JP5841994B2 - 過敏性腸症候群の処置方法及びその治療用組成物 - Google Patents
過敏性腸症候群の処置方法及びその治療用組成物 Download PDFInfo
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- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
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- QNTNKSLOFHEFPK-UPTCCGCDSA-N ubiquinol-10 Chemical compound COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC QNTNKSLOFHEFPK-UPTCCGCDSA-N 0.000 description 1
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Description
、その代謝産物、そのプロドラッグ又はこれらのうちいずれかの薬学的に許容可能な塩を投与する工程を含む方法を提供する。
本明細書で使用するとき及び添付の特許請求の範囲において、単数形(「a」、「an」及び「the」)は、文脈上明確に記載されていない限り、複数の意味を含むことに留意すべきである。
一態様では、本明細書に提示するように、対象の過敏性腸症候群を予防する及び/若しくは処置する又はその症状を和らげるための方法であって、有効量の化合物を対象に投与する工程を含む方法を提供する。
、その代謝産物、そのプロドラッグ又はこれらのうちいずれかの薬学的に許容可能な塩を投与する工程を含む方法を提供する。
、その代謝産物、そのプロドラッグ又はこれらのうちいずれかの薬学的に許容可能な塩を投与する工程を含む方法を提供する。
又はその薬学的に許容可能な塩を投与する工程を含む方法を提供する。
本発明の方法、組成物及び装置で使用される化合物は次の通りである。
、その代謝産物、そのプロドラッグ又はこれらのうちいずれかの薬学的に許容可能な塩である。
、その代謝産物、そのプロドラッグ又はこれらのうちいずれかの薬学的に許容可能な塩である。
又はその薬学的に許容可能な塩である。
一態様では、本発明で使用される化合物は、化合物と薬学的に許容堪能な担体とを含む組成物として投与される。本発明で使用される化合物は、薬学的に許容可能な液体の有機若しくは無機担体、半液体の有機若しくは無機担体又は固体の有機若しくは無機担体等の従来の賦形剤と混合して投与されてよく、前記賦形剤は混合したときに活性な化合物と有害に反応しないものである。好適な薬学的に許容可能な担体とは、水、塩溶液、アルコール、植物油、ポリエチレングリコール、ゼラチン、ラクトース、アミロース、ステアリン酸マグネシウム、タルク、ケイ酸、粘性パラフィン、香油、脂肪酸モノグリセリド及び脂肪酸ジグリセリド、ペンタエリスリトール脂肪酸エステル、ヒドロキシメチルセルロース、ポリビニルピロリドン等が挙げられるが、これらに限定されない。
(−)−ビス(2−[[(2S)−2−({(2R)−2−ヒドロキシ−2−[4−ヒドロキシ−3−(2−ヒドロキシエチル)フェニル]エチル}アミノ)−1,2,3,4−テトラヒドロナフタレン−7−イル]オキシ]−N,N−ジメチル−アセトアミド)一硫酸塩
直腸S状結腸の運動性に対するMN−221の効果
本調査では、過敏性腸症候群(irritable bowel syndrome、IBS)に罹患した被験者の、直腸S状結腸の運動性に対するMN−221の効果について調べる。
被験者
24歳〜52歳の男女が本調査に参加している。IBSの診断は次の基準に基づいて行われる。1)症状が数カ月以上続いている、2)食事の有無にかかわらず腹痛がある、3)便秘である、又は下痢と便秘を併発している、4)正常大腸バリウム注腸及びS状結腸鏡検査、5)乳糖不耐症に関する検査が陰性である、及び6)便培養での所見が陰性である。
12時間絶食後、患者全員に、空気を注入させずにS状結腸鏡検査を行う。1本〜3本のポリエチレン製カテーテルの付いたプローブをS状結腸鏡から挿入して、近位カテーテルが肛門周縁部から約18〜20cmにあり、第2カテーテルの先端部がそれよりも約5cm下にあり、そして第3カテーテルが内括約筋の丁度内側に位置するようにする。2本の遠位カテーテルはそれぞれ約5cm長のバルーンで囲まれている。遠位バルーンを約20ミリリットル(mL)の空気で膨らませて、装置が遠位方向において移動しないようにする。上部直腸内の、中央のカテーテルと接触しているバルーンは、記録セッション中、被験者のうち10人では約80mLの空気で膨らませたままにし、そして残りの2人の被験者では約60mLの空気で膨らませたままにする。3回の試験の間、被験者毎のバルーン容量は同じである。
結果は、平均±標準偏差(SEM)で表す。対照期間と試験期間との差は、対データに関するウィルコクスン符号順位検定(Wilcoxon signed rank test)で検定する。
MN−221の血漿濃度は、液体クロマトグラフィー及び質量分析法で求める。
S状結腸の運動性
基本条件及びプラセボ効果。S状結腸の運動指数は被験者間で大幅に異なり、また、同一被験者でも日によってかなり変化する。運動活性は、主に3種の異なる運動波で構成される。最も一般的な形状は、周波数が2〜3周期/分の圧力波である。振幅は一般に1〜4kPaであり、そして各波の持続時間は10〜25秒である。これら重要な波の合間に、低振幅でしかも周波数が6〜8周期/分の別の波形が現れる場合もある。運動活性の高い期間では、多くの場合、3周期/分の波と7周期/分の小さな重畳波とが群発して基準圧が増大する可能性がある。プラセボ注入後、収縮活動が波の周波数と持続期間と振幅を増大させる傾向がある。その結果、被験者のS状結腸の運動性が高まることが分かる。
近位直腸バルーンで検知された直腸の運動性からは、記録日ごとに運動性にかなり個人差があることが分かった。全対照期間のうち3分の1では、運動性がほぼ0であった。このパターンは、MN−221の注入後も変化しない。
プラセボ注入後は、それ以前の対照期間に比べて心拍数の変化又は血圧の変化がほとんど生じない。MN−221を合計0.50mg静脈内注入した後に、最大血圧の増加、最低血圧の低下及び/又は心拍数の増加はほとんど認められない。MN−221を合計1.0mgまで静脈内注入しても、最大血圧の増加、最低血圧の低下及び/又は心拍数の増加はほとんど生じない。MN−221の注入後、患者は主訴又は不快感のどちらも示さない。その結果、MN−221の使用は、最低血圧の増加及び心拍数の増加を含む望ましくない著しく有害な副作用の発生を伴うテルブタリンの使用に比べて、有害な副作用をほとんど又は全く伴わないことが分かる。
薬剤の注入後、薬剤の血漿濃度が用量依存的に増加する。
本調査からは、MN−221を投与することで、IBSを罹患した被験者のS状結腸の運動性がかなり低下することが分かる。プラセボ注入後、運動性が試験期間中に高まる傾向があり、このことがMN−221の抑制効果を更に際立たせる。MN−221の血漿濃度は、臨床現場で用いられる治療濃度の範囲内であると認められる。
ヒト食道の蠕動運動に対するMN−221の効果
過敏性腸症候群を罹患している被験者は、胸やけ及び嚥下障害を含む上部消化管症状を訴える可能性がある。NM−221は、IBSを罹患している被験者の食道の蠕動運動を抑制し、しかも下部食道括約筋の緊張を阻害する。
圧力計での調査は、3重管を用い、溝それぞれに水0.5mL/分を低コンプライアンス毛管系からかん流させながら行う。溝を圧力トランスデューサにつなげて、グラス(Grass)ポリグラフで記録する。圧力を記録する部位の間隔は約8cmである。一晩絶食させた後、被験者を、経鼻挿入した圧力計プローブで標準化された位置に座らせて検査する。プローブは、下部食道括約筋(lower esophageal sphincter、LES)から約2cm離れた、遠位記録点に配置する。これにより、LESから約18cm離れた位置(食道上部)、LESから約10cm離れた位置(食道中央部)及びLESから約2cm離れた位置(食道下部)の圧力を記録する。
各セッションで休息時の被験者の心拍数を記録して、2分間平均を計算する。手指振戦は光学的方法(例えば、ドラコ(Draco)製オプト・トレモア・グラフ(Opt-Tremor Graph))で評価し、右手中指を選んで測定する。振戦評価をデジタルデータで表示して、動いた距離の合計を毎分ミリメーターで示す。
各セッションでは、静脈血試料を最後の嚥下試験直後に採取する。試料は、遠心分離にかけてから、分析するまで−20℃で保存する。MN−221の血漿濃度は、液体クロマトグラフィーと質量分析法とで求める。
頻脈及び振戦は、次の4段階に分類する:なし、軽度(気にならない)、中程度(気にはなるが、日常生活に支障をきたすほどではない)及び重度(日常生活に支障をきたす)。
食道の蠕動運動
MN−221を経口投与すると、食道の蠕動運動圧が大幅に低下する。この低下は、食道上部、食道中央部及び/又は食道下部ではっきりと認められる。投与から1週間後でもまだ蠕動運動圧が低下する傾向がある。
腸外の変数である心拍数及び手指振戦は、MN−221の投薬中は変化しない。すなわち、心拍数及び振戦はいずれも、投薬前とほぼ同じ状態のままである。投薬期間終了時(例えば、投薬10日目)にも、心拍数又は手指振戦には変化がほとんど認められない。被験者のMN−221耐性は実質上認められない。
MN−221を用いた過敏性腸症候群の処置
35歳男性患者はIBSに付随する症状を訴えており、粘液の流出及び出血を伴う下痢、腹部けいれん痛、並びに/又は潰瘍パッチによる粘膜の炎症及び浮腫が挙げられる。MN−221を5mg含む錠剤で1日3回、少なくとも2ヶ月間患者を処置する。当該期間の後に、患者からは、症状の軽減を含む好ましい効果が報告される。同様の好ましい効果は、IBSに起因する1つ以上の同様の症状を訴えている他の男性又は女性患者にも観られる。
MN−221を用いた過敏性腸症候群の処置
既報では、感作モルモットにオボアルブミンを膀胱内注入することで膀胱収縮が増大することが証明されている。アフルワリア(Ahluwalia)ら著の「感作ラットの膀胱におけるオボアルブミン誘発神経性炎症(Ovalbumin-induced neurogenic inflammation in the bladder of sensitized rats)」、Br. J. Pharmacol. (1998年)第124巻、190〜6頁を参照のこと。本調査では、MN−221が、炎症誘発性の膀胱過活動ラットモデルにおいてオボアルブミン誘発膀胱収縮を抑えるのに役立つことが分かる。このラットモデルは、過敏性腸症候群の動物モデルにもなる。
A.ラットの感作
本調査ではスプラーグドーリー系ラット(n=50、200±250g)を用いる。動物は5つの群(n=10)に分ける。第1群は対照の役割を果たし、第2群はオボアルブミン(OA)で感作する。第3群、第4群及び第5群も前述と同様にして感作されるが、急激なオボアルブミン投与の前にMN−221の経口強制飼養を受ける。
全ての動物に膀胱過活動評価を行う。簡単に言えば、腹面下腹部の中心線に沿って1cm切開する。膀胱を体外に取り出し、そして膀胱穹窿部に挿入したポリエチレンチューブ(例えば、クレイ・アダムス(Clay Adams)製PE50)を利用してカテーテルを挿入して2−0ブレードシルク縫合糸(2-0 braided silk suture)を用いて所定の位置に縫合する。膀胱を腹に戻すとともに、カテーテルラインを切開部から抜き取る。次に、カテーテルを圧力トランスデューサ(例えば、カリフォルニア州モローベイ(Morro Bay)のUFI製)に接続し、そこから輸液ポンプ(例えば、マサチューセッツ州ハーバード・アパレイタス(Harvard Apparatus)製)に接続する。連続充填式膀胱内圧測定中に、圧力を、プログラムLabVIEW(テキサス州ナショナル・インスツルメンツ(National Instruments)製)を利用して圧力トランスデューサで記録する。
処置群の出力である膀胱内圧測定図(CMG)を比較する。無傷ラット膀胱に0.9%生理食塩水を注入すると、正常な比較可能な排尿回数及びNVC数が生じる。OA感作ラットでは、膀胱内OA(10mg/mL)注入は、非感作の食塩水注入値と比べてNVCの増加をもたらす。MN−221で前処理すると、OAが誘発するNVCの変化及びICIの変化が用量依存的に阻害される。対照群(第1群)と種々の処置群(第2〜5群)とでは、排尿頻度にほとんど差が認められない。
は本発明の範囲を例示するものであって、それを限定するものではないと理解されるべきである。本発明の範囲内の他の態様、利点及び変更は、本発明が属する技術分野の当業者には自明であろう。
Claims (14)
- 前記対象がメス又はオスの哺乳動物である、請求項1又は2に記載の薬物。
- 前記化合物が錠剤、カプセル、ゲル又は溶液の形態である、請求項1又は2に記載の薬物。
- 前記薬学的に許容可能な塩が酸付加塩であって、前記酸が塩酸、硫酸、リン酸、酢酸、クエン酸、シュウ酸、マロン酸、サリチル酸、リンゴ酸、グルコン酸、フマル酸、コハク酸、アスコルビン酸、マレイン酸及びメタンスルホン酸から選択される、請求項1に記載の薬物。
- 前記薬物が、1日当たり体重1キログラムにつき0.0001〜500mgの投与量で投与される、請求項1又は2に記載の薬物。
- 前記薬物の投与によって、前記対象における1つ以上の有害な副作用の発生を軽減する、請求項1又は2に記載の薬物。
- 前記対象における1つ以上の有害な副作用の発生数が、テルブタリン、リトドリン又はメルアドリンを投与した対象に認められるこのような発生数に比べて低い、請求項7に記載の薬物。
- 前記1つ以上の有害な副作用が、動悸、末梢部位の振戦、心拍数の増加、血圧低下、肺水腫、低血糖症、既往の糖尿病の悪化、既往のケトアシドーシスの悪化、振戦、神経過敏、めまい、頭痛、眠気、嘔吐、悪心、発汗、筋けいれん並びに心電図(electrocardiogram、ECG)の変化から選択される、請求項7に記載の薬物。
- 対象における心拍数の増加、振戦の増強、平均血圧の低下又はこれら全ての発症数が、テルブタリンを投与した対象に認められるこのような発症数に比べて低い、請求項7に記載の薬物。
- 医薬組成物がさらに薬学的に許容可能な担体を含む請求項12に記載の医薬組成物。
- 医薬組成物がさらに非ステロイド系抗炎症薬、抗生物質、プロバイオティクス、抗プロスタグランジン薬、COX−2阻害薬、局所麻酔薬、緩下剤、下痢止め薬、抗けいれん薬及び抗鬱剤から成る群から選択される1種以上の薬物を含む請求項12又は13に記載の医薬組成物。
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