CN104321074B - 生长抑素类似物与11β‑羟化酶抑制剂的组合 - Google Patents
生长抑素类似物与11β‑羟化酶抑制剂的组合 Download PDFInfo
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Abstract
本发明涉及包括(a)生长抑素类似物和(b)11β‑羟化酶抑制剂的组合;其各自采用游离形式或其药学上可接受的盐形式;所述组合在制备与应激激素水平增加相关的疾病的治疗药物中的应用;包含所述组合的商业包装或产品;以及一种治疗温血动物尤其是人的方法。
Description
技术领域
本发明涉及包括(a)生长抑素类似物和(b)11β-羟化酶抑制剂的组合;其各自采用游离形式或其药学上可接受盐的形式;所述组合在制备与应激激素水平增加相关的疾病治疗药物中的应用;包含所述组合的商业包装或产品;以及一种治疗温血动物尤其是人的方法。
背景技术
生长抑素类是一种已知的小肽类,包括天然产生的生长抑素-14和具有生长抑素相关活性的类似物,如A.S.Dutta,在Small Peptides,第19卷,Elsevier(1993)所公开。本文所用的“生长抑素类似物”指任何具有基于天然产生的生长抑素-14的结构的直链或环状多肽,其中一个或多个氨基酸单元被省略和/或由一个或多个其它氨基取代,和/或其中一个或多个官能团被一个或多个其它官能团取代和/或一个或多个基团被一个或多个其它等排基团取代。一般地,该术语涵盖所有天然抑素-14经修饰的衍生物,其显示与生长抑素相关的活性,如结合5种生长抑素受体(SSTR)中的至少一种,优选在纳摩尔范围内。通常已知的生长抑素类似物是奥曲肽、伐普肽、兰瑞肽、帕瑞肽。
帕瑞肽具有如下化学结构:
帕瑞肽被称为环[{4-(NH2-C2H4-NH-CO-O-)Pro}-Phg-DTrp-Lys-Tyr(4-Bzl)-Phe],其中Phg指-HN-CH(C6H5)-CO-,Bzl指采用游离形式、盐或复合物形式或被保护形式的苄基。
库兴氏综合征是由血液中高水平的皮质醇引起的激素失调。这可能由服用糖皮质激素药物,或由产生皮质醇或促肾上腺皮质激素(ACTH)或CRH的肿瘤引起。库兴氏病指该综合征的一个特定病因:脑下垂体中的肿瘤(腺瘤)生成大量ACTH,使皮质醇升高。这是库兴氏综合征的最常见病因,占70%病例(不含糖皮质激素相关病例)。在施用帕瑞肽的库兴氏病患者中,皮质醇水平的显著降低支持其作为库兴氏病靶向治疗的潜在应用(Colao等.NEngl J Med2012;366:32–42)。
化合物A是合成皮质醇最后步骤的限速酶11β-羟化酶的有效抑制剂。WO2011/088188表明化合物A在治疗表征为应激激素水平增加和/或雄激素水平减少的疾病或紊乱中的潜在应用,包括化合物A在治疗心力衰竭、恶病质、急性冠脉综合征、慢性应激综合征、库兴氏综合征或代谢综合征中的潜在应用。
化合物A也称为(R)-4-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)-3-氟-苯甲腈,具有式(II)。
化合物A可通过WO2007/024945所述的方法合成或生产并表征。
发明内容
本发明特别基于一个10周的概念验证性临床试验所证明的安全性令人满意的化合物A在库兴氏病患者中的功效数据。化合物A在所有患者中成功减少尿游离皮质醇(UFC),大多数患者达到正常UFC范围。然而,对于试验中的一些患者,UFC水平在药物中断后2周恢复到高于正常上限(ULN)。而且在半数患者中,ACTH水平加倍。因此,本发明旨在维持和改善化合物A的效果,一般而言特别是降低皮质醇水平的效果,特别是化合物A对于治疗或改善表征为应激激素水平增加(尤其是皮质醇水平增加)的疾病或紊乱的效果,包括化合物A在治疗心力衰竭、恶病质、急性冠脉综合征、慢性应激综合征、库兴氏综合征或代谢综合征中的潜在应用。
因此,在第一方面,本发明提供(a)化合物A(R)-4-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)-3-氟-苯甲腈;和(b)一种生长抑素类似物的组合(本申请内称为本发明组合),其中(a)和(b)各自以游离形式、复合物形式或药学上可接受的盐形式存在。
在一个优选实施方式中,所述生长抑素类似物是奥曲肽、伐普肽、兰瑞肽、或帕瑞肽。在一个优选实施方式中,所述生长抑素类似物是帕瑞肽或其任意药学上可接受的盐。优选的盐是乳酸盐、天冬氨酸盐、苯甲酸盐、琥珀酸盐和巴莫酸盐,包括单盐和双盐,更优选天冬氨酸双盐和巴莫酸单盐。某些帕瑞肽盐在水性环境下形成凝胶,诸如,天冬氨酸盐如单或双天冬氨酸盐,谷氨酸盐如单或双谷氨酸盐,或琥珀酸盐如单或双琥珀酸盐,乳酸盐,乙酸盐或柠檬酸盐。在一个优选实施方式中,所述的帕瑞肽的药学上可接受的盐是巴莫酸盐。
化合物A的优选盐是磷酸盐或氮盐。更优选是磷酸二氢盐。本申请中所用的术语“磷酸盐”指化合物A与磷酸的酸加成盐。更特定地,指质子化一次的化合物A的磷酸二氢盐,也就是化合物A进行一次质子化后,每个分子因此携带一个正电荷,其平衡离子是H2PO4 -。
令人惊讶地是所述组合维持化合物A的皮质醇降低效果。此外,生长抑素类似物和化合物A的效果可互相协同加强,使得功效更高,所需有效剂量更少。
本发明还关于同时、分开或顺序使用的组合,如组合制剂,包括非固定组合或药物固定组合。固定组合指两种活性成分都存在于一个剂型中,如在一个片剂或一个胶囊中。因此,本发明的药物固定组合包括(a)生长抑素类似物和(b)化合物A,其中(a)和(b)各自以游离形式或药学上可接受的盐形式存在,和任选至少一种药学上可接受的载体。该生长抑素类似物优选是帕瑞肽。
药学上可接受的载体包括任意和全部溶剂、分散介质、涂层、表面活性剂、抗氧化剂、防腐剂(如抗菌剂、抗真菌剂)、等渗剂、吸收延缓剂、盐、防腐剂、药物、药物稳定剂、粘结剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染料、类似的材料和其组合,这些为本领域普通技术人员已知。
本文所用的术语“非固定组合”限定本文所述的组合伴侣(a)和(b)能以不同量的组合伴侣(a)和(b)彼此独立,即同时或在不同时间点给药。术语“非固定组合”包括“试剂盒”。试剂盒的组件可以例如同时或按时间顺序错开施用,即就任何试剂盒组件而言在不同时间点且以相同或不同的时间间隔施用。
优选地,时间间隔如此选择:联用(a)和(b)对所治疗疾病的效果大于仅用组合伴侣(a)和(b)中任意一种的效果。组合制剂中待施用的组合伴侣(a)与组合伴侣(b)总量的比例可改变,例如为了符合待治疗患者亚群的需求或单个患者的需求,其不同的需求可归因于患者的年龄、性别、体重等。优选地,这具有至少一种有益效果,如组合伴侣(a)和(b)的相互提高的效果,特别是协同作用,例如超过加性效应、额外的有利效果、更少的副作用、非有效剂量的组合伴侣(a)和(b)之一或两者的联合治疗效果,且极优选地是组合伴侣(a)和(b)的强协同作用。
一方面,本发明提供本发明组合用于治疗表征为应激激素水平升高的疾病状态。本文所用的术语“应激激素”涉及因响应活体中异常暴露而分泌的激素。应激反应包括激活交感肾上腺髓质***(分泌肾上腺素和去甲肾上腺素)和下丘脑-垂体-肾上腺皮质(HPA)***(分泌皮质醇)。在一个优选实施方式中,应激激素是醛固酮或皮质醇,优选皮质醇。
在一个优选实施方式中,本发明提供本发明组合用于治疗表征为皮质醇水平升高的疾病。本文所用的术语“升高的皮质醇水平”指皮质醇水平高于个体自身的正常皮质醇范围。群体的正常UFC范围是每24小时10-100微克(mcg/24h或μg/24h)。因此,术语“升高的皮质醇水平”可定义为高于30μg/24h、高于50μg/24h、高于70μg/24h、高于85μg/24h或高于100μg/24h。术语“升高的皮质醇水平”可进一步定义为高于125μg/24h、高于125μg/24h或高于200μg/24h。尿游离皮质醇(UFC)以24小时尿游离皮质醇的均值来测量,从2周内收集的4个24小时样品中计算。优选地,术语“升高的皮质醇水平”指高于80μg/24h、高于100μg/24h或高于120μg/24h或高于150μg/24h的水平。
表征为皮质醇水平升高的疾病包括但不限于慢性心力衰竭、伴有运动耐量受损的慢性心力衰竭、伴有肌无力的慢性心力衰竭、心脏性恶病质、COPD诱导性恶病质、肝硬化诱导性恶病质、肿瘤诱导性恶病质、病毒(HIV)诱导性恶病质、急性心力衰竭、急性失代偿性心力衰竭、急性冠脉综合征、慢性应激综合征、库兴氏综合征、代谢综合征和高皮质醇血症(hypercortisolemia)。
慢性心力衰竭以及伴有运动耐量受损和肌无力的慢性心力衰竭的病症显示为血浆醛固酮水平升高,如Bolger等人.Circulation 2002;106:92-99所示;血浆与脱氢表雄甾酮(dihydroepiandrosterone)的比值升高,如Anker等人.European Heart Journal 1999;20:683-693所示;雄激素水平下降,如Jankowaska等人,Circulation 2006;114:1829-1837所示。
心脏性恶病质是慢性心力衰竭的严重并发症,因为患者遭受脂肪组织、瘠瘦组织和骨组织的普遍衰减。心脏性恶病质患者显示醛固酮和皮质醇的血浆水平升高以及脱氢表雄甾酮水平降低,如Anker等人,Circulation 1997;96:526-534所述。
COPD诱导性恶病质、肝硬化诱导性恶病质、肿瘤诱导性恶病质和病毒(HIV)诱导性恶病质表征为血浆醛固酮水平升高,如WO 2000/21509或US 2009/0023639所述,并用合成代谢的雄激素或雄激素衍生物治疗,如Yeh等,Chest 2002;122:421-428和Cuerda等,Nutrition Clinical Practice 2005 20;93-97所报道。
心肌梗死升高了影响心脏重塑的皮质醇水平,如Mihailidu等,Hypertension2009(待刊)所示。皮质醇响应的程度与随后的梗死大小相关,如Bain等,InternationalJournal of Cardiology 1992;27:145-150所示。
伴有身体和心理后果的慢性应激失调与醛固酮和皮质醇水平过高相关联,如Kubzansky和Adler,Neuroscience and Biobehavioral Reviews,2009;5:1-7所述。特别地,过度且持续的皮质醇分泌可导致抑郁、高血糖症和免疫***抑制。
库兴氏综合征描述了一种长期的皮质醇释放过量的病症。皮质醇过量可能直接来自于肾上腺皮质瘤或其次来自于释放促肾上腺皮质激素的垂体(库兴氏病)或异位肿瘤,如Boscaro和Arnaldi,Journal of Clinical Endocrinology and Metabolism 2009;94:3121-3131所示。
代谢综合征定义一种表征为胰岛素抵抗及具有2型糖尿病、中央性和内脏型肥胖、高血压和血脂障碍倾向的代谢失调状态。代谢失调可由肾上腺类固醇醛固酮和皮质醇介导的潜在内分泌失调引起,如Kidamby等.Hypertension 2007;49:704-711所报道。
高皮质醇血症指表征为高水平的循环皮质醇的病症。高水平的血浆皮质醇可直接引起病理状态,表现出病理症状或具有非病理性质的信号。
在一个优选实施方式中,本发明提供本发明组合用以治疗库兴氏综合征。本发明组合维持化合物A的皮质醇降低效果。在不受理论约束或限制下,应理解生长抑素类似物特别是帕瑞肽通过靶向ACTH来改善或维持化合物A的效果。因此,在一个优选实施方式中,库兴氏综合征是一种ACTH依赖性库兴氏综合征,优选库兴氏病。
除了分泌ACTH的垂体瘤引起的ACTH水平升高,其它组织如正常垂体-肾上腺***外的肿瘤,如小细胞肺癌,能产生影响肾上腺的ACTH。因此,在一个实施方式中,库兴氏综合征患者具有升高的非垂体来源ACTH水平。
另一方面,本发明还设想了改良的库兴氏综合征治疗,其中皮质醇增多症是非ACTH依赖性的。在不受理论约束或限制下,帕瑞肽降低ACTH水平,而其增加可能是由化合物A的施用引起。
一方面,本发明提供化合物A用于与生长抑素类似物,优选帕瑞肽的组合以治疗库兴氏综合征。
一方面,本发明提供一种治疗库兴氏综合征的方法,其包括向患者同时、分开或顺序施用(1)化合物A和(2)生长抑素类似物。
一方面,本发明提供本发明组合在制造治疗库兴氏综合征的药物中的应用。
一方面,本发明提供采用游离形式、复合物形式或药学上可接受盐的形式的化合物A在制备与生长抑素类似物联合使用的药物中的应用。
一方面,本发明提供一个包含本发明组合,以及其在库兴氏综合征治疗中同时、分开或顺序使用的说明书的商业包装。
所述生长抑素类似物优选是帕瑞肽。
具体实施方式
下列实施例说明上述发明,但不意在以任何方式限制本发明范围。相关领域技术人员已知的其它测试模型也能确定本发明的有益效果。
实施例1(R)-4-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)-3-氟-苯甲腈的磷酸盐(形式A)
将2g游离碱溶于40ml乙醇且在数分钟进程中加入1当量磷酸。加入后,过滤收集固体。固体在氮流下22℃干燥。收集到约1.8g。
所得盐中磷酸盐与(R)-4-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)-3-氟-苯甲腈的摩尔比是1:1。
在水中,磷酸盐在0.1%目标浓度可溶且于50℃稳定2天。游离碱保持大部分不可溶。其在接触水后的短时间内从自由流动固体转变成油性物质,并在50℃保持2天。
吸湿性
吸附/解吸等温线用VTI 100湿度微量天平(VTI公司,Hialeah,佛罗里达州,美国)测量。测量在25℃进行。样品在N2流下于25℃干燥。
发现磷酸盐的吸湿性在5%RH下仅为0%吸水且在75%相对湿度下为0.9%吸水。
过量固体在各溶剂中于25℃±0.1平衡24小时。上清液中的浓度通过用于有机溶剂的重量测定法和以水性溶剂和丙二醇的HPLC来测量。
获得磷酸盐的下列结果与游离碱比较:
表1-1溶解度概况(mg/ml)
这显示磷酸盐在非水溶剂中的溶解度相对较低,因此该溶剂是该盐的反溶剂,由此有可能实现良好沉淀并因而获得良好产率和纯度。另一方面,水中的溶解度优于游离碱,这对于提供口服或胃肠外制剂是有利的。
熔点通过上述的TG/DTA测定并测定为210.2℃。
实施例2
库兴氏病患者用化合物A(一种有效的11β-羟化酶抑制剂)达到正常尿皮质醇:来自多中心、概念验证性研究的初步结果
引言:库兴氏综合征的临床特征和并发症由长期过量的循环皮质醇引起,其通常由24小时尿游离皮质醇(UFC)定量。化合物A是一种11β-羟化酶的有效抑制剂。由于11β-羟化酶催化皮质醇合成的最终步骤,化合物A可能是针对库兴氏综合征的所有形式的新治疗。
方法:患有中度到重度库兴氏病的成年患者(UFC>1.5x正常上限[ULN],14天中3次采样的平均值)在开放标签的研究中接受10周口服化合物A。化合物A以2mg bid(一天两次)开始给药。剂量递增计划为每2周分别达到5、10、20和50mg bid,直至UFC正常化,在该情形下维持剂量直到第70天治疗停止。由于耐受性,允许减少剂量。在每2周时段的倒数第二天评估UFC。监测患者,直到第84天。主要终点是在第70天时用在第70天前一周收集的3个UFC样品均值,UFC≤ULN或相比基线减少≥50%。
结果:12名患者(年龄为25–55岁;4名男性)入组且至今有9名完成研究。他们的UFC、脱氧皮质醇、ACTH水平在附图中各自显示。9名患者有既往手术史。基线UFC范围是1.6–17.0xULN(平均UFC±SD,μg/24h,346±385;范围115–153)。研究中的全部11名患者的至少1次评估的UFC水平正常。主要终点由完成积极治疗阶段的所有9名患者达到,其中8名在第70天UFC水平正常。治疗停止后,在第84天测量的6名患者的UFC>ULN。与UFC正常化相关的化合物A的中等剂量为5-10mg bid。在第70天,平均SBP比基线降低13.1mmHg。化合物A通常耐受良好;报道最频繁的不良事件是疲劳(7/12)、恶心(4/12)和头痛(3/12)。5名患者经历了ACTH水平>2x基线。4名患者经历了与研究药物相关的低钾血(K+<3.5mmol/L;min 3.1mmol/L)。没有可疑药物相关性的严重不良事件。
结论:化合物A在所述库兴氏病患者的概念验证性研究中显示具有令人满意的安全特性的功效。
实施例3大鼠中化合物A和帕瑞肽的联用研究
该非临床研究的目的是确定化合物A与SOM230联用的毒性。该联合治疗包括向大鼠每日口服施用化合物A以及每日一次皮下注射SOM230。此外,测定化合物A/SOM230的毒代动力学性质。
在超纯水中配制的化合物A通过口服强饲法(5mL/kg)单独或与用醋酸盐缓冲溶液pH 4.5(用于注射USP)配制的SOM230联合施用,并通过皮下注射(肩胛间区域,1mL/kg)施用于5组(10/性别/组)Wistar Hannover大鼠,日剂量为1.5/0.03、5/0.1、20/0.3、20/和/0.3毫克/千克/天的化合物A/SOM230。另一组大鼠(10/性别)通过口服强饲法接受每日剂量的超纯水和通过皮下注射接受醋酸盐缓冲溶液pH 4.5(用于注射USP),并作为对照。给药开始时,动物为约7-8周龄,雄性为176-216g,雌性为123-165g。
研究活动包括涉及每日两次检测死亡率和不健康征兆或治疗反应的临床检测,每日给药前和给药后1小时的笼旁观察,每周详细检测,体重和采食量,两次眼科检查(治疗前和第13周),临床病理学(血液学、凝固和临床生物化学、尿液分析)和给药结束时的免疫学(促肾上腺皮质激素、皮质酮、生长激素、***和皮质酮尿液分析)。在第1天和第11周期间(给药后0.5、1、3、7和24小时)对接受化合物A/SOM230组合的组进行毒代动力学评价。死亡后评价包括肉眼观察、器官重量评价(绝对和相对于身体)和显微镜检查。
存活观察:此研究进行期间没有与化合物A/SOM230相关的死亡、毒性的临床征兆、对采食量的不良影响或眼部改变。
对血清皮质酮(PD标志物)的影响:单独的化合物A或SOM230仅在雌性中引起血清皮质酮减少。联合施用化合物A/SOM230在所测试的全部剂量水平下引起雄性和雌性的血清皮质酮适度减少(表1)。此数据表明化合物A和SOM230联用相比单独的任一试剂具有更好的功效。
表1:施用化合物A/SOM230的大鼠相比对照的血清皮质酮变化
对肾上腺(潜在毒性靶器官)的影响:用化合物A的治疗与肾上腺器官重量增加相关(在雌性中更显著),用SOM230的联合治疗防止化合物A所引起的肾上腺重量增加(表2)。此外,用化合物A的治疗在雌性大鼠中引起肾上腺皮质肥大,而用SOM230的联合治疗在雌性大鼠中防止化合物A所引起的肾上腺肥大。此数据表明用SOM230的联合治疗可防止化合物A所引起的对肾上腺的副作用。
表2:雄性和雌性大鼠的肾上腺重量
综上所述,大鼠每日经口强饲法/皮下注射施用13周的化合物A/SOM230的组合,在存活期内耐受良好,且与单独的SOM230或化合物A相比,不会加剧靶器官毒性。而且,联合治疗看来提供了更好的功效,如更连续下降的血清皮质酮所示,以及提供了更好的安全性,如减少的对肾上腺的不良影响所示。
实施例4库兴氏综合征中化合物A和帕瑞肽的联用研究
研究设计
研究由以下组成:至多60天的筛选期、10-14天的基线期和连续剂量递增的10周(70天)治疗期以及接着的12周化合物A BID治疗期,其中患者以最大耐受剂量继续接受化合物A,若有需要能够进入SOM230解救阶段。第22周时,评估患者以决定其进入两组之一,持续4周:(1)化合物A b.i.d.加帕瑞肽或(2)每日一次服用化合物A。作为解救治疗,如认为必要可更早加入帕瑞肽s.c.(在第10周-第22周之间)。在第26周结束时,每日服用化合物A的患者可选择进入12个月的延长期。
*注:基线UFC>3xULN的患者以5mg bid开始(代替2mg bid)
群体:
研究群体包括患有内源性皮质醇增多症的男性和女性患者,病因是肾上腺库兴氏综合征(非ACTH依赖性)或者来自垂体(库兴氏病)或来自异位起源(异位ACTH)的ACTH的产生增加。患者应当是经历过失败的标准治疗(包括手术)或者是无法进行手术的新患者。
纳入/排除标准:
纳入:
1.18-75岁的男性或女性患者
2.库兴氏综合征的诊断:
由下列标准证明:
a.库兴氏病:
·UFC>1.5XULN(14天内收集的3个24小时尿样的均值)。
·早晨血浆
·通过以下3项中的至少一项确认过量ACTH的垂体起源:
·通过阳性的动态试验(如CRH或高剂量***抑制试验)MRI确认垂体腺瘤(大于或等于6mm)病史,或
·CRH刺激后岩下窦梯度>3的历史或
·既往垂体手术,用组织病理学确认ACTH染色腺瘤
b.肾上腺库兴氏综合征:
·UFC>1.5x ULN(14天内收集的3个24小时尿样的均值)
·早晨血浆ACTH<正常下限,对CRH无响应
·通过以下至少一项来确认皮质醇增多症的肾上腺来源:
·与非ACTH依赖性库兴氏综合征相符的肾上腺损伤的成像证据或
·既往肾上腺手术史,被组织病理学确认生成腺瘤或癌的皮质醇
c.异位ACTH库兴氏综合征:
·UFC>1.5XULN(14天内收集的3个24小时尿样的均值)
·早晨血浆ACTH≥正常下限,对CRH无响应
·通过以下3项中的至少一项来确认过量ACTH的垂体外起源:
·缺少垂体MRI图像和阴性CRH测试以及:
·明显的非垂体ACTH来源(CT和/或奥曲肽显像(octreoscan)下的胸部肿瘤),被病理学证实的任何局部肿瘤或
·CRH刺激后岩下窦梯度≤3或
·既往垂体外手术,被组织病理学确认ACTH染色的腺瘤/癌
3.对于采用下列医学治疗的患者,必须完成清除期,然后进行如下的基线功效评估:
·类固醇生成抑制剂(酮康唑、美替拉酮):1周
·多巴胺激动剂(溴隐亭,卡麦角林),PPAR-γ激动剂(罗格列酮或匹格列酮):4周
·奥曲肽LAR、帕瑞肽LAR和兰瑞肽注射凝胶(autogel):8周
·米非司酮、兰瑞肽SR:4周
·奥曲肽和帕瑞肽(速释制剂):1周
·其它实验治疗:至少5个半衰期
排除:
1.入组时使用其它研究中的新药
2.有对任何研究中的药物或类似化学种类的药物的超敏史。
3.在过去5年内,治疗或未治疗的任何器官***恶性肿瘤史(除了局限性皮肤基底细胞癌和与库兴氏综合征相关的那些,如分泌ACTH的肾上腺癌或类癌瘤/癌以外),无论是否有证据显示局部复发或转移。
4.怀孕或哺乳(哺乳期)妇女
5.有生育可能的妇女
6.可生育男性,除非该受试者同意在整个研究持续期间遵从2种有效避孕方法
7.患者在第一次访视之前的最近6个月中用米托坦治疗
8.压迫视神经交叉的患者,以排除患有导致交叉压迫的肿瘤且需要手术的患者。
9.假库兴氏综合征患者[对于平均UFC<3xULN的患者,需要更多的测试以排除此情况,除非通过组织病理学确认库兴氏病或者异位或肾上腺来源]。为排除假库兴氏综合征,3种试验中的至少2种应该异常:低剂量***抑制试验、***-CRH试验或者午夜唾液或血清皮质醇。
10.肾损伤患者(通过MDRD公式估算的肌酸酐清除率<60mL/min),血清肌酸酐>2.0X ULN。
11.甲状腺生化机能不正常的患者。
12.在筛选前1个月内接受大手术的患者。
13.糖尿病控制不佳的患者,由HbA1C>9%证明。
14.有充血性心力衰竭(NYHA分级III或IV)、不稳定型心绞痛、持续性室性心动过速、临床显著心动过缓、重度心脏传导阻滞、研究开始前有小于1年的急性MI史或临床显著的心血管功能损伤的患者。
15.患有肝病如肝硬化、慢性活动性肝炎或慢性迁延性肝炎的患者,或ALT/AST大于3X ULN、血清胆红素>2.0X ULN的患者。
如果符合任意下列帕瑞肽的排除标准,患者不能使用帕瑞肽。
1.血糖控制差的糖尿病患者,由HbA1c>8%证明
2.有尖端扭转型室性心动过速危险因素的患者,即患者具有QTcF>470ms、低钾血症、低镁症、不受控的甲状腺功能减退、长期QT综合症家族史,或已知延长QT间隔期的伴随用药
3.有肝病如肝硬化、慢性活动性乙型和丙型肝炎史的患者,或者ALT或AST>2X ULN或总胆红素>1.5X ULN的患者
4.存在乙肝表面抗原(HbsAg)
5.存在丙肝抗体(抗HCV)
6.已知的胆囊或胆管疾病,急性或慢性胰腺炎
7.肾上腺库兴氏综合征或异位ACTH库兴氏综合征患者
研究和参照疗法:研究从对新入组患者采用2mg bid的化合物A(若基线mUFC≤3xULN)或5mg bid(若基线mUFC>3xULN)开始,每2周增加他们的剂量直至第10周。所有患者继续化合物A b.i.d.单一疗法到至多第22周。帕瑞肽300μg b.i.d.s.c.可作为附加疗法潜在施用(第22-26周),或如有需要可在更早(第10-22周)作为解救疗法施用。在第22周或更早未接受帕瑞肽的患者可潜在施用化合物A,剂量为每日一次(q.d.)而不是b.i.d.,持续4周。
功效/药效评价:功效评价包括尿游离皮质醇、血浆ACTH、皮质醇、11-脱氧皮质醇和肾素、血浆和尿去氧皮质酮、血浆和尿醛固酮、血浆和尿钠及钾、唾液皮质醇和醛固酮、睾酮和***、LH、FSH、IGF-1、TSH、游离T4、HbA1c和血浆胰岛素。
数据分析:主要变量定义为对化合物A的应答者比例。如果第10周24小时尿样的平均UFC水平≤ULN或显示出比基线减少≥50%,则认为该患者是应答者。由于疾病或治疗相关原因(如死亡、不良事件、临床疾病发展等)停止的患者或第10周24小时均值UFC水平高于正常界限且UFC下降<50%的患者被归类为非应答者。具有<2基线或基线后24小时UFC测量的患者不纳入初步分析。
用精确二项式检验估计应答者比例和相应的95%置信区间。
主要的功效变量定义为第22周时对化合物A的单一疗法的应答者的比例。第22周前需要解救治疗的患者也被归类为非应答者。
应答者进一步分为具有可控UFC和部分可控UFC的患者。
Claims (9)
1.(a)化合物A(R)-4-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)-3-氟-苯甲腈;和(b)生长抑素类似物的组合,其中(a)和(b)各自以游离形式、复合物形式或药学上可接受的盐形式存在,且其中所述生长抑素类似物是帕瑞肽或其药学上可接受的盐。
2.如权利要求1所述的组合,其中所述组合用于同时、分开或顺序使用。
3.如前述权利要求中任一项所述的组合,其中所述组合是固定组合。
4.如权利要求3所述的组合,其中所述组合进一步包括药学上可接受的载体。
5.如权利要求1所述的组合,其中所述组合是非固定组合。
6.如前述权利要求中任一项所述组合用于制造治疗库兴氏综合征的药物的应用。
7.权利要求6所述的应用,其中所述库兴氏综合征是库兴氏病。
8.一种商业包装,其包括如权利要求1-5中任一项的组合,以及其在库兴氏综合征治疗中同时、分开或顺序使用的说明书。
9.权利要求8所述的商业包装,其中所述库兴氏综合征是库兴氏病。
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