JPWO2005011736A1 - Preventive and / or therapeutic agent for Alzheimer's disease - Google Patents

Abstract

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

  The present invention relates to a novel preventive and / or therapeutic agent for Alzheimer's disease.

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.

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.

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.

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.

更に我々は、脳内移行性ＡＣＥ阻害剤による治療が、高血圧を有する軽度から中等度のＡＤの患者において、認知機能の低下を抑制し得るか否か、即ち、治療効果の有無について検討した。我々は、１年間におけるランダム化、前向きの比較試験を行った。対象者は、年齢６５歳以上かつ血圧が１４０／９０ｍｍＨｇ以上で、ＭＭＳＥスコアが１３ないし２３点までの軽度から中等度のＡＤの患者であり、仙台市にある３つの長期療養型施設に入所中の人たちであった。本研究では、エントリー前に使用していたコリンエステラーゼ阻害剤、スタチンもしくは低用量のアスピリンの使用は許可された。１８３名がスクリーニングされ、そのうち１６２名が最終的にエントリーされ、無作為に脳内移行性ＡＣＥ阻害剤投与群［ペリンドプリル（２ｍｇ／ｄａｙ）またはカプトプリル（３７．５ｍｇ／ｄａｙ）投与群（ｎ＝５１、うち１１名が男性、平均年齢７６±２（標準誤差）歳）］（グループＡ）、脳内非移行性ＡＣＥ阻害剤投与群［イミダプリル（５ｍｇ／ｄａｙ）またはエナラプリル（５ｍｇ／ｄａｙ）投与群（ｎ＝５３、うち１２名が男性、平均年齢７７±３歳）］（グループＢ）、もしくはカルシウムチャンネルブロッカー投与群［ニフェジピン（２０ｍｇ／ｄａｙ）またはニルバジピン（４ｍｇ／ｄａｙ）投与群（ｎ＝５８、うち１４名が男性、平均年齢７５±２歳）］（グループＣ）に２００２年１２月に割り付けをした。エントリー時に１６２人中９４人（５８％）がドネペジルを投与されていた。各群において、血圧を含む基礎データや内服薬および合併症に差はなかった。全ての対象者は前向きに１年間フォローされた。結果として、観察期間中全ての対象者は、収縮期血圧で１３２±４ｍｍＨｇ（グループＡ）、１３３±２ｍｍＨｇ（グループＢ）および１３０±３ｍｍＨｇ（グループＣ）と安定した血圧を保っており、低血圧症により離脱したグループＣの１名を除き、研究を完遂した。各グループ群におけるベースラインのＭＭＳＥスコアは１９．３±０．５（標準誤差）（グループＡ）、２０．７±０．４（グループＢ）および２０．５±０．４（グループＣ）であり、３群間で有意差を認めなかった（ｐ＞０．４）。しかし、グループＡにおいては、１年後のＭＭＳＥスコアの減少率は０．６±０．１とグループＢの４．６±０．３（ｐ＝０．００２３）およびグループＣの４．９±０．３（ｐ＜０．００１）と比較して有意に低下していた（図１）。
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.

Furthermore, we examined whether treatment with a brain-translocating ACE inhibitor can suppress a decline in cognitive function in patients with mild to moderate AD with hypertension, that is, whether or not there is a therapeutic effect. We conducted a one-year randomized, prospective comparative study. The subject is a patient with mild to moderate AD with an age of 65 years of age or older, blood pressure of 140/90 mmHg or higher, and an MMSE score of 13 to 23, and is currently entering three long-term care facilities in Sendai. People. The study allowed the use of cholinesterase inhibitors, statins or low doses of aspirin that were used before entry. 183 were screened, of which 162 were finally entered, and were randomly assigned to the brain-translocated ACE inhibitor group [perindopril (2 mg / day) or captopril (37.5 mg / day) group (n = 51 , Of which 11 are male, mean age 76 ± 2 (standard error) years)] (group A), non-migrating ACE inhibitor administration group [imidapril (5 mg / day) or enalapril (5 mg / day) administration group (N = 53, of which 12 are men, mean age 77 ± 3 years)] (Group B), or calcium channel blocker administration group [nifedipine (20 mg / day) or nilvadipine (4 mg / day) administration group (n = 58 , Of which 14 were male, with an average age of 75 ± 2 years)] (Group C). At the time of entry, 94 of 162 (58%) were taking donepezil. There was no difference in basic data including blood pressure, internal medicine and complications in each group. All subjects were followed prospectively for one year. As a result, during the observation period, all subjects maintained stable blood pressures of 132 ± 4 mmHg (Group A), 133 ± 2 mmHg (Group B) and 130 ± 3 mmHg (Group C) at systolic blood pressure, and low blood pressure The study was completed, with the exception of one Group C who withdrew from the disease. Baseline MMSE scores in each group were 19.3 ± 0.5 (standard error) (Group A), 20.7 ± 0.4 (Group B) and 20.5 ± 0.4 (Group C) There was no significant difference between the three groups (p> 0.4). However, in Group A, the rate of decrease in MMSE score after 1 year was 0.6 ± 0.1, 4.6 ± 0.3 (p = 0.0003) for Group B and 4.9 ± for Group C. It was significantly lower than 0.3 (p <0.001) (FIG. 1).
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).

  The present invention has industrial applicability in that it can provide a novel preventive and / or therapeutic agent for Alzheimer's disease.

Claims (6)

A prophylactic and / or therapeutic agent for Alzheimer's disease, comprising an angiotensin converting enzyme inhibitor that migrates into the brain as an active ingredient. The prophylactic and / or therapeutic agent according to claim 1, wherein the prophylactic and / or therapeutic agent is intended for a human having hypertension. The preventive and / or therapeutic agent according to claim 2, wherein the prophylactic and / or therapeutic agent comprises an angiotensin-converting enzyme inhibitor having a capacity to exhibit an antihypertensive effect on hypertension in the brain as an active ingredient. Or therapeutic agent. The prophylactic and / or therapeutic agent according to claim 1, wherein the angiotensin converting enzyme inhibitor that migrates into the brain is perindopril. The prophylactic and / or therapeutic agent according to claim 1, wherein the angiotensin converting enzyme inhibitor that migrates into the brain is captopril. The prophylactic and / or therapeutic agent according to claim 1, wherein the brain angiotensin converting enzyme inhibitor is lisinopril.

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