JP2016028022A - 上皮機能障害の処置におけるアデルミドロールの使用 - Google Patents
上皮機能障害の処置におけるアデルミドロールの使用 Download PDFInfo
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- JP2016028022A JP2016028022A JP2015137093A JP2015137093A JP2016028022A JP 2016028022 A JP2016028022 A JP 2016028022A JP 2015137093 A JP2015137093 A JP 2015137093A JP 2015137093 A JP2015137093 A JP 2015137093A JP 2016028022 A JP2016028022 A JP 2016028022A
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Abstract
Description
単離細胞における試験管内試験
方法
培養ヒトケラチノサイトHaCaTは、グルタミン (2 mM)、ペニシリン (400 U/ml)、ストレプトマイシン (50 mg/ml)、10% ウシ胎仔血清(FBS)を加えたダルベッコ変法イーグル培地(DMEM: Dulbecco’s Modified Eagle Medium) 中で、5% CO2の存在下、37℃で培養した。その後、6ウェルマルチウェル (9x105/ウェル)に播いた細胞のコンフルエンスが70%に達すると、細胞をアデルミドロール10μMまたは担体 (対照、0.05%メタノール)で、24時間、5% CO2の存在下、37℃で刺激した。24時間後、該細胞および上清を、[2H]8アナンダミド (AEA) 10 pmolおよび[2H]52-アラキドニルグリセロール (2-AG) 50 pmol、[2H]4パルミトイルエタノールアミド (PEA)および[2H]2オレオイルエタノールアミド (OEA)を含有する、5倍体積のクロロホルム/メタノール TRIS-HCl 50 mM pH 7.4 (2:1:1)溶液でホモジナイズした (Bisogno et al., 1997)。クロロホルムを用いた4回の抽出により得られた有機脂質層をシリカゲルカラムクロマトグラフィーによる精製に付し、クロロホルム中のメタノール濃度を上昇させることにより溶出した。AEA、2-AG、PEAおよびOEAを含む該クロロホルム/メタノール90:10画分を、大気圧下で化学イオン化を用いて、質量分析器に連結した液体クロマトグラフィーにより解析した(LC-APCI-MS) (Marsicano et al., 2002)。用いた装置は、Shimadzu APCI interfaceを介してShimadzu spectrometer (LCMS-2010) に連結したShimadzu HPLC (LC-10ADVP) を含む。該イオン化源温度は400℃であり、Phenomenex逆相HPLC column (C-18、5ミクロン、150 x 4.6 mm) を用いる。移動相は、メタノール/水/酢酸 (85/15/0.1%)の混合物からなり、1 ml/分の速度でカラムを通過する。質量スペクトルの決定は、選択イオンモニタリング (SIM) [Di Marzo et al. Nature 2001;410:822-825]にしたがって行う。選択イオンは、質量/電荷値 (m/z) 356および348 (重水素化および非重水素化AEAの分子イオン)、384.35および379.35 (重水素化および非重水素化2-AGの分子イオン)、304および300 (重水素化および非重水素化PEAの分子イオン)、328および326 (重水素化および非重水素化OEAの分子イオン)に相当する。pmol/mgで表される脂質抽出物の量は、ANOVAならびにスチューデント-ニューマン-ケウルス検定を用いて比較した。
得られた結果からは、アデルミドロール 10μMで刺激されたHaCat細胞 (66.4±9.6)は、ベース値 (31.6±5.6)と比較して、カンナビノイド模倣性PEAのレベルが有意に高いことが示される(図1)。
ヨード酢酸ナトリウム誘発性骨関節炎
方法
該試験は、試験に用いる前に、標準的な食餌および環境条件(温度21±1℃、湿度60±10%、光条件1日あたり12時間、ならびに水および食物は自由摂取)で、1週間囲いの中においた、Harlan Italyより入手したWistar系統の雄成体ラット(体重200〜250g) を用いて行った。ヨード酢酸ナトリウム(MIA)を2 mg/25μLの用量で、Kolbhenの提唱した方法に基づいて再検討し、右膝蓋下に1回関節内注射を行うことによって、ラットにおいて膝骨関節炎を誘発した。MIAは、解糖系を阻害し、軟骨細胞の代謝を崩壊させ、軟骨組織の分解をもたらすことによって局所的に作用する。骨関節炎の誘導時に、MIAを無菌の生理食塩水に溶解した。関節内投与を行う前に、ラットを、生理食塩水に溶解したペントバルビタールナトリウムを60 mg/kgの用量で0.2 ml/hg腹腔内 (i.p.)投与することにより麻酔をかけた。右膝にMIAの注射投与を受けた動物を骨関節炎(OA) 群とする。右膝に溶媒のみの関節内投与受けた二番目のラット群を対照群とする。
機械アロディニアの評価
機械アロディニア(通常は無痛性である刺激に対する有痛応答)の測定のために、フォンフレー試験を用い (Ugo Basile, Varese, Italy)、ベースであるPerspexプラットホーム上で動かすことのできる接触刺激装置、該ベースプラットホームの角に位置する4つのカラムで支持されている金属グリッド、測定前に少なくとも15〜30分間動物が置かれるようにさらに細分された2つのコンパートメントならびに電気マイクロプロセッサーからなる装置を用いる。接触刺激装置は、操作者がプラットホーム上で動かすことを可能にするハンドルを備えたアルミニウムシリンダー中に位置する。該シリンダー中には、シリンダーより上の位置にある直径0.5 mmのスチールフィラメントを持ち上げる電気トリガーがあり; この機器の起動ボタンは、ハンドルの両側にある。シリンダーより上の位置に、フィラメントと並んで鏡があるために、刺激を膝蓋の正確な位置に適用し、足の動きをモニターすることができる。該マイクロプロセッサーは、機械刺激から、足を離すまでの潜伏時間(秒)およびフィラメントにより足に加えられる力(g)を表すLCDディスプレイを備える。マウスでの測定のためには、潜伏時間が最長で20秒、ならびに力が最大で5gに相当するように設定した。
MIA注射後の動物の右膝の水腫形成を評価するために、デジタルの手動スライドキャリパー (計測能0〜150 mm; 分解能: 0.01 mm; ROHS Compliant Electronic Digital Caliper - 2 Biological Instruments SNC, Italy) を用いた。測定は、各動物の膝蓋の左および右の直径を手動で測定することにより行った(mmで表示)。水腫は、右膝と左膝の体積の差異として算出した。データは図2に示す。
脊髄中における腫瘍壊死因子 (TNF-α)レベルの決定
滑液中のTNF-αレベルの決定は、市販のキット (Biosource International Inc)を使用した ELISA (Enzyme Linked Immuno-Sorbent-Assay) 免疫酵素アッセイを用いて行った。該方法は、抗原が2層抗体の間に補足される手法を用いており、そのため、ELISAサンドウィッチと称される。試料およびビオチン化抗体を、TNF-α特異的抗体でコートしたマイクロタイタープレートのウェルに加え、1回目のインキュベーションを行い、この間に、試料中の特定のサイトカインがプレート上に固定された抗体により露出された抗原結合部位および溶液中に存在するビオチン化抗体の部位の両方と相互作用する。一連の洗浄によって非結合物質を除いた後、酵素であるストレプトアビジンペルオキシダーゼを添加し、これがビオチン化抗体に結合する。2回目のインキュベーションを行った後、洗浄して非結合酵素を除いた後、基質 (Stabilized Chromgen)を含有する溶液を添加する。酵素反応後、生じた生成物の染色強度を分光測定し、これが試料中のTNF-αの濃度に直接比例する。
処理
0日目(T0) MIAの筋肉内投与
1、8および15日目アデルミドロールの筋肉内投与
3種類のアデルミドロール用量を適用した: 1.5; 15および150μg/注射
種々のパラメーターを、パラメーターそれ自体に対して異なるタイミングで測定する(例えば、炎症パラメーターをMIA投与後第1週にのみ評価し、疼痛を、アデルミドロール投与前および60分後に常に測定する)。
水腫に対する効果は、滑液中のTNF-αレベルの低下を伴う(図3)。
膀胱痛症候群(BPS)の患者における膀胱内点滴
方法
2% アデルミドロールおよび0.1% ヒアルロン酸ナトリウム塩を含む無菌液剤を、7人の女性患者に、膀胱を完全に空にした後に、カテーテルを通して膀胱内に点滴注入した。全ての患者は、BPS (膀胱痛症候群)と診断を受けたことが確認されている。殆どの場合、該患者は、他の骨盤疾患 (外陰部前庭炎 4/7; IBS (過敏性腸症候群) 2/7; 線維筋痛症候群 1/7、反復性尿路感染症 (RUTI) 3/7)を併発していた。
Claims (12)
- パルミトイルエタノールアミド分解酵素FAAHおよびNAAAの活性を阻害することなくパルミトイルエタノールアミドの内在レベルを上昇させる、ヒトまたは動物における上皮組織機能不全の処置に用いるための、アデルミドロール。
- ヒトまたは動物における上皮組織機能不全が以下からなる群から選択される、請求項1記載の使用のためのアデルミドロール:
種々の病因の中咽頭および食道性嚥下障害; 胃食道逆流; 輪状咽頭アカラシア; 食道アカラシア; 種々の病因の口内炎; 高齢者の老人性嚥下機能低下; ネコの歯肉口内炎; 歯内治療/歯科矯正ならびに歯科インプラント介入に関連する歯周病; 口腔灼熱症候群 (BMS); 眼瞼水腫; 眼瞼炎、眼瞼結膜炎; 眼瞼の内向きの回転(眼瞼内反)および外転 (眼瞼外反) ; 種々の病因の角膜炎および角結膜炎 (例えば点状表層角結膜炎); 種々の病因の角膜病変; 涙膜の質的量的変化; 涙嚢炎; ブドウ膜炎; 緑内障; 耳道腺の疾患; イヌおよびネコにおける耳血腫; イヌおよびネコにおけるウジの発生による刺激; 足皮膚炎; 鼻炎、鼻気管炎、急性および慢性鼻咽頭炎; 急性および慢性咽頭炎; 急性および慢性気管支炎; 副鼻腔炎、鼻副鼻腔炎; 気管支喘息; 脱毛症; イヌおよびネコにおける鼻皮膚炎; 急性および慢性唾液腺炎; 神経因性掻痒; 尿路上皮の変化に寄与し得る種々の病因の膀胱痛症候群、具体的には間質性膀胱炎、全身性の化学療法による膀胱炎、化学療法剤、例えばエピルビシンまたはマイトマイシンの局所的な膀胱点滴による膀胱炎、骨盤の放射性治療による膀胱炎; 慢性および/または再発性膀胱炎; 上皮の変化に寄与し得る胃腸管障害; 肛門直腸領域の疾患、具体的には後部直腸瘤、直腸炎、直腸粘膜脱、痔核、裂肛、肛門周囲掻痒、イヌにおける肛門嚢疾患および他の会陰機能障害; 小血管炎および中血管炎、具体的には肉芽腫性血管炎、免疫複合体による血管炎; 二次生殖腺、具体的には精嚢および小精管の炎症; ヒトおよび動物における口腔顔面痛症候群; 関節リウマチおよび骨関節炎に関連する滑膜炎。 - パルミトイルエタノールアミドのオキサゾリン誘導体、抗微生物薬、trans-トラウマチン酸およびヒアルロン酸またはその誘導体からなる群から選択される少なくとも1つの有効成分と組み合わせて、連続的にまたは別に投与される、請求項1または2記載の使用のためのアデルミドロール。
- 該抗微生物薬がムラサキバレンギク(Echinacea purpurea)抽出物、サルオガセ(Usnea barbata)抽出物、ウスニン酸、フィトスフィンゴシン、ブロノポールおよびその混合物から選択される、請求項3記載の使用のためのアデルミドロール。
- ヒアルロン酸およびtrans-トラウマチン酸が、ヒアルロン酸trans-トラウマチン酸ナトリウム二重塩の形態で存在する、請求項4記載の使用のためのアデルミドロール。
- 上皮に用いることを意図した液剤形態で投与されるアデルミドロールの量が、0.5〜20 mg/体重1Kgである、請求項1〜4のいずれか記載の使用のためのアデルミドロール。
- アデルミドロールと、パルミトイルエタノールアミドのオキサゾリン誘導体、抗微生物薬、trans-トラウマチン酸およびヒアルロン酸またはその誘導体からなる群から選択される1つ以上の有効成分とを含む、ヒトまたは動物の上皮および粘膜組織機能不全の処置に用いるための、医薬製剤。
- ヒトまたは動物における上皮組織機能不全が請求項2に記載するものである、請求項7記載の使用のための製剤。
- 該微生物薬が、ムラサキバレンギク抽出物、サルオガセ抽出物、ウスニン酸、フィトスフィンゴシン、ブロノポールおよびその混合物から選択される、請求項7〜9のいずれかに記載の使用のための製剤。
- ヒアルロン酸およびtrans-トラウマチン酸が、ヒアルロン酸trans-トラウマチン酸ナトリウム二重塩の形態で存在する、請求項7〜10のいずれか記載の使用のための製剤。
- ヒトおよび動物の両方で用いることを意図した、局所投与用の医薬形態におけるアデルミドロールの重量濃度が0.2%〜7.0%であり、内上皮に適用するための液剤中のアデルミドロールの重量濃度が0.3〜0.5%である、請求項7〜11のいずれか記載の使用のための製剤。
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ES2740928T3 (es) | 2020-02-07 |
CN105250252A (zh) | 2016-01-20 |
PL2965765T3 (pl) | 2019-11-29 |
US20190224145A1 (en) | 2019-07-25 |
KR102490825B1 (ko) | 2023-01-20 |
CY1121957T1 (el) | 2020-10-14 |
CA2896435C (en) | 2023-08-22 |
US11491122B2 (en) | 2022-11-08 |
US20170209395A1 (en) | 2017-07-27 |
PT2965765T (pt) | 2019-07-10 |
BR102015016445A2 (pt) | 2016-01-12 |
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