JP4377586B2 - 炎症性疾患治療用のニコチン性受容体アゴニスト - Google Patents
炎症性疾患治療用のニコチン性受容体アゴニスト Download PDFInfo
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- JP4377586B2 JP4377586B2 JP2002574950A JP2002574950A JP4377586B2 JP 4377586 B2 JP4377586 B2 JP 4377586B2 JP 2002574950 A JP2002574950 A JP 2002574950A JP 2002574950 A JP2002574950 A JP 2002574950A JP 4377586 B2 JP4377586 B2 JP 4377586B2
- Authority
- JP
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- Prior art keywords
- nicotine
- dmpp
- cells
- inflammatory
- nicotinic
- 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.)
- Expired - Fee Related
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
マウスの長期誘発過敏性肺臓炎(HP)に対するニコチン性アゴニストの効果
実施例1:生体内でのHP研究
ニコチンによるニコチン性受容体の刺激が、炎症性サイトカインの抑制および特異抗原による細胞活性化の阻害反応により、HP抗原に対する免疫応答を下方制御しているのではないかという仮説を立てた。
実施例2:サイトカイン発現に対するニコチン性アゴニストの効果を示す試験管内での研究
試験管内モデルにおけるニコチンの抑制作用に関与する機構をさらに明らかにするために、肺胞マクロファージ細胞株を用いた。
実施例3:共刺激分子の発現に対するニコチン性アゴニストの試験管内での効果
B7(CD80)分子の発現に対するニコチンおよびDMPPの効果を試験管内で分析した。AMJ2-C11細胞(マウス肺胞マクロファージ、ATCCより)を40μMのニコチンまたはDMPPとともにインキュベートし、LPS(0.1μg/mL)またはSR抗原(50μg/mL)で48時間刺激した。処理を行った細胞におけるCD80の発現率は、未処理細胞(LPSもしくはSRで刺激し、ニコチンやDMPPなしでインキュベート)で見られる発現のほぼ半分であった(図8(a)および(b))。
実施例4:ヒトBAL細胞(AMおよびリンパ球)に対する研究
一つの目的は、DMPPまたは類似薬で患者を治療することだったので、HP患者由来のリンパ球に対するこの薬物の効果を検証した。HP患者に対してBAL(気管支肺胞洗浄)行った。他のBAL細胞からリンパ球を単離し、PHAで刺激して、DMPPとともにインキュベートした。DMPPの用量応答を、IFN-γに対するサイトカインのmRNA発現量を(RT-PCRにより)分析した(図9)。
実施例5:他のニコチン性アゴニストの短期SR誘発急性炎症に対する効果の調査
Saccharopolyspora rectivirgula(SR)抗原(農夫肺の原因物質)をマウスの鼻腔内に滴下すると、肺において顕著な炎症反応が誘発される。好中球は、炎症部位において漸加するまずはじめの炎症細胞である。DMPP(0.5 mg/kg)、ニコチン(0.5 mg/kg)およびエピバチジン(2μg/kg)でマウスを治療したところ、SR誘発炎症に対して著しい抑制効果が現れた(図11)。ニコチン性アゴニストを6時間おきに50μL量で鼻腔内投与し、SRを点滴し24時間後にマウスを屠殺にした。
II−喘息様の炎症
実施例6:生体内喘息モデル
類似の実験を、オバルビミン感作マウスにおいて行った。DMPPは吸入したアレルゲンおよびメタコリンに対する炎症反応と反応亢進の両方を抑制すると言われている。
AHRの測定
麻酔し、気管切開を行い、コンピュータ制御人口呼吸器(FlexiVENT)を用いて換気したマウスにおいて、メタコリンに応じた気道反応亢進(AHR)を測定した。
実施例7:IL-4 mRNA発現に対するアゴニスト処理の効果
IL-4は喘息の発症に関与することがよく知られているサイトカインであり、IL-4 mRNA発現に対するアゴニスト処理の効果も分析した(53)。ニコチンは用量40μMにおいてLPS誘導性のIL-4のmRNA発現を92%まで減少し、DMMPはIL-4のmRNA発現を完全にブロックした(図21)。以前に実証されたように、細胞をSR抗原で刺激した際はIL-4mRNAは全く発現しなかった(データ表示なし)。
実施例8:好酸球遊出に対する様々なアゴニストの作用
喘息における炎症の下方制御に対するニコチン性アゴニストの効果をさらに調査するた
めに、好酸球遊出に対する様々なアゴニストの作用を分析した。
実施例9:コラーゲンの生産に対するニコチン性アゴニストの効果
喘息は、その慢性化の原因となりうる上皮下コラーゲン沈着を含む気道構造変化を特徴とする。コラーゲンの合成と、繊維芽細胞によるその分解のバランスが崩れることが、気道構造変化のプロセスに関与するようである(56)。予備実験において、本発明者らは、一次正常繊維芽細胞がもたらすコラーゲンA1合成に対するニコチン性アゴニストの効果を調査した。コラーゲンA1遺伝子発現は、RT-PCRによって評価した。
Claims (12)
- 喘息、過敏性肺臓炎(HP)および慢性HPからなる群より選択される肺の炎症性疾患を緩和または予防するための薬剤の製造における、ニコチン、ジメチルフェニルピペラジニウムおよびエピバチジンから選択されるニコチン受容体アゴニストの使用。
- ニコチン受容体アゴニストが、ニコチン、ジメチルフェニルピペラジニウムおよびエピバチジンから選択される請求項1の使用。
- ニコチン受容体アゴニストがジメチルフェニルピペラジニウムである請求項1または2の使用。
- 肺の炎症性疾患が喘息である請求項1から3のいずれかの使用。
- 気管支拡張薬、コルチコステロイド、抗ロイコトリエンおよび免疫抑制剤から選択される他の物質をさらに含む、請求項1から4のいずれかの使用。
- 薬剤が、経口用、舌下用、腹腔内用、静脈内注入用、吸入用、気管内用、鼻用、非経口用、局所用、直接注入用、点滴用または点眼用の薬剤形態である請求項1から5のいずれかの使用。
- 喘息、過敏性肺臓炎(HP)および慢性HPからなる群より選択される肺の炎症性疾患を緩和または予防するための、ニコチン、ジメチルフェニルピペラジニウムおよびエピバチジンから選択されるニコチン受容体アゴニストを含有する薬剤組成物。
- ニコチン受容体アゴニストが、ニコチン、ジメチルフェニルピペラジニウムおよびエピバチジンから選択される請求項7の組成物。
- ニコチン受容体アゴニストがジメチルフェニルピペラジニウムである請求項7または8の組成物。
- 肺の炎症性疾患が喘息である請求項7から9のいずれかの組成物。
- 気管支拡張薬、コルチコステロイド、抗ロイコトリエンおよび免疫抑制剤から選択される他の物質をさらに含む、請求項7から10のいずれかの組成物。
- 薬剤が、経口用、舌下用、腹腔内用、静脈内注入用、吸入用、気管内用、鼻用、非経口用、局所用、直接注入用、点滴用または点眼用の薬剤形態である請求項7から11のいずれかの組成物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002341952A CA2341952A1 (en) | 2001-03-23 | 2001-03-23 | Nicotinic receptor agonists for the treatment of inflammatory pulmonary diseases |
PCT/CA2002/000412 WO2002076434A2 (en) | 2001-03-23 | 2002-03-25 | Nicotinic receptor agonists for the treatment of inflammatory diseases |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2004523588A JP2004523588A (ja) | 2004-08-05 |
JP4377586B2 true JP4377586B2 (ja) | 2009-12-02 |
Family
ID=4168679
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2002574950A Expired - Fee Related JP4377586B2 (ja) | 2001-03-23 | 2002-03-25 | 炎症性疾患治療用のニコチン性受容体アゴニスト |
Country Status (18)
Country | Link |
---|---|
US (3) | US7601720B2 (ja) |
EP (1) | EP1370264B1 (ja) |
JP (1) | JP4377586B2 (ja) |
CN (1) | CN100528159C (ja) |
AT (1) | ATE378051T1 (ja) |
AU (1) | AU2002249023B2 (ja) |
BR (1) | BR0208305A (ja) |
CA (1) | CA2341952A1 (ja) |
DE (1) | DE60223508T2 (ja) |
DK (1) | DK1370264T3 (ja) |
ES (1) | ES2295331T3 (ja) |
IL (1) | IL157757A0 (ja) |
MX (1) | MXPA03008423A (ja) |
NO (1) | NO331674B1 (ja) |
NZ (1) | NZ528042A (ja) |
PL (1) | PL207880B1 (ja) |
RU (1) | RU2299731C2 (ja) |
WO (1) | WO2002076434A2 (ja) |
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PL364348A1 (en) | 2004-01-12 | 2005-07-25 | PHARMENA Sp.z o.o. | Application of quaternary pyridine salts as vessel protection agent |
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CA2944226C (en) | 2014-04-03 | 2021-03-02 | Universite Laval | Method for use of homopiperazinium compounds in the treatment of cancer |
RU2593585C1 (ru) * | 2015-06-26 | 2016-08-10 | Общество с ограниченной ответственностью "Ритек-Фарма" | Способ лечения табакокурения и других форм никотиновой зависимости, а также профилактики рецидивов табакокурения |
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2001
- 2001-03-23 CA CA002341952A patent/CA2341952A1/en not_active Abandoned
-
2002
- 2002-03-25 US US10/469,999 patent/US7601720B2/en not_active Expired - Fee Related
- 2002-03-25 EP EP02717896A patent/EP1370264B1/en not_active Expired - Lifetime
- 2002-03-25 IL IL15775702A patent/IL157757A0/xx not_active IP Right Cessation
- 2002-03-25 CN CNB028071387A patent/CN100528159C/zh not_active Expired - Fee Related
- 2002-03-25 RU RU2003131178/14A patent/RU2299731C2/ru not_active IP Right Cessation
- 2002-03-25 WO PCT/CA2002/000412 patent/WO2002076434A2/en active IP Right Grant
- 2002-03-25 AU AU2002249023A patent/AU2002249023B2/en not_active Ceased
- 2002-03-25 DK DK02717896T patent/DK1370264T3/da active
- 2002-03-25 MX MXPA03008423A patent/MXPA03008423A/es active IP Right Grant
- 2002-03-25 DE DE60223508T patent/DE60223508T2/de not_active Expired - Lifetime
- 2002-03-25 NZ NZ528042A patent/NZ528042A/en not_active IP Right Cessation
- 2002-03-25 JP JP2002574950A patent/JP4377586B2/ja not_active Expired - Fee Related
- 2002-03-25 BR BR0208305-1A patent/BR0208305A/pt not_active IP Right Cessation
- 2002-03-25 PL PL365224A patent/PL207880B1/pl unknown
- 2002-03-25 AT AT02717896T patent/ATE378051T1/de active
- 2002-03-25 ES ES02717896T patent/ES2295331T3/es not_active Expired - Lifetime
-
2003
- 2003-09-19 NO NO20034185A patent/NO331674B1/no not_active IP Right Cessation
-
2009
- 2009-09-03 US US12/553,574 patent/US20100227871A1/en not_active Abandoned
-
2011
- 2011-06-15 US US13/161,035 patent/US8377936B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
EP1370264A2 (en) | 2003-12-17 |
MXPA03008423A (es) | 2004-03-19 |
NO20034185D0 (no) | 2003-09-19 |
RU2003131178A (ru) | 2005-04-10 |
DK1370264T3 (da) | 2008-03-17 |
DE60223508T2 (de) | 2008-09-25 |
EP1370264B1 (en) | 2007-11-14 |
WO2002076434A2 (en) | 2002-10-03 |
CA2341952A1 (en) | 2002-09-23 |
BR0208305A (pt) | 2004-03-09 |
CN1498108A (zh) | 2004-05-19 |
PL207880B1 (pl) | 2011-02-28 |
RU2299731C2 (ru) | 2007-05-27 |
WO2002076434A3 (en) | 2003-07-17 |
CN100528159C (zh) | 2009-08-19 |
ES2295331T3 (es) | 2008-04-16 |
PL365224A1 (en) | 2004-12-27 |
ATE378051T1 (de) | 2007-11-15 |
DE60223508D1 (de) | 2007-12-27 |
US20110245270A1 (en) | 2011-10-06 |
JP2004523588A (ja) | 2004-08-05 |
US20040132737A1 (en) | 2004-07-08 |
NO331674B1 (no) | 2012-02-20 |
NO20034185L (no) | 2003-11-24 |
US7601720B2 (en) | 2009-10-13 |
US8377936B2 (en) | 2013-02-19 |
US20100227871A1 (en) | 2010-09-09 |
AU2002249023B2 (en) | 2006-02-02 |
IL157757A0 (en) | 2004-03-28 |
NZ528042A (en) | 2005-10-28 |
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