CN101500547A - 糖皮质激素受体拮抗剂用于治疗感染性病症的用途 - Google Patents
糖皮质激素受体拮抗剂用于治疗感染性病症的用途 Download PDFInfo
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Abstract
本发明提供了糖皮质激素受体拮抗剂在制备用于在老龄哺乳动物受试者、低血清DHEAS值的哺乳动物受试者、高血清皮质醇/DHEAS比例的受试者或高嗜中性粒细胞计数的受试者中免疫刺激，例如预防或治疗感染或感染性病症的药物的用途。特别地，所述糖皮质激素受体拮抗剂选自如在US6329534和WO200116128中所定义和/或例举的二苯并吡喃衍生物、米非司酮和(11β，17β)－11－(1，3－苯并二氧杂环戊烯－5－基)－17－羟基－17－(1－丙炔基)雌甾－4，9－二烯－3－酮。
Description
本发明涉及糖皮质激素受体(GR)拮抗剂用于在哺乳动物受试者中的免疫刺激作用的用途，并涉及含GR拮抗剂的药物组合物。本发明还涉及用于提供免疫刺激的方法，例如预防或治疗感染或感染性病症。
已知免疫系统受到下丘脑-垂体-肾上腺(HPA)轴和交感-肾上腺-髓质(SAM)轴的影响。所述HPA轴引起糖皮质激素受体拮抗剂(人类的皮质醇)和去氢表雄酮(硫酸酯)(DHEA(S))的释放，该糖皮质激素受体拮抗剂和脱氢表雄酮(硫酸酯)分别抑制和刺激免疫功能。在另一方面，所述SAM轴引起具有免疫抑制作用的儿茶酚胺的释放。
在经受应激的健康的、年轻至中年受试者中的促炎介质和抗炎介质间存在着生理平衡。在老年人中，由于若干免疫系统组件的衰弱(免疫老化)和向慢性促炎状态转移(所谓的“炎性衰老(inf lammaging)”作用(Butcher和Lord，(2004)Aging Cell，pp.151-160)，免疫应答减弱。由于皮质醇的产生与年龄保持适度一致，而DHEA和DHEAS的总水平从第三个十年逐渐降低，并在第八个十年达到其最大值的10-20％，因此Butcher和Lord(2004，supra)提出年龄和应激的模型，其中与年龄相关的皮质醇与DHEAS比例的增加与应激过程中皮质醇的升高共同导致了老年受试者明显的免疫降低。所提出的模型解释了老年受试者在应激状态下更易感染。
基于由老年髋部骨折患者的白细胞所获得的实验数据，提出在应激状态下不时补充DHEA和/或DHEAS作为防止感染的一种方法。(Butcher和Lord(2004，supra)；Butcher等(2005，Aging Cell 5，pp.319-324)。
本发明涉及糖皮质激素受体拮抗剂在制备用于在老龄哺乳动物受试者(例如人类受试者)中免疫刺激的药物的用途，例如预防或治疗的感染或感染性病症。尽管早期的建议是：抵抗糖皮质激素的免疫刺激作用(请参考Regelson 1990a；1990b；1992；Daynes和Araneo1989；Emilie等，1984；Zhang等，1998；Morfin等，US5,763,433；Hampl等1998；Lathe，R.等：WO97/37664；Nakamori等JP2005213156)和长期利用直接作用于GR受体的拮抗剂(米非司酮(RU486)，但是没有关于在正常哺乳动物受试者中经GR拮抗剂所获得的免疫刺激作用的报道。不希望受到理论的限制，认为如通过本发明所提供的在所选择的受试者中的作用可以由相对于在正常受试者中皮质醇和DHEAS对免疫系统的平衡作用，而在老龄群体中增加的皮质醇/DHEAS比值的不平衡的免疫抑制作用加以解释。术语‘哺乳动物受试者’包括提及的人类受试者，其为本发明的优选受试者和在本发明所提供的主题中的优选受试者。
如果有必要使术语‘糖皮质激素受体(GR)拮抗剂’更加清楚，那么可以使用下述定义，即GR拮抗剂是能预防地塞米松的生理作用的化合物，其原因是该拮抗剂直接作用于GR受体。因此，在参考文献(
等，2002)中术语‘糖皮质激素受体拮抗剂’以不寻常的方式使用以描述DHEA对糖皮质激素作用的影响。GR拮抗剂的直接相互作用通常意指化合物具有pKa至少为6的与GR受体的亲和力。更为清楚的是在标准测定中设置pKa对糖皮质激素受体亲和力的最低限制为6、6.5、7、7.5、8或9。如果所述拮抗剂具有剩余激动剂作用，那么作为拮抗剂的部分激动剂，最大激动剂作用应低于地塞米松的最大激动剂作用的50％。
术语‘老龄(aging)受试者’或‘年老(aged)受试者’的意思根据本发明上下文的使用很好理解。尽管这与精确的年龄下限没有联系，但是在人类的情况下所述概念通常指至少55岁的人，但是更清楚的是最低年龄限制为60、65、70或75岁。
优选地，GR拮抗剂选自在US6329534和WO200116128中所定义的和/或例举的二苯并吡喃基衍生物、米非司酮和被称为ORG34517的(11β，17β)-11-(1，3-苯并二氧杂环戊烯(benzodioxol)-5-基)-17-羟基-17-(1-丙炔基)雌甾-4，9-二烯(dien)-3-酮，并且在EP 763 541中具体公开了所述化合物。鉴于ORG 34517的高选择性，它是最优选的。此外，ORG 34517增加了皮质醇和DHEA(S)水平。因此，ORG 34517既拮抗皮质醇的作用又增加DHEA(S)的作用，使得其成为用于在老龄哺乳动物受试者中提供免疫刺激，例如预防或治疗感染或感染性病症的GR拮抗剂的选择。所述GR拮抗剂(特别是ORG 34517)的有益作用可以其校正皮质醇/DHEA(S)比值的影响为基础得以解释。
根据本发明另一方面，其提供了糖皮质激素受体拮抗剂在制备用于在应激状态下老龄哺乳动物受试者中免疫刺激的药物的用途。在本文上下文中，措辞“应激”包含物理和生理应激，其可以是急性的或慢性的。物理应激可由任何物理外伤和损伤，例如手术或骨折引起。生理应激可由出现情绪上的负担，例如失去亲人引起。
根据本发明另一方面，其提供了糖皮质激素受体拮抗剂在制备用于在具有低血清DHEAS值的哺乳动物受试者中的免疫刺激的药物的用途。特别是在外伤后，所述值特别是在人类受试者中通常低于6μM。用于免疫刺激的GR拮抗剂优选用在具有血清值低于4μM的受试者中，特别是人类受试者，并且最优选用在具有血清值低于2μM的受试者中。
根据本发明另一方面，其提供了糖皮质激素受体拮抗剂在制备用于在具有高血清皮质醇/DHEAS摩尔比值的哺乳动物受试者中，特别是人类受试者中免疫刺激的药物的用途。为了清楚，将所述比值进一步指定为高于0.2。优选在具有血清比值高于0.3的受试者中，更优选的在血清比值高于0.4的受试者中使用GR拮抗剂用于免疫刺激。
根据本发明另一方面，其提供了糖皮质激素受体拮抗剂在制备用于在具有高嗜中性粒细胞计数的哺乳动物受试者中，特别是人类受试者中免疫刺激的药物的用途。为了清楚，将所述计数进一步指定为高于6.5 x 109L-1。优选在具有血清计数高于12 x 109L-1的受试者中，最优选的在具有血清计数高于14 x 109L-1的受试者中使用GR拮抗剂用于免疫刺激。
根据本发明另一方面，其提供了糖皮质激素受体拮抗剂在制备用于在具有受损的嗜中性粒细胞功能，例如超氧化物产生减少(使用冷光仪(luminometry)在体外检测)的受试者中免疫刺激的药物的用途。为了清楚，将所述超氧化物生成减少进一步指定为减少超过20％的量。优选在超氧化物生成量的减少超过40％的这类受试者中，特别是人类受试者，最优选在正常超氧化物生成的减少量超过50％的这类受试者中使用GR拮抗剂用于免疫刺激。
优选地，GR拮抗剂在制备用于在具有高嗜中性粒细胞计数和受损的嗜中性粒细胞功能的哺乳动物受试者中免疫刺激的药物。
在本发明的上下文中，感染或感染性病症由任一种介质(例如细菌、病毒或真菌)引起。另外，在发明的上下文中，措辞“感染性病症”指隐性感染或亚临床感染以及不引起显性感染性疾病的病症，但是其中至少有一个与感染性疾病有关的参数，例如白细胞(例如嗜中性粒细胞、嗜碱性粒细胞或嗜酸性粒细胞)计数、或者一些抗体或一些细胞因子的水平高于正常。正常值对于技术人员而言是公知的，并且该值可通过标准医学手册查找。
本发明的具体用途涉及患有伴随由外伤引起的应激的感染或感染性病症的老龄受试者。本发明特别涉及其中受试者患有髋部骨折和/或髋部手术后果的用途。本发明还涉及其中受试者患有伴随心理应激，特别是急性情绪应激的感染或感染性病症的用途。
本发明所预防或治疗的具体感染是上呼吸道感染和尿道感染。
由于老年女性受试者因为病症例如骨质疏松的结果，特别倾向于有通过骨折引起应激的后果，并且由于GR拮抗剂(例如RU486)具有抗黄体素(anti-progestagenic)作用(已经批准RU486用于药物流产)，使得该药不适用于年轻女性或成年女性，因此本发明的另一个益处是使该药用于老年女性受试者。偶然地，ORG 34517的抗黄体素作用仅仅是残留的。
本发明还涉及用于在哺乳动物受试者中免疫刺激(例如预防或治疗感染或感染性病症)的药物组合物，所述哺乳动物受试者选自老龄哺乳动物受试者，低DHEAS值受试者，高皮质醇/DHEAS比例受试者以及高嗜中性粒细胞计数受试者，所述组合物包括选自如在US6329534和WO200116128中所定义和/或例举的二苯并吡喃衍生物、米非司酮和ORG 34517的治疗有效量的糖皮质激素受体拮抗剂，其中ORG 34517是优选的糖皮质激素受体拮抗剂。
最后，本发明还涉及在哺乳动物受试者中提供免疫刺激(例如预防或治疗感染或感染性病症)的方法，所述哺乳动物选自老龄哺乳动物受试者，低DHEAS值受试者，高皮质醇/DHEAS比例受试者以及高嗜中性粒细胞计数受试者，所述方法包括对需要所述治疗的所述受试者给予选自如在US6329534和WO200116128中所定义和例举的二苯并吡喃衍生物、米非司酮和ORG 34517的治疗有效量的糖皮质激素受体拮抗剂，其中ORG 34517是优选的糖皮质激素受体拮抗剂。
本发明的GR拮抗剂可以肠道内或肠道外(enterally ofparentally)给药，并且优选人用日剂量为0.001-10mg/kg体重。GR拮抗剂与可药用的辅料混合可被压制成固体剂量单位，例如丸剂和片剂或被加工成胶囊或栓剂。借助于可药用的液体，GR拮抗剂还可以溶液、悬浮液、乳液的形式作为注射制剂，或作为喷雾剂(例如鼻内喷雾剂)施用。为了生产剂量单位(例如片剂)，预期使用常规添加剂(例如填充剂、着色剂、聚合粘合剂等)。总之，可以使用任何不干扰活性化合物功能的可药用添加剂。适合组合物给药的载体包括以合适的量使用的乳糖、淀粉、纤维素衍生物等或其混合物。
本发明通过下述实施例说明，但不能认为其对本发明的保护范围进行限定。
实施例
应用临床观察以及来自患者和适宜对照的白细胞(特别是嗜中性粒细胞)的测定说明本发明的作用。细胞的天然免疫系统(特别是其嗜中性粒细胞组分)是对抗细菌感染的第一道防线，其似乎是随应激而产生感染的主要形式。嗜中性粒细胞是粒细胞(其本身是一组白细胞)的一种。它们主要的杀菌机制包括吞噬作用和通过释放毒性粒状酶和产生高毒性活性氧(例如超氧化物，通过超氧化物歧化酶)在细胞内杀菌。使用冷光仪(luminometry)可以非常精确和重复性地检测活性氧的产生。
使用冷光仪分析以确定和评价嗜中性粒细胞的功能的主要优点是在体外谨慎地受控条件下(其与体外观察平行)研究实际患者和对照的主要免疫防御细胞。
从通过实验受试者和对照者前臂的静脉穿刺所获得的血液(含有抗凝剂)中分离嗜中性粒细胞。按照不同的离心步骤-通过由NycomedInc.制造的“Lymphoprep”的最后步骤-获得由粒细胞(主要包含嗜中性粒细胞)组成的细胞组分。使用Coulter Counter测定所述细胞组分的数量和组成。所述嗜中性粒细胞经寡肽FMLP刺激，其模拟细菌蛋白。由于通过细胞所产生的氧自由基所发射的光可被鲁米诺“放大”，从而被发光计(Berthold)检测到。所获得峰值的高度可用作嗜中性粒细胞的生理状态的指示。此外，在刺激和检测前使嗜中性粒细胞与实验化合物接触，以观察该化合物对嗜中性粒细胞的生理状态的影响。
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Claims (10)
1.对GR受体有结合亲和力的糖皮质激素受体拮抗剂在制备用于在老龄哺乳动物受试者中免疫刺激的药物中的用途。
2.对GR受体有结合亲和力的糖皮质激素受体拮抗剂在制备用于在具有低血清DHEAS值的哺乳动物受试者中免疫刺激的药物中的用途。
3.对GR受体有结合亲和力的糖皮质激素受体拮抗剂在制备用于在具有高血清皮质醇/DHEAS比值的哺乳动物受试者中免疫刺激的药物中的用途。
4.对GR受体有结合亲和力的糖皮质激素受体拮抗剂在制备用于在具有高嗜中性粒细胞计数的哺乳动物受试者中免疫刺激的药物中的用途。
5.根据权利要求1-4的任一项的用途，用于在应激状态且具有下述a、b或c中至少一种的病症下在老年人类受试者中的免疫刺激：
a)血清DHEAS值低于6μM；
b)血清皮质醇/DHEAS的摩尔比例高于0.2；
c)嗜中性粒细胞计数高于6.5 x 109L-1。
6.根据权利要求1-5的任一项的用途，其中糖皮质激素受体拮抗剂是米非司酮或(11β，17β)-11-(1，3-苯并二氧杂环戊烯-5-基)-17-羟基-17-(1-丙炔基)雌甾-4，9-二烯-3-酮。
7.根据权利要求6的用途，其中所述糖皮质激素受体拮抗剂是(11β，17β)-11-(1，3-苯并二氧杂环戊烯-5-基)-17-羟基-17-(1-丙炔基)雌甾-4，9-二烯-3-酮。
8.根据权利要求1-7的任一项的用途，其中所述受试者患有伴随髋部骨折和/或髋部手术的感染或感染性病症。
9.在哺乳动物受试者中提供免疫刺激的方法，所述哺乳动物受试者选自老龄哺乳动物受试者、具有低血清DHEAS值的受试者、具有高血清皮质醇/DHEAS比例的受试者以及具有高嗜中性粒细胞计数的受试者，所述方法包括给予有此需要的所述受试者治疗有效量的对GR受体有亲和力的糖皮质激素受体拮抗剂。
10.根据权利要求9的方法，其中所述糖皮质激素受体拮抗剂是(11β，17β)-11-(1，3-苯并二氧杂环戊烯-5-基)-17-羟基-17-(1-丙炔基)雌甾-4，9-二烯-3-酮。
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| WO2008017658A3 (en) | 2008-04-10 |
| CA2658016A1 (en) | 2008-02-14 |
| WO2008017658A2 (en) | 2008-02-14 |
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