JP6242350B2 - P75ntrニューロトロフィン結合タンパク質の治療用途 - Google Patents
P75ntrニューロトロフィン結合タンパク質の治療用途 Download PDFInfo
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- JP6242350B2 JP6242350B2 JP2014561516A JP2014561516A JP6242350B2 JP 6242350 B2 JP6242350 B2 JP 6242350B2 JP 2014561516 A JP2014561516 A JP 2014561516A JP 2014561516 A JP2014561516 A JP 2014561516A JP 6242350 B2 JP6242350 B2 JP 6242350B2
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- 239000010937 tungsten Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000000105 vanilloid receptor agonist Substances 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
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- 239000002023 wood Substances 0.000 description 1
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- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
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Description
(a)ニューロトロフィンNGF、BDNF、NT3またはNT4/5の機能性活性に対する効果(ニューロトロフィンの機能性活性の調節または上方制御または下方制御として定義される)、
(b)約0.1nM〜約50nMの間の結合親和性での、NGF、BDNF、NT3またはNT4/5のいずれかに対する結合親和性、
(c)ニューロトロフィンNGF、NT3、BDNFおよびNT4/5、好ましくはヒトNGF、NT3、BDNFおよびNT4/5のそれぞれに対する結合能力。
(a)急性疼痛および/または自発痛、
(b)慢性疼痛およびまたは進行中の疼痛、
(c)関節痛、変形性関節症または関節リウマチから生じる疼痛、炎症性腸疾患、乾癬および湿疹から生じる疼痛のいずれかを含む炎症性疼痛、
(d)侵害受容性疼痛、
(e)有痛性糖尿病性神経障害または帯状疱疹後神経痛と関連する疼痛を含む、神経障害性疼痛
(f)痛覚過敏、
(g)アロディニア、
(h)中枢痛、中枢性卒中後痛、多発性硬化症から生じる疼痛、脊髄損傷から生じる疼痛、またはパーキンソン病またはてんかんから生じる疼痛、
(i)癌性疼痛、
(j)術後疼痛、
(k)消化性内臓痛および非消化性内臓痛を含む内臓痛、胃腸(GI)障害に起因する疼痛、機能性腸疾患(FBD)から生じる疼痛、炎症性腸疾患(IBD)から生じる疼痛、月経困難、骨盤痛、膀胱炎、間質性膀胱炎または膵炎から生じる疼痛、
(l)筋骨格痛、筋肉痛、線維筋痛、脊椎炎、血清陰性(非リウマチ性)関節障害、関節外リウマチ、ジストロフィン異常症、グリコーゲン分解、多発性筋炎、化膿性筋炎、
(m)心臓または血管性疼痛、狭心症、心筋梗塞、僧帽弁狭窄、心膜炎、レイノー現象、浮腫性硬化症(scleredoma)、浮腫性硬化症または骨格筋虚血に起因する疼痛、
(n)片頭痛、前兆を伴う片頭痛、前兆を伴わない片頭痛、群発頭痛、緊張型頭痛を含む、頭痛、
(o)歯痛、顎関節筋膜痛または耳鳴りを含む、口腔顔面痛、または、
(p)背痛、滑液包炎、月経痛、片頭痛、関連痛、三叉神経痛、超増感、脊椎の外傷および/または変性または脳卒中から生じる疼痛、
から選択される。
・オピオイド鎮痛薬、例えばモルヒネ、ヘロイン、ヒドロモルフォン、オキシモルフォン、レボルファノール、レバロルファン、メタドン、メペリジン、フェンタニル、コカイン、コデイン、ジヒドロコデイン、オキシコドン、ヒドロコドン、プロポキシフェン、ナルメフェン、ナロルフィン、ナロキソン、ナルトレキソン、ブプレノルフィン、ブトルファノール、ナルブフィンまたはペンタゾシン;
・非ステロイド性抗炎症薬(NSAID)、例えばアスピリン、ジクロフェナク、ジフルシナル(diflusinal)、エトドラク、フェンブフェン、フェノプロフェン、フルフェニサル、フルルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、ケトロラック、メクロフェナム酸、メフェナム酸、メロキシカム、ナブメトン、ナプロキセン、ニメスリド、ニトロフルルビプロフェン、オルサラジン、オキサプロジン、フェニルブタゾン、ピロキシカム、スルファサラジン、スリンダク、トルメチンまたはゾメピラック;
・バルビツレート鎮静剤、例えばアモバルビタール、アプロバルビタール、ブタバルビタール、ブタルビタール(butabital)、メホバルビタール、メタルビタール、メトヘキシタール、ペントバルビタール、フェノバルビタール(phenobartital)、セコバルビタール、タルブタール、チアミラール(theamylal)またはチオペンタール;
・鎮静作用を有するベンゾジアゼピン、例えばクロルジアゼポキシド、クロラゼペート、ジアゼパム、フルラゼパム、ロラゼパム、オキサゼパム、テマゼパムまたはトリアゾラム;
・鎮静作用を有するH1拮抗薬、例えばジフェンヒドラミン、ピリラミン、プロメタジン、クロルフェニラミンまたはクロルシクリジン;
・鎮静剤、例えばグルテチミド、メプロバメート、メタカロンまたはジクロラルフェナゾン;
・骨格筋弛緩薬、例えばバクロフェン、カリソプロドール、クロルゾキサゾン、シクロベンザプリン、メトカルバモールまたはオルフレナジン;
・NMDA受容体拮抗薬、例えばデキストロメトルファン((+)−3−ヒドロキシ−N−メチルモルフィナン)またはその代謝物デキストロルファン((+)−3−ヒドロキシ−N−メチルモルフィナン)、ケタミン、メマンチン、ピロロキノリンキニン、シス−4−(ホスホノメチル)−2−ピペリジンカルボン酸、ブジピン、EN−3231(MorphiDex(登録商標)、モルヒネおよびデキストロメトルファンの組み合わせ製剤)、トピラマート、ネラメキサン、または、NR2B拮抗薬を含むペルジンホテル、例えばイフェンプロジル、トラキソプロジルまたは(−)−(R)−6−{2−[4−(3−フルオロフェニル)−4−ヒドロキシ−1−ピペリジニル]−1−ヒドロキシエチル−3,4−ジヒドロ−2(1H)−キノリノン;
・α−アドレナリン作用薬、例えばドキサゾシン、タムスロシン、クロニジン、グアンファシン、デキスメタトミジン(dexmetatomidine)、モダフィニル、または4−アミノ−6,7−ジメトキシ−2−(5−メタン−スルホンアミド−1,2,3,4−テトラヒドロイソキノール−2−イル)−5−(2−ピリジル)キナゾリン;
・三環系抗うつ薬、例えばデシプラミン、イミプラミン、アミトリプチリンまたはノルトリプチリン;
・抗痙攣薬、例えばカルバマゼピン、ラモトリジン、トピラマート(topiratmate)またはバルプロエート;
・タキキニン(NK)拮抗薬、特にNK−3、NK−2またはNK−1拮抗薬、例えば(αR,9R)−7−[3,5−ビス(トリフルオロメチル)ベンジル]−8,9,10,11−テトラヒドロ−9−メチル−5−(4−メチルフェニル)−7H−[1,4]ジアゾシノ[2,1−g][1,7]−ナフチリジン−6−13−ジオン(TAK−637)、5−[[(2R,3S)−2−[(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ−3−(4−フルオロフェニル)−4−モルホリニル]−メチル]−1,2−ジヒドロ−3H−1,2,4−トリアゾル−3−オン(MK−869)、アプレピタント、ラネピタント、ダピタントまたは3−[[2−メトキシ−5−(トリフルオロメトキシ)フェニル]−メチルアミノ]−2−フェニルピペリジン(2S,3S);
・ムスカリン拮抗薬、例えばオキシブチニン、トルテロジン、プロピベリン、塩化トロスピウム(tropsium chloride)、ダリフェナシン、ソリフェナシン、テミベリンおよびイプラトロピウム;
・COX−2選択的阻害剤、例えばセレコキシブ、ロフェコキシブ、パレコキシブ、バルデコキシブ、デラコキシブ、エトリコキシブ、またはルミラコキシブ;
・コールタール鎮痛剤、特にパラセタモール;
・神経遮断薬、例えばドロペリドール、クロルプロマジン、ハロペリドール、ペルフェナジン、チオリダジン、メソリダジン、トリフルオペラジン、フルフェナジン、クロザピン、オランザピン、リスペリドン、ジプラシドン、クエチアピン、セルチンドール、アリピプラゾール、ソネピプラゾール、ブロナンセリン、イロペリドン、ペロスピロン、ラクロプリド、ゾテピン、ビフェプルノックス、アセナピン、ルラシドン、アミスルプリド、バラペリドン、パリンドール、エプリバンセリン、オサネタント、リモナバン、メクリネルタント、Miraxion(登録商標)またはサリゾタン;
・バニロイド受容体アゴニスト(例えばレシニフェラトキシン)または拮抗薬(例えばカプサゼピン);
・β−アドレナリン作用薬、例えばプロプラノロール;
・局部麻酔薬、例えばメキシレチン;
・コルチコステロイド、例えばデキサメタゾン;
・5−HT受容体アゴニストまたは拮抗薬、特に5−HT1B/1Dアゴニスト、例えばエレトリプタン、スマトリプタン、ナラトリプタン、ゾルミトリプタンまたはリザトリプタン;
・5−HT2A受容体拮抗薬、例えばR(+)−α−(2,3−ジメトキシ−フェニル)−1−[2−(4−フルオロフェニルエチル)]−4−ピペリジンメタノール(MDL−100907);
・コリン作用性(ニコチン性)鎮痛剤、例えばイスプロニクリン(TC−1734)、(E)−N−メチル−4−(3−ピリジニル)−3−ブテン−1−アミン(RJR−2403)、(R)−5−(2−アゼチジニルメトキシ)−2−クロロピリジン(ABT−594)またはニコチン;
・トラマドール(登録商標);
・PDEV阻害剤、例えば5−[2−エトキシ−5−(4−メチル−1−ピペラジニル−スルホニル)フェニル]−1−メチル−3−n−プロピル−1,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン(シルデナフィル)、(6R,12aR)−2,3,6,7,12,12a−ヘキサヒドロ−2−メチル−6−(3,4−メチレンジオキシフェニル)−ピラジノ[2’,1’:6,1]−ピリド[3,4−b]インドール−1,4−ジオン(IC−351またはタダラフィル)、2−[2−エトキシ−5−(4−エチル−ピペラジン−1−イル−1−スルホニル)−フェニル]−5−メチル−7−プロピル−3H−イミダゾ[5,1−f][1,2,4]トリアジン−4−オン(バルデナフィル)、5−(5−アセチル−2−ブトキシ−3−ピリジニル)−3−エチル−2−(1−エチル−3−アゼチジニル)−2,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン、5−(5−アセチル−2−プロポキシ−3−ピリジニル)−3−エチル−2−(1−イソプロピル−3−アゼチジニル)−2,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン、5−[2−エトキシ−5−(4−エチルピペラジン−1−イルスルホニル)ピリジン−3−イル]−3−エチル−2−[2−メトキシエチル]−2,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン、4−[(3−クロロ−4−メトキシベンジル)アミノ]−2−[(2S)−2−(ヒドロキシメチル)ピロリジン−1−イル]−N−(ピリミジン−2−イルメチル)ピリミジン−5−カルボキサミド、3−(1−メチル−7−オキソ−3−プロピル−6、7−ジヒドロ−1H−ピラゾロ[4,3−d]ピリミジン−5−イル)−N−[2−(1−メチルピロリジン−2−イル)エチル]−4−プロポキシベンゼンスルホンアミド;
・カンナビノイド;
・代謝型グルタミン酸受容体サブタイプ1(mGluR1)拮抗薬;
・セロトニン再取り込み阻害剤、例えばセルトラリン、セルトラリン代謝物デメチルセルトラリン、フルオキセチン、ノルフルオキセチン(フルオキセチンデスメチル代謝物)、フルボキサミン、パロキセチン、シタロプラム、シタロプラム代謝物デスメチルシタロプラム、エスシタロプラム、d,l−フェンフルラミン、フェモキセチン、イフォキセチン、シアノドチエピン、リトキセチン、ダポキセチン、ネファゾドン、セリクラミンおよびトラゾドン;
・ノルアドレナリン(ノルエピネフリン)再取り込み阻害剤、例えばマプロチリン、ロフェプラミン、ミルタザピン(mirtazepine)、オキサプロチリン、フェゾラミン、トモキセチン、ミアンセリン、ブプロプリオン、ブプロプリオン代謝物ヒドロキシブプロプリオン、ノミフェンシンおよびビロキサジン(Vivalan(登録商標))、特に選択的ノルアドレナリン再取り込み阻害剤、例えばレボキセチン、特に(S,S)−レボキセチン;
・二重セロトニン−ノルアドレナリン再取り込み阻害剤、例えばベンラファキシン、ベンラファキシン代謝物O−デスメチルベンラファキシン、クロミプラミン、クロミプラミン代謝物デスメチルクロミプラミン、デュロキセチン、ミルナシプランおよびイミプラミン;
・誘導型一酸化窒素合成酵素(iNOS)阻害剤、例えばS−[2−[(1−イミノエチル)アミノ]エチル]−L−ホモシステイン、S−[2−[(1−イミノエチル)−アミノ]エチル]−4,4−ジオキソ−L−システイン、S−[2−[(1−イミノエチル)アミノ]エチル]−2−メチル−L−システイン、(2S,5Z)−2−アミノ−2−メチル−7−[(1−イミノエチル)アミノ]−5−ヘプテン酸、2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)−ブチル]チオ]−5−クロロ−3−ピリジンカルボニトリル;2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)ブチル]チオ]−4−クロロベンゾニトリル、(2S,4R)−2−アミノ−4−[[2−クロロ−5−(トリフルオロメチル)フェニル]チオ]−5−チアゾールブタノール、2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)ブチル]チオ]−6−(トリフルオロメチル)−3ピリジンカルボニトリル、2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)ブチル]チオ]−5−クロロベンゾニトリル、N−[4−[2−(3−クロロベンジルアミノ)エチル]フェニル]チオフェン−2−カルボキサミジン、またはグアニジノエチルジスルフィド;
・アセチルコリンエステラーゼ阻害剤、例えばドネペジル;
・プロスタグランジンE2サブタイプ4(EP4)拮抗薬、例えばN−[({2−[4−(2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル)フェニル]エチル}アミノ)−カルボニル]−4−メチルベンゼンスルホンアミドまたは4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸;
・ロイコトリエンB4拮抗薬;例えば1−(3−ビフェニル−4−イルメチル−4−ヒドロキシ−クロマン−7−イル)−シクロペンタンカルボン酸(CP−105696)、5−[2−(2−カルボキシエチル)−3−[6−(4−メトキシフェニル)−5E−ヘキセニル]オキシフェノキシ]−吉草酸(ONO−4057)またはDPC−11870、
・5−リポキシゲナーゼ阻害剤、例えばジレウトン、6−[(3−フルオロ−5−[4−メトキシ−3,4,5,6−テトラヒドロ−2H−ピラン−4−イル])フェノキシ−メチル]−1−メチル−2−キノロン(ZD−2138)、または2,3,5−トリメチル−6−(3−ピリジルメチル)、1,4−ベンゾキノン(CV−6504);
・ナトリウムチャンネルブロッカー、例えばリドカイン;または
・5−HT3拮抗薬、例えばオンダンセトロン;
および、それらの薬学的に許容できる塩および溶媒和物、
から選択される。
(a)第1、第2または第7態様またはそれらの好ましい実施態様によるp75NTR(NBP)、または第3および第4態様による核酸分子またはベクター、または第9態様の医薬組成物;および、
(b)疼痛および/または疼痛の症状の予防または治療のいずれか1つまたは複数のための、または、疼痛および/または疼痛の症状の発生を改善する、制御する、減少させる、または、疼痛および/または疼痛の症状の発達または進行を遅らせるための、個体への有効量の前記p75NTR(NBP)、核酸分子、ベクターまたは医薬組成物の投与に関する指示書
を含むキットが提供される。
磁気ビーズを土台としたNGF(Millipore Corp;MA)を用いたアッセイおよびビオチン化ヤギポリクローナル抗ヒトNGF抗体(Novus Biologicals;CO)を用いた免疫沈降の後に、SISCAPA(Siscapa http://siscapa.com/home.html)を行ない、それから続けて、LC−MS/MS(LLOQ 7pg/ml)中で判定して、ヒト血漿中にp75NTR/NGF複合体が存在することの直接の証拠が得られた。ポリクローナル抗NGF抗体は、ヒト血清/血漿におけるフリーのNGFを定量するために用いた。
NGF機能に対するp75NTR(NBP)の効果を、TrkAを発現するU20S細胞において、および、TrkAおよびp75NTRを共発現するU20S細胞において、調べた(Discoverx Corp CA)。アッセイは、PathHunterの方法論(Discoverx Corp CA)に従って実施し、要するに、TrkAおよびTrkA+p75NTRを発現するU20S細胞を、DiscoveRx Corporationから購入した。TrkAを発現するU20S細胞、および、TrkA+p75NTRを共発現する細胞を、最小必須培地(MEM;Sigma Aldrich)+0.5%ウマ血清(Sigma Aldrich)に、40,000細胞/ウェルの密度で蒔いて、37℃で一晩培養した。プレートを、使用の30分前にインキュベーターから取り出して、室温で保管した。
BDNF機能に対するp75NTR(NBP)の効果を、TrkBを発現するU20S細胞において、および、TrkBおよびp75NTRを共発現するU20S細胞において、調べた(Discoverx Corp CA)。アッセイは、PathHunterの方法論(DiscoverxCorpCA)に従って実施し、要するに、TrkBおよびTrkB+p75NTRを発現するU20S細胞を、DiscoveRx Corporationから購入した。TrkBを発現するU20S細胞、および、TrkB+p75NTRを共発現する細胞を、最小必須培地(MEM;Sigma Aldrich)+0.5%ウマ血清(Sigma Aldrich)に、40,000細胞/ウェルの密度で蒔いて、37℃で一晩培養した。プレートを、使用の30分前にインキュベーターから取り出して、室温で保管した。
p75NTR(NBP)は、細胞表面上にTrkAおよび/またはTrkA+p75を発現するPC−12およびN2OS細胞において、NGFの活性を著しく阻害することが示された(図7)。
雄のSprague Dawleyラットを、イソフルラン(誘導には酸素中に5%、管理には酸素中に1.5〜2.0%)で麻酔した。腰部椎弓切除術により脊髄を露出して、脊髄のL4〜L6領域を露出させて、タングステン微小電極を背角に挿入して、分離された広ダイナミックレンジの神経細胞から記録した。記録ユニットのスパイク振幅がベースラインノイズのレベルの少なくとも3倍であるように、それぞれのWDR神経細胞を分離した。応答は、neurolog AC結合型増幅器を用いて増幅して、CED spike 2 ソフトウェアを用いて記録した。薬適用の前に、3つの安定したベースラインの応答(10%未満の変動)を、自然な刺激(ブラシ、フォンフレイ(von Frey)、ピンチおよび熱)の範囲まで取得した。ブラシ刺激は、きめの細かい綿の束で、末梢受容野の中央をストロークすることにより与えた。フォンフレイフィラメントおよび熱(43度に設定した持続的なウォータージェットを用いる)は、10秒間与えた。ピンチは5秒間与えた。安定したベースラインの応答が得られた時点で、BDNFのみ(0.1% BSA中に500ng)またはBDNF(500ng)+p75NTR(NBP)(500ng、注入の前に40分間、事前インキュベート)を、インスリンシリンジを用いて、25μlの容量で受容野の中央にアプライした。薬の効果を150分間フォローして、10分間隔で試験を行なった。実験の終了時に、ラットを頚椎脱臼により屠殺した。
<動物のUV曝露>
Charles Riverの雄のSprague Dawleyラット(175〜200g)を、2%イソフルラン(isofluorane)O2混合物で麻酔した。右後足の足底面が300mJ/cm2のUVで照射される間、(Saalmann CupCube system,Saalmann GmbH,Germany;λ=280−400nm)ノーズコーンを介して麻酔を維持した。UV源に取り付けられた成形デリバリーカラー(8×12mm)を用いて、ラットの後足の足底面に照射源を取り付けた(Pfizer施設管理およびエンジニアリングチーム)。UV源の強度は、SEL005/WBS320/TDフィルターを備えたABLE 1400Aラジオメーターを用いて較正した(ABLE Instruments and Controls Ltd)。使用したUV曝露は、ナイーブラットにおいて皮膚の紅斑を生じさせ、他の有害事象は生じない(体重減少無し、ストレスの兆候または明らかな不快感無し)。
Hargreavesら(1988)の改変法の後にラット足底テスト(Ugo Basile,Italy)を用いて、温痛覚過敏を評価した。テストの前にラットを装置に慣れさせた(15〜30分)。足底テストは、高架式ガラステーブル上の3つの個々のパースペックスのボックスで構成された。装置あたり6匹のラットを同時にテストできるように、2匹のラットを各ボックス内で飼った。
アロディニアの評価の前に、底が針金のテストケージに動物を慣れさせる。フルアップダウンの測定が行われる前に、馴化の第1日目に15g、8g+4gのフィラメント、第2日目に4gのフィラメントの適用により、動物をフォンフレイヘアー(von Frey Hairs)に慣れ親しませる。静的アロディニアは、後足の足底面に対して、昇順の力(0.6、1、1.4、2、4、6、8、10、15および26グラム)で、フォンフレイヘアー(Stoelting,Wood Dale,Illinois,U.S.A.)の適用により評価する。各フォンフレイヘアーは、最大で6秒間、または引込み応答が起きるまで、足に適用する。フォンフレイヘアーに対する引込み応答が実証された時点で、引込みを生じたものより低いフィラメントでスタートして、続いて、残りのフィラメントで、降順の力で、引込みが生じなくなるまで、足を再試験する。最も強い力の26gが足を持ち上げて応答を生じさせるので、カットオフポイントを示す。各動物は、この様式で両後足を試験される。応答を生じさせるために必要とされる最低量の力は、足引込み閾値(paw withdrawal threshold)(PWT)としてグラムで記録される。静的アロディニアは、通常のラットでは刺激とならない4gまたはそれ未満の刺激に動物が反応する場合に、有りと定義される。
[参考文献]
Claims (14)
- 疼痛を治療するための医薬組成物であって、配列番号2の配列のp75NTRニューロトロフィン結合タンパク質p75NTR(NBP)、および、薬学的に許容できる担体および/または賦形剤を含む、医薬組成物。
- 請求項1に記載の医薬組成物であって、
前記p75NTR(NBP)が、
(a)トランスフェリンまたはその部分、
(b)アルブミンまたはその部分、
(c)免疫グロブリンFcまたはその部分、および
(d)ポリエチレングリコールポリマー鎖、
から選択される1つまたは複数の補助分子に結合されたp75NTR(NBP)を含むことを特徴とする、
医薬組成物。 - 請求項2に記載の医薬組成物であって、
前記p75NTR(NBP)が、1つまたは複数のリンカーを介して、前記の1つまたは複数の補助分子に結合されていることを特徴とする、
医薬組成物。 - 請求項3に記載の医薬組成物であって、
前記リンカーが:
(a)共有結合、
(b)非共有結合、
(c)ペプチド結合、または
(d)1アミノ酸、またはペプチドを含む複数アミノ酸、
から選択されることを特徴とする、
医薬組成物。 - 請求項2から4のいずれか一項に記載の医薬組成物であって、
前記p75NTR(NBP)が、1よりも多い補助分子に結合されており、
各補助分子が、同一または異なるもののいずれかであることを特徴とする、
医薬組成物。 - 請求項5に記載の医薬組成物であって、
前記の、1よりも多い補助分子が、リンカーを介してp75NTR(NBP)に結合された補助分子の多量体を含み、
各分子は、同一のものであっても異なるものであってもよい、
医薬組成物。 - 請求項1から6のいずれか一項に記載の医薬組成物であって、
前記p75NTR(NBP)は、
(a)配列番号2の配列のp75NTR(NBP)、および、
(b)免疫グロブリンFc
から構成されることを特徴とする、
医薬組成物。 - 請求項7に記載の医薬組成物であって、
前記免疫グロブリンFcは、配列番号12、配列番号15または配列番号16から選択される、
ことを特徴とする、
医薬組成物。 - 請求項7または8に記載の医薬組成物であって、
前記p75NTR(NBP)は、(c)リンカーをさらに含む、
医薬組成物。 - 請求項9に記載の医薬組成物であって、
前記リンカーは、配列番号17、配列番号18または配列番号19から選択されることを特徴とする、
医薬組成物。 - 請求項1から10のいずれか一項に記載の医薬組成物であって、
前記疼痛は:
(a)急性疼痛および/または自発痛、
(b)慢性疼痛およびまたは進行中の疼痛、
(c)関節痛、変形性関節症または関節リウマチから生じる疼痛、炎症性腸疾患から生じる疼痛のいずれか一つを含む炎症性疼痛、
(d)侵害受容性疼痛、
(e)有痛性糖尿病性神経障害または帯状疱疹後神経痛と関連する疼痛を含む、神経障害性疼痛、
(f)痛覚過敏、
(g)アロディニア、
(h)中枢痛、中枢性卒中後痛、多発性硬化症から生じる疼痛、脊髄損傷から生じる疼痛、またはパーキンソン病またはてんかんから生じる疼痛、
(i)癌性疼痛、
(j)術後疼痛、
(k)消化性内臓痛および非消化性内臓痛を含む内臓痛、胃腸(GI)障害に起因する疼痛、機能性腸疾患(FBD)から生じる疼痛、炎症性腸疾患(IBD)から生じる疼痛、月経困難、骨盤痛、膀胱炎、間質性膀胱炎または膵炎から生じる疼痛、
(l)筋骨格痛、筋肉痛、線維筋痛、脊椎炎、血清陰性(非リウマチ性)関節障害、関節外リウマチ、ジストロフィン異常症、グリコーゲン分解、多発性筋炎、化膿性筋炎、
(m)心臓または血管性疼痛、狭心症、心筋梗塞、僧帽弁狭窄、心膜炎、レイノー現象、浮腫性硬化症、浮腫性硬化症または骨格筋虚血に起因する疼痛、
(n)片頭痛、前兆を伴う片頭痛、前兆を伴わない片頭痛、群発頭痛、緊張型頭痛を含む、頭痛、
(o)歯痛、顎関節筋膜痛または耳鳴りを含む、口腔顔面痛、または
(p)背痛、滑液包炎、月経痛、片頭痛、関連痛、三叉神経痛、超増感、脊椎の外傷および/または変性または脳卒中から生じる疼痛、
から選択されることを特徴とする、
医薬組成物。 - 請求項1から11のいずれか一項に記載の医薬組成物であって、
第2の薬理学的に活性の化合物と組み合わせて、別々に、連続して、または同時に使用されるものであることを特徴とする、
医薬組成物。 - 請求項12に記載の医薬組成物であって、
組み合わせる前記の第2の薬理学的に活性の化合物は;
・モルヒネ、ヘロイン、ヒドロモルフォン、オキシモルフォン、レボルファノール、レバロルファン、メタドン、メペリジン、フェンタニル、コカイン、コデイン、ジヒドロコデイン、オキシコドン、ヒドロコドン、プロポキシフェン、ナルメフェン、ナロルフィン、ナロキソン、ナルトレキソン、ブプレノルフィン、ブトルファノール、ナルブフィンおよびペンタゾシンからなる群から選択されるオピオイド鎮痛薬;
・アスピリン、ジクロフェナク、ジフルシナル(diflusinal)、エトドラク、フェンブフェン、フェノプロフェン、フルフェニサル、フルルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、ケトロラック、メクロフェナム酸、メフェナム酸、メロキシカム、ナブメトン、ナプロキセン、ニメスリド、ニトロフルルビプロフェン、オルサラジン、オキサプロジン、フェニルブタゾン、ピロキシカム、スルファサラジン、スリンダク、トルメチンおよびゾメピラックからなる群から選択される非ステロイド性抗炎症薬(NSAID);
・アモバルビタール、アプロバルビタール、ブタバルビタール、ブタルビタール(butabital)、メホバルビタール、メタルビタール、メトヘキシタール、ペントバルビタール、フェノバルビタール(phenobartital)、セコバルビタール、タルブタール、チアミラール(theamylal)およびチオペンタールからなる群から選択されるバルビツレート鎮静剤;
・クロルジアゼポキシド、クロラゼペート、ジアゼパム、フルラゼパム、ロラゼパム、オキサゼパム、テマゼパムおよびトリアゾラムからなる群から選択される鎮静作用を有するベンゾジアゼピン;
・ジフェンヒドラミン、ピリラミン、プロメタジン、クロルフェニラミンおよびクロルシクリジンからなる群から選択される鎮静作用を有するH 1 拮抗薬;
・グルテチミド、メプロバメート、メタカロンおよびジクロラルフェナゾンからなる群から選択される鎮静剤;
・バクロフェン、カリソプロドール、クロルゾキサゾン、シクロベンザプリン、メトカルバモールおよびオルフレナジンからなる群から選択される骨格筋弛緩薬;
・デキストロメトルファン((+)−3−ヒドロキシ−N−メチルモルフィナン)またはその代謝物デキストロルファン((+)−3−ヒドロキシ−N−メチルモルフィナン)、ケタミン、メマンチン、ピロロキノリンキニン、シス−4−(ホスホノメチル)−2−ピペリジンカルボン酸、ブジピン、EN−3231(MorphiDex(登録商標)、モルヒネおよびデキストロメトルファンの組み合わせ製剤)、トピラマート、ネラメキサン、および、ペルジンホテル、およびイフェンプロジル、トラキソプロジルおよび(−)−(R)−6−{2−[4−(3−フルオロフェニル)−4−ヒドロキシ−1−ピペリジニル]−1−ヒドロキシエチル−3,4−ジヒドロ−2(1H)−キノリノンからなる群から選択されるNR2B拮抗薬、からなる群から選択されるNMDA受容体拮抗薬;
・ドキサゾシン、タムスロシン、クロニジン、グアンファシン、デキスメタトミジン(dexmetatomidine)、モダフィニル、および4−アミノ−6,7−ジメトキシ−2−(5−メタン−スルホンアミド−1,2,3,4−テトラヒドロイソキノール−2−イル)−5−(2−ピリジル)キナゾリンからなる群から選択されるα−アドレナリン作用薬;
・デシプラミン、イミプラミン、アミトリプチリンおよびノルトリプチリンからなる群から選択される三環系抗うつ薬;
・カルバマゼピン、ラモトリジン、トピラマート(topiratmate)およびバルプロエートからなる群から選択される抗痙攣薬;
・(αR,9R)−7−[3,5−ビス(トリフルオロメチル)ベンジル]−8,9,10,11−テトラヒドロ−9−メチル−5−(4−メチルフェニル)−7H−[1,4]ジアゾシノ[2,1−g][1,7]−ナフチリジン−6−13−ジオン(TAK−637)、5−[[(2R,3S)−2−[(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ−3−(4−フルオロフェニル)−4−モルホリニル]−メチル]−1,2−ジヒドロ−3H−1,2,4−トリアゾル−3−オン(MK−869)、アプレピタント、ラネピタント、ダピタントおよび3−[[2−メトキシ−5−(トリフルオロメトキシ)フェニル]−メチルアミノ]−2−フェニルピペリジン(2S,3S)からなる群から選択される、タキキニン(NK)拮抗薬、またはNK−3、NK−2またはNK−1拮抗薬;オキシブチニン、トルテロジン、プロピベリン、塩化トロスピウム(tropsium chloride)、ダリフェナシン、ソリフェナシン、テミベリンおよびイプラトロピウムからなる群から選択されるムスカリン拮抗薬;
・セレコキシブ、ロフェコキシブ、パレコキシブ、バルデコキシブ、デラコキシブ、エトリコキシブ、およびルミラコキシブからなる群から選択されるCOX−2選択的阻害剤;
・パラセタモール;
・ドロペリドール、クロルプロマジン、ハロペリドール、ペルフェナジン、チオリダジン、メソリダジン、トリフルオペラジン、フルフェナジン、クロザピン、オランザピン、リスペリドン、ジプラシドン、クエチアピン、セルチンドール、アリピプラゾール、ソネピプラゾール、ブロナンセリン、イロペリドン、ペロスピロン、ラクロプリド、ゾテピン、ビフェプルノックス、アセナピン、ルラシドン、アミスルプリド、バラペリドン、パリンドール、エプリバンセリン、オサネタント、リモナバン、メクリネルタント、Miraxion(登録商標)およびサリゾタンからなる群から選択される神経遮断薬;
・レシニフェラトキシンまたはカプサゼピン;
・プロプラノロール;
・メキシレチン;
・デキサメタゾン;
・エレトリプタン、スマトリプタン、ナラトリプタン、ゾルミトリプタンおよびリザトリプタンからなる群から選択される、5−HT受容体アゴニストまたは拮抗薬、または5−HT 1B/1D アゴニスト;
・R(+)−α−(2,3−ジメトキシ−フェニル)−1−[2−(4−フルオロフェニルエチル)]−4−ピペリジンメタノール(MDL−100907);
・イスプロニクリン(TC−1734)、(E)−N−メチル−4−(3−ピリジニル)−3−ブテン−1−アミン(RJR−2403)、(R)−5−(2−アゼチジニルメトキシ)−2−クロロピリジン(ABT−594)およびニコチンからなる群から選択されるコリン作用性(ニコチン性)鎮痛剤;
・トラマドール(登録商標);
・5−[2−エトキシ−5−(4−メチル−1−ピペラジニル−スルホニル)フェニル]−1−メチル−3−n−プロピル−1,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン(シルデナフィル)、(6R,12aR)−2,3,6,7,12,12a−ヘキサヒドロ−2−メチル−6−(3,4−メチレンジオキシフェニル)−ピラジノ[2’,1’:6,1]−ピリド[3,4−b]インドール−1,4−ジオン(IC−351またはタダラフィル)、2−[2−エトキシ−5−(4−エチル−ピペラジン−1−イル−1−スルホニル)−フェニル]−5−メチル−7−プロピル−3H−イミダゾ[5,1−f][1,2,4]トリアジン−4−オン(バルデナフィル)、5−(5−アセチル−2−ブトキシ−3−ピリジニル)−3−エチル−2−(1−エチル−3−アゼチジニル)−2,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン、5−(5−アセチル−2−プロポキシ−3−ピリジニル)−3−エチル−2−(1−イソプロピル−3−アゼチジニル)−2,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン、5−[2−エトキシ−5−(4−エチルピペラジン−1−イルスルホニル)ピリジン−3−イル]−3−エチル−2−[2−メトキシエチル]−2,6−ジヒドロ−7H−ピラゾロ[4,3−d]ピリミジン−7−オン、4−[(3−クロロ−4−メトキシベンジル)アミノ]−2−[(2S)−2−(ヒドロキシメチル)ピロリジン−1−イル]−N−(ピリミジン−2−イルメチル)ピリミジン−5−カルボキサミド、および3−(1−メチル−7−オキソ−3−プロピル−6、7−ジヒドロ−1H−ピラゾロ[4,3−d]ピリミジン−5−イル)−N−[2−(1−メチルピロリジン−2−イル)エチル]−4−プロポキシベンゼンスルホンアミドからなる群から選択されるPDEV阻害剤;
・カンナビノイド;
・代謝型グルタミン酸受容体サブタイプ1(mGluR1)拮抗薬;
・セルトラリン、セルトラリン代謝物デメチルセルトラリン、フルオキセチン、ノルフルオキセチン(フルオキセチンデスメチル代謝物)、フルボキサミン、パロキセチン、シタロプラム、シタロプラム代謝物デスメチルシタロプラム、エスシタロプラム、d,l−フェンフルラミン、フェモキセチン、イフォキセチン、シアノドチエピン、リトキセチン、ダポキセチン、ネファゾドン、セリクラミンおよびトラゾドンからなる群から選択されるセロトニン再取り込み阻害剤;
・マプロチリン、ロフェプラミン、ミルタザピン(mirtazepine)、オキサプロチリン、フェゾラミン、トモキセチン、ミアンセリン、ブプロプリオン、ブプロプリオン代謝物ヒドロキシブプロプリオン、ノミフェンシンおよびビロキサジン(Vivalan(登録商標))、レボキセチン、および(S,S)−レボキセチンからなる群から選択されるノルアドレナリン(ノルエピネフリン)再取り込み阻害剤;
・ベンラファキシン、ベンラファキシン代謝物O−デスメチルベンラファキシン、クロミプラミン、クロミプラミン代謝物デスメチルクロミプラミン、デュロキセチン、ミルナシプランおよびイミプラミンからなる群から選択される二重セロトニン−ノルアドレナリン再取り込み阻害剤;
・S−[2−[(1−イミノエチル)アミノ]エチル]−L−ホモシステイン、S−[2−[(1−イミノエチル)−アミノ]エチル]−4,4−ジオキソ−L−システイン、S−[2−[(1−イミノエチル)アミノ]エチル]−2−メチル−L−システイン、(2S,5Z)−2−アミノ−2−メチル−7−[(1−イミノエチル)アミノ]−5−ヘプテン酸、2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)−ブチル]チオ]−5−クロロ−3−ピリジンカルボニトリル;2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)ブチル]チオ]−4−クロロベンゾニトリル、(2S,4R)−2−アミノ−4−[[2−クロロ−5−(トリフルオロメチル)フェニル]チオ]−5−チアゾールブタノール、2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)ブチル]チオ]−6−(トリフルオロメチル)−3ピリジンカルボニトリル、2−[[(1R,3S)−3−アミノ−4−ヒドロキシ−1−(5−チアゾリル)ブチル]チオ]−5−クロロベンゾニトリル、N−[4−[2−(3−クロロベンジルアミノ)エチル]フェニル]チオフェン−2−カルボキサミジン、およびグアニジノエチルジスルフィドからなる群から選択される誘導型一酸化窒素合成酵素(iNOS)阻害剤;
・ドネペジル;
・N−[({2−[4−(2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル)フェニル]エチル}アミノ)−カルボニル]−4−メチルベンゼンスルホンアミドおよび4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸からなる群から選択されるプロスタグランジンE 2 サブタイプ4(EP4)拮抗薬;
・1−(3−ビフェニル−4−イルメチル−4−ヒドロキシ−クロマン−7−イル)−シクロペンタンカルボン酸(CP−105696)、5−[2−(2−カルボキシエチル)−3−[6−(4−メトキシフェニル)−5E−ヘキセニル]オキシフェノキシ]−吉草酸(ONO−4057)およびDPC−11870からなる群から選択されるロイコトリエンB4拮抗薬、
・ジレウトン、6−[(3−フルオロ−5−[4−メトキシ−3,4,5,6−テトラヒドロ−2H−ピラン−4−イル])フェノキシ−メチル]−1−メチル−2−キノロン(ZD−2138)、および2,3,5−トリメチル−6−(3−ピリジルメチル)、1,4−ベンゾキノン(CV−6504)からなる群から選択される5−リポキシゲナーゼ阻害剤;
・リドカイン;および
・オンダンセトロン;
および、それらの薬学的に許容できる塩および溶媒和物
から選択されることを特徴とする、
医薬組成物。 - 請求項1から13のいずれか一項に記載の医薬組成物であって、
疼痛の発生を予防する、改善する、制御する、減少させる、または、疼痛の症状の発達または進行を遅らせる、のいずれか1つまたは複数での使用のための、
医薬組成物。
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