JP5733601B2 - 劇症型炎症の予防および/または治療剤 - Google Patents
劇症型炎症の予防および/または治療剤 Download PDFInfo
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- JP5733601B2 JP5733601B2 JP2010159031A JP2010159031A JP5733601B2 JP 5733601 B2 JP5733601 B2 JP 5733601B2 JP 2010159031 A JP2010159031 A JP 2010159031A JP 2010159031 A JP2010159031 A JP 2010159031A JP 5733601 B2 JP5733601 B2 JP 5733601B2
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Description
(1)2つの既知化合物が、未知の属性として、劇症型炎症に対する治療効果を示すこと;および、
(2)上記(1)に記載の治療効果が、上記化合物の有する、好中球からのミエロペルオキシダーゼ(MPO;Myeloperoxidase)の放出を阻害する作用(MPO放出阻害作用;こちらも未知の属性である)に基づくものであること、
の2つの知見を得て、これらの知見に基づき、本発明を完成させるに至った。
劇症型炎症の予防および/または治療剤の製造における、スピラマイシンもしくはジョサマイシン(ロイコマイシンA3)、またはこれらの製薬上許容されうる塩の使用;
劇症型炎症の予防および/または治療における、スピラマイシンもしくはジョサマイシン(ロイコマイシンA3)、またはこれらの製薬上許容されうる塩の使用;
スピラマイシンもしくはジョサマイシン(ロイコマイシンA3)、またはこれらの製薬上許容されうる塩の有効量を、必要とする患者に投与することを含む、劇症型炎症の予防および/または治療方法。
1056種のマクロライド系化合物の合成分子について、以下の手法により、ヒトおよびマウスのそれぞれの好中球からのMPO放出阻害活性をスクリーニングした。具体的には、ヒトまたはマウスの好中球(1×106細胞/mL)に対し、それぞれの化合物(被験化合物)を5μg/mLの濃度で添加し、サイトカラシンB(5μg/mL)およびfMetLeuPhe(ホルミルメチオニルロイシルフェニルアラニン;走化性因子)(ヒト:10−6M、マウス:10−5M)の存在下、37℃にて10minインキュベートした際の好中球の脱顆粒の阻害活性を、MPO放出活性を測定することにより評価した。被験化合物を添加しないものを0%阻害率とし、被験化合物の阻害活性の「%阻害」により評価した。
2−1:実験動物
BALB/cマウスは、SPF環境下(国立感染症研究所の動物室管理室−感染区)で飼育し、インフルエンザウイルスの感染実験に供した。実験に使用するマウスの管理・処置は、千葉大学の動物実験ガイドラインおよび国立感染症研究所の動物実験ガイドラインの動物愛護の規定に基づいて行った。
インフルエンザウイルスのPR8(H1N1)株の溶液を1%FBS−DMEMを用いて調製し、上記BALB/cマウスに30μL経鼻投与した(投与されたウイルス量は0.75LD50=321.42pfu/マウスであった)。次いで、上述した3種のマクロライド系化合物をそれぞれ、ウイルス投与日から1日一回(ウイルス投与日を含む)、PBS−エタノール溶液として5日間連続投与(腹腔内注射、33mg/Kg(マクロライド系化合物換算))し(計6回投与)、肺炎の劇症化抑制効果を判定した(実験群)。なお、コントロール(陰性対照群)としては、マクロライド系化合物に代えて同量のPBS−エタノールを投与したマウスを用いた(各群:N=6)。
上記「2−2」に記載の実験群および比較対照群のマウスについて、生存率を評価した。これに基づいて作成した生存曲線を図1に示す。
上記で調製した肺サンプルについて、光学顕微鏡を用いて検鏡し、実験群と比較対照群との間で肺組織傷害の程度の差異を評価した。比較対照群およびM1を投与した実験群についての顕微鏡観察写真を図2に示す。なお、図2に示す写真は、インフルエンザウイルス投与から7日後に調製した肺サンプルの観察写真である。
上記で調製したBALFサンプルをCytofuge2(IRIS)にて1000rpm×2minでサイトスピンすることにより細胞をスライドガラスに接着させ、Diff−quick(シスメックス)にて当該細胞を染色した。なお、ここで用いた「Diff−quick」は、ギムザ染色と同様な染色が得られる迅速な鑑別用染色液セットである。また、必要に応じて、抗体による染色も実施した。そして、染色後のサンプルについて、光学顕微鏡を用いて検鏡し、実験群M1と比較対照群との間で浸潤炎症細胞の数を比較した。結果を図3に示す。
上記で調製した血漿サンプルおよびBALFサンプルについて、以下の手法により、23種類のサイトカイン・ケモカインのレベルの挙動を同時にかつ網羅的に測定・解析した。この際、血漿サンプルおよびBALFサンプル中のサイトカイン・ケモカインレベルの測定・解析には、Bio−PlexTMSuspension Array System(バイオラッド)を用いた。具体的には、サンプリングしたプレートを、シール・遮光し、1100rpm×30sec、300rpm×30min振とう、吸引ろ過にて3回洗浄し、二次抗体を各ウェルに25μLずつ添加した後、プレートをシール・遮光し、1100rpm×30sec、300rpm×30min振とう、吸引ろ過にて3回洗浄した。その後、ストレプトアビジン−PE溶液を各ウェルに50μLずつ添加し、プレートをシール・遮光し、1100rpm×30sec、300rpm×10min振とう、吸引ろ過にて3回洗浄した。ASSAY BUFFERを各ウェルに125μLずつ添加し、プレートをシールし、1100rpm×30sec振とう後、シールを剥がし、Bio−Plex Array Readerにて測定した。
上記で調製した肺サンプルおよび脾臓サンプルについて、リアルタイムPCR法により、インフルエンザウイルスMタンパク質のmRNA量を定量することにより、インフルエンザウイルス抗原の検出を行った。
上記の各試験において劇症型肺炎の治療効果を示した2種のマクロライド系化合物(M1およびM3)について、NMR(核磁気共鳴)法によりその化学構造を確認した。その結果、2種のいずれも16員環マクロライド系化合物であることが判明した。また、2種のいずれも既に抗菌薬として市販されている化合物と同一の構造を有していた。そこで、構造解析および抗菌活性の比較を行い、既知化合物と同一の化合物であることを確認した。具体的には、「M1」はスピラマイシンと同一の化合物であり、「M3」はジョサマイシン(ロイコマイシンA3)と同一の化合物であった。
Claims (3)
- スピラマイシンもしくはジョサマイシン(ロイコマイシンA3)、またはこれらの製薬上許容されうる塩を有効成分として含有する、インフルエンザウイルスの感染による劇症型肺炎の予防および/または治療剤。
- 前記インフルエンザウイルスが、H5N1型またはH1N1型である、請求項1に記載
の剤。 - インフルエンザウイルスの感染による劇症型肺炎の予防および/または治療剤の製造における、スピラマイシンもしくはジョサマイシン(ロイコマイシンA3)、またはこれらの製薬上許容されうる塩の使用。
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