JP2005509588A - 小腸バクテリアの異常増殖(sibo)およびsibo−関連状態を診断および治療する方法 - Google Patents
小腸バクテリアの異常増殖(sibo)およびsibo−関連状態を診断および治療する方法 Download PDFInfo
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- JP2005509588A JP2005509588A JP2002582263A JP2002582263A JP2005509588A JP 2005509588 A JP2005509588 A JP 2005509588A JP 2002582263 A JP2002582263 A JP 2002582263A JP 2002582263 A JP2002582263 A JP 2002582263A JP 2005509588 A JP2005509588 A JP 2005509588A
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Abstract
Description
本発明は、医療技術に関する。本発明は、小腸バクテリアの異常増殖(SIBO)およびSIBOによって引起される状態を診断し、また治療する方法に関するものである。
本明細書全体を通して、様々な刊行物を括弧内に引用する。これら刊行物の開示内容全体を、本特許出願の参考とし、本発明が関連する分野の現状をより一層十分に説明する。
小腸バクテリアの異常増殖(SBBO)としても知られる、小腸バクテリアの異常増殖(SIBO)は、結腸由来の好気性および嫌気性腸内バクテリアが、通常は余りバクテリア汚染されていない小腸内で増殖する、異常な状態である。SIBOは、小腸排出物1mL当たり106 CFUを越えるものとして定義される (R.M. Donaldson, Jr., 腸における正常なバクテリア密度およびその腸機能との関連 (Normal bacterial populations of the intestine and their relation to intestinal function), N. Engl. J. Med., 1964, 270: 938- 45)。典型的には、この症状は、腹痛、鼓腸、ガス発生および腸の性質における変更、例えば便秘および下痢を含む。
過敏性腸症候群(IBS)は、全胃腸管疾患の中で最も一般的なものであり、11-14%の成人が罹患しており、また全体の50%を越える患者が、消化障害を示す (G. Triadafilo- poulos等, 線維筋肉痛における腸不全 (Bowel dysfunction in fibromyalgia), Diges- tive Dis. Sci., 1991, 36(1): 56-64; W.G. Thompson, 過敏性腸症候群:発生病理および管理 (Irritable Bowel syndrome: pathogenesis and management), Lancet, 1993, 341:1569-72)。IBSに罹患した少数の人々のみが実際に医学的な治療を求めているに過ぎないと考えられている。IBS患者は、非対称性の症状、例えば主として排便に関連する腹痛、交互の下痢と便秘、腹部膨満、ガス発生および便における過度の粘性を示す。
高い繊維質含有率の食事は、便の嵩を増し、また腸を移動する時間を短縮する。しかし、西洋以外の国々、例えば中国およびインドにおけるIBSの存在、および二重ブラインドテストにおける、食物繊維サプルメントによるIBS治療の失敗は、IBSの原因に関する繊維仮説と矛盾する (W. Bi-zhen & P. Qi-Ying, 見掛け上健康な中国人の腸機能疾患 (Functional bowel disorders in apparently healthy Chinese people), Chin. J. Epidemiol., 1988, 9:345- 49; K.W. Heaton, 過敏性腸症候群における食物繊維の役割 (Role of dietary fibre in irritable bowel syndrome), R.W. Read編, Irritable bowel syndrome, Grune & Stratton, London, 1985, pp. 203-22,; W.G. Thompson等, 機能性腸疾患および機能性腹痛(Functional bowel disorders and functional abdominal pain), Gastroenterol. Int., 1992, 5: 75-92)。
例えば、腸の不随意筋を弛緩させるのに使用される、ポリペプチドホルモンであるリラキシンの投与が、IBSと関連する痛みを緩和するものとして教示されている治療である (S.K. Yue, Method of treating myofascial pain syndrome with relaxin, 米国特許第5,863,552号)。
Borody等は、IBS、小腸バクテリア異常増殖および急性または慢性腸バクテリア感染における便秘の治療のための、ピコサルフェート-含有便通剤処方物の使用を教示している (T.J. Borody等, Picosulfate-containing preparation for colonic evacuation, 米国特許第5,858,403号)。BarodyもIBSの治療における抗‐炎症剤の使用を教示している (T.J. Barody, Treatment of non-inflammatory and non-infectious bowel disorders, 米国特許第5,519,014号)。更に、IBSにおける便秘は、アミジノウレア化合物で治療されている (J. Yelnosky等, Amidinoureas for treating irritable bowel syndrome, 米国特許第4,701,457号および同第4,611,011号)。
他の生理的な異常性も、多くの患者におけるCFSと関連しており、神経-媒介低血圧、低コルチソリズム(hypocortisolism)、および免疫調節障害を包含する (P.H. Levine, 1998)。CFS患者のある小集団は、悪化した気分、低下した作業能力、および冬季期間の覚醒の困難さ、周期的な情緒障害の発生を訴えている (M. Terman等, 1998)。
結局、CFSの診断および治療は、根本的に治療可能な病因ではなく、絶えず症状に向けられていた。例えば、リラキシンの使用は、不随意筋を弛緩させ、結果的にCFSに関連する痛みを緩和するものと記載されている (S.K. Yue, Method of treating myofascial pain syndrome with relaxin, 米国特許第5,863,552号)。
種々の重篤度の免疫学的応答が、過敏性腸症候群、線維筋肉痛、慢性骨盤痛症候群、慢性疲労症候群、損傷を受けた知的活動性および/または記憶、うつ状態、自閉症、ADHD、自己免疫疾患、およびクローン病、に導く可能性があるが、明らかにこれらの診断的カテゴリー各々に対する病因的因子を決定して、診断テストおよび治療を効果的に行える必要がある。
Bagnol等は、筋層間神経叢における比較的多数のκオピオイドレセプタを含む、ラット胃腸管の様々な細胞層内のμおよびκオピオイドレセプタの、比較免疫可視化(immuno-visualization)を報告している (Bagnol, D.等, Cellular localization and distribution of the cloned mu and kappa opioid receptors in rat gastrointestinal tract, Neuroscience, 1997, 81(2): 579-91)。これら著者は、オピオイドレセプタが、該胃腸管において、ニューロン活性に直接影響を与えることを示唆した。
従って、SIBOおよびSIBOにより引起される状態、例えば過敏性腸症候群、線維筋肉痛、慢性骨盤痛症候群、慢性疲労症候群、自閉症、うつ病、損傷知的活動性および/または記憶、糖摂取渇望、ADHD、MS、SLE、および他の自己免疫疾患、およびクローン病に関する、診断テストおよび治療法を導くことができる、根本的な原因因子に対する要求がある。本発明の上記および他の利点を以下に説明する。
本発明は、小腸バクテリアの異常繁殖(SIBO)およびSIBOにより引起される状態の診断および治療に関する。ここに記載するSIBOにより引起される状態とは、過敏性腸症候群(IBS)、クローン病(CD)、線維筋肉痛(FM)、慢性骨盤痛症候群(CPPS)、慢性疲労症候群(CFS)、うつ病、損傷知的活動性、損傷記憶、口臭、耳鳴り、糖摂取渇望、自閉症、注意力欠乏/活動亢進障害(ADHD)、薬物過敏、および自己免疫疾患、例えば多発性硬化症(MS)、全身性エリテマトーデス(SLE)を包含する。
更に別の本発明の局面では、ヒト対象における、小腸バクテリア異常繁殖(SIBO)またはSIBOによって引起される状態を治療する上記方法は、該ヒト対象における、SIBOに対するマスト細胞-媒介免疫応答を阻害するのに十分な量で、該内腔壁中のマスト細胞膜の安定化剤を含む薬理的に許容される組成物を、該対象に投与する工程を含む。
本発明は、またSIBOが検出されたヒト対象における、SIBOまたはSIBOにより生じる状態の相対的な重篤度を測定する方法をも意図する。この方法は、適当な検出手段により、SIBOの有無を検出し、またSIBOの存在が該対象中に検出された場合には、この方法は、更に適当な検出手段により、腸内透過性の相対的なレベル、該対象におけるSIBOまたはSIBOにより生じる状態の相対的な重篤度を示す、異常に高い腸内透過性を検出することを含む。
本発明の上記したおよびその他の利点は、以下に記載する本発明の好ましい態様に関する詳細な説明において、一層十分に記載されるであろう。
ヒト対象の上部胃腸管は、盲腸、結腸、大腸および肛門を除く全消化器官を含む。幾つかの消化過程、例えば澱粉の加水分解は、口および食堂で開始され、消化サイトとして特に重要なのは、胃および小腸(小さな腸)である。この小腸は十二指腸、空腸および回腸を含む。この用語は当分野において一般的に使用されるので、小腸の近位セグメントまたは近位腸は、幽門から腸中央までの小腸の、最初のほぼ半分を含む。遠位セグメントまたは遠位の腸は、腸中央から回腸-盲腸弁までの小腸の、ほぼ第二の半分を含む。
ここで使用する「吸収」とは、粘膜上皮細胞の障壁を介する、腸の内腔から血液および/またはリンパ系への、物質の輸送を包含する。
小腸バクテリアの異常繁殖(SIBO)は、結腸由来の好気性および嫌気性腸内バクテリアが、通常は比較的バクテリア感染のない、小腸内で増殖する異常な状態である。SIBOは、小腸流出物1mL当たり、106 CFUを超える状態として定義される (R.M. Donaldson, Jr.のNormal bacterial populations of the intestine and their relation to intestinal function, N. Engl. J. Med. 1964, 270: 938-45)。
小腸バクテリアの異常繁殖を検出するためのもう一つの好ましい方法は、十二指腸、空腸および/または回腸の壁を、内視鏡検査により肉眼的に検査することである。
上記説明は、小腸バクテリアの異常繁殖を検出する方法の、単なる例示的な、かつ非-限定的な例に過ぎない。
最も好ましい該硫黄-含有ガスは硫化水素またはスルフヒドリル化合物である。
該バクテリア集団に対する栄養素の枯渇は、多くの手段の何れかにより行うことができる。
所定の結果に応じて、有用な活性剤は、活性脂質;セロトニン、セロトニンアゴニストまたはセロトニン再摂取阻害剤;ペプチドYYまたはペプチドYY官能性類似体;CGRPまたはCGRP官能性類似体;アドレナリン作動性アゴニスト;オピオイドアゴニスト;またはこれらの任意の組合せ;セロトニンレセプタ、ペプチドYYレセプタ、アドレナリンレセプタ、オピオイドレセプタ、CGRPレセプタ、またはこれらの組合せに対するアンタゴニストを含む。同様に有用なものは、セロトニンレセプタ、ペプチドYYレセプタ、CGRPレセプタ、アドレナリンレセプタおよび/またはオピオイドレセプタのアンタゴニストである。
CGRPレセプタアンタゴニストは、ヒトCGRP(8-37)を含む (例えば、Foxx- Orenstein等, Gastroenterol. 1996, 111(5): 1281-90)。
有用なアドレナリン作動性アゴニストは、ノルエピネフリンを含む。
アドレナリン作動性またはアドレナリンレセプタアンタゴニストは、β-アドレナリンレセプタアンタゴニストを含み、これは更にプロプラノロールおよびアテノロールを含む。これらは、好ましくは0.05-2mg/kgなる用量で使用する。
ここで使用する「活性脂質」とは、脂肪消化物の加水分解された最終製品と、実質的に類似する構造並びに機能をもつ、消化されたまたは実質的に消化された分子を包含する。加水分解された最終製品の例は、ジグリセライド、モノグリセライド、グリセロール等の分子、および最も好ましくは遊離の脂肪酸またはその塩である。
本発明を実施するのに使用する脂肪酸の例は、カプロン(caprolic)酸、カプリル(caprulic)酸、カプリン酸、ラウリン酸、ミリスチン酸、オレイン酸、パルミチン酸、ステアリン酸、パルミトレイン酸、リノール酸、リノレン酸、トランス-ヘキサデカン酸、エライジン酸、コロンビン(columbinic)酸、アラキジン酸、ベヘン酸、エイコセン酸、エルカ酸、ブラシジン酸、セトレイン酸、ネルボン酸、ミード(Mead)酸、アラキドン酸、チムノドン(timnodonic)酸、クルパノドン酸またはドコサヘキサエン酸等を含む。好ましい態様において、該活性脂質は、オレイン酸である。
本発明による、該活性剤を含む製薬上許容される組成物は、経口または小腸用途に適した形状、例えば錠剤、トローチ、ロゼンジ、水性または油性懸濁液、分散性の粉剤または顆粒剤、エマルション、硬質または軟質カプセル、エリキシル剤または小腸用処方物の形状にある。経口用途用の組成物は、医薬組成物の製造に係る当業者には公知の任意の方法に従って調製される。組成物は、また米国特許第4,256,108号、同第4,160,452号および同第4,265,874号に記載されている技術によって被覆して、制御された放出性を持つ浸透圧性治療用錠剤を製造することができる。制御放出組成物用の他の技術、例えば米国特許第4,193,985号、同第4,690,822号および同第4,572,833号に記載されている技術を、本発明の製薬上許容される組成物の処方において利用することができる。
有利な毎日の投与養生をもたらすように、生物学的活性を高めるために、本発明では、食物、栄養素および/または薬物を摂取する前に、本発明の組成物を投与することができる。
上記のように、本発明の技術は、哺乳動物の、該近位または遠位の腸における第一の位置で生じた、セロトニン作動性の神経シグナルを、該上部胃腸管における第二の位置で伝達または複製することにより、実施することも可能である。例えば、該第一の位置は、近位の腸にあり、また該第二の位置は該近位腸の何処かまたは遠位の腸にあり得る。あるいは逆に、該第一の位置は、遠位の腸にあり、また該第二の位置は該遠位の腸の何処か、または近位の腸内にあり得る。
あるいは、該活性剤はPYY、またはPYY官能性類似体である。PYYまたはPYY官能性類似体は、脂肪または5-HTに応答して、PYY-感受性の主感覚ニューロンを活性化する。該PYY-感受性の主感覚ニューロンの主な神経伝達物質は、カルシトニン遺伝子-関連ペプチド(CGRP)であるので、もう一つの態様では、CGRPまたはCGRP官能性類似体が、該活性剤である。
あるいはまた、該活性剤は、オピオイドレセプタアゴニストであって、該オピオイド介在ニューロンを介して、神経シグナル伝達を活性化し、もしくは増強する。
ヒト対象における、小腸バクテリアの異常繁殖(SIBO)またはSIBOにより生じる状態を治療する方法の、別の局面では、上記のような適当な手段により、該ヒト対象においてSIBOの存在が検出された後に、製薬上許容される消毒組成物を、該小腸の内腔に導入して、該SIBO状態を構成するバクテリアと接触させる。この消毒組成物は、該小腸における該バクテリアの生育を阻害するのに十分な量で導入され、かくして少なくとも部分的に、該ヒト対象におけるSIBOを撲滅する。
過酸化水素を含む、消毒または殺菌組成物の態様は、脊椎における内用としては公知である(例えば、カナダ、モントリオールのUltra Bio-Logics Inc.のウルトラダイン(Ultradyne))。好ましくは、約1%〜約3%(v/v)濃度の過酸化水素水性溶液を、経口で、あるいは小腸投与により内腔に、最も有利には摂食(ingestion)により導入する。
ヨウ素化合物または塩を含む消毒または殺菌組成物の態様も、公知であり、例えばポビドン-ヨウ素溶液である。
上記のように、ヒト対象における、小腸バクテリアの異常繁殖(SIBO)またはSIBOによって生じる状態の本発明による治療法は、場合により、以下に記載するような、小腸バクテリアの異常繁殖を少なくとも部分的に撲滅する、他の適当な方法と組み合わせて、同時にまたは順次実施することができる。
小腸バクテリアの異常繁殖を少なくとも部分的に撲滅する、もう一つの好ましい方法は、食事間の段階III消化の際の、腸の運動性を、該バクテリアの異常繁殖を少なくとも部分的に撲滅するための幾つかの方法の何れかにより、例えば該対象の食事を、小腸の運動性を正常なレベルまで高めるように適当に改善(例えば、食物繊維を増やすことにより)し、あるいは化学的プロカイネティック (Prokinetic) 剤を該対象に投与することにより、規格化するかあるいは増大することである。この方法は、該対象において胆汁酸の生産量が低い場合または不足している場合の、胆汁酸置換療法を包含する。
場合により、このキットはまた上記のように、SIBOを少なくとも部分的に撲滅するのに有用な組成物をも含む。
本発明のキットに組み込まれた成分は、動作性および利用性を保存するあらゆる便利かつ適当な方法で保存された状態で、実施者に渡される。例えば、該成分は、溶解、脱水または凍結乾燥された状態であり得、これらは室温、冷蔵または凍結温度にて供給できる。
実施例1:データベースの組成物
セダーズ-シナイメディカルセンターGIモーティリティープログラム(Cedars-Sinai Medical Center GI Motility Program)からの202名のヒト対象からデータを集め、健康の履歴に係る広範な調査表を完成させた。これら患者は全て、30名を越える個人的な消化器専門医によって、ラクツロース呼気水素テスト(LBHT)が必要とされたものである。これら患者は、呼気テストに付すように、その消化器専門医によって選ばれた。というのは、彼らが、SIBOに匹敵する症状を有していたからである。しかし、該調査票は、一般的な危険率、関連する状態およびこれら患者に見出された症状に集中しており、具体的にSIBOの発生率を示していない。抗生物質による治療の後、59名の対象が、実際に追跡LBHTおよび追跡調査に戻された。これは、治療に対する応答性の過小評価をもたらす恐れがある。というのは、十分に応答できなかった患者のみが、SIBOの撲滅処理にかけるべく、戻されたに過ぎないからである。
対象は、一夜の絶食後にテストした。ゼロ時間において、各対象は、10gのラクツロースを放出する、15mlのクロヌラック処方物を飲下し、その後5-20分毎に2-4時間に渡り終端-呼気サンプル50 cm3を気密性サンプル採取バッグに集めた。次に、各呼気サンプルをガスクロマトグラフィー(WI 53051, メノモニーフォールズの、クイントロンインスツルメント(Quintron Instrument)社、E.F.ブルーワーコ(Brewer Co)部門から入手できるクイントロンモデル(Quintron Model) DP)により水素含有率につき分析し、該装置の製造業者により指示されたように、クインガス(QuinGas)標準を使用して標準化した。比較のために、抗-微生物剤治療養生の前後における、水素ピークをプロットした。第二の水素ピークに関する正常な範囲は、0〜20ppmであった。
202名のヒト対象を、LBHTによりSIBOについて評価した。データベースにおけるこれら202名の対象のうち、95名がIBSであるとの診断がなされた。更に、症状の調査表を、これら対象がIBSに関するローム(Rome)基準を満たすかどうかを判断するのに利用し、該対象のうち4名が該ローム基準を満たしていなかった。クローン病は、該対象のうち14名に見られ、また4名は潰瘍性大腸炎の病歴を有していた。これら22名の対象を排除した後に、73名の対象が残された。
以前にIBSであるとの診断を受けていないと主張した107名の対象のうち、78名がロームの基準を満たした。クローン病である21名、潰瘍性大腸炎である5名および腸輸送時間の短い1名を除外し、51名の対象が残された。これら対象から集めたデータを、IBSに罹っている疑いのある前の73名から得たデータと共にプールして、元の202名の対象のうちの全体として124名(61%)の対象を確保した。
57名のIBS対象の内、41名(72%)は、SIBOであった。9名の正常なコントロール対象の内、1名の対象(11%)のみが、SIBOであった(χ2=9.9、OR=20.5、CI:2.2-481.8、p<0.01)。これらの結果は、正常なコントロールと比較して、IBSにおけるSIBOの罹患率が極めて高いことから、IBSとSIBOとが関連性を持つことを確証している。
線維筋肉痛:データベースの202名の患者の内、37名(18%)が、線維筋肉痛の疑いがあると診断された。これら37名の内28名は、テストによればSIBOにつき正であった。しかし、テストの結果SIBOにつき負であると診断された9名の内6名は、テスト前の3ヶ月以内に、抗生物質を摂取していたので、排除した。従って、線維筋肉痛の疑いがある30名の対象の内28名(93%)は、SIBOであり、これは線維筋肉痛の疑いがあるとの診断と、SIBOの存在との間に、強い関連性があることを立証している。
ネオマイシン治療(1日当たり2回、500mg、10日間継続)の後、28名の対象の内10名が回復し、また治療後のLBHTは、SIBOが少なくとも部分的に撲滅されたことを確認した。これら10名の対象は、VAS計数によるその症状における全体的な改善を、63±19%であると報告した。図3は、ネオマイシン治療の前後の、線維筋肉痛の疑いがあると診断された対象により報告された、様々な症状のVAS評点を比較して示す。症状は鼓腸、ガス発生、下痢、関節痛および治療に対する疲れを含んでいた。対象に、最も改善された症状がどれであるか尋ねた。5名の対象が、痛みが最も改善された旨を報告し、3名の対象は、疲労の程度が最も改善された旨を報告し、また他の2名の対象は、胃の障害が最も改善された旨を報告した。VAS評点の改善の程度と、LBHTに見られる残留水素ピークの量との間には、負の相関性があった(ピアーソン(Pearson)=0.689; p=0.02; 図4)。
SLE:データベースにおける202名の対象中の15名(7.4%)が、SLEであると診断された。これら15名の対象中の、13名(87%)が、LBHTの結果が示すように、バクテリアの異常繁殖を示した。SLEに罹った15名の対象中の4名が、ネオマイシン(1日当たり2回、500mg投与、10日間)で治療した後に、追跡LBHTおよび評価表処理に戻された。これら4名に関するLBHTの結果は、SIBOについて負であり、また他の重要な症状は、治療後にかなり改善された(表3)。
この対象をLBHTに掛けたところ、SIBOの存在が明らかとなった。この対象を、ネオマイシンで治療(1日当たり2回、500mg投与、10日間)し、少なくとも部分的なバクテリアの異常繁殖の撲滅が見られた後、彼女はその腸症候群の解消を示した。更に、彼女は、学校での評価Cを経た後、平均評価Aを得始めた。彼女は、十分に集中できるようになり、またその教師は彼女の視点および態度における変化に気付いた。ほぼ2ヵ月後、この対象は、注意力に関する問題を再発したが、これはLBHTにより検出されたように、バクテリアの異常繁殖の再発と一致していた。ネオマイシンによる治療(1日当たり2回、500mg投与、10日間)を繰り返した後に、該対象は、彼女は再度集中力を改善し、かつ腸症候群を解消した。
LBHTにより、この患者にはSIBOが検出された。その後の抗生物質による治療は、このSIBO状態を完全に撲滅し、また彼女は楽しげに、彼女の腸を含めて、完全に正常であると感じるので、彼女に対して指定されていた、精神医学的な薬物治療の必要性は最早ないと報告した。彼女は、今や再び自動車を運転することができる。この自動車の運転は、彼女の障害のある記憶および走行中の集中の困難さのために、以前は不可能であった。彼女のSIBO状態の治療(1日当たり2回、ネオマイシンを500mg投与、10日間)は、彼女の生活の質における劇的な改善を生み出した。
該データベースにおける202名の対象の内、39名(19%)は、クローン病の疑いがあるとの診断を受けた。これら39名の内8名は、腸輸送時間が短く、また1名の対象は、LBHTにおいて水素もメタンも生成しなかったので、これら9名を除外した。残り30名の対象の内、22名がSIBOであった。しかし、LBHTにおいて負の結果を示した、8名の対象の内5名は、テスト前3ヶ月以内に抗生物質による治療を受けていた。これら対象を除外した場合、クローン病の疑いがあると診断された、25名中22名(88%)の対象が、SIBOであり、このことはクローン病の疑いありとの診断結果とSIBOの存在との間に強い関連性があることを示している。
選択の偏りを補正するために、パイロット研究を行って、以前の3ヶ月以内に、セダーズシナイメディカルセンターのIBDセンターにて、クローン病の疑いがあるとの診断を受けた対象におけるSIBOの発症率を決定した。これら対象の内6名をLBHTに掛けた。そのうち5名(83%)が、SIBOについて正であった。
抗生物質による治療(ネオマイシンで10日間継続)の後、これら6名の対象の内2名は、追跡のために戻した。治療後のLBHTは、これら両対象において、SIBOが少なくとも部分的に撲滅されていることを示した。彼らは、夫々その症状における全体的な改善度が60%および80%であると報告した。この改善は、下痢、ガスおよび鼓腸の実質的な低下を含むと述べていた。
様々な診断部門の中で、異常繁殖および水素の生成における層別化が見られる。例えば、線維筋肉痛におけるSIBOの治療の、二重ブラインド研究の際(図4)に、LBHTの際の水素生産レベルが、実施例3に記載した、IBS発症率に係る研究における対象と比較して、この大将軍においてより高いことに気付いた。バクテリア濃度が、水素生産レベルと関連性をもつことから、このことは、異常繁殖の程度が、IBSに罹った対象に比較して、線維筋肉痛を持つ患者においてより高いことを示す。
診断部門に関連する、呼気水素濃度の層別化は、以下の通りである:IBS/クローン病(40-70ppmの水素);CFS(50-100ppmの水素);およびFM(100-250ppmの水素)。
臨床的な実験は、SIBOが抗生物質による治療後の約2ヶ月以内に再発する傾向があることを示した。段階III食間運動性の欠如が、IBSまたは線維筋肉痛に罹った対象におけるSIBOに起因するものであることを立証するために、IBSまたはFMであると診断されたヒト対象について、十二指腸間圧力測定法を実施した。
十二指腸間圧力測定法:段階III食間(絶食中の)運動性を、15名のヒト対象について評価した。十二指腸間圧力測定法は、8-チャンネルの小腸圧力測定用カテーテル(各チャンネルは5cm間隔で配置されている)を、透視的な案内手段を用いて、小腸内に配置することにより実施した。該カテーテルに配置後に、マノメータの読みを、アンドルファー(Arndorffer)灌流装置を用いて記録し、メドトロニクス/シネクチックスポリグラフ(Medtronics/Synectics Polygraf)および関連するポリグラムソフトウエアを用いて、シグナルを集めた。これらデータを、食間運動性の特徴につき評価した。
モチリンアゴニストとしてのエリスロマイシンは、段階III食間運動を誘発し得る(例えば、M.J. Clark等, Erythromycin derivatives ABT229 and GM611 act on Motilin receptors in the rabbit duodenum, Clin. Exp. Pharmacol. Physiol. 1999, 26(3): 242-45)。従って、再発したIBSに罹っている2名の対象は、エリスロマイシンによるプロカイネティック剤治療を受けた。
これら結果は、IBSに罹っていると診断された対象における、SIBOおよびIBSの再発を防止する上で、エリスロマイシンによるプロカイネティック剤治療が有効であることを立証している。
食物に膵臓酵素を補給することにより、食物栄養そのより容易な効果的吸収および消化が可能となり、結果として補給のない場合よりも、消化された食物栄養素のより高い効率での、小腸における吸収が可能となる。これは、SIBO状態に関与するバクテリアに対して、相対的な栄養素の枯渇状態をもたらす。この治療様式の一例は、変更された腸の習慣性、鼓腸、ガス、膨満および極めて緊急を要する排便に、長年に渡り悩まされてきた、19歳の男性に関する症例があった。これら症状の全てが、過敏性腸症候群(IBS)と一致していた。LBHTの結果に基いて、この患者は、SIBOに罹患しているものと診断された。抗生物質による治療後に、が患者は、その症状におけるかなりの改善を示した。しかし、この患者のSIBO状態は、抗生物質耐性のために管理が困難になった。該患者の食物への、膵臓酵素の添加(各食事の直前に摂取される、カプセル中に10,000単位のヒト由来の膵臓酵素を添加)を含む、別の治療養生を処方した。この治療により、該患者は、その胃腸管障害が、約30-40%だけ改善されたことを報告したが、これは彼のSIBO状態の部分的な撲滅に相当する。治療は、少なくとも8ヶ月間継続し、その間症状における改善は持続した。
バクテリアの代謝が、腸バクテリアの醗酵反応中に製造される水素を除去するための、主なメカニズムである。具体的には、水素はメタンの製造中におよび硫酸塩の硫化物への還元において消費され、これら2つの経路は相互に排他的である。腸内硫化物は、腸の上皮を損傷することが知られているので、メタンに関するテストにおいて正である(有害な硫化物を生成しない)、小腸バクテリアの異常繁殖(SIBO)に罹った患者の中で、下痢は余り優勢な症状ではないと仮定されている。
IBSの疑いがあると診断された、成人男性対象は、LBHTにより検出された如く、SIBOであることが分かった。肛門直腸間の圧力測定法は、この対象における直腸過敏症を明らかにした。該患者のSIBO状態の、抗生物質治療による撲滅後、肛門直腸間の圧力測定を繰り返したところ、彼の直腸の痛覚過敏が解消されていることを示した。
IBSに罹っている2名の成人女性は、そのSIBO-関連痛覚過敏を治療するために、付随的な薬物処理を必要とした。第一の症例において、SIBOは抗生物質による治療で撲滅された。しかし、この対象は、直腸の頑固な膨満感を訴えており、SIBOに関連する残留痛覚過敏と一致した。次に、この対象をコルペルミン(Colpermin:ペパーミント油)カプセルおよびエラビル(夜間に5mg投与)を投与したが、これらは該対象のSIBO-関連痛覚過敏症状を軽減した。これは、恐らく腸壁の張力を減じ、かつ圧受容器の活性化を減じることによるものと考えられる。
SIBOが、遠位の腸に到達する食物中の栄養成分によって促進され、該遠位の腸において、該栄養成分は、該SIBO状態の原因となるバクテリア群によって、その炭素およびエネルギーが利用されるという仮定に基いて、ローム基準に従って各々IBSであると診断され、また各々LBHTによりSIBOであることが分かっている、10名の患者(8名の女性;2名の男性;年齢範囲:17-64歳;何れも腸の切除を受けていない)を、近位腸において吸収される、全小腸栄養素(TEN)処方物(MNミネアポリスのSandoz Nutrition社から入手できる、ビボネックス(VivonexTM) T.E.N.)で処理した。ビボネックスは、グルタミンに富む全小腸栄養素製品であり、必須アミノ酸対非-必須アミノ酸の比56:44で、遊離アミノ酸としてタンパクを含み、また特に麦芽デキストリンおよび変性澱粉等の炭水化物、ベニバナ油、および全必須ビタミン類およびミネラルを含む。ビボネックスは水で復元するための粉剤の形状で入手できる(80.5g(2.84oz)のパケット;その1パケットを250mLの水と混合することにより、300mLの処方物が得られる)。各患者に、その体重、身長および他の関連する因子に基いて、製造業者の指示に従って、必要な1日当たりのカロリーを満足するような所定量の復元したビボネックスを投与した。これら患者は、他の如何なる栄養分の摂取も禁止されたが、水は自由に摂取させた。このTEN養生の14日後に、各患者は、その正常な食事に戻された。
実施例12:SIBO-関連状態を治療するための、活性脂質の利用
オレエートおよびオレイン酸は、上部腸輸送を遅延し、また迅速上部腸輸送および下痢症状を持つ患者における下痢を軽減する
上部の腸を介する迅速な輸送は、下痢、消化不良および吸収不良、並びに体重減をもたらす可能性があり、またオピエートもしくは抗-コリン作動性薬物による薬物治療が、しばしば必要とされる。脂肪酸を、上部腸輸送を遅延し、かつ迅速輸送および下痢症状を示す患者における下痢を軽減できるか否かをテストした。
以下に説明するように(実施例14)、十二指腸(幽門から10cm)および中腸(幽門から160cm)ロウ管を備えた4匹のイヌにおいて、腸輸送を、単離した150cmのテストセグメント(ロウ管間)について比較した。但し、0、15、30または60mMのオレエートを、pH7.0のリン酸バッファー中の混合ミセル溶液として、分間に渡り、2mL/分なる割合で、近位または遠位セグメント何れかに放出した。オレエートを受取らなかった腸セグメントは、pH7.0のリン酸バッファーで、2mL/分にて灌流した。この灌流開始の60分後に、約20μCiの99mTc-DTPA(ジエチレントリアミンペンタ酢酸)を、ボルス(丸塊)として該テストセグメントに放出した。次いで、腸内輸送を、該中腸ロウ管の迂回させた排出物から、5分毎に採取した1mlのサンプルの、放射能を計数することにより測定した。
活性脂質は、上部腸内輸送時間を増大する:正常な対象(n=5)に関する平均輸送時間はオレイン酸投与量0gに対して118.7±9.8分、オレイン酸投与量4gに対して136.0±15.4分(p<0.05、t-テスト)であった。正常な対象に関する平均のAUCは、オレイン酸投与量0gに対して1438.9±208.5分、オレイン酸投与量4gに対して1873.3±330.5分(p<0.05、t-テスト)であった。IBD患者(n=18)に関する平均輸送時間は、オレイン酸投与量0gに対して79.1±11.0分、オレイン酸投与量4gに対して114.6±16.0分(p<0.05、t-テスト)であった。IBD患者に関する平均のAUCは、オレイン酸投与量0gに対して687.3±98.2分、オレイン酸投与量4gに対して1244.9±250.4分(p<0.05、t-テスト)であった。
これらデータは、オレイン酸が腸内輸送時間を遅延させ、また結果的に正常な対象の群およびIBD患者群両者において、上部腸領域において食物栄養素を吸収する機会を、実質的に増加することを示している。このように、SIBO状態を持つ個人において、バクテリアに対してその多くの栄養分を枯渇させる方法に従って治療することにより、所望の生育状態が得られる。
以前の研究は、過敏性腸症候群(IBS)に罹っている患者が、高い血漿内5-ヒドロキシトリプタミン(5-HT)濃度をもつことを示した。上記のように、IBSは小腸内バクテリアの異常繁殖(SIBO)と関連しており、またIBSの症状がSIBOを抗生物質で撲滅することにより軽減されることが明らかとなっているので、SIBOの撲滅がIBS患者における血漿内5-HT濃度を減じるであろうとの仮説を、IBSとSIBOとの間の関連性に係る、更なる証拠を得るためにテストした。IBSであると診断された7名のヒト対象の、血漿内5-HT濃度を、二重ブラインドプラシーボ制御試験の一環として、SIBOの撲滅前およびその成功後で比較した。ラクツロース呼気水素テスト(LBHT)を実施して、ベースラインにおけるおよび撲滅が達成された時点のSIBOを求めた。絶食状態における血液サンプルを、ベースラインにおいて、およびSIBOの撲滅が確認された日に採取した。該血漿内5-HT濃度(ng/mL)を、ELISA(NJ、フランダースのKit-Research Diagnostics Inc.)により各サンプルについて測定した。一対のt-テストを行って、SIBO撲滅前後の5-HT濃度(平均値±SE)を比較した。
これらの結果は、血漿内5-HT濃度が、撲滅前の0.7±0.4 ng/mLから該対象内のSIBO撲滅後の0.5±0.5 ng/mLに減少することを示した(p<0.05)。かくして、IBS患者におけるSIBOの撲滅は、絶食時の血漿内5-HTの濃度を減じ、これはIBSとSIBOとの間の関連性に関する更なる証拠を与える。
以下に記載する実験は、以前に記載した、多重フィステル処理犬モデルに基くものであり、各々約25kgの外科的にフィステル処理した雄または雌の雑種犬を使用した(H.C. Lin等, Inhibition of gastric emptying by glucose depends on length of intestine exposed to nutrient, Am. J. Physiol. 1989, 256: G404-G411)。これら犬の小腸は、幽門から回腸-盲腸弁までの、長さ約300cmであった。十二指腸フィステルは、幽門から15cmの部分に位置し、中腸フィステルは、幽門から160cmの部分に位置していた。閉塞用のフォーリー(Foley)カテーテル(内腔表面との水密封止を得るために、膨張されるバルーンカテーテル)を、十二指腸フィステルおよび中腸フィステルの遠方の肢に配置し、脂肪または他のテスト試薬を、このように隔室化処理した、腸の近位部分、即ち該フィステル間に、あるいは該腸の隔室化した遠位部分、即ち中腸フィステルを越える部分に、内腔を介して投与した。灌流液を、該カテーテルを介して、2mL/分なる流量で、テスト部分にポンプ輸送した。テスト試薬は、バッファー灌流液と共に投与したが、幾つかのテスト試薬は、特に記載した場合には、静脈内経路で投与した。
具体的には、オンダンセトロンは該灌流物中のマーカーの回収率を、オレエートの灌流中に、41.6±4.6%(平均値±SE)(内腔オレエート+内腔標準塩水、即ち図10におけるオレエート-NS)から、73.7±10.6%(内腔オレエート+内腔オンダンセトロン、即ち図10におけるオレエート-Ond)まで高めるが、バッファーの灌流中は、96.0±4.0%(内腔リン酸バッファー+内腔標準塩水、即ち図10におけるバッファー-NS)から、57.9±15.9%(内腔バッファー+内腔オンダンセトロン、即ち図10におけるバッファー-Ond)まで、回収率を低下した。これらの結果は、脂肪誘発空腸ブレーキによる腸内輸送の遅延およびバッファー拡張による腸内輸送の促進両者は、オンダンセトロン-感受性5-HT3-媒介経路に依存することを、暗示する。
オレエートは、該回腸ブレーキを誘発した(24.1%のマーカー回収率[図12の回腸ブレーキ]対該バッファーコントロールに対する81.2%のマーカー回収率)。この回腸ブレーキは、用量依存性様式で、該近位腸に放出されるオンダンセトロンにより壊滅される(オンダンセトロン6.25mgにおいて、35.4%のマーカー回収率、オンダンセトロン12.5mgにおいて、55.8%のマーカー回収率およびオンダンセトロン25gにおいて、77.6%のマーカー回収率)。
結果を図13に示す。回腸ブレーキ(20±1.8%なるマーカー回収率)と比較して、該マーカー回収率は、内腔経由のオンダンセトロン投与により78±2.4%まで増大した(p<0.005)。オンダンセトロンの静脈内投与は、該回腸ブレーキに何等実質的な効果を示さなかった(13±2.0%なるマーカー回収率)。これらの結果は、該5-HT3レセプタアンタゴニストが、全身的ではなく、小腸内で機能していることを暗示する。
内腔5-HTが、脂肪と類似する5-HT3レセプタを介して、腸内輸送を遅延する可能性があるという仮説をテストするために、0.7mg/kgのオンダンセトロン、5-HT3レセプタアンタゴニストまたは緩衝された塩水(pH7.0)を、該輸送の測定開始時点で、ボルスとして、近位または遠位腸の何れかに供給した。4匹の犬をテストした。
結果を図14に示す。遠位腸(35.2±2.2%なるマーカー回収率)に投与された5-HT(0.1 mg/kg/h)による腸内輸送の遅延は、夫々73.8±9.5%(図14における近位Ond(Ond-Prox))対79.5±2.4%(図14における遠位のOnd(Ond-Dis))なる%マーカー回収率によって示されるように、近位または遠位腸に添加されたオンダンセトロンにより壊滅された(p<0.001)。
腸内輸送の遅延における5-HTの用量-依存型効果を、追加の実験において確認した。放射性マーカーの積算%回収率は、5-HTの灌流量が0から0.1mg/kg/hに増加すると、用量-依存型様式で低下し、このことは腸内輸送が、内腔5-HTにより遅延されることを示唆する。しかし、輸送速度は、該5-HTの用量が0.3mg/kg/hまで増大した場合には、顕著に加速された(表7)。
結果を図15に示す。腸内輸送は、用量-依存型の様式で、近位腸における5-HTによって、大幅に遅延された(p<0.00001)。バッファーの灌流中のマーカー回収率は、75.0±4.4%であり、一方0.066mg/kg/hなる用量においては、マーカー回収率は、16.9±3.7%に低下し、また用量0.1mg/kg/hの場合と有意な差異はなかった。0.05mg/kg/hなる中間的な用量において、マーカー回収率は33.2±14.0%であり(バッファーvs 0.05mg/kg/h;p<0.005)、また0.033mg/kg/hという最小の用量において、マーカー回収率はバッファーコントロールと有意な差異はなかった。
また、実施例14(8)の結果は、インビトロモデルにおける5-HTの効果に反して、内腔経路で投与された5-HTが、全動物を意図したモデルにおいて、用量依存的な様式で、腸内輸送を遅延することを示しており、このことは、腸内輸送の遅延が、外因的な神経に依存していることを暗示する。
近位腸の5-HTの量は、遠位腸の灌流物を、バッファーからオレエートに切換えた場合に、82.7±20.53ngから、211.75±35.44ng (p<0.005)まで増加した。このことは、5-HTが、脂肪に対する中継的なシグナルとして、遠位腸における脂肪に応答して、近位腸から遊離されることを暗示している。
脂肪も、5-HTの遊離に関する化学的な開始剤であり、従ってこれらの結果は、長距離の腸-腸接続または反射を介する5-HTの遊離と一致している。
結果を図16に示す。近位腸を横切る腸内輸送は、該近位または遠位腸の何れかにおける5-HTにより遅延され、このことは、マーカー回収率が、近位腸の5-HT(図16の5-HT-Prox)に対する85.0±7.3%(図16における塩水-Prox) (p<0.005)から、20.1±4.5%への、および遠位腸の5-HTに対する76.1±1.3%(図16の塩水-Dist)から35.2±2.3%(図16の5-HT-Dist) (p<0.005)への減少により立証された。
これら結果は、5-HTによる腸内輸送の遅延が、長距離の領域-領域反射に依存していることを暗示しており、これは遠位腸に導入された5-HTが、物理的に分離された近位腸を介して腸内輸送を遅延したからである。
この結果は、静脈内PYY投与無しに、灌流中に、60mMのオレエートを遠位腸に投与(近位腸にはバッファーのみ)した場合の応答に匹敵(509.8μgの5-HT;n=1)し、このことは、遠位腸内の脂肪によって刺激される、近位腸における5-HTの遊離が、PYYにより媒介され得ることを暗示している。
PYYによる腸内輸送の遅延は、静脈内投与されたプロプラノロールによって壊滅された(78.1±2.2%のマーカー回収率引くPYY[図18のバッファーコントロール]対静脈内投与PYYによる回収率11.8±5.4%[図18のPYY-NS])。プロプラノロールの存在下で、マーカー回収率は66.3±3.1%に増大した(図18のPYY-Prop)。実施例14(11)の結果と一致するこの結果は、PYYによる輸送の遅延が、プロプラノロール-感受性アドレナリン作動性経路に依存することを暗示しており、これは、PYYに対する応答が、アドレナリン作動性遠心性、例えば脊椎前神経節から突出している外因性神経に関与しているという仮説を支持している。
5-HTによる腸内輸送の遅延は、プロプラノロールの静脈内投与によって壊滅された(83.3±3.3%のマーカー回収率引く5-HT[図19のバッファーコントロール]対遠位腸への5-HTの投与による回収率36.1±2.3%[図19の5-HT-NS])。プロプラノロールの存在下で、マーカー回収率は77.7±7.6%に増大した(図19の5-HT-Prop)。この結果は、5-HTによる輸送の遅延が、プロプラノロール-感受性外因性アドレナリン作動性経路に依存することを暗示しており、これは、恐らく、遠位腸の脂肪に対する応答と同様な理由によるものと考えられる。
結果を以下の表9に示す。これらの結果は、アドレナリン作動性およびセロトニン作動性経路両者が、腸内輸送の遅延に関与していることを示している。
上記実施例は例示的なものであり、本発明の態様の全てを説明するものではない。
Claims (45)
- ヒト対象における小腸バクテリアの異常増殖(SIBO)またはSIBOに起因する状態を治療する方法であって、
該対象内において、適当な検出手段によって、SIBOの存在を検出し、ここで増殖中のバクテリア群は、該対象の小腸内に存在し、あるいは該手段によってSIBOが存在しないことを検出し、かつSIBOの存在が、該対象において検出された場合には、
該小腸内の該バクテリアの増殖を阻害するのに十分に、該バクテリア群の栄養分を枯渇させ、該ヒト対象におけるSIBOを少なくとも部分的に撲滅することを特徴とする、上記方法。 - 該SIBOに起因する状態が、過敏性腸症候群、線維筋肉痛、慢性骨盤痛症候群、慢性疲労症候群、うつ病、知的活動障害、記憶障害、口臭、耳鳴り、糖摂取渇望、自閉症、注意力欠乏/活動亢進障害、薬物過敏、自己免疫疾患、およびクローン病からなる群から選択される、請求項1記載の方法。
- 該自己免疫疾患が、全身性エリテマトーデスあるいは多発性硬化症である、請求項2記載の方法。
- 更に、該ヒト対象において、SIBOが存在する場合に、
ある持続期間に渡り、該対象の胃腸管上部に達した際に、少なくとも部分的に予備消化される、栄養素から本質的になる食物を、該対象に消費させ、該持続期間が、該ヒト対象におけるSIBOを、少なくとも部分的に撲滅するのに十分な期間である、請求項1記載の方法。 - 該期間が、少なくとも約3日間である、請求項4記載の方法。
- 該少なくとも部分的に予備消化される栄養素が、食用全腸栄養素処方中に含まれている、請求項4記載の方法。
- 更に、該対象に、食事前にまたは実質的に食事と同時に、膵液酵素サプルメントを投与して、該食事中に含まれる栄養素を、該膵液酵素サプルメントの活性により、該対象の上部胃腸管内で、少なくとも部分的に予備消化する、請求項4記載の方法。
- 更に、該ヒト対象において、SIBOが存在する場合に、
該栄養素による、該ヒト対象の該上部胃腸管の通過を遅らせることによって、該ヒト対象の該上部胃腸管における、該栄養素の消化および吸収を増強し、該バクテリア群に対して、少なくとも部分的に該栄養素を枯渇させる、請求項1記載の方法。 - 更に、経口または腸内放出経路によって、該ヒト対象に薬理的に許容される組成物を投与する工程を含み、該ヒト対象が、その腸管壁内のペプチドYY-感受性主感覚ニューロンから、脊椎前の腹腔ガングリオンまで突出し、固有のコリン作動性求心性神経系路を有し、また該ガングリオンから該腸粘膜中の1以上のクロム親和性細胞および/または筋層間神経叢および/または粘膜下の神経叢においてオピオイド介在ニューロンと結合したセロトニン作動性介在ニューロンまで突出した、アドレナリン作動性遠心性神経系路を有し、該オピオイド介在ニューロンが、該ガングリオンまで突出した腸遠心性オピオイド経路によって、1以上のニューロン接続により、中枢神経系と結合し、かつ該ガングリオンから突出した腸に戻り、
該薬理的に許容される組成物が、活性薬物を含み、該活性薬物が(A) 活性脂質、(B) セロトニン、セロトニンアゴニスト、またはセロトニン再摂取阻害剤、(C) ペプチドYYまたはペプチドYY-機能性類似体、(D) カルシトニン遺伝子-関連ペプチドまたはその機能性類似体、(E) アドレナリン作動性アゴニスト、(F) オピオイドアゴニスト、(G) (A)、(B)、(C)、(D)、(E)および/または(F)の任意の組合せ、および(H) (B)、(C)、(D)、(E)および/または(F)の何れかに対するレセプタのアンタゴニスト
からなる群から選択され、該活性薬物が、該コリン作動性腸遠心性経路、少なくとも一つの脊椎前ガングリオン経路、該アドレナリン作動性遠心性神経経路、該セロトニン作動性介在ニューロンおよび/または該オピオイド介在ニューロンを、(A)〜(G)の何れかの作用によって活性化するような量および条件下で放出され、結果的に該対象における上部胃腸管移動速度を緩慢にし、該ヒト対象の上部胃腸管における、該栄養素の消化および/または吸収を増強する、請求項8記載の方法。 - 担体および該担体中の本質的に活性脂質からなる分散体を含む、胃腸管移動を遅延させる組成物を、投与する工程を含み、該活性脂質が、飽和または不飽和脂肪酸、完全に加水分解された脂肪およびその混合物からなる群から選択される、該脂質と該対象の小腸との接触を促進し、胃腸管移動を遅延させ、かつ少なくとも部分的に該ヒト対象におけるSIBOを撲滅する、請求項8記載の方法。
- 該活性脂質が(A) カプロン酸、カプリル酸、カプリン酸、ラウリン酸、ミリスチン酸、オレイン酸、パルミチン酸、ステアリン酸、パルミトレイン酸、リノール酸、リノレン酸、トランス-ヘキサデカン酸、エライジン酸、コロンビン酸、アラキジン酸、ベヘン酸、エイコセン酸、エルカ酸、ブラシジン酸、セトレイン酸、ネルボン酸、ミード酸、アラキドン酸、チムノドン酸、クルパノドン酸、またはドコサヘキサエン酸;(B) (A)の何れかの製薬上許容される塩;および(C) (A)または(B)の任意の混合物からなる群から選択される、請求項10記載の方法。
- 該活性脂質が、オレイン酸または製薬上許容されるオレイン酸塩を含む、請求項11記載の方法。
- 該活性脂質が、完全に加水分解された脂肪を含む、請求項10記載の方法。
- 該活性脂質が脂肪酸または製薬上許容されるその塩を含む、請求項10記載の方法。
- 該活性脂質が、(A) (C4-C24)飽和および不飽和脂肪酸からなる群から選択される脂肪酸;(B) (A)の何れかの製薬上許容される塩;または(C) (A)および/または(B)の任意の混合物である、請求項10記載の方法。
- 該脂肪酸が、オレイン酸、製薬上許容されるオレイン酸塩、またはこれらと他の脂肪酸またはその塩との混合物を含む、請求項10記載の方法。
- 経口投与が、被覆または未被覆の微小球または粒子、分散性の粉末または顆粒状処方物、懸濁液、エマルション、溶液、シロップ、エリキシル、あるいは被覆または未被覆錠剤、トローチ、カプセル、カプレットまたはロゼンジの摂取により行われる、請求項9記載の方法。
- 経口投与が、被覆または未被覆の微小球または粒子、分散性の粉末または顆粒状処方物、懸濁液、エマルション、溶液、シロップ、エリキシル、あるいは被覆または未被覆錠剤、トローチ、カプセル、カプレットまたはロゼンジの摂取により行われる、請求項10記載の方法。
- 該活性薬物が、セロトニン、セロトニンアゴニスト、セロトニン再摂取阻害剤、5-HT3レセプタアンタゴニストおよび5-HT4レセプタアンタゴニストからなる群から選択される、請求項9記載の方法。
- 該活性薬物がセロトニンであり、該セロトニンを、該ヒト対象に、食事前にまたは実質的に食事と同時に、体重1kg当たり約0.03〜約0.1mgなる範囲の量で投与する、請求項19記載の方法。
- ヒト対象における小腸バクテリアの異常増殖(SIBO)またはSIBOに起因する状態を治療する方法であって、
該対象内において、適当な検出手段によって、SIBOの存在を検出し、ここで増殖中のバクテリア群は、該対象の小腸内に存在し、あるいは該手段によってSIBOが存在しないことを検出し、かつSIBOの存在が、該対象において検出された場合には、
該小腸内の該バクテリアの増殖を阻害するのに十分な量の、製薬上許容される殺菌組成物を、該対象小腸の内腔に導入して、該ヒト対象におけるSIBOを少なくとも部分的に撲滅することを特徴とする、上記方法。 - 該製薬上許容される殺菌組成物が、本質的に(A) 過酸化水素;(B) ビスマス‐含有化合物;(C) ヨウ素‐含有化合物;または(D) (B)または(C)の塩からなる、請求項21記載の方法。
- 該SIBOに起因する状態が、過敏性腸症候群、線維筋肉痛、慢性骨盤痛症候群、慢性疲労症候群、うつ病、知的活動障害、記憶障害、口臭、耳鳴り、糖摂取渇望、自閉症、注意力欠乏/活動亢進障害、薬物過敏、自己免疫疾患、およびクローン病からなる群から選択される、請求項21記載の方法。
- 該自己免疫疾患が、全身性エリテマトーデスあるいは多発性硬化症である、請求項23記載の方法。
- ヒト対象における小腸バクテリアの異常増殖(SIBO)またはSIBOに起因する状態を治療する方法であって、
該対象内において、適当な検出手段によって、SIBOの存在を検出し、ここで増殖中のバクテリア群は、該対象の小腸内に存在し、あるいは該手段によってSIBOが存在しないことを検出し、かつSIBOの存在が、該対象において検出された場合には、
該ヒト対象におけるマスト細胞‐媒介免疫応答を阻害するのに十分な量の、該小腸内腔壁におけるマスト細胞膜の安定化剤を含む、製薬上許容される組成物を、該対象に投与することを特徴とする、上記方法。 - 該SIBOに起因する状態が、線維筋肉痛、慢性骨盤痛症候群、慢性疲労症候群、うつ病、知的活動障害、記憶障害、口臭、耳鳴り、糖摂取渇望、自閉症、注意力欠乏/活動亢進障害、薬物過敏、自己免疫疾患、およびクローン病からなる群から選択される、請求項25記載の方法。
- 該自己免疫疾患が、全身性エリテマトーデスあるいは多発性硬化症である、請求項26記載の方法。
- 該マスト細胞膜の安定化剤がオキサタミドまたはクロモグリケートである、請求項25記載の方法。
- ヒト対象における、SIBOの異常な存在し易さにつきスクリーニングする方法であって、該対象から血清サンプルを得、該血清サンプル中のセロトニン、一種以上の非‐複合胆汁酸、および/または葉酸塩の濃度を定量的に測定し、これらの一種以上の異常に高い血清濃度が、SIBOが該対象に存在する通常の確率を越えるものであることを示す指標であることを特徴とする、上記方法。
- ヒト対象における小腸バクテリアの異常増殖(SIBO)の検出する方法であって、
該ヒト対象が、制御された量の基質を摂取した後に、該ヒト対象によって吐出されるガス混合物中の、メタン、水素、および少なくとも一種の硫黄‐含有ガスの相対的な量を検出する工程を含み、該混合ガスが、少なくとも部分的に、該ヒト対象の腸内微生物叢によって生成されることを特徴とする、上記方法。 - 該基質が、同位体標識された糖またはヒトによっては余り消化されない糖である、請求項30記載の方法。
- 該糖が、グルコース、ラクトース、スクロース、ラクツロースまたはキシロースである、請求項31記載の方法。
- 該吐出ガス混合物中の、メタン、水素、および少なくとも一種の硫黄‐含有ガスの相対的な量の検出を、ガスクロマトグラフィーおよび/または放射線検出装置によって行う、請求項30記載の方法。
- 該吐出ガス混合物中の、メタン、水素、および少なくとも一種の硫黄‐含有ガスの相対的な量の検出を、マススペクトロメトリーにより行う、請求項30記載の方法。
- 該吐出ガス混合物中の、メタン、水素、および少なくとも一種の硫黄‐含有ガスの相対的な量の検出を、薄層クロマトグラフィー、高圧液体クロマトグラフィー、電気化学的ボルタメトリックセンサまたはポーラログラフィーセルを使用して行う、請求項30記載の方法。
- 該少なくとも一種の硫黄‐含有ガスが、硫化水素またはスルフヒドリル化合物である、請求項30記載の方法。
- 該少なくとも一種の硫黄‐含有ガスが、メタンチオール、ジメチルスルフィド、ジメチルジスルフィド、アリルメチルスルフィド、アリルメチルスルフィド、アリルメチルジスルフィド、アリルジスルフィド、アリルメルカプタン、またはメチルメルカプタンである、請求項30記載の方法。
- SIBOが検出されたヒト対象における、SIBOまたはSIBOに起因する状態の相対的な重篤度を決定する方法であって、
適当な検出手段によって、該対象におけるSIBOの存在を検出し、あるいは該手段によってSIBOが存在しないことを検出し、該対象において、SIBOが検出された場合には、適当な検出手段によって、該対象中の腸内透過性の相対的なレベルを検出する工程を含み、異常に高い腸内透過性が、該対象における比較的高い重篤度でのSIBOまたはSIBOに起因する状態の存在を示すことを特徴とする、上記方法。 - SIBOまたはSIBOに起因する状態を診断するためのキットであって、少なくとも一つの呼気採取用容器、予め測定された量の基質、およびヒト対象が所定量の該基質を摂取した後に、該対象によって吐出されたガス混合物中の、メタン、水素および少なくとも一種の硫黄-含有ガスの相対的な量を測定することによって、SIBOの有無を検出するための、ユーザーに対する指示を含むことを特徴とする、上記キット。
- 該予め測定された量の基質が、同位体で標識されており、またはヒトによっては余り消化されない、請求項39記載のキット。
- 該予め測定された量の基質が、グルコース、ラクトース、スクロース、ラクツロースまたはキシロースである、請求項39記載のキット。
- 該予め測定された量の基質が糖である、請求項39記載のキット。
- 更に、メタン、水素および少なくとも一種の硫黄-含有ガスの標準化されたサンプルをも含む、請求項39記載のキット。
- 該少なくとも一種の硫黄-含有ガスが、硫化水素またはスルフヒドリル化合物である、請求項39記載のキット。
- 該少なくとも一種の硫黄-含有ガスがメタンチオール、ジメチルスルフィド、ジメチルジスルフィド、アリルメチルスルフィド、アリルメチルスルフィド、アリルメチルジスルフィド、アリルジスルフィド、アリルメルカプタン、またはメチルメルカプタンである、請求項39記載の方法。
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