JP2015511636A - 免疫関連疾患及び酸化的ストレス関連疾患の予防または治療用組成物 - Google Patents
免疫関連疾患及び酸化的ストレス関連疾患の予防または治療用組成物 Download PDFInfo
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Abstract
Description
本発明は丁香、全蠍、鏡面朱砂、牛黄、ビャッキョウサン、白附子、枯白礬、紫河車、竜脳及び砒素化合物を含む、砒素化合物の毒性が効果的に減少された免疫関連疾患または酸化的ストレス関連疾患の予防または治療用組成物に関するものである。
本発明による砒素化合物含有丸薬を製造するために、それぞれの薬剤(砒素化合物として砒霜(三酸化砒素)、丁香、全蠍、鏡面朱砂、牛黄、ビャッキョウサン、白附子、枯白礬、紫河車、竜脳)を京東市場で選別して購入した。その後、砒霜40g、丁香200g、全蠍2400g、鏡面朱砂250g、牛黄300g、ビャッキョウサン600g、白附子450g、枯白礬 600g、紫河車2400g及び竜脳30gをそれぞれ秤量して粉砕した後、混合機(G&S Korea)で混合する。その後、混合した薬剤の結合のために、適量の蜂蜜を投入して攪拌し、製造された練り物を製丸機(大成製薬機械製作所で注文制作、PM TECK自動化機器)で抜いた後、切断機(大成製薬機械製作所で注文制作、PM TECK自動化機器)に投入して丸薬を製造した。上記のように製造された丸薬を以下の試験で用いた。
四塩化炭素(CCl4)は代表的な肝毒性化学物質で肝細胞の損傷に係わる研究に広く利用されている。四塩化炭素は肝細胞内での酵素性代謝過程で生成されるフリーラジカルが蓄積して、細胞膜の脂質過酸化(lipid peroxidation)、タンパク質の酸化的変形またはDNA損傷をもたらす酸化的ストレス(oxidative stress)で細胞損傷を誘発する。
8週齢の雄Spargue−Dawley Rat(samtako、韓国)を購入して、世明大学清浄動物飼育室で、温度23±1℃、湿度50±5%で、明るいところで12時間、暗いところで12時間の条件で5日間適応させながら、体重が平均235gに達したとき実験に利用した。全実験期間中、飼料(第一製糖 韓国)と飲水は自由に摂取するようにした。本動物実験は世明大学動物実験倫理委員会の承認(smeac11−08−01)を得て実施された。
正常群(normal群)は実験開始日から毎日蒸溜水1mlを7日間経口投与し、最終投与1時間の後にオリーブオイル(1ml/体重kg)を腹腔内投与した。
検査項目
1)体重及び体重増加率
すべての動物の体重を実験開始日(1日)から4日、7日及び実験終了日(8日)に測定した。体重増加率は(7日間増加された体重/実験開始日の体重)×100で計算した。
実験終了日に剖検して肝臓を摘出し、周辺結合織を注意深く除去した後、肝臓重量を測定した。肝臓/体重比(肝臓重量/体重)×100で計算した。
オリーブオイルまたはCCl4を腹腔内投与した後24時間目にラットをエーテルで軽く麻酔し、心臓を通じて血液を採取して血清分離管に注入した。血清分離管を冷蔵状態で3,500rpmの速度で10分間遠心して血清を分離し、自動生化学分析器(Hitachimodular、Japan)を利用してmodified IFCC方法で血清ALT及びASTを測定した。測定の時、AST(Roche、USA)及びALT(Roche、USA)試薬を利用した。
肝臓の重量を測定した後、中葉(median lobe)の右側部位の一部を摘出して肝組織内脂質過酸化含量測定に用いた。
脂質過酸化含量測定はOhkawaの方法(Ohkawa et al.,J.Med.Chem.,40,pp.559−573、1997)に準じてチオバルビツール酸法(Thiobarbituric acid assay)を利用して脂質過酸化の最終産物であるマロンジアルデヒドを指標で定量した。即ち、肝組織を10倍(v/w)用量の1.15%塩化カリウム溶液に均質化して均質液を製造した。続いて、上記均質液0.2ml、8.1%ドデシル硫酸ナトリウム(SDS)0.2ml、20%酢酸(pH3.5)1.5ml、5%ブチル化ヒドロキシトルエン(Butylated hydroxytoluene)0.5ml及び0.8%チオバルビツール酸1.5mlを混合し、100℃が保持される恒温槽で60分間反応させて、室温で1時間放置した後3,000rpmで10分間遠心分離し、上層液を取って532nmでのUV分光器で吸光度を測定した。
摘出された中葉の左側部位を10%中性緩衝ホルマリン(Neutral Buffered Formalin:NBF)溶液に1日間固定し、一般のアルコール脱水過程とキシレン透明化過程を経た後パラフィンブロックを作った。5μm厚さのパラフィン薄切片を製作して、ヘマトキシリン及びエオシン染色して光学顕微鏡で病理学的所見を比較して観察した。
A.肝保護効果
1)体重の差
正常群での体重は実験期間の間増加しつづあり、実験8日には絶食によって体重が減少した。
ラットのCCl4-誘導された肝毒性での体重に対する試料物質前処理が及ぼす影響
2)肝臓重量及び肝臓/体重比の差
実験終了日に測定した肝臓重量及び肝臓/体重比は対照群が正常群に比べて全部有意に高く現われた。
ラットのCCl4で誘導された肝毒性での肝臓重量及び肝臓/体重比に対する試料物質前処理が及ぼす影響
対照群の血中ALT及びAST活性は正常群に比べて全部有意に高かった。
ラットのCCl4-誘導された肝毒性での血中ALT及びAST活性に対する試料物質前処理が及ぼす影響
対照群の肝組織中で、脂質過酸化物であるマロンジアルデヒド(MDA)の含量は正常群に比べて有意に高かった。
ラットのCCl4で誘導された肝毒性での肝組織の脂質過酸化物含量に対する試料物質前処理が及ぼす影響
正常群の肝組織は、図1のa及びbから確認することができるように、中心静脈、門脈三管、肝細胞板及び洞様毛細血管のすべての構造がよく維持されており、肝細胞も正常な構造を取っていた。対照群の肝組織では中心静脈の周りに広範囲な肝細胞壊死が観察され、壊死周辺の肝細胞は多様な大きさの恐怖変性及び脂肪変化が観察された。壊死した部位では多量の炎症細胞の浸潤が確認された。門脈三管の周りの肝細胞は比較的正常な構造を保持していた(図2のa及びb参照)。
B.安全性分析
1)体重の差
実施例1の丸薬の安全性を評価するための安全性試験群での体重及び体重増加率は正常群に比べてやや高く現われたが、有意な差はなかった(表6)。
ラットの体重に対する高濃度試料処理時(安全性試験群)の効果
実施例1の丸薬の安全性を評価するための安全性試験群での肝臓重量及び肝臓/体重比は正常群と類似に現われた(表7)。
ラット肝臓重量及び肝臓/体重比に対する高濃度試料処理時(安全性試験群)の効果
実施例1の丸薬の安全性を評価するための安全性試験群での血中ALT及びASTは全部正常群と類似するように現れた(表8)。
ラットの血中ALT及びAST活性に対する高濃度試料処理時(安全性試験群)の効果
実施例1の丸薬の安全性を評価するための安全性試験群での肝組織の中でマロンジアルデヒド(MDA)の含量は正常群に比べて有意に低かった(表9)。
ラットの肝組織内のMDA含量に対する高濃度試料処理時(安全性試験群)の効果
確認の結果、正常群の肝組織は、中心静脈、門脈三管、肝細胞板及び洞様毛細血管のすべての構造がよく保持されており、肝細胞も正常な構造を取っていた(図6のa及びb参照)。高濃度の丸薬のみを投与した安全性試験群でも肝組織は全部正常な構造を保持していた(図7のa及びb参照)。
フリーラジカル消去活性試験は化学的に安定したフリーラジカルである2,2−ジフェニル−1−ピクリルヒドラジル(DPPH)を利用して抗酸化効果を分かることができる方法として、上記DPPHは515nm〜520nmの付近で最大吸光度を有し、抗酸化活性のある物質と遇うと電子を供与しラジカル(DPPH)が消滅されて色が変わる。化学的に安定性のあるDPPHは各種抗酸化成分が内在された抽出物、飲料とオイル、純粋フェノール化合物などの抗酸化効果を分析することができる。
1)実験材料の準備
実施例1で製造された丸薬200gを精密に取った後蒸溜水2Lを添加して熱水抽出した。その後、減圧濃縮器を用いて濃縮した後、凍結乾燥して収率46.08%のきれいな粉末を製造した。この粉末を以後の実験で試料として用いた。
2−1)DPPHフリーラジカル消法能
凍結乾燥した試料を0.8、4、20、100及び200mg/mlの濃度になるように試液を調剤した後、96ウェルプレートに10μlずつ添加した。各ウェルに40μlのEtOHを添加した後、DPPH2.5mMを添加して30分間反応させた。この反応液を515nmで吸光度を測定してフリーラジカル消法能(%)を計算した。
凍結して乾燥された試料を0.8、4、20、100及び200mg/mlの濃度になるように試液を調剤した後、各試液を1mlずつ15mlのチューブに分注した。各チューブに1mM硝酸ナトリウム溶液を2mlずつ添加した後、pH1.2の塩酸溶液、pH3.0のクエン酸緩衝液及びpH6.0のクエン酸緩衝液を各チューブに7mlずつ添加し、37℃で1時間反応させた。この反応液を1mlの2%酢酸溶液及びグリス(griess)試薬を添加し、さらに15分間反応させた後、520nmで吸光度を測定して亜硝酸消法能(%)を計算した。
マウスの大食細胞であるRAW264.7細胞に試料を処理して免疫細胞に対する試料の細胞毒性を確認した。
大食細胞であるRAW264.7細胞を96ウェルプレートに各ウェル当たり0.5×104個ずつプレートに分注して24時間培養した。その後、各ウェルにLPS1μg/ml及び蛍光ビッドが付着されたIgGを処理し、試料を濃度別(10、50、100及び200μg/ml)で処理した。24時間後、各ウェルの培地を取り除いた後、40μg/mlのトリパンブルー溶液で洗浄した。洗浄されたプレートを励起(excitation)485nm及び放出(emission)535nmの蛍光波長で測定し、正常群に対する大食能の比率(%)で換算してグラフで表した。
マウス大食細胞であるRAW264.7細胞を各ウェル当たり1×104個ずつ96ウェルプレートに分注して24時間培養した。その後、各ウェルに1μg/mlのLPSを処理し、試料を濃度別(0、10、50、100及び200μg/ml)で処理した。4時間後各ウェルの培地を100μlずつ取ってグリス試薬を添加し、さらに15分間反応させた後、540nmで吸光度を測定して亜硝酸除去能(%)を計算した。
ヒスタミン分泌に対する試料の影響を確認するために、ヒト肥満細胞であるHMC細胞を利用してヒスタミン分泌量を測定した。
ヒト気管支上皮細胞であるA549細胞を利用して気管支上皮細胞に対する試料の細胞毒性を確認した。
ヒト気管支上皮細胞であるA549細胞を24ウェルプレートに1×105個ずつ分注して24時間培養した。その後、試料を各濃度別(50及び20μg/ml)で処理し、LPSを利用して炎症反応を誘導した。
実験結果は平均±SEMで表し、一方向分散分析(one−way ANOVA)を利用して統計処理した後、信頼区間(P value)が0.05より小さい場合、有意性があることと判定した。
1)DPPHフリーラジカル消法能
それぞれの試料を濃度別に試液を調剤した後、DPPHを添加してフリーラジカル消法能を測定した結果、図8で確認することができるように、0.8、4、20、100及び200mg/mlの濃度でそれぞれ6.7±2.0、17.9±1.6、49.9±8.7、76.1±6.9及び92.3±11.0%のフリーラジカル消法能を示した。試料の投与濃度が増加するほどDPPHフリーラジカル消去能が増加することを確認することができた。
試料の亜硝酸塩(nitrite)の生成抑制に対する効果を確認するために、0.8、4、20、100及び200mg/mlの試料をpH1.2の塩酸溶液、pH3.0のクエン酸緩衝液及びpH6.0のクエン酸緩衝液での亜硝酸塩の消去能力を測定した。
マウス大食細胞であるRAW264.7細胞に試料を処理して、免疫細胞に対する試料の細胞毒性を確認した。
マウス大食細胞であるRAW264.7細胞に蛍光ビッドが付着されたIgGを処理し、試料を濃度別に処理して試料の大食細胞活性に対する影響を測定した。
マウス大食細胞であるRAW264.7細胞をLPSを処理し、試料を濃度別に処理してNO生成に対する試料の影響を確認した。
ヒスタミン分泌に対する試料の影響を確認するために、ヒト肥満細胞であるHMC細胞を利用してヒスタミン分泌量を測定した。
ヒト気管支上皮細胞であるA549細胞に試料を処理して気管支上皮細胞に対する試料の細胞毒性を確認した。
試料のサイトカイン分泌に対する影響を調べるために、LPSを利用して刺激したA549細胞に試料を50及び200μg/mlを投与した。その後、RayBioヒトサイトカイン抗体アレイキットを利用してサイトカイン分泌量を測定した。
Claims (10)
- 丁香、全蠍、鏡面朱砂、牛黄、ビャッキョウサン、白附子、枯白礬、紫河車、竜脳及び砒素化合物を含む免疫関連疾患予防または治療用組成物。
- 前記免疫関連疾患は、免疫介在性炎症疾患、非免疫介在性炎症疾患、感染症、免疫不全疾患及び新生物(neoplasia)からなる群から選択されることを特徴とする請求項1に記載の組成物。
- 前記免疫関連疾患は、後天性免疫欠乏症(AIDS)、肝炎、肝硬化、癌、喘息、アレルギー性鼻炎、アトピー性皮膚炎、食物過敏症またはじんま疹であることを特徴とする請求項2に記載の組成物。
- 丁香、全蠍、鏡面朱砂、牛黄、ビャッキョウサン、白附子、枯白礬、紫河車、竜脳及び砒素化合物を含む酸化的ストレス関連疾患予防または治療用組成物。
- 前記酸化的ストレス関連疾患は、脂質代謝疾患、動脈硬化症、心不全症、高血圧性心臓疾患、不整脈、心筋梗塞症、狭心症、老化、免疫疾患または癌であることを特徴とする請求項4に記載の組成物。
- 前記砒素化合物は、三酸化砒素(As2O3)、六酸化砒素(As4O6)、三臭化砒素(AsBr3)、三塩化砒素(AsCl3)、三ヨウ化砒素(AsI3)及びメラルソプロール(Melarsoprol)からなる群から選択されることを特徴とする請求項1または4に記載の組成物。
- 前記組成物が、砒素化合物1〜7重量部、丁香15〜25重量部、全蠍200〜270重量部、鏡面朱砂20〜30重量部、牛黄25〜35重量部、ビャッキョウサン50〜65重量部、白附子38〜48重量部、枯白礬50〜65重量部、紫河車200〜270重量部及び竜脳0.5〜6重量部を含むことを特徴とする請求項1または4に記載の組成物。
- 前記組成物が、砒素化合物3〜5重量部、丁香17〜22重量部、全蠍220〜250重量部、鏡面朱砂22〜27重量部、牛黄27〜31重量部、ビャッキョウサン55〜62重量部、白附子41〜46重量部、枯白礬55〜62重量部、紫河車220〜250重量部及び竜脳2〜4重量部を含むことを特徴とする請求項1または4に記載の組成物。
- 丁香、全蠍、鏡面朱砂、牛黄、ビャッキョウサン、白附子、枯白礬、紫河車、竜脳及び砒素化合物を含む抗酸化組成物。
- 丁香、全蠍、鏡面朱砂、牛黄、ビャッキョウサン、白附子、枯白礬、紫河車、竜脳及び砒素化合物を含む、砒素化合物の毒性低減用組成物。
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