JP5674652B2 - 神経障害の処置のためのアセトアセテートのモノグリセリドおよび誘導体 - Google Patents
神経障害の処置のためのアセトアセテートのモノグリセリドおよび誘導体 Download PDFInfo
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- JP5674652B2 JP5674652B2 JP2011516889A JP2011516889A JP5674652B2 JP 5674652 B2 JP5674652 B2 JP 5674652B2 JP 2011516889 A JP2011516889 A JP 2011516889A JP 2011516889 A JP2011516889 A JP 2011516889A JP 5674652 B2 JP5674652 B2 JP 5674652B2
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Description
[0003] アルツハイマー病(AD)は、主に高齢者が罹患する進行性神経変性障害である。1984年、BlassおよびZemcov(Blass and Zemcov 1984)は、ADがコリン作動性ニューロンのサブ集団における代謝速度低下から生じると提唱した。しかし、ADはコリン作動系に限定されず、多数のタイプの伝達系および幾つかの別個の脳領域をも伴うことが明らかになった。代謝速度低下はグルコース利用の低下に関係すると思われる。脳イメージング技術によりAD患者の脳における放射性標識グルコースの取込み低下が明らかになった;これらの欠陥は認知症の臨床徴候が起きる以前に十分に検出できる(Reiman, Caselli et al. 1996)。脳グルコース代謝の測定により、AD患者ではグルコース代謝が20〜40%低下し、その結果、危険なほど低いATPレベルになることが指摘されている。
[0007] パーキンソン病(PD)は進行性神経変性障害であり、アルツハイマー病に次ぐ第2の最も一般的な神経変性疾患である。PDの推定有病率は米国集団全般において0.3パーセントであり、85歳より高齢者においては4〜5パーセントの有病率である。PDは運動異常を特徴とし、これには振戦、筋肉強直、随意運動欠如、および体位不安定が含まれる。PDの主要な神経病理学的特徴は、黒質緻密部(substantia nigra pars compacta)(SNpc)におけるドーパミン作動性ニューロンの損失、および残存するドーパミン作動性ニューロンにおける好酸性細胞質内封入体(レーヴィ体)の存在である。
[0013] FRDAは、進行性の運動失調、肥大性心筋症、インスリン抵抗性糖尿病の早期発症、廃疾、および早死を特徴とする劣性疾患である。FRDAは、フラタキシン(frataxin)、すなわちアミノ酸210個の核コード化ミトコンドリアタンパク質の欠乏により起きる遺伝子障害である。このタンパク質のレベルが低いのは、イントロンGAA反復配列が拡張してmRNAレベルの低下をもたらすことによるものである。FRDA患者はミトコンドリア酵素アコニターゼの活性低下を示す。アコニターゼは、クエン酸からイソクエン酸への変換、すなわちクレブス回路(クエン酸回路またはTCA回路としても知られる)の第1段階に関与する。ヒト患者におけるフラタキシンの欠乏は主にTCA回路の欠陥をもたらすと考えられる。
[0016] GLUTl欠乏性てんかんは、乳児発作、発達遅延、および精神発育遅滞を伴う後天性小頭症を特徴とする。GLUTl欠乏性てんかんは、GLUTlの遺伝子における幾つかのタイプの変異から起きる。グルコース輸送体1(GLUTl)は、血流から脳内へのグルコース輸送に関与する主要なタンパク質である。標準的な食事条件下では、脳はエネルギーをほぼ完全に血中グルコース(血糖)に依存している。しかし、ある状況、たとえば飢餓状態では、ケトン体がグルコースと異なるエネルギー源を供給することができる。ケトン体は脳内への輸送のためにGLUTlに依存しないので、GLUTl欠乏症候群においてエネルギーを供給できる。したがって、ケトン体療法はこれらの患者の終生治療のための実用的な方法になる可能性がある。
[0018] レプレコーニズムおよびラブソン−メンデンホール症候群は、インスリン抵抗性、持続性高血糖および成長遅滞を特徴とする、稀な疾患である。20歳を超えて生存する対象は稀である。これらの症候群はインスリン受容体遺伝子の変異から起き、これによってインスリンに対する受容体の親和性が低下する。現在の処置は漸増用量のインスリン投与からなる(1日当たり最高数千単位)。インスリン受容体へのインスリンの結合が乏しいため、この処置によって弱い効果が得られるにすぎない。ケトン体はインスリンによるPDH多酵素複合体の刺激作用を模倣し、これによりクレブスTCA回路の代謝産物レベルを上昇させ、ATPの形でのエネルギー出力を増大させて、代謝効率を高めることが示された。ケトン強化食またはケトン生成食は、これらの状態の有効な処置となる可能性がある。
[0020] 他の多数の疾患および症候群が代謝低下に関連する。そのような状態には、大動脈冠動脈バイパス移植(CABG)認知症、加齢性記憶障害、麻酔誘発性記憶喪失、外傷性脳傷害、ハンチントン病、および他の多数の疾患が含まれる。代謝介入がそのような疾患に罹患している人々を救済できるのは明らかである。
[0022] ケトン体をベースとする療法がそのような疾患に適切な可能性はあるが、現在の方法は非実用的または不適切である。ケトン生成食は低い炭水化物摂取量を継続的に厳守する必要があり、これがそれらの遵守を困難にしている。
[0069] マウス薬物動態(PK)試験
[0070] 本発明者らは、モノアセトアセチンをマウスに経口(po)および腹腔内(ip)投与した後、種々の時点でケトン体の血中レベルを調べた。
[0073] ラットモデルにおいて血清ケトンレベルを上昇させるためのモノアセトアセチンの使用
[0074] Sprague−Dawleyラットに標準的な市販のラット用固形飼料を与える。15日間の順化後、2グループのラットにl〜5g/kg/日のモノアセトアセチンを含有する実験食を与える。対照グループは標準的な等カロリー固形飼料で飼育し続ける。
[0078] MPTP病変マウスにおける神経保護効果
[0079] AC−0523の可能な療法効力を調べるために、パーキンソン病(PD)のマウスモデルにおいてAC−0523の神経保護効果の効力を検査する小規模パイロット実験を実施した。l−メチル−4−フェニル−l,2,3,6−テトラヒドロピリジン(MPTP)は、ミトコンドリア電子伝達系の複合体I(NADH−ユビキノンオキシドレダクターゼ)を遮断し、典型的なPDの症状およびドーパミン作動性ニューロンの損失を引き起こす。
[0085] MPTP処理した被験動物におけるAC−0523の神経保護の役割が支持される。AC−0523をも投与したMPTP処理マウスのSNcにおけるTH+細胞数は、生理食塩水またはAC−1202のみを投与されたMPTP処理マウスより高く、MPTPを投与されなかったマウスに匹敵した。尾状被殻(caudate−putamen)のTH密度は、MPTPと生理食塩水で処理した動物において最低であり、MPTPとAC0523を投与された被験動物において最高であった。
[0086] アルツハイマー病におけるモノアセトアセチンの安全性、耐容性および有効性の評価
[0087] 軽度ないし中等度のほぼ確実なアルツハイマー病被験者にモノアセトアセチンを1日1回、90日間投与する。ランダム化二重盲検式プラセボ対照付き平行多センター方式を採用する。最高4週間のスクリーニング期間後、被験者に化合物2またはプラセボのいずれかを90日間投与し、続いて2週間のウォッシュアウト期間を置く。
[0091] 栄養ドリンク剤および他の配合物
[0092] A.そのまま飲める飲料(Ready to Drink Beverage).下記の成分を用いて、そのまま飲める飲料を調製する:乳化モノアセトアセチン5〜100g/ドリンク、L−カルニチン250〜1000mg/ドリンク、および嗜好性、安定性などを高めるために用いる多様な矯味矯臭剤その他の成分。
Claims (9)
- 有効量のモノアセトアセチンまたはその医薬的に許容できる塩を含む、アルツハイマー病またはパーキンソン病の処置のための医薬組成物であって、その際、組成物はD−β−ヒドロキシ酪酸またはそれの対応する塩の供給源を含まず、組成物はアルツハイマー病またはパーキンソン病に罹患している患者に、その患者の血中ケトン体レベルを上昇させるのに有効な量で投与される、上記医薬組成物。
- D−β−ヒドロキシブチレートとアセトアセテートの生理的比率が正常範囲である患者の血中に、上昇したレベルのケトン体が存在する、請求項1に記載の医薬組成物。
- モノアセトアセチンが0.1g/kg/日〜10g/kg/日の範囲の用量で投与される、請求項1又は2に記載の医薬組成物。
- 投与後の2時間目に、患者の血中ケトン体レベルが0.2mM〜20mMに上昇する、請求項1〜3のいずれか1項に記載の医薬組成物。
- ApoE4対立遺伝子が欠損している哺乳動物が処置のために選択される、請求項1〜4のいずれか1項に記載の医薬組成物。
- 炭水化物源を更に含む、請求項1〜5のいずれか1項に記載の医薬組成物。
- 炭水化物源がグルコースである、請求項6に記載の医薬組成物。
- 組成物がさらに炭水化物源を含む、請求項1〜5のいずれか1項に記載の医薬組成物。
- 炭水化物源がグルコースである、請求項8に記載の医薬組成物。
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CA2729622C (en) | 2017-07-25 |
AU2009266869A1 (en) | 2010-01-07 |
AU2016238886A1 (en) | 2016-10-20 |
AU2016238886B2 (en) | 2018-07-05 |
KR20110043648A (ko) | 2011-04-27 |
EP2303036A1 (en) | 2011-04-06 |
JP2011526929A (ja) | 2011-10-20 |
CA2729622A1 (en) | 2010-01-07 |
US9125881B2 (en) | 2015-09-08 |
AU2009266869B2 (en) | 2016-07-07 |
CN105640931A (zh) | 2016-06-08 |
CN102105071A (zh) | 2011-06-22 |
US20110178032A1 (en) | 2011-07-21 |
WO2010003114A1 (en) | 2010-01-07 |
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