている。Ａβは神経細胞から常時分泌されているが、少なくとも健康な脳においては、分泌後すばやく分解され脳内に蓄積しないと言われている。岩田らは、ニュートラルエンドペプチダーゼ（ＮＥＰ）がＡβ代謝の中心的な役割を果たすと報告している（文献７：Ｉｗａｔａ Ｎ，Ｔｓｕｂｕｋｉ Ｓ，Ｔａｋａｋｉ Ｙ，ｅｔ ａｌ．Ｉｄｅｎｔｉｆｉｃａｔｉｏｎ ｏｆ ｔｈｅ ｍａｊｏｒ Ａβ１−４２ ｄｅｇｒａｄｉｎｇ ｃａｔａｂｏｌｉｃ ｐａｔｈｗａｙ ｉｎ ｂｒａｉｎ ｐａｒｅｎｃｈｙｍａ：ｓｕｐｐｒｅｓｓｉｏｎ ｌｅａｄｓ ｔｏ ｂｉｏｃｈｅｍｉｃａｌ ａｎｄ ｐａｔｈｏｌｏｇｉｃａｌ ｄｅｐｏｓｉｔｉｏｎ．Ｎａｔ Ｍｅｄ ２０００；６：１４３−１５０．）。ＡβとＮＥＰはお互いに関与し合い、病気の進展に寄与するものと考えられる。そこで、脳内のＡβを低下させる治療法が有効ではないかと考えられる。例えば、Ａβに対する受動的かつ能動的な免疫療法が、トランスジェニックマウスにおいて異常な記憶ならびに学習行動を改善させることが報告されている（文献８：Ｓｃｈｅｎｋ Ｄ，Ｂａｒｂｏｕｒ Ｒ，Ｄｕｎｎ Ｗ ｅｔ ａｌ．Ｉｍｍｕｎｉｚａｔｉｏｎ ｗｉｔｈ ａｍｙｌｏｉｄ−ｂｅｔａ ａｔｔｅｎｕａｔｅｓ Ａｌｚｈｅｉｍｅｒ−ｄｉｓｅａｓｅ−ｌｉｋｅ ｐａｔｈｏｌｏｇｙ ｉｎ ｔｈｅ ＰＤＡＰＰ ｍｏｕｓｅ．Ｎａｔｕｒｅ １９９９；４００：１７３−１７７．）。ＡＤの患者においては、Ａβに対する免疫療法が神経病理の異常を改善させ、アストロサイトーシスを減少させ、Ａβで満たされたミクログリア細胞を減少させることが予想される。しかし、現状では、ワクチンの開発および実質的普及までには長い時間が必要で、且つ、副作用として６％のケースに髄膜脳炎が認められている（文献９：Ｓｃｈｅｎｋ Ｄ．Ａｍｙｌｏｉｄ−β ｉｍｍｕｎｏｔｈｅｒａｐｙ ｆｏｒ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ：ｔｈｅ ｅｎｄ ｏｆ ｔｈｅ ｂｅｇｉｎｎｉｎｇ．Ｎａｔ Ｒｅｖ Ｎｅｕｒｏｓｃｉ ２００２；３：８２４−８２８．）。その髄膜脳炎を除けば、Ａβに対する抗体療法はＡＤの病状進展を劇的に改善させることができると報告されている（文献１０：Ｈｏｃｋ Ｃ，Ｋｏｎｉｅｔｚｋｏ Ｕ，Ｓｔｒｅｆｆｅｒ ＪＲ，ｅｔ ａｌ．Ａｎｔｉｂｏｄｉｅｓ ａｇａｉｎｓｔ β−ａｍｙｌｏｉｄ ｓｌｏｗ ｃｏｇｎｉｔｉｖｅ ｄｅｃｌｉｎｅ ｉｎ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ．Ｎｅｕｒｏｎ ２００３；３８：５４７−５５４．）。よって、Ａβに対する能動的な免疫療法は、今後更なる研究を必要とするものと思われる。
高血圧は血管性痴呆のみならず、ＡＤの病状進展に関与する事が知られている。例えば、収縮期高血圧を有する高齢者では、カルシウムチャンネルブロッカーであるニトレンジピンを用いた降圧療法が１０００人／年あたりの痴呆の発症を７．７人／年から３．８人／年に減らすと報告されている（文献１１：Ｆｏｒｅｔｔｅ Ｆ，Ｓｅｕｘ Ｍ−Ｌ，Ｓｔａｅｓｓｅｎ ＪＡ，ｅｔ ａｌ．Ｐｒｅｖｅｎｔｉｏｎ ｏｆ ｄｅｍｅｎｔｉａ ｉｎ ｒａｎｄｏｍｉｚｅｄ ｄｏｕｂｌｅ−ｂｌｉｎｄ ｐｌａｃｅｂｏ−ｃｏｎｔｒｏｌｌｅｄ ｓｙｓｔｏｌｉｃ ｈｙｐｅｒｔｅｎｓｉｏｎ ｉｎ Ｅｕｒｏｐｅ（ｓｙｓｔ−Ｅｕｒ）ｔｒｉａｌ．Ｌａｎｃｅｔ １９９８；３５２：１３４７−１３５１．）。ある種の降圧療法は、血管性痴呆のみならずＡＤの発症を予防する可能性が示唆される。例えば、これまでＡＤの患者で、カルシウムチャンネルブロッカーによる神経保護作用が報告されている。Ａβは神経細胞内のカルシウムイオンの濃度を上昇させ、この機序によりオキシダントやサイトカインなどの神経毒に対する脳の感受性を高め、モノアミン神経伝達物質の代謝を抑制する可能性が示唆されている（文献１２：Ｈｅｃｋｂｅｒｔ ＳＲ，Ｌｏｎｇｓｔｒｅｔｈ Ｊｒ ＷＴ，Ｐｓａｔｙ ＢＭ，ｅｔ ａｌ．Ｔｈｅ ａｓｓｏｃｉａｔｉｏｎ ｏｆ ａｎｔｉｈｙｐｅｒｔｅｎｓｉｖｅ ａｇｅｎｔｓ ｗｉｔｈ ＭＲＩ ｗｈｉｔｅ ｍａｔｔｅｒ ｆｉｎｄｉｎｇｓ ａｎｄ ｔｈｅ Ｍｏｄｉｆｉｅｄ Ｍｉｎｉ−Ｍｅｎｔａｌ Ｓｔａｔｅ Ｅｘａｍｉｎａｔｉｏｎ ｉｎ ｏｌｄｅｒ ｐａｔｉｅｎｔｓ．Ｊ Ａｍ Ｇｅｒｉａｔｒ Ｓｏｃ １９９７；４５：１４２３−１４３３．）。
本発明は、以上の背景技術に鑑み、新規なアルツハイマー病の予防および／または治療剤を提供することを目的とする。Although research on the treatment of Alzheimer's disease (AD) has been conducted energetically, there are still no reports on its complete prevention and treatment. So far, estrogen and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to contribute to the treatment of AD, but the effect is not always clear (Reference 1: Kyomen HH, Hennen J, Gottlieb GL, et al. (Estrogen and non-cognitive psichiatrical signs and symptoms in elderly patients with dementia. Am J Psychiat 2002; 159: 1225-1227.). Since the accumulation of amyloid β protein (Aβ) is involved in the pathology of AD, in the treatment of AD so far, the precursor amyloid precursor protein (APP) of nerve growth factor and apoprotein E (Apo) -E) has been attempted to suppress the accumulation of Aβ (Reference 2: Arai H. Biological markers for the clinical diagnosis of Alzheimer's disease. Tohoku J Exp Med 1996-1997; 17: ) This method is not necessarily successful. Until now, it is said that the onset of AD involves the reduction of many neurotransmitters and neuropeptides such as acetylcholine, noradrenaline, serotonin, glutamic acid, somatostatin and corticotropin-releasing factor (the above-mentioned literature 2, literature 3: Jia YX, Li JQ, Matsui T, et al. Neurochemical regu- lation of swallowing reflex in guinea pigs. Geriatr Gerontool Internet 2001; 1: 56-61. However, neither is enough.
Among these treatments for AD, approaches to cholinergic factors have been attempted. For example, there is a report that dysfunction of cholinergic nerves in the brain is observed in AD patients, and the acetylcholinesterase inhibitor donepezil increases acetylcholine (Ach) in the brain. Has been developed as. And donepezil has been reported to improve the MMSE (Mini-Mental State Examination) score of AD patients in a dose-dependent manner (Reference 4: Rogers SL, Farlow MR, Doody RS, et al. A 24-week). , Double-blind, placebo-controlled trie of donepezil in patents with Alzheimer's disease. Neurology 1998; 50: 136-145.). Donepezil is said to improve the MMSE score of 2 to 3 out of 30 points in AD patients for 2 to 3 months after the start of prescription, but only 1 point improvement compared to the non-treatment group after 6 months It is reported that it stays at the above (reference 4 mentioned above). As described above, the effect of donepezil on AD is limited. We have previously reported that Kami-Untan-To (KUT), which enhances choline acetyltransferase activity in Japanese and Chinese medicines, shows an MMSE score improvement effect in patients with mild to moderate AD ( Reference 5: Wang Q, Iwasaki K, Suzuki T, et al. Potentation of brain acetylcholine neurones by Kami-Untan-To (KUT) in aged mice: implications. 6, Reference 6: Suzuki T, Arai H, Iwasaki K et al. A Japan herbal medicine (K mi-Untan-To) in the treatment of Alzheimer's disease: a pilot study.Alzheimers Rep 2001; 5: 177-182).. However, it is said that the effect of Kamibokubokuto has a limit similar to donepezil. It is said that there is a difference in the mechanism of potentiation of acetylcholine between donepezil and Kamiyokubokuto, and there is room for further investigation of the combination therapy.
As described above, it is said that Aβ accumulation in the brain is involved in the pathology of AD. Although Aβ is constantly secreted from nerve cells, it is said that at least in a healthy brain, it is rapidly degraded after secretion and does not accumulate in the brain. Iwata et al. Have reported that neutral endopeptidase (NEP) plays a central role in Aβ metabolism (Reference 7: Iwata N, Tsubuki S, Takaki Y, et al. Identification of the major Aβ 1-42 degrading catalysis. (pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 2000; 6: 143-150.). Aβ and NEP are thought to be involved in each other and contribute to the progression of the disease. Therefore, it is considered that a treatment method for reducing Aβ in the brain is effective. For example, passive and active immunotherapy against Aβ has been reported to improve abnormal memory and learning behavior in transgenic mice (Ref. 8: Schenk D, Barbour R, Dunn W et al. Immunization with). (Amyloid-beta attaches Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400: 173-177.). In AD patients, immunotherapy against Aβ is expected to ameliorate neuropathological abnormalities, reduce astrocytosis, and reduce Aβ-filled microglial cells. However, at present, it takes a long time to develop and substantially spread the vaccine, and meningoencephalitis has been observed in 6% of cases as a side effect (Reference 9: Schenk D. Amyloid-β immunotherapy for). Alzheimer's disease: the end of the beginning. Nat Rev Neurosci 2002; 3: 824-828.). Except for its meningoencephalitis, antibody therapy against Aβ has been reported to dramatically improve AD disease progression (Reference 10: Hock C, Konietzko U, Stiffer JR, et al. Antibodies against β -Amyloid slow cognitive deline in Alzheimer's disease. Neuron 2003; 38: 547-554.). Therefore, active immunotherapy against Aβ may require further research in the future.
It is known that hypertension is involved not only in vascular dementia but also in the progression of AD pathology. For example, in elderly patients with systolic hypertension, antihypertensive therapy using nitrendipine, a calcium channel blocker, reduces the incidence of dementia per 1,000 people / year from 7.7 / year to 3.8 / year. (Reference 11: Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomized double-blinded-pure-controlled-type. 1351.). Certain antihypertensive therapies suggest the possibility of preventing the development of AD as well as vascular dementia. For example, neuroprotective effects by calcium channel blockers have been reported so far in AD patients. It has been suggested that Aβ increases the concentration of calcium ions in nerve cells, and this mechanism increases the brain's sensitivity to neurotoxins such as oxidants and cytokines, and may suppress the metabolism of monoamine neurotransmitters (references) 12: Heckbert SR, Longstreth Jr WT, Psaty BM, et al.The association of antihypertensive agents with MRI white matter findings and the Modified Mini-Mental State Examination in older patients.J Am Geriatr Soc 1997; 45: 1423-1433). .
In view of the above background art, an object of the present invention is to provide a novel preventive and / or therapeutic agent for Alzheimer's disease.
近年、レニンアンギオテンシン系（ＲＡＳ）のある因子が、学習および記憶のプロセスに重要な役割を演じている事が報告されている（文献１３：Ｈｉｒａｗａ Ｎ，Ｕｅｈａｒａ Ｙ，Ｋａｗａｂａｔａ Ｙ，ｅｔ ａｌ．Ｌｏｎｇ−ｔｅｒｍ ｉｎｈｉｂｉｔｉｏｎ ｏｆ ｒｅｎｉｎ−ａｎｇｉｏｔｅｎｓｉｎ ｓｙｓｔｅｍ ｓｕｓｔａｉｎｓ ｍｅｍｏｒｙ ｆｕｎｃｔｉｏｎ ｉｎ ａｇｅｄ Ｄａｈｌ ｒａｔｓ．Ｈｙｐｅｒｔｅｎｓｉｏｎ １９９９；３４：４９６−５０２．，文献１４：Ｓａｖａｓｋａｎ Ｅ，Ｈｏｃｋ Ｃ，Ｏｌｉｖｉｅｒｉ Ｇ，ｅｔ ａｌ．Ｃｏｒｔｉｃａｌ ａｌｔｅｒａｔｉｏｎｓ ｏｆ ａｎｇｉｏｔｅｎｓｉｎ−ｃｏｎｖｅｒｔｉｎｇ ｅｎｚｙｍｅ，ａｎｇｉｏｔｅｎｓｉｎ ＩＩ ａｎｄ ＡＴ１ ｒｅｃｅｐｔｏｒ ｉｎ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｅｍｅｎｔｉａ．Ｎｅｕｒｏｂｉｏｌ Ａｇｉｎｇ ２００１；２２；５４１−５４６．）。さらに、以前の研究によって、ＡＤの患者の海馬や傍海馬回および前頭葉の皮質のアンギオテンシン変換酵素（ＡＣＥ）活性が上昇していることが明らかにされている（前述の文献１３と文献１４）。脳内ＡＣＥ活性の上昇は、ＡＤの認知機能の障害に直接関与している可能性が示唆される。なぜなら、ＡＣＥ活性の上昇に伴うアンジオテンシンＩＩの増加は、神経細胞終末からのアセチルコリンの放出を抑制すると考えられるからである。よって、脳内のＡＣＥ活性の調節が、治療法に結びつく可能性が示唆される。ＡＣＥ阻害剤が実際の臨床の現場に登場してから久しいが、脳内移行性［血液脳関門（ＢＢＢ）通過性］という観点からは、それぞれの種類により千差万別である（文献１５：Ｃｕｓｈｍａｎ ＤＷ，Ｗａｎｇ ＦＬ．Ｆｕｎｇ ＷＣ，ｅｔ ａｌ．Ｄｉｆｆｅｒｅｎｔｉａｔｉｏｎ ｏｆ ａｎｇｉｏｔｅｎｓｉｎ−ｃｏｎｖｅｒｔｉｎｇ ｅｎｚｙｍｅ（ＡＣＥ）ｉｎｈｉｂｉｔｏｒｓ ｂｙ ｔｈｅｉｒ ｓｅｌｅｃｔｉｖｅ ｉｎｈｉｂｉｔｉｏｎ ｏｆ ＡＣＥ ｉｎ ｐｈｙｓｉｏｌｏｇｉｃａｌｌｙ ｉｍｐｏｒｔａｎｔ ｔａｒｇｅｔ ｏｒｇａｎｓ．Ａｍ Ｊ Ｈｙｐｅｒｔｅｎｓ １９８９；２：２９４−３０６．）。脳内移行性のＡＣＥ阻害剤は、脳内のレニンアンギオテンシン系に直接作用し、降圧以外の効果も期待される。我々はこの点に着目し、脳内移行性のＡＣＥ阻害剤のＡＤに対する有用性を見出すことで本発明を完成するに至った。
本発明は、上記の経緯からなされたものであり、本発明のＡＤの予防および／または治療剤は、請求の範囲第１項記載の通り、脳内移行性のＡＣＥ阻害剤を有効成分とすることを特徴とする。
また、請求の範囲第２項記載の予防および／または治療剤は、請求の範囲第１項記載の予防および／または治療剤において、前記の予防および／または治療剤が高血圧を有するヒトを対象としたものであることを特徴とする。
また、請求の範囲第３項記載の予防および／または治療剤は、請求の範囲第２項記載の予防および／または治療剤において、前記の予防および／または治療剤が高血圧に対して降圧作用を示す容量の脳内移行性のアンギオテンシン変換酵素阻害剤を有効成分とすることを特徴とする。
また、請求の範囲第４項記載の予防および／または治療剤は、請求の範囲第１項記載の予防および／または治療剤において、前記の脳内移行性のアンギオテンシン変換酵素阻害剤がペリンドプリルであることを特徴とする。
また、請求の範囲第５項記載の予防および／または治療剤は、請求の範囲第１項記載の予防および／または治療剤において、前記の脳内移行性のアンギオテンシン変換酵素阻害剤がカプトプリルであることを特徴とする。
また、請求の範囲第６項記載の予防および／または治療剤は、請求の範囲第１項記載の予防および／または治療剤において、前記の脳内移行性のアンギオテンシン変換酵素阻害剤がリシノプリルであることを特徴とする。
本発明によれば、新規なアルツハイマー病の予防および／または治療剤が提供される。In recent years, it has been reported that a factor of the renin angiotensin system (RAS) plays an important role in the learning and memory process (Reference 13: Hirawa N, Uehara Y, Kawabata Y, et al. Long-). term inhibition of renin-angiotensin system sustains memory function in aged Dahl rats.Hypertension 1999; 34:. 496-502, literature 14: Savaskan E, Hock C, Olivieri G, et al.Cortical alterations of angiotensin-converting enzyme, angiotensin II and AT1 receptor in A zheimer's dementia.Neurobiol Aging 2001; 22; 541-546).. Furthermore, previous studies have revealed that angiotensin-converting enzyme (ACE) activity is increased in the hippocampus and parahippocampal gyrus and frontal cortex of AD patients (reference documents 13 and 14 described above). It is suggested that the increase in ACE activity in the brain may be directly involved in impaired cognitive function of AD. This is because an increase in angiotensin II accompanying an increase in ACE activity is considered to suppress the release of acetylcholine from nerve cell terminals. Thus, it is suggested that modulation of ACE activity in the brain may lead to therapeutic methods. It has been a long time since an ACE inhibitor appeared in actual clinical settings, but from the viewpoint of translocation into the brain [permeability through the blood-brain barrier (BBB)], there are many differences depending on each type (Reference 15: Cushman DW, Wang FL.Fung WC, et al.Differentiation of angiotensin-converting enzyme (ACE) inhibitors by their selective inhibition of ACE in physiologically important target organs.Am J Hypertens 1989; 2: 294-306).. ACE inhibitors that migrate into the brain act directly on the renin-angiotensin system in the brain, and are expected to have effects other than antihypertensive. We focused on this point, and completed the present invention by finding the usefulness of ACE inhibitor having intracerebral migration to AD.
The present invention has been made from the above-mentioned circumstances, and the preventive and / or therapeutic agent for AD of the present invention comprises, as described in claim 1, an ACE inhibitor that migrates into the brain as an active ingredient. It is characterized by that.
The preventive and / or therapeutic agent according to claim 2 is a prophylactic and / or therapeutic agent according to claim 1, wherein the prophylactic and / or therapeutic agent is intended for a human having hypertension. It is characterized by that.
Further, the preventive and / or therapeutic agent according to claim 3 is the prophylactic and / or therapeutic agent according to claim 2, wherein the preventive and / or therapeutic agent has a hypotensive action on hypertension. It is characterized by comprising an angiotensin-converting enzyme inhibitor having the capacity shown in the brain as an active ingredient.
The prophylactic and / or therapeutic agent according to claim 4 is the prophylactic and / or therapeutic agent according to claim 1, wherein the angiotensin converting enzyme inhibitor that migrates into the brain is perindopril. It is characterized by that.
The prophylactic and / or therapeutic agent according to claim 5 is the prophylactic and / or therapeutic agent according to claim 1, wherein the angiotensin converting enzyme inhibitor that migrates into the brain is captopril. It is characterized by that.
The prophylactic and / or therapeutic agent according to claim 6 is the prophylactic and / or therapeutic agent according to claim 1, wherein the angiotensin converting enzyme inhibitor that migrates into the brain is lisinopril. It is characterized by that.
According to the present invention, a novel preventive and / or therapeutic agent for Alzheimer's disease is provided.
図１は、３群のベースラインおよびエンドポイントのＭＭＳＥスコアを示す。各群は、脳内移行性ＡＣＥ阻害剤投与群（グループＡ：●）、脳内非移行性ＡＣＥ阻害剤投与群（グループＢ：○）、カルシウムチャンネルブロッカー投与群（グループＣ：▲）である。３群間ではベースラインのＭＭＳＥスコアに差は認めない。しかし、グループＡの対象者の１年後のＭＭＳＥスコアの低下率は、グループＢおよびグループＣの対象者に比べ有意に抑制されていた。ＭＭＳＥはＭｉｎｉ−Ｍｅｎｔａｌ Ｓｔａｔｅ Ｅｘａｍｉｎａｔｉｏｎの略である。
図２は、アルツハイマー病の予防的および治療的戦略のダイヤグラムを示す。脳内移行性ＡＣＥ阻害剤は、脳内のサブスタンスＰを増加させ、それによりＮＥＰ活性が増強され脳内のＡβの蓄積を防ぐ。また、日常生活における種々の刺激が脳内のサブスタンスＰを増加させ、同様の機序でＡβの蓄積を抑制する。FIG. 1 shows the baseline and endpoint MMSE scores for the three groups. Each group is a brain migration ACE inhibitor administration group (Group A: ●), a brain non-migration ACE inhibitor administration group (Group B: ○), a calcium channel blocker administration group (Group C: ▲). . There is no difference in baseline MMSE scores between the three groups. However, the rate of decrease in the MMSE score after 1 year for subjects in Group A was significantly suppressed compared to subjects in Group B and Group C. MMSE is an abbreviation for Mini-Mental State Examination.
FIG. 2 shows a diagram of preventive and therapeutic strategies for Alzheimer's disease. Brain-increasing ACE inhibitors increase substance P in the brain, thereby enhancing NEP activity and preventing the accumulation of Aβ in the brain. In addition, various stimuli in daily life increase substance P in the brain and suppress Aβ accumulation by the same mechanism.
我々は、脳内移行性のＡＣＥ阻害剤に、ＡＤの発症予防および治療（病状の進展抑制）効果があることを発見した。その機序としては、脳内に移行したＡＣＥ阻害剤が脳内のサブスタンスＰ（ＳＰ）を増加させ、ＮＥＰの活性を高め、活性化したＮＥＰが蓄積したＡβを分解し、ＡＤの発症を抑制し病状の進展を阻止するものと考えられる。また、脳内におけるＡＣＥ阻害剤によるアンギオテンシンＩＩの産生抑制は、アンギオテンシンＩＩによるアセチルコリンの放出阻害を低減化し、ＡＤの発症予防効果につながるものと考えられる。
本発明において、ＡＤの予防および／または治療剤の有効成分となる脳内移行性のＡＣＥ阻害剤は、アンギオテンシンＩが昇圧活性を有するアンギオテンシンＩＩに変換されるのを防止するものであって、ＢＢＢを通過して脳内に移行する特性を有するものであれば、どのようなものであってもよい。市販のＡＣＥ阻害剤の中では、ペリンドプリル（ｐｅｒｉｎｄｏｐｒｉｌ），カプトプリル（ｃａｐｔｏｐｒｉｌ），リシノプリル（ｌｉｓｉｎｏｐｒｉｌ）が該当する。しかし、イミダプリル（ｉｍｉｄａｐｒｉｌ）やエナラプリル（ｅｎａｌａｐｒｉｌ）は脳内非移行性のＡＣＥ阻害剤なので、本発明におけるＡＤの予防および／または治療剤の有効成分にはなり得ない。なお、本発明におけるＡＣＥ阻害剤の脳内移行性とは、ＡＣＥ阻害剤の通常の投与量、例えば、高血圧を有するヒトに対して降圧作用を示す投与量の範囲でのＡＣＥ阻害剤の投与において、脳内のＡＣＥ活性に変動を来たしうる程度のＢＢＢ通過性を示す特性をいうが、脳内移行性の有無は、実験科学的には、前述の文献１５や後述の文献１６に記載の方法で評価することができる。
本発明のＡＤの予防および／または治療剤は、ＡＣＥ阻害剤の本来の作用、即ち、降圧作用を発揮させるためのＡＣＥ阻害剤の投与方法によって投与することが実用的であるが（特に高血圧を有するヒトに投与する場合に好適である）、投与方法は、これに限定される訳ではなく、経口的，非経口的，局所的，経皮的な投与方法で投与することができる。なお、その投与量は、例えば、有効成分、投与方法、ＡＤの程度、投与対象者の健康状態などにより適宜決定されるものであるが、一般に、体重７０ｋｇのヒトについて、１日当たり、約０．５ｍｇ〜約１ｇの範囲である。We have found that ACE inhibitors that migrate into the brain have the effect of preventing and treating AD (suppressing the progression of disease states). The mechanism is that the ACE inhibitor that has entered the brain increases substance P (SP) in the brain, increases the activity of NEP, degrades Aβ accumulated by activated NEP, and suppresses the onset of AD It is thought to prevent the development of the disease state. In addition, suppression of angiotensin II production by an ACE inhibitor in the brain is thought to reduce the inhibition of acetylcholine release by angiotensin II and lead to an AD prevention effect.
In the present invention, an intracerebral ACE inhibitor that is an active ingredient of an agent for the prevention and / or treatment of AD prevents angiotensin I from being converted to angiotensin II having pressor activity, and BBB Any material may be used as long as it has a characteristic of passing through the brain and moving into the brain. Among commercially available ACE inhibitors, perindopril, captopril, and lisinopril are applicable. However, imidapril and enalapril are non-migrating ACE inhibitors in the brain, and therefore cannot be active ingredients of the preventive and / or therapeutic agents for AD in the present invention. In the present invention, the ACE inhibitor translocation into the brain refers to the usual dose of the ACE inhibitor, for example, the administration of the ACE inhibitor in the range of a dose exhibiting a hypotensive effect on a human having hypertension. In addition, it refers to the property of passing through the BBB to such an extent that the ACE activity in the brain can be changed. The presence or absence of intracerebral migration is determined experimentally by the method described in Reference 15 or Reference 16 described later. Can be evaluated.
It is practical to administer the prophylactic and / or therapeutic agent for AD of the present invention by the ACE inhibitor administration method for exerting the original action of the ACE inhibitor, ie, the antihypertensive action (especially hypertension). The administration method is not limited to this and can be administered by oral, parenteral, topical or transdermal administration methods. The dose is appropriately determined depending on, for example, the active ingredient, the administration method, the degree of AD, the health condition of the administration subject, and the like, but generally about 0. 0 per day for a human weighing 70 kg. The range is from 5 mg to about 1 g.
我々は、脳内移行性の高いＡＣＥ阻害剤（前述の文献１５，文献１６：Ｃｈａｉ ＳＹ，Ｐｅｒｉｃｈ Ｒ，Ｊａｃｋｓｏｎ Ｂ，ｅｔ ａｌ．Ａｃｕｔｅ ａｎｄ ｃｈｒｏｎｉｃ ｅｆｆｅｃｔｓ ｏｆ ａｎｇｉｏｔｅｎｓｉｎ−ｃｏｎｖｅｒｔｉｎｇ ｅｎｚｙｍｅ ｉｎｈｉｂｉｔｏｒｓ ｏｎ ｔｉｓｓｕｅ ａｎｇｉｏｔｅｎｓｉｎ−ｃｏｎｖｅｒｔｉｎｇ ｅｎｚｙｍｅ．Ｃｌｉｎ Ｅｘｐ Ｐｈａｒｍａｃｏｌ Ｐｈｙｓｉｏｌ １９９２；１９：７−１２．）がＡＤの発症の抑制効果があるかどうかにつき検討を行った。我々は、１９９３年１月から２００３年３月までに、高血圧を有する高齢者で、ＡＣＥ阻害剤とその他の降圧薬を服用している患者におけるＡＤの発症率を８年間にわたり東北大学病院の医療用コンピューターを用いて検索した。対象者は６５歳以上の高齢者で、過去に痴呆の病歴を有さず、降圧薬により血圧が１５０／９０ｍｍＨｇ以下にコントロールされている患者で、それぞれ脳内移行性ＡＣＥ阻害剤投与群としてペリンドプリル（２ｍｇ／ｄａｙ）またはカプトプリル（３７．５ｍｇ／ｄａｙ）またはリシノプリル（１０ｍｇ／ｄａｙ）投与群、脳内非移行性ＡＣＥ阻害剤投与群としてイミダプリル（５ｍｇ／ｄａｙ）またはエナラプリル（５ｍｇ／ｄａｙ）投与群、カルシウムチャンネルブロッカー投与群としてニフェジピン（２０ｍｇ／ｄａｙ）またはニルバジピン（４ｍｇ／ｄａｙ）投与群、βブロッカー投与群としてアテノロール（５０ｍｇ／ｄａｙ）またはメトプロロール（６０ｍｇ／ｄａｙ）投与群、もしくは降圧利尿剤投与群としてトリクロールメチアジド（２ｍｇ／ｄａｙ）またはフロセミド（４０ｍｇ／ｄａｙ）投与群とした。我々は無作為に６５歳から７２歳までの患者（平均年齢６９歳、４６％が女性）４，１２４人をエントリーし、平均８±１（標準誤差）年間にわたり経過観察を行った。その結果、４，１２４人のうち脳血管性痴呆およびＡＤを含めた痴呆患者は計１０５名（２．５％）みられ、そのうち９０名がＡＤの患者であることをＮＩＮＣＤＳ−ＡＤＲＤＡ診断基準（文献１７：ＭｃＫｈａａｎ Ｇ，Ｄｒａｃｈｍａｎ Ｄ，Ｆｏｌｓｔｅｉｎ Ｍ，ｅｔ ａｌ．Ｃｌｉｎｉｃａｌ ｄｉａｇｎｏｓｉｓ ｏｆ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ：Ｒｅｐｏｒｔ ｏｆ ｔｈｅ ＮＩＮＣＤＳ−ＡＤＲＤＡ ｗｏｒｋ ｇｒｏｕｐ ｕｎｄｅｒ ａｕｓｐｉｃｅｓ ｏｆ ｔｈｅ Ｄｅｐａｒｔｍｅｎｔ ｏｆ Ｈｅａｌｔｈ ａｎｄ Ｈｕｍａｎ Ｓｅｒｖｉｃｅｓ Ｔａｓｋ Ｆｏｒｃｅ ｏｎ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ．Ｎｅｕｒｏｌｏｇｙ １９８４；３４：９３９−９４４．）に従って確認した。それぞれの降圧薬投与群における比較検討では、ＡＤの発症率はＡＣＥ阻害剤投与群全体では２．１％、カルシウムチャンネルブロッカー投与群では２．１％、βブロッカー投与群では２．６％、そして降圧利尿剤投与群では２．６％であり、いずれも有意差を認めなかった。しかし、ＡＣＥ阻害剤のサブグループ解析では、脳内移行性ＡＣＥ阻害剤投与群において、脳内非移行性ＡＣＥ阻害剤投与群およびその他の降圧薬投与群に比較して有意にＡＤの発症率が低下していた（オッズ比０．２５、９５％信頼区間０．０８〜０．７５、ｐ＝０．０１４）（表１）。スタチンなどのその他の薬物の使用頻度には、グループ間の差を認めなかった。
ＡＣＥはサブスタンスＰ（ＳＰ）や他のタキキニンを含む多種多様の短鎖ペプチドの分解作用も有することから、ＡＣＥ阻害剤はＳＰや他のタキキニンの作用を増強する事が知られている（文献１８：Ｓｅｋｉｚａｗａ Ｋ，Ｊｉａ ＹＸ，Ｅｂｉｈａｒａ Ｔ，ｅｔ ａｌ．Ｒｏｌｅ ｏｆ ｓｕｂｓｔａｎｃｅ Ｐ ｉｎ ｃｏｕｇｈ．Ｐｕｌｍ Ｐｈａｒｍａｃｏｌ １９９６；９：３２３−３２８．，文献１９：Ｅｂｉｈａｒａ Ｔ，Ｓｅｋｉｚａｗａ Ｋ，Ｏｈｒｕｉ Ｔ，ｅｔ ａｌ．Ａｎｇｉｏｔｅｎｓｉｎ−ｃｏｎｖｅｒｔｉｎｇ ｅｎｚｙｍｅ ｉｎｈｉｂｉｔｏｒ ａｎｄ ｄａｎａｚｏｌ ｉｎｃｒｅａｓｅ ｓｅｎｓｉｔｉｖｉｔｙ ｏｆ ｃｏｕｇｈ ｒｅｆｌｅｘ ｉｎ ｆｅｍａｌｅ ｇｕｉｎｅａ ｐｉｇｓ．Ａｍ Ｊ Ｒｅｓｐｉｒ Ｃｒｉｔ Ｃａｒｅ Ｍｅｄ １９９６；１５３：８１２−８１９．）。多くの臓器においてはＳＰの増加によりＮＥＰが活性化すると報告されている（前述の文献１８）。活性化したＮＥＰはＡβを分解し、これによってＡＤの発症を抑制し、またＡＤの進展を抑制する可能性が示唆されている（前述の文献７）。よって、我々は、脳内移行性ＡＣＥ阻害剤がアセチルコリン依存性経路ならびにＡβ依存性経路を介してＡＤ予防および／または治療剤として作用する可能性を見出した（図２）。しかし、アセチルコリン依存性経路を介しての効果は、ドネペジルの効果から考えると限界があるものと思われる。我々は、脳内移行性ＡＣＥ阻害剤が高血圧の患者におけるＡＤの発症を１／４に減らす事を発見しているが、更に、脳内移行性ＡＣＥ阻害剤による治療効果は、受動的かつ能動的なＡβに対する髄膜脳炎のないワクチンと同じように有効である可能性が示唆された。現在、日本の厚生労働省の統計によると６９歳の日本人における８年後のＡＤの発症率は約４％と予想されている。日本では脳血管性痴呆の発症率も未だ高く、降圧療法が脳血管性痴呆の発症を抑制することが期待されるが、更に我々の研究によって脳内移行性ＡＣＥ阻害剤のＡＤの発症抑制および病状進展の抑制効果が明らかにされた。
その他として、現在、認知機能訓練による介入によって認知機能を改善させる試みがなされている（文献２０：Ｂａｌｌ Ｋ，Ｂｅｒｃｈ ＤＢ，Ｈｅｌｍｅｒｓ ＫＦ，ｅｔ ａｌ．Ｅｆｆｅｃｔｓ ｏｆ ｃｏｇｎｉｔｉｖｅ ｔｒａｉｎｉｎｇ ｉｎｔｅｒｖｅｎｔｉｏｎｓ ｗｉｔｈ ｏｌｄｅｒ ａｄｕｌｔｓ．ＪＡＭＡ ２００２；２８８：２２７１−２２８１．）。高齢になっても現役で働き続ける人の認知機能が、退職後４年を経た高齢者に比べ明らかに良いとする報告がある（文献２１：Ｒｏｇｅｒｓ ＲＩ，Ｍｅｙｅｒ ＪＳ，Ｍｏｒｔｅｌ ＫＦ．Ａｆｔｅｒ ｒｅａｃｈｉｎｇ ｒｅｔｉｒｅｍｅｎｔ ａｇｅ ｐｈｙｓｉｃａｌ ａｃｔｉｖｉｔｙ ｓｕｓｔａｉｎｓ ｃｅｒｅｂｒａｌ ｐｅｒｆｕｓｉｏｎ ａｎｄ ｃｏｇｎｉｔｉｏｎ．Ｊ Ａｍ Ｇｅｒｉａｔｒ Ｓｏｃ １９９０；３８：１２３−１２８．）。更に、歯ブラシによる口腔の刺激によって、唾液中へのＳＰの放出が増強されるとの報告もある（文献２２：Ｙｏｓｈｉｎｏ Ａ，Ｅｂｉｈａｒａ Ｔ，Ｅｂｉｈａｒａ Ｓ，ｅｔ ａｌ．Ｄａｉｌｙ ｏｒａｌ ｃａｒｅ ａｎｄ ｒｉｓｋ ｆａｃｔｏｒｓ ｆｏｒ ｐｎｅｕｍｏｎｉａ ａｍｏｎｇ ｅｌｄｅｒｌｙ ｎｕｒｓｉｎｇ ｈｏｍｅ ｐａｔｉｅｎｔｓ．ＪＡＭＡ ２００１；２８６：２２３５−２２３６．）。喀痰中のＳＰの濃度は、肺炎を繰り返す日常生活動作（ＡＤＬ）の低下した患者では低いと報告されている（文献２３：Ｎａｋａｇａｗａ Ｔ，Ｏｈｒｕｉ Ｔ，Ｓｅｋｉｚａｗａ Ｋ，ｅｔ ａｌ．Ｓｐｕｔｕｍ ｓｕｂｓｔａｎｃｅ Ｐ ｉｎ ａｓｐｉｒａｔｉｏｎ ｐｎｅｕｍｏｎｉａ．Ｌａｎｃｅｔ １９９５；３４５：１４４７．）。よって、身体的刺激によって、ＡＤＬを高める方法がＳＰの増加をもたらし、ＮＥＰの活性を高め脳内のＡβの分解を促進する可能性が示唆される。誤嚥性肺炎の患者では、ＡＣＥ阻害剤やドーパミンアゴニストによる治療が、気道および咽頭粘膜内のＳＰを増加させ、誤嚥に対する防御効果を有することが明らかにされている（文献２４：Ｙａｍａｙａ Ｍ，Ｙａｎａｉ Ｍ，Ｏｈｒｕｉ Ｔ，Ａｒａｉ Ｈ，Ｓａｓａｋｉ Ｈ．Ｉｎｔｅｒｖｅｎｔｉｏｎｓ ｔｏ ｐｒｅｖｅｎｔ ｐｎｅｕｍｏｎｉａ ａｍｏｎｇ ｏｌｄｅｒ ａｄｕｌｔｓ．Ｊ Ａｍ Ｇｅｒｉａｔｒ Ｓｏｃ ２００１；４９：８５−９０．，文献２５：Ｙａｍａｙａ Ｍ，Ｏｈｒｕｉ Ｔ，Ｋｕｂｏ Ｈ，Ｅｂｉｈａｒａ Ｓ，Ａｒａｉ Ｈ，Ｓａｓａｋｉ Ｈ．Ｐｒｅｖｅｎｔｉｏｎ ｏｆ ｒｅｓｐｉｒａｔｏｒｙ ｉｎｆｅｃｔｉｏｎｓ ｉｎ ｔｈｅ ｅｌｄｅｒｌｙ．Ｇｅｒｉａｔｒ Ｇｅｒｏｎｔｏｌ Ｉｎｔｅｒｎａｔ ２００２；２：１１５−１２１．）。我々は、誤嚥性肺炎のみならずＡＤの予防および／または治療においても、ＳＰが重要な役割を演じているものと考える。よってＳＰを増加させる各種の刺激がＡＤの発症抑制および治療に役立つのではないかと考える（図２）。We have developed an ACE inhibitor with high brain translocation (the above-mentioned literature 15, literature 16: Chai SY, Perich R, Jackson B, et al. Acte and chronic effects of angiotensin-inducing enzyme inhibitors. It was examined whether Clin Exp Pharmacol Physiol 1992; 19: 7-12.) Has an inhibitory effect on the onset of AD. From January 1993 to March 2003, we have reported the incidence of AD in patients with high blood pressure who are taking ACE inhibitors and other antihypertensive drugs for 8 years. Search using a computer. The subjects are elderly patients over 65 years old who have no history of dementia and whose blood pressure is controlled to 150/90 mmHg or less with antihypertensive drugs. (2 mg / day) or captopril (37.5 mg / day) or lisinopril (10 mg / day) administration group, imidapril (5 mg / day) or enalapril (5 mg / day) administration group as a non-in-brain ACE inhibitor administration group , Nifedipine (20 mg / day) or nilvadipine (4 mg / day) administration group as calcium channel blocker administration group, atenolol (50 mg / day) or metoprolol (60 mg / day) administration group, or antihypertensive diuretic administration group as β blocker administration group As tricrawl Thiazide (2 mg / day) or furosemide (40 mg / day) was administered group. We randomly enrolled 4,124 patients aged 65 to 72 (mean age 69 years, 46% female) and followed up for an average of 8 ± 1 (standard error) years. As a result, a total of 105 (2.5%) dementia patients including cerebrovascular dementia and AD were observed among 4,124 persons, and 90 of them were AD patients. NINCDS-ADRDA diagnostic criteria ( Document 17: McKhaan G, Drachman D, Folstein M, et al.Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA work group under auspices of the Department of Health and Human Services Task Force on Alzheimer's disease.Neurology 1984; 34: 939-944.). In a comparative study in each antihypertensive drug administration group, the incidence of AD was 2.1% in the entire ACE inhibitor administration group, 2.1% in the calcium channel blocker administration group, 2.6% in the β blocker administration group, and In the antihypertensive diuretic administration group, it was 2.6%, and no significant difference was observed. However, in the subgroup analysis of ACE inhibitors, the incidence of AD was significantly higher in the brain-transferred ACE inhibitor administration group than in the brain non-transferring ACE inhibitor administration group and other antihypertensive drug administration groups. (Odds ratio 0.25, 95% confidence interval 0.08 to 0.75, p = 0.014) (Table 1). There was no difference between groups in the frequency of use of other drugs such as statins.
Since ACE also has the action of degrading a wide variety of short peptides including substance P (SP) and other tachykinins, ACE inhibitors are known to enhance the action of SP and other tachykinins (Reference 18). : Sekizawa K, Jia YX, Ebihara T, et al. Role of substance Pin cou.Pulm Pharmacol 1996; 9: 323-328., Reference 19: Ebihara T, Sekizawa T., Sekizawa T. inhibitor and danazol increase sensitivity of cow reflex in female guinea pigs.Am J Respir Crit Ca e Med 1996; 153: 812-819).. In many organs, it has been reported that NEP is activated by an increase in SP (Reference 18 described above). It has been suggested that activated NEP degrades Aβ, thereby suppressing the onset of AD and suppressing the progression of AD (Reference 7 described above). Thus, we have found that brain-translocated ACE inhibitors can act as AD preventive and / or therapeutic agents via acetylcholine-dependent pathways and Aβ-dependent pathways (FIG. 2). However, the effect through the acetylcholine-dependent pathway seems to be limited considering the effect of donepezil. Although we have found that brain-translocated ACE inhibitors reduce the onset of AD in hypertensive patients by a quarter, the therapeutic effects of brain-translocated ACE inhibitors are also passive and active. This suggests that it may be as effective as a vaccine without typical meningoencephalitis against Aβ. Currently, according to statistics from the Japanese Ministry of Health, Labor and Welfare, the incidence of AD in a 69-year-old Japanese is estimated to be about 4% after 8 years. In Japan, the incidence of cerebrovascular dementia is still high, and antihypertensive therapy is expected to suppress the onset of cerebrovascular dementia. The inhibitory effect on disease progression was revealed.
In addition, an attempt is currently being made to improve cognitive function through intervention by cognitive function training (Reference 20: Ball K, Berch DB, Helmers KF, et al. Effects of cognitive training with with adults with JAMA 2002; JAMA 2002). : 2271-2281.). There is a report that the cognitive function of people who continue to work actively even when they are elderly is clearly better than elderly people who have passed 4 years after retirement (Reference 21: Rogers RI, Meyer JS, Mortel KF. After reaching retirement ageage) (physical activity sustains cerebral perfusion and cognition. J Am Geriatr Soc 1990; 38: 123-128.). Furthermore, there is a report that stimulation of the oral cavity with a toothbrush enhances the release of SP into saliva (Reference 22: Yoshino A, Ebihara T, Ebihara S, et al. Dairy oral care and risk factors for pneumonia mongolia. elderly nursing home patents. JAMA 2001; 286: 2235-2236.). The concentration of SP in sputum has been reported to be low in patients with reduced daily activities of life (ADL) that repeat pneumonia (Reference 23: Nakagawa T, Ohru T, Sekizawa K, et al. Sutum subsistence p in aspiration pneumonia). Lancet 1995; 345: 1447.). Therefore, it is suggested that a method of increasing ADL by physical stimulation leads to an increase in SP, and may increase the activity of NEP and promote the degradation of Aβ in the brain. In patients with aspiration pneumonia, treatment with ACE inhibitors and dopamine agonists has been shown to increase SP in the airways and pharyngeal mucosa and have a protective effect against aspiration (Reference 24: Yamaya M, Yanai M, Ohrui T, Arai H, Sasaki H. Interventions to prevent pneumonia amongolder adults. J Am Geriatra Soc 2001; 49: 85-90. , Sasaki H. Prevention of respiratory influences in the elderly.Geriatr Gertonol Internet 2002; 2: 15-121.). We believe that SP plays an important role in the prevention and / or treatment of AD as well as aspiration pneumonia. Therefore, it is considered that various stimuli that increase SP may be useful for the onset suppression and treatment of AD (FIG. 2).
本発明は、新規なアルツハイマー病の予防および／または治療剤を提供することができる点において産業上の利用可能性を有する。 The present invention has industrial applicability in that it can provide a novel preventive and / or therapeutic agent for Alzheimer's disease.
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| PCT/JP2004/002721 WO2005011736A1 (en) | 2003-07-30 | 2004-03-04 | Drug for preventing and/or treating alzheimer’s disease |
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| JP2011136932A (en) * | 2009-12-28 | 2011-07-14 | Calpis Co Ltd | Composition for improving cerebral function and method for improving cerebral function |
| RU2530601C2 (en) * | 2012-10-05 | 2014-10-10 | Федеральное Государственное Бюджетное Учреждение Науки Институт Молекулярной Биологии Им. В.А. Энгельгардта Российской Академии Наук (Имб Ран) | Zinc-dependent beta-amyloid dimer formation inhibitor |
| JP6344796B2 (en) * | 2014-09-30 | 2018-06-20 | 森永乳業株式会社 | Alzheimer-type dementia remedy for elderly |
| CN112469439A (en) * | 2018-05-15 | 2021-03-09 | 万能溶剂有限公司 | With leukotriene A4Hydrolase modulators for the treatment of aging-related diseases |
| JP6589011B2 (en) * | 2018-05-17 | 2019-10-09 | 森永乳業株式会社 | Oral composition for improving brain dysfunction |
| WO2023076679A1 (en) | 2021-11-01 | 2023-05-04 | Alkahest, Inc. | Benzodioxane modulators of leukotriene a4 hydrolase (lta4h) for prevention and treatment of aging-associated diseases |
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| US5098889A (en) * | 1990-09-17 | 1992-03-24 | E. R. Squibb & Sons, Inc. | Method for preventing or inhibiting loss of cognitive function employing a combination of an ace inhibitor and a drug that acts at serotonin receptors |
| DE4224133A1 (en) * | 1992-07-22 | 1994-01-27 | Thomae Gmbh Dr K | Benzimidazoles, medicaments containing these compounds and process for their preparation |
| US5668117A (en) * | 1991-02-22 | 1997-09-16 | Shapiro; Howard K. | Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicaments |
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| JP2001316287A (en) * | 2000-05-01 | 2001-11-13 | Bml Inc | Alzheimer's disease treatment |
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