JP6762620B2 - Cognitive decline inhibitor consisting of hydrogen gas - Google Patents
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- JP6762620B2 JP6762620B2 JP2018129003A JP2018129003A JP6762620B2 JP 6762620 B2 JP6762620 B2 JP 6762620B2 JP 2018129003 A JP2018129003 A JP 2018129003A JP 2018129003 A JP2018129003 A JP 2018129003A JP 6762620 B2 JP6762620 B2 JP 6762620B2
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- 208000010877 cognitive disease Diseases 0.000 title claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title claims description 9
- 239000003112 inhibitor Substances 0.000 title claims description 7
- 230000006999 cognitive decline Effects 0.000 title claims description 5
- 230000003920 cognitive function Effects 0.000 claims description 9
- 239000007789 gas Substances 0.000 claims description 8
- 230000032683 aging Effects 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000006735 deficit Effects 0.000 claims description 4
- 201000004810 Vascular dementia Diseases 0.000 claims description 3
- 230000007423 decrease Effects 0.000 claims description 2
- 206010027175 memory impairment Diseases 0.000 claims 1
- 238000012360 testing method Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 5
- 208000028698 Cognitive impairment Diseases 0.000 description 4
- 230000019771 cognition Effects 0.000 description 3
- 230000003930 cognitive ability Effects 0.000 description 3
- 230000001149 cognitive effect Effects 0.000 description 3
- 230000006866 deterioration Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000036542 oxidative stress Effects 0.000 description 3
- 208000000044 Amnesia Diseases 0.000 description 2
- 208000026139 Memory disease Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 238000001793 Wilcoxon signed-rank test Methods 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- -1 amnesia Chemical compound 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000117 blood based biomarker Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 230000003931 cognitive performance Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
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- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
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- 230000006996 mental state Effects 0.000 description 1
- 208000027061 mild cognitive impairment Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
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- 235000021590 normal diet Nutrition 0.000 description 1
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Description
本発明は、水素ガスからなる認識機能低下抑制剤に関する。 The present invention relates to a cognitive function deterioration inhibitor composed of hydrogen gas.
１．はじめに
認知機能の低下は、歳を重ねる過程で最も目立ち、制御することが困難な特徴の一つである老化を伴う。臨床上様々な結果が混ざり合う、老齢に関係する認知障害に取り組むために様々な薬理学的・非薬理学的な手段が使われた。水素分子（Ｈ２）は、多機能で治療的な性質を備える新しい生医学ガスである。Ｈ２は、幾つかの動物モデルが患う認知障害と神経変性を緩和することが最近報告されたが、これまでの研究では、臨床試験で有効性
の評価はなされていなかった。我々は、このオープンラベル予備実験で、４週間のＨ２吸入が６５歳以上の女性の認知機能に与える効力を分析した。
1. 1. INTRODUCTION Cognitive decline is associated with aging, one of the most prominent and difficult to control features of aging. Various pharmacological and non-pharmacological means have been used to address age-related cognitive deficits, a mixture of clinically diverse outcomes. Hydrogen molecule (H 2 ) is a new biomedical gas with multifunctional and therapeutic properties. H2 has recently been reported to relieve cognitive impairment and neurodegeneration in some animal models, but previous studies have not evaluated its efficacy in clinical trials. We, in this open-label pilot study, four weeks of H 2 inhalation were analyzed the effect to be given to women of cognitive function 65 years of age or older.
本明細書を以下の発明の記載を包含する。
（１）水素ガスを含む加齢に起因する認識機能の低下抑制剤。
（２）水素ガスからなる加齢に起因する認識機能の低下抑制剤。
（３）水素ガスを含む、記憶喪失、アルツハイマー病、及び血管性認知症を含む認知障害抑制剤。
２．マテリアルと方法
本オープンラベル予備実験(ClinicalTrials.gov、NCT02830854に登録済)への参加を志願した参加者(ｎ＝１３)は、地域社会に住む老齢の女性(６８．０±３．０歳、体重６６．９±１０．３kg、身長１６１．１±５．８cm)であった。除外基準としては、重篤な疾病か精神病併発症がある。本調査は、ヘルシンキ宣言のガイドラインに準拠して実行され、地元のＩＲＢが本調査プロトコルを承認した。参加者は全員、インフォームドコンセントを提出し、調査中は通常のライフスタイルを維持し、通常の食事摂取を続けるように要求された。参加者は、４週間に渡って１日当たり１５分間、Ｈ２を吸入した。Ｈ２ガス(４％)は、生物学的ガス供給装置(日本国神奈川県のＭＩＺ株式会社)から提供され、治験中、研究査察官が日々のＨ２吸入について監視した。ベースラインから４週目までの期間の治療効能の主要評価指標は、ミニメンタルステート検査（Mini Mental State Exam、ＭＭＳＥ)スコアの変化であった。さらに、他の認識力マーカーの検査と副作用の評価を、ベースラインと、調査開始から４週間後に行なった。参加者の認知機能は、ＭＭＳＥとアルツハイマー病検査尺度のサブスケール(ADAS-Cog)を使って評価された。ＭＭＳＥは、高齢者の認知障害度を判断するために臨床・調査環境で広範囲に使われる３０ポイント・アンケート調査である。ADAS-Cogは、11個のタスクから成る認識力検査装置であり、認知症の検査のために、記憶障害、言語障害、実行障害、注意力欠如、その他の認識力を判断するものである。上述の検査に加えて、参加者は、副作用(例えば、吐気、頭痛)の自己申告・自由回答式アンケート調査によって、調査期間中、H2インターベンションの有害事象を報告するように要求された。ウィルコクソンの符号順位検定を使って、インターベンションの期間に参加者の応答の間に有意な差があるかどうかを確証した(ベースライン対投与後)。有意度Ｐ≦０．０５に設定された。
The present specification includes the following description of the invention.
(1) An agent containing hydrogen gas, which suppresses deterioration of cognitive function due to aging.
(2) An agent composed of hydrogen gas that suppresses deterioration of cognitive function due to aging.
(3) A cognitive impairment inhibitor containing hydrogen gas, including amnesia, Alzheimer's disease, and vascular dementia.
2. 2. Materials and Methods Participants (n = 13) who volunteered to participate in this open-label preliminary experiment (ClinicalTrials.gov, registered with NCT02830854) were older women (68.0 ± 3.0 years) living in the community. The weight was 66.9 ± 10.3 kg and the height was 161.1 ± 5.8 cm). Exclusion criteria include serious illness or complications of psychosis. The study was conducted in accordance with the guidelines of the Declaration of Helsinki and the local IRB approved the study protocol. All participants submitted informed consent and were required to maintain a normal lifestyle and continue to eat a normal diet during the study. Participants inhaled H2 for 15 minutes per day for 4 weeks. H2 gas (4%) is provided by a biological gas supply apparatus (Kanagawa, Japan in MIZ Ltd.), during the study, research inspectors were monitored for daily H 2 inhalation. The primary endpoint of therapeutic efficacy during the period from baseline to week 4 was the change in the Mini Mental State Exam (MMSE) score. In addition, tests for other cognitive markers and side effect assessments were performed at baseline and 4 weeks after the start of the study. Participant cognitive function was assessed using the MMSE and the Alzheimer's Disease Test Scale subscale (ADAS-Cog). The MMSE is a 30-point questionnaire survey that is widely used in clinical and research environments to determine the degree of cognitive impairment in the elderly. ADAS-Cog is a cognitive test device consisting of 11 tasks, which judges memory disorder, speech disorder, execution disorder, lack of attention, and other cognitive ability for dementia test. In addition to the tests mentioned above, participants were required to report adverse events of H2 intervention during the study period by self-reported, open-ended questionnaire survey of side effects (eg, nausea, headache). Wilcoxon signed rank tests were used to confirm whether there was a significant difference between participants' responses during the duration of the intervention (baseline vs. post-dose). The significance P ≦ 0.05 was set.
３．結果
参加者は全員、追跡調査の手続きを終えた。即ち、Ｈ２インターベンションの副作用も報告した。有害事象によって調査から除外された者はいなかった。生活規制の順守率は９５．８％であった。表１に、調査中の認知機能の変化を示す(ベースライン対４週間の追跡調査)。
3. 3. Results All participants have completed the follow-up process. In other words, it was also reported side effects of H 2 intervention. No one was excluded from the study due to adverse events. The compliance rate of living regulations was 95.8%. Table 1 shows changes in cognitive function during the study (baseline vs. 4-week follow-up).
Ｈ２インターベンションによって、ＭＭＳＥ総スコア(平均値１３．７％、Ｐ＜０．０１)が著しく増加し、これによって、ベースラインにおける軽度認知障害(スコア３０のうちの２５．６)から、追跡調査時における正常な認識力(カット・スコア２７よりも大きいスコア)まで認知機能が改善した。さらに、Ｈ２の吸入によってADAS-Cogスコアは著しく改善し、単語再生テスト（Ｐ＜０．０１）ではパフォーマンスの改善が認められ、投与後には単語認識力が改善した（Ｐ＝０．０１）。ADAS-Cogスコアにおけるその他の９領域(名前を呼ぶ作業、命令、構造的実行、 思考実行、方位、会話能力、テスト命令の記憶、喚語障害、理解)が、両方のテスト時に正しく実行された(例えば、スコア＝０)(非開示)。 With H 2 intervention, MMSE total score (mean 13.7%, P <0.01) are significantly increased, thereby, mild cognitive impairment at baseline (25.6 of score 30), tracking Cognitive function improved to normal cognitive ability (score greater than cut score 27) at the time of the survey. Furthermore, ADAS-Cog score was significantly improved by inhalation of H 2, improved performance in word reproduction test (P <0.01) was observed, word cognition is improved after administration (P = 0.01) .. The other nine areas of the ADAS-Cog score (name-calling tasks, commands, structural executions, thinking executions, orientations, conversational abilities, test command memory, speech impairment, comprehension) were performed correctly during both tests ( For example, score = 0) (not disclosed).
４．考察
ヒト初回投与では、高齢者の認知パフォーマンスに対するＨ２の効能を調べるオープン・ラベル治験では、4週間に渡って毎日15分間、Ｈ２ガスを吸入することによって、健康に見える６５歳以上の女性の集団の認識力マーカーが改善した。投与後には、１２人の女性（１３人中）のＭＭＳＥスコアが高くなり、Ｈ２インターベンション後のADAS-Cog検査では、単語認識力の向上が報告された。さらに、Ｈ２の吸入による、主観的に報告されていた副作用の兆候がなかったため、受入れ可能な安全性を持つと考えられた。本予備実験は、先行する動物研究結果を確証するものと考えられるため、年齢に関わる認識力の健康を維持するためにはＨ２ガスは有益な薬剤であると考えられる。認知障害は、高齢者の酸化ストレスと密接な関係があるように考えられる。外来のＨ２は、選択的に作用する抗酸化剤として働くため、中枢神経系における酸化還元反応バランスの維持、もしくは、その回復を助けるので、認識力の寿命が延びることになる。Nagataらの報告によれば、Ｈ２の消費によって脳の酸化ストレスが低下し、酸化ストレスが引き起こす、マウスの海馬依存の学習と記憶処理の低下が防止された。従って、無作為化比較試験では、インターベンション中にその他の認知機能マーカー(例えば、脳機能画像解析、脳脊髄液と血液に基づくバイオマーカー)を監視することによって、Ｈ２ガスが、大きなサンプルだけでなく、人間における認識力を向上させるパワーを実際に生みだすことが確証された。上手に設計された臨床試験で有効性と安全性が証明されれば、今後、Ｈ２ガスは、記憶喪失、アルツハイマー病、血管性認知症等の認知障害に対する革新的な治療薬であると考えることができる。
4. In consideration humans first administration, in the open-label clinical trial to investigate the efficacy of H 2 on cognitive performance in the elderly, for 15 minutes every day for four weeks, by inhaling the H 2 gas, women over the 65-year-old looks healthy The cognitive markers of the population improved. After administration, 12 women (out of 13) had higher MMSE scores, and ADAS-Cog tests after H2 intervention reported improved word recognition. In addition, there were no subjectively reported signs of side effects from inhalation of H2, suggesting that it is acceptable safety. This preliminary experiment, because it is considered that confirms previous animal findings, in order to maintain the health of cognition related to age is believed to H 2 gas is a beneficial agent. Cognitive impairment appears to be closely related to oxidative stress in the elderly. Of H 2 extraneous, to act as an antioxidant that acts selectively, maintenance of the oxidation-reduction reaction balance in the central nervous system, or because they help the recovery, so that the life of the cognition extends. According to Nagata et al reported, oxidative stress in the brain is reduced by the consumption of H 2, caused by oxidative stress, decrease in learning and memory processes in the hippocampus-dependent mice is prevented. Therefore, in randomized controlled trials, H 2 gas is only in large samples by monitoring other cognitive function markers (eg, brain function image analysis, cerebrospinal fluid and blood-based biomarkers) during interventions. Instead, it was confirmed that it actually produces the power to improve cognitive ability in humans. If clinical trials in efficacy and safety is demonstrated well designed, future, H 2 gas is considered memory loss, Alzheimer's disease, as an innovative treatment for cognitive disorders such as vascular dementia be able to.
Claims (3)
前記認知機能の低下が、血管性認知症を除く記憶障害、言語障害、実行障害、注意力欠如、および、アルツハイマー病からなる群から選択され、
水素ガスの吸入によりヒトに投与される認知機能の低下の抑制剤。 It is an agent containing hydrogen gas that suppresses the decline in human cognitive function caused by aging.
The cognitive decline was selected from the group consisting of memory impairment, speech impairment, execution impairment, attention deficit, and Alzheimer's disease, excluding vascular dementia.
An inhibitor of cognitive decline that is administered to humans by inhalation of hydrogen gas.
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