TW200820977A - Use of glucocorticoid receptor antagonists for treatment of infectious conditions - Google Patents
Use of glucocorticoid receptor antagonists for treatment of infectious conditions Download PDFInfo
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- TW200820977A TW200820977A TW096126375A TW96126375A TW200820977A TW 200820977 A TW200820977 A TW 200820977A TW 096126375 A TW096126375 A TW 096126375A TW 96126375 A TW96126375 A TW 96126375A TW 200820977 A TW200820977 A TW 200820977A
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- glucocorticoid receptor
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- immunostimulation
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Description
200820977 九、發明說明 【發明所屬之技術領域】 本發明係關於糖皮質素受體（GR )拮抗劑於哺乳動 物對象的免疫刺激作用之用途，及關於一種含GR拮抗劑 的藥學組成物。本發明也係關於一種提供免疫刺激的方法 ，諸如用於預防或治療感染，或感染狀況。 φ 【先前技術】 免疫系統係已知會受丘腦-垂體-賢上腺（ΗΡΑ )軸及 交感神經-腎上腺-髓狀（SAM)軸所影響。ΗΡΑ軸引起糖 皮質素受體激動劑（人體之皮質醇）與脫氫表雄酮（硫酸 鹽）〔DHEAS ( S )〕的釋放，彼等可分別抑制和刺激免 疫功能。另一方面，SAM軸也引起兒茶酚胺類（ catecholamines)的釋放，其具免疫抑制性。 於患有壓力的健康年輕至中年對象中，具有在前炎性 φ 媒介體與抗炎性媒介體之間的生理平衡。在年長對象中， 免疫回應會由於免疫系統中數種成分衰退的結果而鈍化（ 免疫老化）並轉爲慢性前炎性狀態（所謂的“炎性老化（ inflammaging ) ’’）作用（Butcher and Lord，(2004) Aging Cell, pp. 151-160 )。當皮質醇產生隨著年齡而保持相當 固定之時，DHEA及DHEAS的總含量會由第三十年期逐 漸地衰減至第八十年期的10 - 20%最大値，Butcher和 Lord ( 20 04前文）提出年齡與壓力模式，其中皮質醇對 DHEA比例的年齡相關性增加，結合壓力期間釋放的提升 200820977 皮質醇，可導致老年對象的免疫力明顯降低。此係提出用 以解釋老年對象在壓力狀態下的遠更易於受到感染之事實 〇 基於來自老年髖部骨折對象的白血球所得實驗數據， 提出在壓力期間補充DHEA及/或DHEAS作爲一種預防 感染的措施（Butcher and Lord ( 2004，supra) ; Butcher 等人，（2005，Aging Cell 5，pp. 3 1 9-324 ) 〇 Φ 【發明內容】 本發明係關於糖皮質素受體拮抗劑於製備免疫刺激用 藥劑上的用途，該等藥劑係用於諸如對老年哺乳動物對象 ，如人類對象，感染或感染狀況的預防或治療。儘管有早 期提出的製衡糖皮質類固醇激素之免疫刺激性效用（參閱 :Regelson 1 9 9 0a; 1 990b; 1 992; D a y n e s and Araneo 1 989; Emilie 等人，1 984; Zhang 等人，1 998; Morfin 等人， _ US5,763,433; Hampl 等人 1998; Lathe，R·等人： WO 97/37664; Nakamori 等人 JP 2005213156)及 GR 受體 直接作用性拮抗劑，美服培酮（RU486 )由來已久的可取 用性，但仍沒有報告論及GR拮抗劑所得在正常哺乳動物 對象體內的免疫刺激性效用。於不希望受到理論所約束之 下，在本發明所提供的應選對象內之效用可以用相較於正 常對象體內平衡的皮質醇/DHEAS對免疫系統的平衡影響 ，在老年對象體內增加的皮質醇/D HE AS比例之不平衡的 免疫壓制作用來解釋。術語“哺乳動物對象，，包括對人類對 •5- 200820977 象的指稱，其係本發明所提供的所用及在該主體內容之中 的較佳對象。 若於術語“糖皮質素受體（GR )拮抗劑”中需要更高 的明晰性，可以使用下述定義：GR拮抗劑爲一種由該拮 抗劑對 GR受體的直接作用所致而可防止地塞米松（ dexamethasone)的生理效應之化合物。所以，於Sacco 等人2002年的參考資料中，術語“糖皮質素受體拮抗劑” φ 係以不尋常方式來描述DHEA對糖皮質素作用之影響。 GR拮抗劑的直接相互作用通常意味著該化合物對GR受 體具有至少6的PKa之結合親和力。於對糖皮質素受體親 和力的標準檢定中，甚至可對pKa的最低限値更清晰地設 定到6、6 · 5、7、7 · 5、8或9。若拮抗劑具有殘留激動劑 效應，作爲該拮抗劑的部分激動劑，則最大激動劑效應必 須低於地塞米松的最大激動劑效應之50%。 術語“老化對象”或“年老對象”之意義在根據本發明的 φ 用途之範疇中有充分地理鮮。儘管與實際上的年齢下限沒 有關聯，此一般慨念於人的情況中常指稱至少55歲的人 ，但更清晰的最低年齢限値是設定在60、65、70或75歲 〇 較佳地，該GR拮抗劑係選自US 6329534及 WO 2 00116128中所定義及/或例舉的二苯并吡喃基衍生 物、美服培酮和（Ηβ，17β) - 11- ( 1，3 —苯并二of唑—5 —基）—17-羥基—17 -（1 一丙炔基）雌—4,9 一二烯一 3一酮（其可稱爲ORG 34517)及在EP 763 541中特定揭 -6 - 200820977 示出的化合物所組成之群組。ORG 345 1 7以其高選擇性而 爲最佳者。再者，ORG 34517可增加皮質醇和DHEA(S )兩者的含量。所以，ORG 34517可同時拮抗皮質醇的作 用及增加DHEA ( S )的作用，使GR拮抗劑成爲提供免疫 刺激，諸如老化哺乳動物之感染或感染狀況的預防或治療 作用，之選擇。該等GR拮抗劑，及特別者ORG 345 1 7之 有益效用可就彼等對皮質醇/DHEA ( S )比的矯正作用爲 基礎來解釋。 根據其另一方面，本發明提供糖皮質素受體拮抗劑對 於在壓力狀況下的老化哺乳動物對象免疫刺激所用藥劑的 製備上之用途。於本發明上下文之中，表達語“壓力”包括 生理壓力和心理壓力；其中任一者都可爲急性或慢性者。 生理壓力可由任何物理性創傷或傷害所引起，諸如手術或 骨折。心理壓力可由情緒負擔性事件所造成，諸如喪親。 根據其另一方面，本發明提供糖皮質素受體拮抗劑對 於帶有低血清DHEAS値的哺乳動物對象免疫刺激所用藥 劑的製備上之用途。尤其是在創傷之後，在特別者人類對 象中，該値通常都低於6 μΜ。GR拮抗劑對於免疫刺激之 用途，更佳者係用於具有血清値低於4 μΜ的對象且最佳 者用於血清値低於2 μΜ的對象，特別是人類對象。 根據其另一方面，本發明提供糖皮質素受體拮抗劑對 於帶有高血清皮質醇/DHEAS莫耳比的哺乳動物對象，特 別是人類對象，免疫刺激所用藥劑的製備上之用途。爲清 晰起見，該比例可更進一步地指定爲高於0.2。GR拮抗劑 200820977 於免疫刺激的用途更佳地係用於具有高於0.3血清比的對 象且最佳者具有高於0.4血清比的對象。 根據其另一方面，本發明提供糖皮質素受體拮抗劑對 於具有高嗜中性白血球計數的哺乳動物對象，特別是人類 對象，免疫刺激所用藥劑的製備上之用途。爲清晰起見， 該計數可進一步地指定爲高於6·5 χΙΟ9 Γ1。GR拮抗劑於 免疫刺激的用途較佳地係用於具有高於12x1 Ο9 I·1之計數 φ 的對象且最佳者用於具有高於1 4 X 1 Ο9 Κ 1之計數的對象。 根據其另一方面，本發明提供糖皮質素受體掊抗劑對 於具有受損的嗜中性白血球功能，諸如減低的超氧化物產 生（其可於試管內（in vitro )使用發光光度測定法（ Luminometery )來測定）之對象免疫刺激所用藥劑的製備 上之用途。爲清晰起見，該減低超氧化物產生可進一步地 指定爲多達超過20%的減量。GR拮抗劑於免疫刺激的用 途較佳地係用於該超氧化物的產生量之減低超過40 %的 φ 對象，且最佳者用於該減低達到超過正常超氧化物產生的 50%之對象。 較佳地，GR拮抗劑係用於同時顯示高嗜中性白血球 計數及受損的嗜中性白血球功能兩者之哺乳動物對象的免 疫刺激所用藥劑之製備上。 於本發明之上下文中，感染或感染狀況可由數種藥劑 的任何一種引起，例如細菌、病毒或真菌類。同樣於本發 明之上下文中，表達語“感染狀況”係表隱性感染（silent infection)或次臨床症狀感染（subclinical infection)以 200820977 及不會導致顯性傳染病的狀況，但其中至少一種與傳染病 有關的參數，諸如白血球（例如嗜中性白血球、嗜鹼細胞 或嗜酸性細胞）細胞計數或某些抗體或某些細胞激素（ cytokine )的含量高於正常値。正常値係專家所知且可於 標準醫學手冊中找到者。 根據本發明之特別用途，其係關於老化對象，其患有 由創傷所致壓力倂發的感染或感染狀況。本發明特別關於 φ 其中該對象患有髖骨骨折及/或髖骨手術所致結果之用途 。本發明也關於其中該對象患有心理壓力，特別是急性情 緒壓力，伴隨著感染或感染狀況之用途。 可根據本發明預防或治療的特殊感染爲上呼吸道感染 及尿道感染。 由於諸如骨質疏鬆症的狀況，老化雌性對象可能特別 易患有因骨折引致壓力的後果，且由於諸如RU 486之GR 拮抗劑會有抗-妊娠前作用（anti-pro gestagen ic action ) φ ( RU 486係經認可用於醫用流產者），此使得彼等不適 用於年輕雌性或成年雌性，而本發明的另一優點爲其可用 於老化雌性對象。順便地，0RG 345 1 7的抗-妊娠前效應 僅爲剩餘性者。 本發明也關於供免疫刺激用之藥學組成物，諸如用於 預防或治療哺乳動物對象的感染或感染狀況者，該等對象 係選自老化哺乳動物對象、帶有低DHEAS値的對象、帶 有高皮質醇/DHEAS比的對象及帶有高嗜中性白血球計數 之對象，該組成物包含治療有效量的選自於US 6329534 200820977 與WO 200116128中所定義及/或例舉的二苯并吡喃基衍 生物、美服培酮、和ORG 345 17之中的糖皮質素受體拮 抗劑，其中ORG 345 1 7爲較佳的糖皮質素受體拮抗劑。 最後，本發明也關於一種用以提供免疫刺激作用，諸 如感染或感染狀況的預防或治療，給選自老化哺乳動物對 象、帶有低DHEAS値的對象、帶有高皮質醇/DHEAS比 的對象與帶有高嗜中性白血球計數的對象之中的哺乳動物 φ 對象之方法，包括投予治療有效量的選自於US 6329534 與WO 200 1 1 61 28中所定義及/或例舉的二苯并吡喃基衍 生物、美服培酮、和ORG 345 17之中的糖皮質素受體拮 抗劑給需要此等治療的對象，ORG 345 1 7爲最佳的糖皮質 素受體拮抗劑。 根據本發明的GR拮抗劑可經腸地或非經腸地投藥， 且對於人類，較佳地以0.001 - 10毫克每公斤體重之每曰 劑量投藥。與藥學上適當的輔助劑混合之後，可將GR拮 # 抗劑壓縮成固體劑量單位，諸如九劑或片劑，或製成膠囊 劑或栓劑，利用藥學上適當的液體，也可將GR拮抗劑以 溶液、懸浮液、乳狀液的注射製劑施用，或以噴霧，例如 鼻噴劑之形式施用。對於劑量單位，例如片劑的製備，涵 蓋習用添加劑的使用諸如塡充劑、著色劑、聚合物型黏合 劑及類似物。通常，可以使用不會干擾活性化合物之功能 的任何藥學上可接受的添加劑。可與組成物一起投予的適 當載劑包括以適當量使用的乳糖、澱粉、纖維素衍生物及 類似物，或彼等之混合物。 -10- 200820977 【實施方式】 本發明要以下面實例來示範說明，彼等 爲對本發明範圍的限制。 實施例. 可以使用以得自病患的白血球細胞（尤 φ 血球）及適當的對照組進行之臨床觀察及檢 明的效用。細胞的先天免疫系統，且特別者其 球成份，係針對細菌感染的第一線防禦，細菌 伴同壓力的主要感染形式。嗜中性白血球係一 其本身爲一組白血球細胞）。彼等的關鍵殺菌 噬作用和經由釋放毒性粒狀酵素及產生高毒性 種（諸如超氧化物，透過超氧化物岐化酶作用 殺死。活性氧物種的產生可用發光光度測定法 • 且可複現地測量。 採用發光光度測定法測定和評估嗜中性白 之主要優點在於可在小心控制的試管內（in 下，倂及試管內觀察，來硏究實際病患和對照 疫保護細胞。 嗜中性白血球係從試驗對象和對照組的前 穿刺所得血液離析出（使用抗凝血劑）。下面 步驟-最後步驟係透過由 N y c 〇 m e d 11 “Lymphoprep”·得到粒細胞所組成的細胞部分 施例不應視 爲嗜中性白 來展示本發 嗜中性白血 感染似乎爲 種粒細胞（ 機制涉及吞 反應性氧物 )的細胞內 非常精確地 血球的機能 vitro )條件 組的主要免 臂經由靜脈 的差示離心 IX.所製的 ，其主要包 -11 - 200820977 含嗜中性白血球。該細胞部分的數目及組成係使用庫爾特 計數器（Coulter Counter )來測定。嗜中性白血球係用寡 肽FMLP予以剌激，該肽係模擬細菌蛋白質。因所致細胞 產生氧自由基之結果而發出的光係用Lumin〇l“放大”並用 發光光度計（Berthold )測定。所得峰的高度可用爲嗜中 性白血球的生理狀況之指標。此外，可在刺激與測量之前 ，將嗜中性白血球與實驗化合物接觸，以觀察嗜中性白血 球對生理狀況的影響。
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Claims (1)
- 200820977 十、申請專利範園 1. 一種糖皮質素受體（GR)拮抗劑經由對GR受體 具有結合親和力而於老化哺乳動物對象的免疫刺激所用藥 物的製造上之用途。 2· —種糖皮質素受體拮抗劑經由對GR受體具有結合 親和力而於帶有低血清DHEAS値的哺乳動物對象之免疫 刺激所用藥物的製造上之用途。 3· —種糖皮質素受體拮抗劑經由對GR受體具有結合 親和力而於帶有高血清皮質醇/DHEAS比的哺乳動物對象 之免疫刺激所用藥物的製造上之用途。 4· 一種糖皮質素受體拮抗劑經由對GR受體具有結合 親和力而於有高嗜中性白血球計數的哺乳動物對象之免疫 刺激所用藥物的製造上之用途。 5·根據申請專利範圍第1至4項中任一項之糖皮質 素受體拮抗劑的用途，其係用於製造處於壓力狀況下且具 有a、b或c中至少一項的老化人類對象之免疫刺激所用 藥物： a )低於6μΜ之血清DHEAS値； b) 高於0.2之血清皮質醇/DHEAS莫耳比； c) 高於6.5 χΙΟ9 K1之嗜中性白血球計數。 6.根據申請專利範圍第1項之用途，其中該糖皮質 素受體拮抗劑爲美服培酮（mifepristone)或（11β，17β) —11— (1，3- 苯并二嘴哩—5- 基）—17-經基—17— (1 一丙炔基）雌一 4,9 一二烯一 3-酮。 -14- 200820977 7. 根據申請專利範圍第6項之用途，其中該糖皮質 素受體拮抗劑爲（11β，17β) - 11一（1，3-苯并二嚀唑-5 一基）一 17 —羥基一 17-（1 一丙炔基）雌—4,9一二烯— 3 -酮。 8. 根據申請專利範圍第1項之用途，其中該對象患 有髖骨骨折及/或髖骨手術伴隨的感染或感染狀況。 9. 一種藥用組成物，其包括糖皮質素受體拮抗劑， φ 其經由對GR受體具有結合親和力而用於選自老化哺乳動 物對象、帶有低血清DHE AS値的對象、帶有高血清皮質 醇/DHE AS比的對象及帶有高嗜中性白血球計數的對象之 中的哺乳動物對象之免疫刺激。 1 0.根據申請專利範圍第9項之組成物，其中該糖皮 質素受體拮抗劑爲美服培酮或（1 1β，17β ) - 1 1 — ( 1，3 -苯并二嚀唑一 5-基）一 17 —羥基一 17 —（1 一丙炔基）雌 一 4，9 —二烯一 3 -酮。 -15- 200820977 無 ·· 明 說 單 簡 號 符 Λ 為代 圖件 表元 代之 定圖 指表 ••案代 圖本本 表、、 代 定一二 指CC 七 八、本案若有化學式時，請揭示最能顯示發明特徵的化學 式：無 -3-
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| US8986677B2 (en) * | 2012-07-30 | 2015-03-24 | Pop Test Cortisol Llc | Therapeutic compositions and methods |
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| CO5180649A1 (es) | 1999-09-01 | 2002-07-30 | Abbott Lab | Antagonistas de los receptores de los glucocorticoides para el tratamiento de la diabetes para el tratamiento de la diabetes |
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