JP6484561B2 - Lactobacillusfermentum(ラクトバチルス・ファーメンタム)me−3を用いる治療方法 - Google Patents
Lactobacillusfermentum(ラクトバチルス・ファーメンタム)me−3を用いる治療方法 Download PDFInfo
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Description
a)糖化ヘモグロビンHbAlcのレベルの減少;
b)細胞レベルの低度な炎症の減少又は予防;及び
c)アディポネクチンのレベルの増加
の一以上によって、炎症性疾患、及び特にメタボリックシンドローム関連状況の(例えばアジュバント成分としての)予防、症状の緩和、治療及び/又は、アジュバント治療の提供における使用のためのLactobacillus fermentum ME-3を含む組成物を提供する。
a)糖化ヘモグロビンHbAlcのレベルの減少;
b)細胞レベルの低度な炎症の減少又は予防;及び
c)アディポネクチンのレベルの増加
の一以上によって、被験者における炎症性疾患、及び特にメタボリックシンドローム関連状況の(例えばアジュバント成分としての)予防、症状の緩和、治療及び/又は、アジュバント治療の提供方法もまた提供する。
a)糖化ヘモグロビンHbAlcのレベルの減少;
b)細胞レベルの低度な炎症の減少又は予防;及び
c)アディポネクチンのレベルの増加
の一以上によって、炎症性疾患、及び特にメタボリックシンドローム関連状況の(例えばアジュバント成分としての)予防、症状の緩和、治療及び/又は、アジュバント治療のための医薬及び/又はアジュバント医薬の製造における使用のためのLactobacillum fermentum ME-3 DSM 14241株もまた提供する。
a)糖化ヘモグロビンHbAlcのレベルの減少;
b)細胞レベルの低度な炎症の減少又は予防;及び
c)アディポネクチンのレベルの増加
の好ましくは少なくとも二つ、好ましくは全てが生じる。好ましくは、これらは同時に生じる。
炎症、慢性的な低度炎症及び非特異的ヘモグロビン(Hb)糖化は、前糖尿病、糖尿病及び循環器疾患の最も重要なリスク要因の幾つかである。一般に、健常な被験者で見られる参照範囲は約20〜40 mmol/mol(4%〜5.9% 糖化ヘモグロビン)である(「ヘモグロビンA1c試験」、MedicineNet.com)。約48 mmol/mol(又は≧6.5% 糖化ヘモグロビン)と同等又はそれ以上の糖化ヘモグロビンのレベルとして定義され得る(Kekkonen RA, et al. World J Gastroenterol. 2008;14(13):2029-36)異常なHb糖化は、加齢の生理学及び特に2型糖尿病の病態生理学と関連する。したがって、あらゆる異常なヘモグロビン糖化、すなわち約40 mmol/mol(又は≧5.9% ヘモグロビン)を超える糖化は、CVDの発症を高め得る。
アディポネクチンは、もっぱら脂肪細胞によって生産されるアディポカインポリペプチドホルモンである。アディポカインの中で、アディポネクチンは最も豊富である。
アディポネクチンは、グルコース制御及び脂肪酸酸化をはじめとする多くの代謝過程を調節し、健常な個体において、典型的に血中に約5〜21 ng/mlで存在する。アディポネクチンのレベルは、標的被験者集団において低減され、典型的に約10-20 ng/ml未満、又は約20 ng/ml、15 ng/ml、10 ng/ml、8 ng/ml、5ng/ml未満又はさらにそれより低い。
低度な炎症(LGI)は、典型的に被験者の血管系及び脂肪組織で生じる。LGIは、典型的に、その本質において慢性的である。細胞レベルの低度な炎症の周知のマーカーとして、高感度C反応性タンパク質(hsCRP)及びIL-6が挙げられる。
Lactobacillus fermentum ME-3が炎症性及び抗炎症性マーカーのプロフィールを変更する根底にあるメカニズムによって、本発明者は、プロバイオティック細菌株が、炎症性疾患、及び特にメタボリックシンドローム関連状況の予防、症状の緩和、治療及び/又はアジュバント治療の提供に有用であることを見出した。特に、本発明は、炎症性疾患の予防、症状の緩和、治療として用い得、及び/又はアジュバント治療となり得、ここで前記炎症性疾患又は障害は、CVD、神経変性疾患、アルツハイマー疾患、アテローム性動脈硬化、癌、脳卒中、代謝疾患、メタボリックシンドローム、前糖尿病又は2型糖尿病である。
本発明の文脈において、Lactobacillus fermentum ME-3は、食品製品、食品サプリメント、又は医薬組成物等の任意の好適な処方において投与され得る。プロバイオティック組成物の処方は、WO 2010/06992、WO 2002/005829、EP 1699474に開示されている。
代謝疾患、メタボリックシンドローム、前糖尿病又は2型糖尿病を治療するのに典型的に用いられる医薬、及び/又はさらなる抗炎症剤が挙げられる。他の活性化合物もまた、株であり得る。さらなるプロバイオティクスの例として、例えば、Pediococcus(ペディオコッカス)、他のlactobacillus(ラクトバチルス)、Bifidobacterium(ビフィズス菌)の株が挙げられる。
を含む。
用語「含む」は、「からなる」等を包含し、例えば、Xを「含む」組成物は、排他的にXからなり得、又は何か追加を含み得る、例えばX+Y。
本発明の様々な態様を以下に示す。
1.前糖尿病、循環器疾患及び2型糖尿病から選択されるメタボリックシンドローム関連疾患の予防、症状の緩和、又は治療における使用のための、Lactobacillus fermentum(ラクトバチルス・ファーメンタム)ME-3 DSM 14241株を、単独で又はアジュバント成分として含む組成物。
2.被験者における、同時の:
a)糖化ヘモグロビンHbAlcのレベルの減少;
b)細胞レベルの低度な炎症の減少又は予防;及び
c)アディポネクチンのレベルの増加
によって、前糖尿病、循環器疾患及び2型糖尿病から選択されるメタボリックシンドローム関連疾患の予防、症状の緩和、又は治療における使用のための、Lactobacillus fermentum ME-3 DSM 14241株を、単独で又はアジュバント成分として含む組成物。
3.Lactobacillus fermentum ME-3 DSM 14241株を含む、有効量の組成物の被験者への投与を含む、被験者における前糖尿病、循環器疾患及び2型糖尿病から選択されるメタボリックシンドローム関連疾患の、単独での又はアジュバント成分としての予防、症状の緩和、又は治療方法。
4.Lactobacillus fermentum ME-3 DSM 14241株を含む、有効量の組成物の被験者への投与を含み、被験者における、同時の:
a)糖化ヘモグロビンHbAlcのレベルの減少;
b)細胞レベルの低度な炎症の減少又は予防;及び
c)アディポネクチンのレベルの増加
によって、
被験者における前糖尿病、循環器疾患及び2型糖尿病から選択されるメタボリックシンドローム関連疾患の、単独での又はアジュバント成分としての予防、症状の緩和、又は治療方法。
5.細胞レベルの炎症の減少又は不存在が、炎症性マーカーのhsCRP及びIL-6を用いて測定される、上記1若しくは2に記載の組成物、又は上記3若しくは4に記載の方法。
6.被験者が、前記メタボリックシンドローム関連疾患について無症候である、上記1〜5のいずれかに記載の組成物又は方法。
7.無症候の被験者が、≦10 mg/lのCRPレベルを有する、上記6に記載の組成物又は方法。
8.無症候の被験者が、3〜10 mg/lのCRPレベルを有する、上記7に記載の組成物又は方法。
9.前記組成物が、食品製品、食品サプリメント、又は医薬組成物である、上記1〜8のいずれかに記載の組成物又は方法。
10.食品製品が、メディカルフード製品又は機能性食品製品である、上記9に記載の組成物又は方法。
11.食品製品が、乳、ヨーグルト、チーズ、ケフィア(kefir)、若しくは乳若しくはホエーベースの発酵乳製品等の乳製品、又はチョコレート製品である、上記9又は10に記載の組成物又は方法。
12.抗炎症組成物、一以上のビタミン、及び/又はモナコリンK等の他の活性化合物の前に、同時に、又は後に前記組成物が投与される、上記1〜11のいずれかに記載の組成物又は方法。
13.前記組成物が、さらに一以上のビタミン及び/又はモナコリンKを含む、上記1〜12のいずれかに記載の組成物又は方法。
14.前記組成物が、Lactobacillum fermentum ME-3 DSM 14241株を、カプセル化形態で、凍結乾燥形態で、被覆形態で、カプセルに、錠剤に又は粉末に含む、上記1〜13のいずれかに記載の組成物又は方法。
15.前記組成物が、106〜1011 CFUのLactobacillum fermentum ME-3 DSM 14241株を含む、上記1〜14のいずれかに記載の組成物又は方法。
低度な炎症マーカーであるhsCRP、HBA1c、IL-6、アディポネクチン及び非特異的糖化マーカーへの、プロバイオティックLactobacillus fermentum ME-3の効果をモニターした。
市販の統計ソフトウェアパッケージ(Statistics for Windows, Stat Soft Inc.及びGraph Pad PRISM Version 2.0)、及びsoftware R, version 1.6.0 for Windows (www.r-project.org)を用いて計算を行った。全ての値を平均値と標準偏差で表した(平均値±SD)。群間の統計的に有意な差は、Student t検定を用いて決定した。全ての分析において、<0.05のP値を、統計的に有意であるとみなした。変数間の相関を、線形回帰分析(software R, version 2.0.1 for Windows)を用いて試験した。
21人の患者(80.4±9.9歳、9人の男性/12人の女性)は、8〜22(12±6.6)日間の初期の脳卒中を有していた。無作為二重盲検試験の被験者を、無作為に2群に分配し、凍結乾燥したLf ME-3の3つのカプセル(カプセルあたり109CFU)(LfME-3群、10人の被験者)又は3つのカプセル(250mgのサッカロース及び微細セルロースを含む、コントロール群、11人の被験者)のいずれかを1日2回、3週間消費するように割り当てた。機能的な能力(機能的独立尺度(Functional Independence Measure−FIM)及びスカンジナビア脳卒中スケール(Scandinavian Stroke Scale−SSS))並びに脳卒中患者の臨床指標を、3週間の処置期間の前及び後に評価した。状態の上昇へのusCRPの使用は、炎症、又は健常な個体と関連すると考えられる。
本発明者はまた、無作為二重盲検プラセボ対照臨床試験(タルトゥ大学のヒト研究に関する倫理審査委員会は、ME-3を含まないプラセボケフィア群(55より多い人々)とME-3ケフィア群(55より多い人々)を比較する試験のプロトコル(参考:210/T-3)を許可した。)を行った(論文準備中)。8週のデータ対4週のデータは、プラセボケフィアではなく、Lactobacillus fermentum ME-3を富ませたケフィアの消費が、HbA1cのレベルを有意に減少させたことを示す(p=0.015)。さらに、8週で、ME-3ケフィアのみが、IL-6(p<0.01)のレベル、TG/HDL-Chol比(インスリン抵抗性のマーカー、p=0.02)、並びにOxLDLのレベルを有意に減少させ、アディポネクチンのレベルを優位に増加させた(p<0.003)。したがって、これらのデータは共に、Lactobacillus fermentum ME-3を含む組成物が、メタボリックシンドローム関連状況(前糖尿病、糖尿病、循環器疾患)のリスクを予防し、症状を緩和し、治療するのに役立つことを示している。8週のデータ対4週のデータは、プラセボケフィアではなく、Lactobacillus fermentum ME-3を富ませたケフィアの消費が、HbA1cのレベルを有意に減少させたことを示した(p=0.015)。
25人の無症候のボランティア(16人の女性及び9人の男性)を、臨床非盲検試験に募った。排除の判断基準は、以下の通り:進行中の急性感染;糖尿病;食品アレルギー又は胃腸疾患の病歴;先月の間のいずれかの抗菌剤の使用又は非ステロイド系抗炎症薬及び抗糖尿病薬、スタチン又はホルモン避妊をはじめとするいずれかの通常の併用医薬の使用;妊娠又は授乳;アルコール乱用;薬の使用;特別な食事;である。処置の間、及び前二週間、参加者に対して、ビタミン又はミネラルの補給、慣れた食事習慣及び毎日の身体活動の変更、及びプロバイオティクスベースの食品又は他のケフィア/ヨーグルトの使用を避けるように依頼した。全ての参加者は、書面にしたインフォームドコンセントに署名し、いつでも試験を止める選択肢を有していた。タルトゥ大学の、ヒト研究に関する倫理審査委員会は、試験のプロトコル(プロトコル 229/T-18)を許可した。本試験は、世界医師会のヘルシンキ宣言に従って行われた。
市販の統計ソフトウェアパッケージ(Statistics for Windows, Stat Soft Inc.及びGraph Pad PRISM Version 2.0)、及びsoftware R, version 1.6.0 for Windows (www.r-project.org)を用いて計算を行った。全ての値を平均値と標準偏差で表した(平均値±SD)。群間の統計的に有意な差は、Student t検定を用いて決定した。全ての分析において、<0.05のP値を、統計的に有意であるとみなした。変数間の相関を、線形回帰分析(software R, version 2.0.1 for Windows)を用いて試験した。
Lactobacillus fermentum ME-3 チョコレートベースの組成物
凍結乾燥したLactobacillus fermentum ME-3のチョコレート中の、3週間42℃での安定性を調べた。用いた材料は、(Probiotical SpA, Novara、イタリアによって生産された)凍結乾燥したLactobacillus fermentum ME-3 108CFU/g、及び市販の異なるカカオ濃度を有するチョコレートであった。それぞれ85%、70%、56%及び30%のカカオからなる50グラムのチョコレートを熱水で融解し、恒温装置を用いて42℃で維持した。CFUの評価を、0時点、第一週、第二週及び第三週で行った。チョコレートサンプルを秤量し、1:9の比でPBSバッファーの各量を添加した。101〜108の希釈を行い、deMan、Rogosa and Sharpe(MRS)培地に播種した。
Claims (9)
- 前糖尿病、循環器疾患及び2型糖尿病から選択されるメタボリックシンドローム関連疾患について無症候であり、3〜10 mg/lのCRPレベルを有する被験者における、同時の:
a)糖化ヘモグロビンHbAlcのレベルの減少;
b)細胞レベルの低度な炎症の減少又は予防;及び
c)アディポネクチンのレベルの増加
による、前記メタボリックシンドローム関連疾患の予防のための、Lactobacillus fermentum ME-3 DSM 14241株を、単独で又はアジュバント成分として含む組成物。 - 細胞レベルの炎症の減少又は不存在が、炎症性マーカーのIL-6を用いて測定される、請求項1に記載の組成物。
- 前記組成物が、食品製品、食品サプリメント、又は医薬組成物である、請求項1又は2に記載の組成物。
- 食品製品が、メディカルフード製品又は機能性食品製品である、請求項3に記載の組成物。
- 食品製品が、乳、ヨーグルト、チーズ、ケフィア(kefir)、若しくは乳若しくはホエーベースの発酵乳製品等の乳製品、又はチョコレート製品である、請求項3又は4に記載の組成物。
- 抗炎症組成物、一以上のビタミン、及び/又はモナコリンK等の他の活性化合物の前に、同時に、又は後に前記組成物が投与される、請求項1〜5のいずれか一項に記載の組成物。
- 前記組成物が、さらに一以上のビタミン及び/又はモナコリンKを含む、請求項1〜6のいずれか一項に記載の組成物。
- 前記組成物が、Lactobacillum fermentum ME-3 DSM 14241株を、カプセル化形態で、凍結乾燥形態で、被覆形態で、カプセルに、錠剤に又は粉末に含む、請求項1〜7のいずれか一項に記載の組成物。
- 前記組成物が、106〜1011 CFUのLactobacillum fermentum ME-3 DSM 14241株を含む、請求項1〜8のいずれか一項に記載の組成物。
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