JP2010059096A - C型肝炎ウイルス産生抑制剤 - Google Patents
C型肝炎ウイルス産生抑制剤 Download PDFInfo
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- JP2010059096A JP2010059096A JP2008226425A JP2008226425A JP2010059096A JP 2010059096 A JP2010059096 A JP 2010059096A JP 2008226425 A JP2008226425 A JP 2008226425A JP 2008226425 A JP2008226425 A JP 2008226425A JP 2010059096 A JP2010059096 A JP 2010059096A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
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Abstract
Description
(i)4位炭素及び8位炭素の結合
(ii)4位炭素及び6位炭素の結合
(iii)4位炭素及び8位炭素の結合並びに2位炭素及び7位酸素の結合
Proanthocyanidin BP 1 (Unspecified),
Proanthocyanidin RP 4 (C129 H106 O67),
Proanthocyanidin RP 3 (C136 H120 O70),
Proanthocyanidin CS 4 (C136 H120 O70),
Proanthocyanidin CS 3 (C127 H128 O69),
Proanthocyanidin CS 2 (C113 H110 O62),
Proanthocyanidin CS1 (C121 H118 O65),
Proanthocyanidin RP 2 (C120 H114 O64),
Proanthocyanidin RP1 (C125 H130 O69),
Proanthocyanidin T4 (C128 H122 O65),
Proanthocyanidin T3(C105 H102 O59),
Proanthocyanidin T2 (C67 H54 O29),
Proanthocyanidin T1 (C87 H72 O43),
Proanthocyanidin C1 (C45 H38 O18)
(1)前処理加工:
葉、皮、果実、茎、根等の全草部位に応じて、あらかじめ水洗、濾別などにより物理的に不純物を除く。あるいは、葉緑素、繊維素等、本発明のPAC以外の成分を溶媒で留去することもできる。この溶媒には、留去する対象により異なるが、クロロホルム、ヘキサン、アセトン等を用いることができる。生の素材は、そのまま粉砕しても乾燥後粉砕して、粉末状で次工程に供してもよいし、生素材からの搾汁液、抽出液を次工程に供してもよい。搾汁又は抽出液は、濃縮又は乾燥して粉末状で次工程に供してもよい。
前工程で得られた加工処理物は、次に溶媒抽出する。溶媒抽出には、下記の溶媒を適宜組み合わせて、必要に応じ多段抽出する。使用する抽出溶媒は特に制限されないが、水又は水と相溶性のある極性溶媒の使用が好適である。水と相溶性のある極性溶媒としては、水、メタノール、エタノール、プロパノール、ブタノール等の炭素数1〜4の低級アルキルアルコール;エチレングリコール、ブチレングリコール、プロピレングリコール、グリセリンなどの多価アルコールを挙げることができる。アルコールとしては、安全性の観点から低級アルコール、特にメタノールやエタノールの使用が実際的である。
得られた抽出物は、必要に応じてろ過又は遠心分離により固形物を除去する。濾液は、次工程の要求に応じてそのまま用いるか、又は溶媒を留去して一部濃縮もしくは乾燥して用いてもよい。必要に応じて、これらの抽出、濃縮物は精製する。精製方法は、特に限定されないが、例えばカラム法や溶媒による分割法などを挙げることができる(例えば、WO2000−64883号公報参照)。
本実施例において、抗レプリコン活性試験(レプリコンアッセイ)及び細胞毒性試験は、以下のように行った。
HCV−RNAのコピー数を定量するために、HCV−RNAの中にレポーター遺伝子としてホタル由来のルシフェラーゼ遺伝子を導入した。ルシフェラーゼ遺伝子の導入は、Kriegerら(Kriegerら、 “J. Virol.”、 2001年、 第75巻、 p.4614−4624参照)の方法に従い、HCV遺伝子のIRES(Internal Ribosome Entry Site)の直下に、ネオマイシン耐性遺伝子と融合する形で行った。In vitroで、当該RNAを合成後、エレクトロポレーション法でHuh−7細胞に導入し、G418耐性クローンとして単離した。ホタル・ルシフェラーゼHCVレプリコン細胞(3−1)を、5%ウシ胎児血清(Hyclone cat. no. SH30071.03)を含むダルベッコMEM(Gibco cat. no. 10569−010)に懸濁し、96穴プレートに5000細胞/ウェルで播種し、5%CO2、37℃の条件で一夜培養した。
細胞毒性の測定には、Cell counting kit−8((株)同仁化学研究所カタログNo.CK04)を用いた。クリアープレートに10μlのCell counting kit−8を添加し、37℃で30〜60分間保温した。96穴プレートリーダーにて、波長450nm、対照波長630nmで吸光度を測定した。細胞未添加の値を、バックグランドとして全ての値から差し引き、試料未添加の値を阻害率0%として、各試料のCC50(50%細胞阻害濃度)を算出した。
ブルーベリー葉に含まれるHCVレプリコン産生抑制活性を有する化合物の同定
1.抽出及び液−液分配
凍結粉砕したラビットアイブルーベリー(Vaccinium virgatum Aiton)の葉1gに、メタノール100mlを加えて15分間浸透抽出した。デカンテーションにより上澄みを回収し、No.2の濾紙でろ過し、メタノール抽出物(MeOH Extract)440mgを得た。そのメタノール抽出物にクロロホルム100mlを加え、遠心分離(1,000ppm、10min)によって上清部と沈殿部とに分け、沈殿部をメタノールに溶解後、エバポレーターで濃縮し、凍結乾燥した(CMW−ppt:63.7mg)。さらに、上清部に水150mlとMeOHを加え、液−液抽出を行い、クロロホルム相を回収した。さらにクロロホルムを100ml加えてよく振盪し、クロロホルム相を回収し、先の回収液をと合わせエバポレーターで濃縮後、凍結乾燥した(CMW−C:56.3mg)。水相も濃縮後、凍結乾燥した(CMW−W:284.2mg)。
(HPLCによる溶出位置の確認)
まず、HCVレプリコン産生抑制活性を有する化合物の逆相HPLCによる溶出パターンの確認を行った。HPLCは、UV検出器とフォトダイオードアレイ検出器を備えた「Prominence System」((株)島津製作所製、商品名)を用いた。その他の分離条件は下記に示す。
・装置:Shimadzu Prominence LC−20A
・カラム:Atlantis dC18, 4.6mm I.D.×150mm, 3μm(Waters製)、40℃
・移動相(溶出液):(A)0.05%(v/v)トリフルオロ酢酸
(B)アセトニトリル
・グラジエント:溶出液B 15%(0分)→25%(12.5分)→100%(17.5分)→100%(25分)
・移動相流速:0.70ml/分
・検出器:UV 254nm
最初の分取は、分離カラムを「Atlantis T3」(4.6mm×150mm、3μm、Waters製)の逆相カラムを用いた他は、上記と同じシステムを用いて行った。移動相(溶出液)の組成も上記と同じにしたが、グラジエントプログラムは以下のように変更した。
溶出液B 30%(0分)→30%(7.5分)→100%(12.5分)→100%(20分)
装置とカラムは分取1と同じ条件にし、グラジエントプログラムを以下のようにした。
溶出液B 20%(0分)→20%(7.5分)→100%(12.5分)→100%(20分)
溶出液Bをアセトニトリルからメタノールに変更し、以下のプログラムで分取を行った。
溶出液B 40%(0分)→65%(12.5分)→100%(17.5分)→100%(25分)
HPLCによる分取によって精製したHCVレプリコン産生抑制の活性画分の構成元素をEPMA(「EPMA−1600」、(株)島津製作所製、商品名)を用いて以下の条件で測定した。
加速電圧:15kV、ビーム電流:100nA、ビーム径:50μm
サンプルは前もってカーボン蒸着を行った。図6に示されるように、この精製画分は、窒素(N)を含まず、炭素(C)と酸素(O)と水素(H)で構成されていることが判明した。
ブルーベリー葉からHCVレプリコン産生抑制活性を指標にして調製した精製化合物の組成を推定するため、LC/MS−IT−TOF(Liquid Chromatography/Mass Spectrometry−Ion Trap−Time of Flight)を用いて解析を実施した。装置は、フォトダイオードアレイを装備した「Prominence HPLCシステム」((株)島津製作所製)に「MS−IT−TOF」((株)島津製作所製)検出器を備えたシステムを使用した。その他の分析条件は以下に示す。
・装置:Shimadzu LC/MS−IT−TOF
・カラム:Atlantis T3, 2.1mm I.D.×100mm, 3μm(Waters製)、40℃
・移動相(溶出液):(A)0.05%(v/v)トリフルオロ酢酸
(B)アセトニトリル
・グラジエント:B 10%(0分)→25%(7.5分)→100%(12.5分)→100%(20分)
・移動相流速:0.25ml/分
・検出器1:フォトダイオードアレイ280nm
・検出器2:APCI−MS
(Negative−Ion Mode、インターフェイス電圧:−3.0kV、インターフェイス温度:450℃、CDL温度:200℃、ネブライズガス流量:2.0L/分、ドライガス圧力:70kPa、ヒートブロック温度:200℃)
下記文献の方法に従い、ポーター法を用いて精製画分の分析を行った。
・Porter L. J. et al.、 “Phytochemistry”、 1986年、 第25巻、 p.223−230
・Shoji T. et al.、 “J. Agric. Food Chem.”、 2006年、 第54巻、 p.884−892
精製画分をメタノールに溶解し、その200μlに5%(v/v)塩酸を含む1−ブタノール750μlと1%(w/v)硫酸鉄アンモニウムを含む2mol/L塩酸50μlを添加し、105℃で40分間反応させた。反応液を室温に戻し、540nmにおける吸光度を測定した。コントロールとしてプロシアニジンB2(Sigma社製)を用いた。
LC/MSを用いて上記ポーター法反応分解物の分析を実施した。もしブルーベリー葉から精製したレプリコン産生抑制活性を有する化合物がPACであれば、アントシアニジンを検出するはずである。LC/MSに用いた装置及び条件は下記の通りである。
・装置:Shimadzu LC/MS−IT−TOF
・カラム:Atlantis T3, 2.1mm I.D.×100mm, 3μm(Waters製)、40℃
・移動相(溶出液):(A)5mMギ酸アンモニウムを含む0.5%(v/v)ギ酸
(B)アセトニトリル
・グラジエント:溶出液B 10%(0分)→40%(15分)→100%(15分)→100%(22.5分)
・移動相流速:0.25ml/分
・検出器1:フォトダイオードアレイ540nm
・検出器2:ESI−MS
(Positive−Ion Mode、インターフェイス電圧:4.5kV、
CDL温度200℃、ネブライズガス流量:1.5L/分、
ドライガス圧力:200kPa、ヒートブロック温度:200℃)
上記実施例の結果より、ブルーベリー葉由来のHCVレプリコン産生抑制活性化合物の主成分がPACであることが示された。次いでここでは、PACの構成単位、結合様式及び重合度を調べるために、Guyotらの方法(Guyot S. et al.、 “J. Agric. Food Chem.”、 2001年、 第49巻、 p.14−20参照)に基づきチオール開裂分析を行った。
式
平均重合度(mDP)=[ターミナルユニット+エクステンションユニット]/[ターミナルユニット]
標品としてカテキンとエピカテキンを用い、チオール開裂の反応中に生じる遊離のフラバン−3−オールの異性化も考慮に入れて補正を行った(Gu L. et al.、 “J. Agric. Food Chem.”、 2002年、 第50巻、 p.4852−4860参照)。
ブルーベリー葉由来活性化合物PACを、メタノールで1mg/mlに調製し、50μlを取り、3.3%(v/v)塩酸メタノール50μlを加え、5%(v/v)トルエン−α−チオール100μlを加え、50℃で30分間反応させた後、反応液を5倍にメタノールで希釈し、HPLCに供した。HPLC条件を以下に示す。
・装置:Shimadzu Prominence LC−20A
・カラム:Atlantis T3, 4.6mm I.D.×150mm, 3μm(Waters製)、40℃
・移動相(溶出液):(A)0.05%(v/v)トリフルオロ酢酸
(B)アセトニトリル
・グラジエント:溶出液B 15%(0分)→25%(10分)→100%(40分)→100%(45分)
・移動相流速:0.70ml/分
・検出器:UV280nm
上記反応物を同様にLC/MSに供し各検出ピークの同定を行った。分析条件は下記に示す。
・装置:Shimadzu LC/MS−IT−TOF
・カラム:Atlantis T3, 2.1mm I.D.×100mm(Waters製)
・移動相(溶出液):(A)0.05%(v/v)トリフルオロ酢酸
(B)アセトニトリル
・グラジエント:溶出液B 15%(0分)→25%(10分)→60%(40分)→100%(40分)
・移動相流速:0.25ml/分
・検出器1:フォトダイオードアレイ280nm
・検出器2:ESI−MS
(Positive−Ion Mode、インターフェイス電圧:4.5kV、
CDL温度200℃、ネブライズガス流量:1.5L/分、
ドライガス圧力:200kPa、ヒートブロック温度:200℃)
式
mDP=[(ベンジルチオエーテル付加物×n)の総和+(遊離フラバン−3−オール×n)の総和]/[遊離フラバン−3−オールの総和]
PACを含有する素材の抽出及びそのレプリコン産生抑制活性
1.各素材からのPACの調製
実施例1の結果より、ブルーベリー葉由来のHCVレプリコン産生抑制活性を有する化合物がPACであることが示された。このPACは、上述のとおり、広く植物界から見いだされている。PACを含有することが報告されている下記に挙げる素材(試料1〜9及び試料N)を入手し、PAC画分を調製して、レプリコン産生抑制活性を調べた。
・試料2:ブルーベリー実
・試料3:サトイモ皮
・試料4:マツ樹皮抽出物(ピクノジェノールTM)
・試料5:ブドウ種子抽出物(グラヴィノールTM:キッコーマン株式会社)
・試料6:リンゴポリフェノール(アップルフェノンTM:アサヒビール株式会社)
・試料7:グランベリー(クランベリーパウダー:キッコーマン株式会社
・試料8:ストロベリー果実(ストロベリーパウダー:ナチュリ・フルーツ)
・試料9:落花生種皮
・試料N:クロトン樹液(Sangre de Drago; Raintree Nutrition, Inc.)
ラビットアイブルーベリー種(Vaccinium virgatum Aiton)の生葉を、凍結乾燥(FTS System、Dura−Top MP&Dura−Dry MP)し、超遠心粉砕機(MRK&RETSCH、EM−1)で粉砕することで、ブルーベリー葉の凍結乾燥粉末を得た。この凍結乾燥粉末10gに100mlのヘキサンを加え、室温で30分間振盪抽出し、デカンテーションにより残渣を回収した。この抽出操作を3回繰り返し、ブルーベリー葉ヘキサン洗浄物を得た。
試料2、3及び9は、素材を直接入手して、試料4〜9は、PACを含有している製品を購入して、100%メタノールで抽出を行い、減圧濃縮後、凍結乾燥した。その後、上記調製と同じように、セファデックスLH−20でPAC画分を調製した。
各起源から抽出された上記試料1〜9及びNについて、上述のポーター法とチオール開裂反応を用いて、PAC純度、各フラバン−3−オール組成及び平均重合度を調べた。表4に、各試料のPAC画分の平均重合度及び組成を示す。
ブルーベリー葉由来PACの大量調製
ブルーベリー葉凍結乾燥粉末105gに、クロロフィルを除く目的でアセトン1200mlを加え、室温で10分間振盪抽出し、デンカンテーションにより上清を除去した。この操作を5回繰り返し、アセトン洗浄物を得た。その後、上記試料1の調製と同じ方法で、メタノール抽出物を約30g得た。但し、使用した各溶媒量は1200mlずつとした。
表4〜6から明らかなように、チオール開裂分析で組成分析をした結果、PAC中のプロデルフィニジンユニット(R1=R2=R3=OH)の含量が高いと、試料Nのように、IC50が1.0μg/ml以上、かつIC50に対するCC50の比(Ratio)が10以下となり、抗HCV剤としては使用できない。すなわち、本発明のPAC組成物は、重合度が3以上で、デルフィニジン含量が低いほど、レプリコン産生抑制活性値が高くなり、抗HCV剤として有用である。
Claims (8)
- プロアントシアニジンからなる組成物を有効成分とするC型肝炎ウイルス産生抑制剤であって、
前記組成物中のプロアントシアニジンは、下記一般式(1)
[式(1)中、R1及びR3はそれぞれ独立に水素原子又は水酸基、R2は水酸基、R4は水素原子又は一価の有機基を、それぞれ示す。]
で表されるフラバン−3−オール骨格が、下記(i)、(ii)又は(iii)の結合様式で3以上互いに結合した構造を有しており、
(i)4位炭素及び8位炭素の結合
(ii)4位炭素及び6位炭素の結合
(iii)4位炭素及び8位炭素の結合並びに2位炭素及び7位酸素の結合
前記組成物中のプロアントシアニジンにおける全フラバン−3−オール骨格のうち、前記一般式(1)中のR1及びR3がいずれも水酸基であるフラバン−3−オール骨格の割合が40%以下である、C型肝炎ウイルス産生抑制剤。 - 前記一般式(1)中のR4が、置換基を有していてもよいガレート基を示す、請求項1記載のC型肝炎ウイルス産生抑制剤。
- C型肝炎ウイルス活性を50%阻害するのに要する濃度が、細胞増殖活性を50%阻害するのに要する濃度に対し1/10以下である、請求項1又は2記載のC型肝炎ウイルス産生抑制剤。
- 前記組成物中のプロアントシアニジンが、前記一般式(1)で表されるフラバン−3−オール骨格が、前記(i)、(ii)又は(iii)の結合様式で5〜10互いに結合した構造を有する、請求項1〜3のいずれか一項に記載のC型肝炎ウイルス産生抑制剤。
- 請求項1〜4のいずれか一項に記載のC型肝炎ウイルス産生抑制剤を含有する、C型肝炎ウイルス由来の肝疾患の治療剤。
- 請求項1〜4のいずれか一項に記載のC型肝炎ウイルス産生抑制剤を含有する、C型肝炎ウイルス由来の肝疾患の発症又は進展抑制剤。
- 請求項1〜4のいずれか一項に記載のC型肝炎ウイルス産生抑制剤を含有する、C型肝炎ウイルス由来の肝疾患の、発症若しくは進展の抑制用又は治療用医薬組成物又はそのプロドラッグ。
- 請求項1〜4のいずれか一項に記載のC型肝炎ウイルス産生抑制剤を含有する、C型肝炎ウイルス由来の肝疾患の、発症若しくは進展の抑制用又は治療用飲食組成物。
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JP2014510740A (ja) * | 2011-03-28 | 2014-05-01 | サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィク(セー.エヌ.エール.エス) | C型肝炎ウイルスによる感染に対する抗ウイルス剤としてのエピガロカテキンガレートの使用 |
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WO2014188325A1 (en) * | 2013-05-20 | 2014-11-27 | Indus Biotech Private Limited | A method of managing hepatic fibrosis, hepatitis c virus and associated condition |
CN105473129A (zh) * | 2013-06-26 | 2016-04-06 | 戴安娜植物科学公司 | 在化妆品、饮食补充剂和/或功能食物中掺入培养的越橘细胞 |
CN104628697A (zh) * | 2013-11-15 | 2015-05-20 | 李锦梁 | 一种原青花素浸提工艺 |
TWI611806B (zh) * | 2016-11-15 | 2018-01-21 | 景鑫生物科技股份有限公司 | 南洋山蘇水萃物的用途 |
WO2019204471A1 (en) * | 2018-04-20 | 2019-10-24 | Yale University | Treatment of hepatitis c |
CN109096236A (zh) * | 2018-08-13 | 2018-12-28 | 安徽兆龙生物科技有限公司 | 蓝莓原花青素生物提取方法 |
WO2022205137A1 (zh) * | 2021-03-31 | 2022-10-06 | 贝尔克斯生技股份有限公司 | 高聚原花青素组合物及其应用 |
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JP2003277271A (ja) * | 2002-03-26 | 2003-10-02 | Norioki Ko | 抗癌剤 |
JP2006511509A (ja) * | 2002-11-22 | 2006-04-06 | フェノーリックス、エルエルシー | 全フェノールに富む組成物を製造するための効果的方法 |
WO2005030200A1 (ja) * | 2003-09-26 | 2005-04-07 | Kirin Beer Kabushiki Kaisha | 自己免疫疾患治療剤 |
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JP2007119398A (ja) * | 2005-10-28 | 2007-05-17 | Japan Science & Technology Agency | C型肝炎ウイルス産生抑制材料とその製法 |
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JP2014510740A (ja) * | 2011-03-28 | 2014-05-01 | サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィク(セー.エヌ.エール.エス) | C型肝炎ウイルスによる感染に対する抗ウイルス剤としてのエピガロカテキンガレートの使用 |
JP2012250940A (ja) * | 2011-06-03 | 2012-12-20 | Kumamoto Univ | C型肝炎の予防、治療又は改善用組成物 |
JP2018030998A (ja) * | 2016-07-29 | 2018-03-01 | ザ プロクター アンド ギャンブル カンパニー | タンニンを含む組成物の使用 |
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US8846751B2 (en) | 2014-09-30 |
JP4892690B2 (ja) | 2012-03-07 |
US20110288164A1 (en) | 2011-11-24 |
US20100055065A1 (en) | 2010-03-04 |
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