JP5747983B2 - 関節炎治療剤 - Google Patents
関節炎治療剤 Download PDFInfo
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- JP5747983B2 JP5747983B2 JP2013510006A JP2013510006A JP5747983B2 JP 5747983 B2 JP5747983 B2 JP 5747983B2 JP 2013510006 A JP2013510006 A JP 2013510006A JP 2013510006 A JP2013510006 A JP 2013510006A JP 5747983 B2 JP5747983 B2 JP 5747983B2
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- 231100000820 toxicity test Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- A61K31/716—Glucans
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Description
したがって、関節炎などの関節損傷に使用される従来の治療法は、限定的な有効性を有して明白な有毒性副作用を伴うため、長期間に渡って使用し続けることはできず、その有効性が制限されるため、既存の治療法が持つ短所を克服した新たな新規治療法や治療剤が切に求められている実情にある。
実験例1−1:実験準備
β−1,3−1,6−分岐D−グルカンのうちの1つである、商業的に購入可能なポリカン(Polycan)TM(1.7brix)[Glucan Corp.Ltd.,KOREA]を準備し、前記ポリカン(Polycan)TMの対照薬品としてジクロフェナクナトリウム(Diclofenac sodium)[Sigma,USA]を準備した。実験動物としては、Sprague−Dawley Rats(6週齢雄、SLC.,JAPAN)[ANNEX I〜III]を準備した。
実験群を計6群に分け、各群ごとに前記Sprague−Dawley Ratsを8匹ずつ準備した。骨関節炎を誘発させないラットとして、滅菌蒸溜水を投与した正常群であるSham対照群を準備した。また、陰性対照群として骨関節炎誘発後に何の処理もしないOA対照群と、陽性対照群として骨関節炎誘発後に2mg/kgのジクロフェナクナトリウム投与群を準備した。
ポリカン85、42.5および21.25mg/kgを毎日84日間経口投与した。前記投与時、滅菌蒸溜水を媒体として使用し、5ml/kgで投与した。また、前記ポリカンを培養液に希釈し、1ml/kgの濃度で単回関節嚢内に注入した。
前記実験動物であるマウスをゾレチル(Zoletile 50:Vir bac Lab.,France)で麻酔した後に左側関節嚢を露出し、Anterior cruciate ligament transactionおよびpartial medial meniscectomyを実施して骨関節炎を誘発した。Sham手術群では関節嚢を切除して臓器内側の半月板(medial meniscus)を確認した後、切除せずに関節嚢を閉じた。
投与日から84日間の体重と膝関節厚さの変化を1週間に1回ずつ測定して観察し、最終犠牲日に膝関節の最大伸長角度およびcapsule露出後の膝関節厚さをそれぞれ測定し、Safranin O染色下に大腿骨および脛骨のMakin scoreと軟骨の厚さをそれぞれ組織形態計測(histomorphometry)的に測定し、大腿骨および脛骨関節面の軟骨においてそれぞれBrdU免疫反応性も評価した。
実験例2−1:体重の変化
図1に示すように、実験例1のように行った結果、全実験期間で正常群(Sham対照群)および陰性対照群(OA対照群)で意味のある体重および増体量の変化は認められなかった。84日間の増体量が、OA対照群ではSham対照群に比べて−0.82%の変化を示し、ジクロフェナクナトリウム2mg/kg、ポリカン85、42.5、および21.25mg/kg投与群ではそれぞれOA対照群に比べて−2.98、1.76、7.76、および8.88%変化を示した。
図2を参照すれば、骨関節炎対照群(OA対照群)の場合、正常対照群(Sham対照群)に比べて有意性のある(p<0.01)誘発膝関節厚さの増加がそれぞれ投与日から観察された。一方、前記3種類の容量のポリカンおよびジクロフェナクナトリウム投与群ではそれぞれ投与21日後から骨関節炎誘発対照群に比べて有意性のある(p<0.01またはp<0.05)膝関節厚さの減少が認められた。最終解剖検査時、膝関節の厚さは、OA対照群ではSham対照群に比べて18.66%の変化を示し、ジクロフェナクナトリウム2mg/kg、ポリカン85、42.5、および21.25mg/kg投与群ではそれぞれOA対照群に比べて−5.79、−5.61、−4.28、および−5.74%変化を示した。
すべてのOA誘発群では、Sham対照群と比較して有意性のある(p<0.01)capsule露出後の関節厚さの増加がそれぞれ認めら、ジクロフェナクナトリウムおよびすべてのポリカン投与群では、骨関節炎誘発対照群と類似した厚さをそれぞれ示した。Joint capsule露出後、膝関節の厚さは、OA対照群ではSham対照群に比べて15.40%の変化を示し、ジクロフェナクナトリウム2mg/kg、ポリカン85、42.5、および21.25mg/kg投与群ではそれぞれOA対照群に比べて−0.99、−2.77、−1.00、および−2.17%変化を示した。
図3を参照すれば、OA対照群の場合、Sham対照群に比べて有意性のある(p<0.01)膝関節最大伸張角度の増加が認められたが、すべてのポリカン処理群およびジクロフェナクナトリウム投与群では、OA対照群に比べて有意性のある(p<0.01)膝関節最大伸張角度の減少がそれぞれ認められた。膝関節最大伸張角度は、OA対照群の場合はSham対照群に比べて159.39%の変化を示し、ジクロフェナクナトリウム2mg/kg、ポリカン85、42.5、および21.25mg/kg投与群ではそれぞれOA対照群に比べて−18.18、−18.52、−28.96、および−24.07%変化を示した。
Mankin scoreは関節炎の程度を示す数値であって、伸長角、傷み、発熱、厚さなどを包括して数値として示す値であり、数値が少ないほど正常に近い。図4を参照すれば、OA対照群では、Sham対照群に比べて有意性のある(p<0.01)脛骨および大腿骨関節面軟骨のMankin scoreの増加がそれぞれ認められたが、すべてのポリカン処理群およびジクロフェナクナトリウム投与群では、OA対照群に比べて著しく大腿骨および脛骨Mankin scoreの減少がそれぞれ認められた。
図5を参照すれば、OA対照群では、Sham対照群に比べて有意性のある(p<0.01)脛骨および大腿骨関節面軟骨厚さの減少がそれぞれ認められたが、すべてのポリカン処理群およびジクロフェナクナトリウム投与群では、OA対照群に比べて有意性のある(p<0.01)脛骨および大腿骨軟骨厚さの増加がポリカン21.25mg/kg投与群を除いてそれぞれ認められた。
図6を参照すれば、OA対照群では、Sham対照群に比べて有意性のある(p<0.01)脛骨および大腿骨関節面軟骨のBrdU免疫反応細胞数の減少がそれぞれ認められたが、ポリカン85および42.5mg/kg投与群では、OA対照群に比べて有意性のある(p<0.01)BrdU免疫反応性を示す軟骨細胞の数的増加が脛骨および大腿骨関節面軟骨でそれぞれ認められた。
実験例3−1:組織処理
胸腺および脾臓の周辺結合組織を分離して10%中性ホルマリンに固定させた後、一般的な方法によって脱水およびパラフィン包埋を実施して3〜4μmの縦方向(longitudinal)切片を製作し、Hematoxylineosin染色を実施して光学顕微鏡下で観察した。
ポリカンがコラーゲンとして誘発されたリューマチ関節炎(RA)DBAマウスの免疫異常に及ぼす影響を評価するために、胸腺全体および皮質の厚さ、脾臓全体、および白色水質の直径、白色水質の単位面積(1mm2)あたりの数を40倍顕微鏡視野で自動映像分析装置(DMI−300 Image Processing:DMI,Korea)を利用してそれぞれ測定し、以前の方法[Dudler et al.,2000:van Holten et al.,2004:Kim et al.,2007]によって膝関節の大腿骨および脛骨関節面軟骨の厚さ、プロテオグリカン(proteoglycans)消失程度、および浸食(erosion)をそれぞれ100倍顕微鏡視野で自動映像分析装置(DMI−300 Image Processing:DMI,Korea)を利用して評価した。
コラーゲンを利用したRA誘発マウスモデルは、現在の多様な物質のRAに対する効力評価に最も広く利用されている動物モデルのうちの1つであり[Liu et al.,2008:Miyake et al.,2008:Panayi et al.,2008]、自己免疫によるRAの誘発が招来する。したがって、コラーゲン誘発RA時、胸腺と脾臓のリンパ球増加など典型的な免疫増加が起こると知られている[Agata et al.,2000:Chen and Wei,2003:Zhang et al.,2004]。したがって、前記コラーゲンを利用したRA誘発マウスの胸腺と脾臓を観察して本願発明の効果を分析した。
前記実験例による結果、ジクロフェナクナトリウムおよびポリカン85mg/kg投与群に限定して胸腺皮質厚さの有意性のない増加が認められたが、胸腺では正常対照群(Sham対照群)と比較して有意性のある変化がすべてのRA誘発群で認められなかった。
脾臓白色水質の数は、RA対照群ではSham対照群に比べて19.40%の変化を示し、ジクロフェナクナトリウム、ポリカン21.25、42.5、および85mg/kg投与群ではRA対照群に比べて5.00、−6.25、−5.00、および−13.75%の変化をそれぞれ示した。
下記表では、8匹の動物モデルの±SD(平均±標準偏差に変更)値で示し、*p<0.01および**p<0.05でSham対照群と比較した。†p<0.01リューマチ関節炎対照群(RA対照群)と比較した。
コラーゲン誘発関節炎では、組織学的に関節軟骨のプロテオグリカンの消失とこれに伴う浸食(erosion)、すなわち典型的なRAが観察されるものと知られている[Williams et al.,1992:Dudler et al.,2000:van Holten et al.,2004:Kim et al.,2007]。本実験の結果でも、正常対照群(Sham対照群)に比べて有意性のある(p<0.01)膝関節の大腿骨および脛骨関節面軟骨のプロテオグリカンの減少、erosion scoreの増加、および軟骨厚さ自体の減少がRA誘発対照群でそれぞれ認められた。
大腿骨関節軟骨のSafranin O scoreは、RA対照群では正常対照群(Sham対照群)に比べて1000.00%の変化を示し、ジクロフェナクナトリウム、ポリカン21.25、42.5、および85mg/kg投与群ではRA対照群に比べて−63.64、−36.36、−63.64、および−59.09%の変化をそれぞれ示した。
下記表3を参照すれば、処理群は対照群に比べてSafranin値、erosion値、および脛骨関節軟骨厚さは著しく減少することが分かる。また、下記表は、16関節の±SDで示し、p<0.01および**p<0.05でSham対照群と比較した。†p<0.01リューマチ関節炎対照群(RA対照群)と比較した。
脛骨関節軟骨のSafranin O scoreは、RA対照群ではSham対照群に比べて209.09%の変化を示し、ジクロフェナクナトリウム、ポリカン21.25、42.5、および85mg/kg投与群ではRA対照群に比べて−29.41、−29.41、−50.00、および−73.53%の変化をそれぞれ示した。
下記表3を参照すれば、処理群はリューマチ対照群(RA対照群)に比べてSafranin値およびerosion値は減少する傾向を示し、脛骨関節軟骨の厚さは増加することが分かる。また、下記表は16関節の±SDで示し、p<0.01および**p<0.05でSham対照群と比較した。†p<0.01リューマチ関節炎対照群(RA対照群)と比較した。
実験例4−1:マウス準備
6週齢の雄ICRマウスと雌ICRマウス(Charles River,Japan)それぞれ20匹を準備した。前記マウスを20〜25℃の温度、30〜35%の湿度でポリカーボネートケージごとに5匹ずつ置いた。昼と夜のサイクルを12時間:12時間とした。さらに、制限をおかずに水を供給し、すべてのネズミは犠牲前まで夜間は食事を与えなかった。
ポリカンTM(Glucan Corp.Ltd.,Korea)は茶色を帯びた粘液質であるが、均一な溶液である。前記ポリカンを4℃の冷蔵室に保管した。雄および雌マウスのグループごとに、それぞれ1000、500、および250mg/kgで試験物を経口投与した。マウスは下記表5のようにグループ分けして番号を付けた。
LD50は、Probit方法によって計算された。統計学的分析は、Windowに使用されるSPSS(Release 6.1.3,SPSS Inc.,USA)を使用して行われた。
表5に示す条件のように、それぞれの投与量を異にして経口投与したすべてのマウスの日経過による生存率を下記表6に示した。
本発明は、上述した実施形態および添付の図面によって限定されることはなく、添付する特許請求の範囲によってその範囲が定められる。したがって、特許請求の範囲に記載された本発明の技術的な思想を逸脱しない範囲内で、当技術分野の通常の知識を有する者によって多様な形態の置換、変形、および変更が可能であり、これも本発明の範囲に属する。
Claims (4)
- 下記式(I)で表されるβ−1,3−1,6−分岐D−グルカンを含み、下記式(I)のうち、1,6−分岐グルコースの残基に乳酸が結合したことを特徴とする、骨関節炎を治療、または緩和するための骨関節炎治療剤。
- 前記β−1,3−1,6−分岐D−グルカンは、前記グルコース1〜20個ごとにグルコースが1,6結合をする、請求項1に記載の骨関節炎治療剤。
- 製薬学的有効量の請求項1または2に記載の骨関節炎治療剤を投与することを含む、人間を除いた動物の骨関節炎の治療、予防、または緩和方法。
- 前記骨関節炎治療剤を21.25mg/kg〜85mg/kgの投与量で投与する、請求項3に記載の人間を除いた動物の骨関節炎の治療、予防または緩和方法。
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JP2013510006A Active JP5747983B2 (ja) | 2010-05-12 | 2010-05-12 | 関節炎治療剤 |
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SG11201708106TA (en) * | 2015-04-08 | 2017-10-30 | Euglena Co Ltd | Suppressive agent for rheumatoid arthritis, prophylactic agent for rheumatoid arthritis, therapeutic agent for rheumatoid arthritis, and food for suppressing rheumatoid arthritis |
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US20020009463A1 (en) * | 2000-02-23 | 2002-01-24 | Jan Raa | Novel, non-antigenic, mucosal adjuvant formulation which enhances the effects of substances, including vaccine antigens, in contact with mucosal body surfaces |
JP2002204687A (ja) * | 2000-11-09 | 2002-07-23 | Onaka Yasushi | β−1.3−1.6グルカン(アウレオバシジウム培養液)の医療、保健、福祉、食品および各種産業分野での応用 |
JP3523220B2 (ja) * | 2001-05-14 | 2004-04-26 | 一光化学株式会社 | 皮膚塗布剤 |
US7018986B2 (en) * | 2002-09-20 | 2006-03-28 | Immudyne | Use of beta glucans for the treatment of osteoporosis and other diseases of bone resorption |
JP4375266B2 (ja) * | 2004-03-29 | 2009-12-02 | ダイソー株式会社 | β−1,3−1,6−D−グルカンおよびその用途 |
KR20040052608A (ko) * | 2004-04-14 | 2004-06-23 | 주식회사 글루칸 | 베타-글루칸을 유효성분으로 함유하는 골다공증 예방 및치료용 조성물 |
KR100603069B1 (ko) * | 2005-03-16 | 2006-07-24 | 주식회사 글루칸 | 수용성의 산성 베타 글루칸을 주성분으로하는 염증 치료용조성물 |
KR100684916B1 (ko) * | 2005-10-26 | 2007-02-20 | 주식회사 글루칸 | 베타 글루칸을 유효성분으로 포함하는 골절치료용 약학조성물 |
US7943666B2 (en) * | 2006-07-24 | 2011-05-17 | Trinity Laboratories, Inc. | Esters of capsaicin for treating pain |
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2010
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JP2013526515A (ja) | 2013-06-24 |
WO2011142488A1 (ko) | 2011-11-17 |
US20130079299A1 (en) | 2013-03-28 |
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