JP5519906B2 - 肝臓疾患の支持療法 - Google Patents
肝臓疾患の支持療法 Download PDFInfo
- Publication number
- JP5519906B2 JP5519906B2 JP2007508672A JP2007508672A JP5519906B2 JP 5519906 B2 JP5519906 B2 JP 5519906B2 JP 2007508672 A JP2007508672 A JP 2007508672A JP 2007508672 A JP2007508672 A JP 2007508672A JP 5519906 B2 JP5519906 B2 JP 5519906B2
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- Prior art keywords
- diltiazem
- liver
- thiamine
- membrane
- calcium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229940080350 sodium stearate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 1
- 239000011747 thiamine hydrochloride Substances 0.000 description 1
- 229960000344 thiamine hydrochloride Drugs 0.000 description 1
- 150000003544 thiamines Chemical class 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
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- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003253 viricidal effect Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
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- 102000038650 voltage-gated calcium channel activity Human genes 0.000 description 1
- 108091023044 voltage-gated calcium channel activity Proteins 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
- A61K31/51—Thiamines, e.g. vitamin B1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
肝臓内の細胞膜の構造および機能の進行性破壊は、ほとんど全ての形態の慢性の非悪性肝臓疾患の重要な要素である。それは、肝臓機能の全体的損傷に寄与し、細胞死を導き、そして一次疾患プロセスの効果を補足または増強する。
・その剤は、高濃度のNADPH2によって誘導されるフリーラジカルを吸収または破壊する抗酸化剤として作用すべきであり、そしてそれは、低酸素症および他の形態の酸化的損傷を起こす。
・その剤は、フリーラジカルが形成される予定であり、そしてそれらが損傷を与えている細胞内および膜内の両方で、それの膜保護および抗酸化剤効果を発揮すべきである。
・その剤は、ミトコンドリア内で抗酸化剤として作用すべきである。
・その剤は、ミトコンドリアのカルシウム・チャネルを阻害して、低酸素症の間に起こるNADPH2の上昇を減じるべきである。
・その剤は、細胞のカルシウム過負荷の条件下で、ミトコンドリアに、ATPを生成することを継続させるべきである。
・その剤は、カルシウムの濃度を増大させることによって、ホスホリパーゼの活性を防止すべきである。
・その剤は、血液供給における減少が、細胞膜での細胞膨張および酸化的変化を引き起すことを防止または減じるべきである。
●B型およびC型肝炎、および他の形態を含めたウイルス性肝炎
●アルコール性肝炎
●肝硬変
●門脈高血圧
●毒素、薬剤、および異常な免疫状態によって引き起される他の形態の非悪性肝臓疾患
●化学療法中の肝臓機能不全
●放射線療法後の肝臓機能不全
●加齢しつつある肝臓
において肝臓を保護するために使用されうる。
細胞膜(ジルチアゼム)および細胞質ゾル(チアミン)内のジルチアゼムおよびチアミンの抗酸化剤効果は、付加的であり、そしておそらく独立であると思われる。
経口で投与される製剤からの活性な医薬品の徐放を有効にする多くの技術がある。これらの方法は、カプセル、錠剤、または他の媒体の崩壊を遅延することが意図される技術、カプセル、錠剤、または他の媒体の溶解性を遅延することが意図される技術、および活性剤が、その物質が重合体または他の大型分子から放出されるまで吸収が起こりえないように重合体または他の大型分子に結合されうる技術を含みうる。徐放のこのような様々な方法を達成する手段は、多様であり、そしてシェラック・コーティングの層のような周知の古い方法、そして合成およびセルロース重合体を使用するか、または少なくとも1つの孔を有する膜被覆剤を供するより現代的な技術を含む。
インビトロ研究 ジルチアゼムの肝臓保護効果
細胞膜におけるジルチアゼムの保護効果を、3週齢メス子豚の肝臓から得た子豚の肝臓のミクロソーム膜で実験した。ミクロソーム:分画を、1時間、37℃で、血管活性D−ジルチアゼム、または血管不活性L−ジルチアゼム(0−1000μM)のいずれかで、続いてフリーラジカルジェネレーターAAPH(2,2’−アゾビス−(2−アミジノプロパン)ジヒドロクロリド)の1時間で処理した。インキュベーションに続いて、ミクロソーム混合物を、2000rpmで遠心分離して、過剰のAAPHおよびジルチアゼムを除去した。その後、ミクロソーム膜中の反応性酸素種介在脂質過酸化の範囲を、蛍光標識ジクロロフルオレッセン(DCF、15分間10μ)を使用して測定した。画像解析。画像解析から得られた結果は、AAPHで誘発されるフリーラジカル放出におけるDCF活性での減少によって示されるとおり、L−ジルチアゼムでなくD−ジルチアゼムが、膜酸化の用量依存阻害を生じることを示した。
ジルチアゼム+チアミンの肝臓保護効果
肝性肝臓ミクロソームを、先に記述されるとおりの4匹の健全な子豚から得た。研究のために必要とされるまで、ミクロソームを、−80℃で保存した。ミクロソームの濃度は、1mg/mlであった。ジルチアゼム濃度は、50および500μMであった。試験されたチアミン濃度は、10、50および100μMを含んだ。フリーラジカルジェネレーターAAPHは、1mMであった。その研究は、我々の先の報告で記述されるとおり、プレートリーダーにより染料DCFHの蛍光活性を解析することによって、肝臓の脂質過酸化産物を検出した。
ミトコンドリアにおけるジルチアゼム+チアミンの肝臓保護効果
ミトコンドリアの懸濁液における研究は、エネルギー生産におけるジルチアゼムおよびチアミンの組合せの効果を試験するために始められうる。
患者における肝臓保護効果
以下の臨床プロトコールを使用して、低用量、徐放のジルチアゼムの肝臓保護効果を研究および実証しうる。
抗ウイルス療法で治療されていなかったか、またはリバビリンと共に、またはなしにインターフェロンでの治療に応答しなかった、C型肝炎を有する10名またはそれより多くの患者を、研究に召集して、徐放製剤中の25mgおよび50mgのジルチアゼムの効果を実験する。各患者は、ALT(アミノ−アラミン−トランスフェラーゼ)の上昇した血漿濃度によって立証されるとおり、安定であるが、異常な肝臓機能試験を示すにちがいない。HIV感染を示さないか、または明らかなアルコール摂取問題がある患者に優先すべきである。各製剤は、14日間、1日1回用量として与えられる。
抗酸化剤効果とミトコンドリアのカルシウム阻害の両方を有する肝臓選択的膜安定化剤(ジルチアゼムのような)の使用は、補完療法であるので、そのような薬剤の肝臓選択的製剤は、頻繁に、ウイルス性肝炎の治療において抗ウイルス処置(リバビリンのような)と、アルコール性肝炎の場合にはチアミン、または門脈高血圧の場合にはプロプラノロールと同時処方される。
カルシウム・チャネル・ブロッカーおよび比較的親水性の抗酸化剤の放出制御製剤
以下の放出制御製剤を、製剤しうる。
コア
薬剤成分:ジルチアゼム(20から70mgまで)チアミン(1から20mgまで)の2から70%w/wの混合物
結合剤:3から98重量%まで
被覆剤
膜重合体:50から99%まで
灌流促進剤:0から40%まで
可塑剤:0から30%まで
12時間かけての放出のための以下の低用量の徐放製剤を、米国特許第5,834,024号の方法によって製剤しうる。
コア
ジルチアゼム:30mg
チアミン:3mg
ヒドロキシプロピルセルロース3.5g
糖球体28g
被覆剤
ユードラジッドRL:0.5g
ユードラジッドRS:6.8g
トリエチルシトレート 0.7g
ラウリル硫酸ナトリウム 0.2g
タルク 4.1g
以下の徐放カプセル製剤を、米国特許第6,074,669号の方法によって製剤しうる。
成分 mg/カプセル
塩酸ジルチアゼム 40
チアミン2ユードラジッドL−100 65
メトセルK−100−M 175
ヒドロキシプロピルセルロース(HPC−M) 125
ラクトース 100
ステアリン酸マグネシウム 7
エアロジル 8
総量 720
米国特許第5,616,345号の方法によって、以下の方法を使用して、ジルチアゼムとチアミンとの制御された放出製剤を製剤しうる。
イソプロパノール中の5%エチルセルロース20重量部
の被覆剤溶液を使用して、標準被覆鍋中で、粉末を、スターチ/糖の種(直径0.6−0.71mm)(0.5kg)に塗布しうる。
その後、製剤されるべきペレットの活性コアは、
イソプロパノール中の5%エチルセルロース90重量部
イソプロパノール中の5%ポリビニルピロリドン10重量部
より構成される膜溶液によって包まれうる。
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Claims (9)
- ウイルス性肝炎を罹患しているヒト対象の治療のための経口投与用の医薬品を製造するためのジルチアゼムとチアミンの使用であって、前記ジルチアゼムと前記チアミンは徐放製剤に含まれ、前記投与用の1日当たりのジルチアゼムの用量が、20から70mgまでの範囲内にあり、そして前記投与用の1日当たりのチアミンの用量が、1から20mgまでの範囲内にある、ジルチアゼムとチアミンの使用。
- 前記ジルチアゼムが、1日当たり50mg未満の用量で投与されるために前記徐放製剤に含まれる、請求項1に記載の使用。
- 前記ジルチアゼムが、1日当たり20から50mgまでの用量で投与されるために含まれ、そして前記チアミンが、1日当たり1から5mgまでの用量で投与されるために含まれる、請求項1に記載の使用。
- 前記対象が、C型ウイルス性肝炎に罹患している、請求項1〜3のいずれかに記載の使用。
- 経口投与用の徐放組成物の形態でウイルス性肝炎を治療するための医薬組成物であって、ジルチアゼムとチアミンが徐放製剤中に含まれ、前記ジルチアゼムが1日当たり20から70mgまでの用量を供するように存在し、そして前記チアミンが1日当たり1から20mgまでの用量を供するように存在する、医薬組成物。
- 20から70mgまでのジルチアゼムの一日の投与量、および1から5mgまでの範囲にあるチアミンの一日の投与量を供するための、請求項5に記載の医薬組成物。
- ジルチアゼムの平均日用量が、20から50mgまでの範囲内にある、請求項6に記載の医薬組成物。
- 前記徐放組成物が、高分子化合物で被覆されたマルチ微粒子、高分子化合物で被覆された錠剤、高分子化合物で被覆されたミニ錠剤、および親水性マトリックス錠剤より構成される群から選択される形態にある、請求項5に記載の医薬組成物。
- カプセル、錠剤またはカプレットの形態にある、請求項5に記載の医薬組成物。
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AU2004902151 | 2004-04-22 | ||
AU2004902151A AU2004902151A0 (en) | 2004-04-22 | Method of supportive treatment of liver disease | |
AU2004902447 | 2004-05-07 | ||
AU2004902447A AU2004902447A0 (en) | 2004-05-07 | Method of supportive treatment of liver disease | |
PCT/AU2005/000561 WO2005102353A1 (en) | 2004-04-22 | 2005-04-21 | Supportive treatment of liver disease |
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JP (1) | JP5519906B2 (ja) |
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AR (1) | AR048832A1 (ja) |
CA (1) | CA2563058C (ja) |
HK (1) | HK1100206A1 (ja) |
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WO (1) | WO2005102353A1 (ja) |
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US20110274755A1 (en) * | 2004-04-22 | 2011-11-10 | Smith Howard J | Supportive treatment of liver disease |
AR048832A1 (es) * | 2004-04-22 | 2006-05-31 | Smith Howard J & Ass Pty Ltd | Tratamiento de soporte de enfermedades hepaticas |
EP2346519B1 (en) | 2008-10-02 | 2015-12-02 | George Zabrecky | Methods and formulations for treating chronic liver disease |
CN102573864A (zh) * | 2009-10-15 | 2012-07-11 | 霍华德·J·史密斯及同仁控股有限公司 | 肝病的治疗方法 |
JP2013139391A (ja) * | 2010-04-09 | 2013-07-18 | Hokkaido Univ | ウイルス感染抑制および/または感染症治療剤 |
US8809265B2 (en) | 2011-10-21 | 2014-08-19 | Abbvie Inc. | Methods for treating HCV |
US8466159B2 (en) | 2011-10-21 | 2013-06-18 | Abbvie Inc. | Methods for treating HCV |
DK2583677T1 (da) | 2011-10-21 | 2015-01-19 | Abbvie Inc | Fremgangsmåder til behandling af HCV omfattende mindst to direktevirkende antivirale midler, ribavirin, men ikke inteferon |
US8492386B2 (en) | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
FR3033701B1 (fr) | 2015-03-19 | 2021-01-15 | Univ Claude Bernard Lyon | Nouvelles compositions antivirales pour le traitement de la grippe |
JP7129703B2 (ja) | 2016-04-28 | 2022-09-02 | エモリー ユニバーシティー | アルキン含有ヌクレオチド及びヌクレオシド治療組成物並びにそれらに関連した使用 |
FR3081325B1 (fr) * | 2018-05-23 | 2020-10-09 | Univ Claude Bernard Lyon | Diltiazem pour son utilisation dans le traitement des infections microbiennes |
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US452555A (en) * | 1891-05-19 | Ice-pick | ||
US4917899A (en) | 1983-12-22 | 1990-04-17 | Elan Corporation Plc | Controlled absorption diltiazem formulation |
US5002776A (en) | 1983-12-22 | 1991-03-26 | Elan Corporation, Plc | Controlled absorption diltiazem formulations |
IE56999B1 (en) | 1983-12-22 | 1992-03-11 | Elan Corp Plc | Pharmaceutical formulation |
US4894240A (en) | 1983-12-22 | 1990-01-16 | Elan Corporation Plc | Controlled absorption diltiazem formulation for once-daily administration |
US5219621A (en) | 1987-10-16 | 1993-06-15 | Elan Corporation, Plc | Methods of treatment with diltiazem formulations |
US5854233A (en) * | 1993-09-08 | 1998-12-29 | Pharmacy And Therapeutic Advisory Consultancy Ltd. | Method of treating liver disease and like indications with vasodilating agents |
US5834024A (en) * | 1995-01-05 | 1998-11-10 | Fh Faulding & Co. Limited | Controlled absorption diltiazem pharmaceutical formulation |
DE19515971A1 (de) * | 1995-05-02 | 1996-11-07 | Bayer Ag | Kombinationspräparate mit vaskulärer Wirkung |
US20030049840A1 (en) * | 1998-10-07 | 2003-03-13 | Demetriou Achilles A. | Cell preconditioning and cryopreservation medium |
JP3923793B2 (ja) * | 2001-11-30 | 2007-06-06 | 大日本印刷株式会社 | 画像形成方法及び画像形成物 |
EP1340622B1 (en) * | 2002-03-01 | 2006-12-13 | Dai Nippon Printing Co., Ltd. | Thermally transferable image protective sheet, method for protective layer formation, and record produced by said method |
AR048832A1 (es) * | 2004-04-22 | 2006-05-31 | Smith Howard J & Ass Pty Ltd | Tratamiento de soporte de enfermedades hepaticas |
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AR048832A1 (es) | 2006-05-31 |
CA2563058A1 (en) | 2005-11-03 |
CA2563058C (en) | 2012-10-16 |
US20070292507A1 (en) | 2007-12-20 |
WO2005102353A1 (en) | 2005-11-03 |
IL178366A0 (en) | 2007-02-11 |
EP1755615A1 (en) | 2007-02-28 |
EP1755615B1 (en) | 2013-11-27 |
IL178366A (en) | 2014-01-30 |
HK1100206A1 (en) | 2007-09-14 |
EP1755615A4 (en) | 2009-07-29 |
US7977326B2 (en) | 2011-07-12 |
KR20070014185A (ko) | 2007-01-31 |
JP2007533667A (ja) | 2007-11-22 |
KR101312010B1 (ko) | 2013-09-30 |
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