CN109475554A - 基于脂核苷酸的ards治疗 - Google Patents
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Abstract
因此,公开了用于治疗ARDS的组合物和方法。特别地,公开了用于治疗ARDS的组合物,包括在药学上可接受的载体中的一种、两种或更多种二磷酸胞苷(CDP)共轭的前体,其选自由CDP‑胆碱、CDP‑乙醇胺和CDP‑甘油二酯(CDP‑DAG)组成的组。
Description
相关申请数据
本申请要求2016年6月27日提交的美国临时申请62/355,096号的权益,该申请通过引用整体并入本文。
背景技术
急性呼吸窘迫综合症(ARDS,也称为急性肺损伤或急性低氧性呼吸衰竭)是一种临床综合症,其特征在于严重受损的肺泡气体交换的急性发作。ARDS可由直接肺损伤(感染、有毒气体吸入等)或创伤、脓毒症或其他身体损伤的间接结果引起。在美国,每年发生大约200,000宗人类ARDS个案。ARDS也可以在其他动物身上发展。一旦发展了ARDS,唯一的治疗选择是ICU中的非针对性支持性管理。目前,大约40%的任何形式ARDS的人类患者死亡,并且更多人类患者患有严重的肺功能缺陷,降低了生活质量。
流感是美国每年人类死亡率的第八大原因,每年约有200,000宗住院治疗个案和超过30,000宗死亡个案。流感也具有显著的大流行潜力。例如,1918年的“西班牙流感”大流行导致全世界超过5000万人死亡。流感还具有用于生物战和生物恐怖主义的潜力。大约20%的重症流感患者发展ARDS,这与预后不良有关。非常需要能够预防、延迟或控制严重流感发展为ARDS的新疗法:对于其他起因的ARDS也是如此。
主要由磷脂组成的肺表面活性剂对正常肺功能非常重要,并且由肺泡II型(ATII)细胞合成。磷脂对于细胞和细胞器代谢和功能的很多其他方面也是至关重要的。来自ARDS患者的支气管肺泡灌洗液(BALF)的磷脂含量通常较低,尽管尚未确定这个作用的潜在机制。将人工表面活性剂(例如Survanta)直接施用到肺中对于治疗人类的新生儿呼吸窘迫综合症(新生儿RDS)非常有效。然而,在人类ARDS患者中进行表面活性剂替代疗法的近期试验尚无定论或未显示出益处。
发明内容
本文显示,流感诱导的ARDS的发展由ATII细胞中磷脂和用于合成磷脂的二磷酸胞苷(CDP)共轭的(conjugated)脂核苷酸(liponucleotide)前体的水平降低所致。这伴随着降低的BALF表面活性剂磷脂含量。所公开的数据表明,流感感染导致ATII细胞减少合成用于合成磷脂的CDP共轭的脂核苷酸前体。这可能由于所述细胞中的流感病毒感染和/或复制而直接发生,或者由于目前已知或将来发现的宿主因子的作用而间接发生,所述宿主因子在其他细胞中响应于作用于所述细胞的病毒感染而被诱导。因此,如本文所公开,在发生损伤或疾病发作之前或之后补充脂核苷酸CDP-胆碱、CDP-乙醇胺、CDP-甘油二酯(CDP-DAG)或其任何组合可以绕过由脂核苷酸合成减少引起的磷脂合成中的阻断(block),从而改善易受损伤的细胞中的ATII细胞脂核苷酸合成,所述损伤导致所述细胞的正常磷脂产生被延迟和/或完全抑制。这种补充可以导致ATII细胞和表面活性剂磷脂水平上升,从而促进改善的ATII细胞和肺功能。这将预防或延迟流感感染受试者中ARDS的发展,或将降低当前的ARDS的严重性,从而提高流感存活率,并降低与ARDS和机械通气相关的长期临床后遗症的发生率和严重性。这些包括但不限于肺功能降低、肺纤维化、抑郁、创伤后应激障碍和本领域技术人员已知的其他疾病。由于本文描述了由其他损伤引起的ARDS的BALF表面活性剂水平的类似下降,所以这种疗法可以在各种递送模式具有普遍的患者结果益处和对ARDS具有广泛适用性。
关注这些脂质的另一个原因是它们对细胞和细胞器代谢和功能的许多其他方面至关重要。ATII细胞具有高代谢活性,因此严重依赖线粒体(Mi)功能来产生能量。Mi功能对其他肺细胞也很重要。Mi膜含有大量的磷脂,其对维持正常的Mi结构和功能起了重要作用。因此,磷脂合成的改变也可能损害Mi的存活力、功能和ATP的产生。这将对ATII细胞功能产生影响。Mi磷脂组合物的变化还可以促进线粒体自噬、Mi依赖性ATII细胞凋亡和Mi DNA的释放,其可以具有促炎作用并且可以促成ARDS的发展。本文公开的数据显示,流感诱导的ARDS的发展与ATII细胞中失调的氧化磷酸化和异常线粒体(Mi)形态相关,其可通过使用CDP-胆碱处理来逆转。因此,如本文所公开,在补充脂核苷酸CDP-胆碱、CDP-乙醇胺、CDP-DAG或其任何组合可以绕过由脂核苷酸合成减少引起的磷脂合成中的阻断,从而改善易受损伤的ATII细胞和/或其他肺细胞中的Mi结构和功能,所述损伤导致所述细胞的正常磷脂产生被延迟、受损和/或完全抑制。
已知或将来发现的所有肺细胞中所有其他细胞器的质膜和脂质膜都预期含有大量磷脂,这对于所述细胞器的正常功能是非常重要的。因此,磷脂合成的改变将损害质膜和细胞器膜的完整性和功能。这将对ATII细胞和其他肺细胞功能和存活力产生影响。因此,在有或没有化学修饰的情况下,补充脂核苷酸CDP-胆碱和/或CDP-乙醇胺和/或CDP-DAG可以绕过由脂核苷酸合成减少引起的磷脂合成中的阻断,从而改善易受损伤的细胞中的ATII细胞和其他肺细胞质膜和细胞器结构和功能,所述损伤导致所述细胞的正常磷脂产生被延迟和/或完全抑制。
因此,公开了用于预防、延迟发展或治疗ARDS的组合物和方法。例如,公开了一种组合物,包括在药学上可接受的载体中的一种、两种或更多种二磷酸胞苷(CDP)共轭的前体,选自由CDP-胆碱、CDP-乙醇胺和CDP-DAG组成的组。
DAG是由两个通过酯键共价键合到甘油分子上的脂肪酸(酰基)链组成的甘油酯。存在两种可能的形式:1,2-甘油二酯和1,3-甘油二酯。在一些实施例中,CDP-DAG含有衍生自短链脂肪酸(具有少于6个碳的脂族尾部)、中链脂肪酸(具有6至12个碳的脂族尾部)、长链脂肪酸(具有13至21个碳的脂族尾部)或非常长链的脂肪酸(具有超过22个碳的脂族尾部)的酰基链。脂肪酸可以是天然来源,或者根据本领域技术人员已知的任何方法通过化学合成产生。在一些实施例中,两个酰基链在1、2位。在一些实施例中,两个酰基链在1、3位。在一些实施例中,两个酰基链具有相同的长度(含有相同数量的碳)。在一些实施例中,两个酰基链具有不同的长度。在一些实施例中,CDP-DAG的DAG组分的一个或两个酰基链是单不饱和的(含有一个顺式和/或反式构型的双键)。在一些实施例中,CDP-DAG的DAG组分的一个或两个酰基链是多不饱和的(含有多于一个顺式和/或反式构型的双键)。在一些实施例中,CDP-DAG的DAG组分的一个或两个酰基链是饱和的(不含双键)。在一些实施例中,一个或两个酰基链是化学修饰的。化学修饰包括但不限于甲基化、酯化、酰胺化、硝化、亚硝基化、氧化、硫酸化、乙酰化、醇解、酸解、生物素化、萤光团共轭,以及本领域技术人员已知的其他修饰。
在一些实施例中,CDP-胆碱的CDP组分是化学修饰的。化学修饰包括但不限于甲基化、酯化、酰胺化、硝化、亚硝基化、氧化、硫酸化、乙酰化、醇解、酸解、生物素化、萤光团共轭,以及本领域技术人员已知的其他修饰。
在一些实施例中,CDP-乙醇胺的CDP组分是化学修饰的。化学修饰包括但不限于甲基化、酯化、酰胺化、硝化、亚硝基化、氧化、硫酸化、乙酰化、醇解、酸解、生物素化、萤光团共轭,以及本领域技术人员已知的其他修饰。
在一些实施例中,CDP-DAG的CDP组分是化学修饰的。化学修饰包括但不限于甲基化、酯化、酰胺化、硝化、亚硝基化、氧化、硫酸化、乙酰化、醇解、酸解、生物素化、萤光团共轭,以及本领域技术人员已知的其他修饰。
在一些实施例中,CDP-胆碱的胆碱组分是化学修饰的。化学修饰包括但不限于甲基化、酯化、酰胺化、硝化、亚硝基化、氧化、硫酸化、乙酰化、醇解、酸解、生物素化、萤光团共轭,以及本领域技术人员已知的其他修饰。
在一些实施例中,CDP-乙醇胺的乙醇胺组分是化学修饰的。化学修饰包括但不限于甲基化、酯化、酰胺化、硝化、亚硝基化、氧化、硫酸化、乙酰化、醇解、酸解、生物素化、萤光团共轭,以及本领域技术人员已知的其他修饰。
在一些实施例中,CDP-DAG的甘油组分是化学修饰的。化学修饰包括但不限于甲基化、酯化、酰胺化、硝化、亚硝基化、氧化、硫酸化、乙酰化、醇解、酸解、生物素化、萤光团共轭,以及本领域技术人员已知的其他修饰。
在一些实施例中,可以并入两种或更多种CDP-胆碱前体的混合物,所述CDP-胆碱前体具有或不具有CDP和/或胆碱的不同化学修饰。
在一些实施例中,可以并入两种或更多种CDP-乙醇胺前体的混合物,所述CDP-乙醇胺前体具有或不具有CDP和/或乙醇胺链的不同化学修饰。
在一些实施例中,可以并入两种或更多种CDP-DAG前体的混合物,所述CDP-DAG前体具有或不具有CDP和/或酰基链的不同酰化或化学修饰。
在一些实施例中,CDP共轭的前体以至少0.1ng/kg的单位剂量共同存在,包括0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0ng/kg。
在一些实施例中,CDP-胆碱和/或CDP-乙醇胺和/或CDP-DAG以相同的浓度或比率存在。在一些实施例中,至少两种CDP共轭的前体以相等的浓度或比率存在,其可以高于或低于第三种CDP共轭的前体,所述第三种CDP共轭的前体可以不存在。在一些情况下,CDP共轭的前体之一以至少是其他一个或两个CDP共轭的前体的2、3、4、5、6、7、8、9或10倍的浓度或比率存在。
所公开的组合物还可含有其他活性和非活性成分。例如,在一些实施例中,组合物可含有额外的脂质部分、核苷酸、有机酸、氨基酸或糖。
还公开了一种用于预防受试者中ARDS发展的方法,涉及在感染一种或多种流感病毒株之前向受试者施用有效量的组合物作为预防,所述组合物包括CDP共轭的前体,选自由CDP-胆碱、CDP-乙醇胺、CDP-DAG和其组合组成的组。
还公开了一种用于预防受试者中ARDS发展的方法,涉及在受试者已感染一种或多种流感病毒株之后但所述受试者已发展ARDS之前向受试者施用有效量的组合物,所述组合物包括CDP共轭的前体,选自由CDP-胆碱、CDP-乙醇胺、CDP-DAG和其组合组成的组。
还公开了一种用于治疗受试者的ARDS的方法,涉及向患有ARDS的受试者施用有效量的组合物,所述组合物包括CDP共轭的前体,选自由CDP-胆碱、CDP-乙醇胺、CDP-DAG和其组合组成的组。
所公开的方法可用于预防、延迟发展或治疗任何形式的ARDS,其可以由直接肺损伤(感染、有毒气体吸入、癌症、酸吸入、胸部创伤等)引起,或者作为其他身体部位的创伤、脓毒症、缺血/再灌注、手术或其他原因(见表1)的间接结果。在一些情况下,ARDS是由流感或其他呼吸道病毒、细菌或真菌感染引起的。
在一些情况下,受试者具有大约550至750mmHg(≤100kPa)的PaO2/FiO2比率,这在临床上认为是正常的。替代地,受试者具有大于92%的动脉O2饱和度。在其他情况下,在现在和将来,受试者具有正常的肺顺应性,并且没有通过放射线照相术、CT扫瞄、磁共振成像或其他成像方式显示的非心源性肺水肿的证据。在一些情况下,由于患有与流感感染和/或ARDS发展风险增加相关的并存病(co-morbidity),合理的医学判断可能要求受试者需要预防性活疗,这些并存病包括但不限于I型糖尿病、II型糖尿病、肥胖症、妊娠、癫痫、既往存在的肺疾病、既往存在的心血管疾病、既往存在的肾脏疾病,或者目前已知或将来发现的与发展ARDS的风险增加相关的任何其他并存病。在其他情况下,受试者可能是临床正常的,但是因为暴露于流感病毒、流感感染受试者或其他已知ARDS起因的风险增加而需要预防性治疗,从而保持重要人员的可用性。
在一些情况下,受试者的PaO2/FiO2比率大约为201至300mmHg(≤39.9kPa)、101至200mmHg(≤26.6kPa)或≤100mmHg(≤13.3kPa)。在一些情况下,受试者的PaO2/FiO2比率为小于300mmHg、小于200mmHg,或者小于100mmHg。这三个类别对应于轻度、中度和重度ARDS,如目前按柏林标准临床定义。在其他情况下,受试者可以具有大约300至550mmHg(≤73.3kPa)的PaO2/FiO2比率,这在临床上认为是中度异常。替代地,受试者具有小于92%的动脉O2饱和度。在其他情况下,在现在和未来,受试者具有降低了的肺顺应性,或通过放射线照相术、CT扫瞄、磁共振成像或其他成像方式显示的非心源性肺水肿的证据。在临床或实验情况下,受试者可能已经或将要被发现与ARDS存在和严重性相关的其他措施的改变,包括但不限于肺泡液清除受损,促炎细胞因子、趋化因子和肺和/或血液中的其他炎症介质升高,抗炎细胞因子、趋化因子和肺和/或血液中的其他炎症介质减少,肺和/或血液中的白细胞增加,以及肺组织中的细胞死亡增加。
所公开的组合物可以例如通过静脉内、口服、肌肉内、腹膜内、通过肺内滴注或通过吸入(例如雾化干粉或雾化液滴)施用。通过不同途径递送的组合物可包含不同的制剂。
在一些实施例中,方法还涉及使用表面活性剂疗法治疗受试者。在一些实施例中,方法还包括使用以下各项治疗受试者:气管插管、气管切开术、气管造口术、机械通气、有或没有呼气末正压(PEEP)、俯卧位或仰卧位、补充氧气、一氧化氮、体外膜肺氧合、β-肾上腺素能激动剂或拮抗剂、皮质类固醇和其他抗炎剂、抗生素、抗病毒药、抗真菌药、细胞因子、任何来源的干细胞、静脉注射液、全血或血液成分、肠外或肠内营养制剂、血管扩张剂、血管收缩剂、利尿剂、胰岛素或其他合成或天然激素,或其任何组合,或发现对未来的实验和/或临床情况有益的任何其他治疗。
在附图和以下描述中阐述了本发明的一个或多个实施例的细节。根据说明书和附图以及权利要求,本发明的其他特征、目的和优点将显而易见。
附图说明
图1是示出感染对ATII细胞DPPC(16∶0/16∶0)表面活性剂的影响的图。#=P<0.001。
图2是显示感染对ATII细胞DPPG(16∶0/16∶0)表面活性剂的影响的图。*=P<0.05,#=P<0.001。
图3是显示感染对ATII细胞PE(16∶0/18∶2)表面活性剂的影响的图。#=P<0.001。
图4是显示感染对BALF磷脂甘油的影响的图。#=P<0.001。
图5是显示CDP-胆碱(Kennedy)途径的DPPC合成的示意图。
图6是显示感染对ATII细胞DAG(18∶1/18∶2)的影响的图。*=P<0.05,#=P<0.001。
图7是显示感染对ATII细胞胆碱-P(18∶1/18∶2)的影响的图。
图8是显示感染对ATII细胞CDP-胆碱的影响的图。
图9是显示治疗方法的示意图。
图10是显示随着时间(感染后的日数)CDP-胆碱治疗(▲)对小鼠O2SATS的影响的图。#=P<0.001。
图11是显示随着时间(感染后的日数)CDP-胆碱治疗(▲)对小鼠活动(rmp/小鼠)的影响的图。*=P<0.05,#=P<0.001。
图12是柱状图,显示仅第5天CDP-胆碱治疗对小鼠O2SATS的影响。*=P<0.05,#=P<0.001。
图13是显示制剂治疗小鼠O2SATS的影响的条形图。#=P<0.001。
图14是一组三张透射电子显微照片,显示CDP-胆碱治疗对ATII细胞层状体(由表面活性剂脂质和蛋白质组成)的超微结构的影响。
图15是一组三张透射电子显微照片,显示流感感染对ATII细胞线粒体(Mi)的超微结构的影响。
具体实施方式
术语“受试者”指任何作为施用或治疗目标的个体。受试者可以是脊椎动物,例如哺乳动物或鸟类。因此,受试者可以是人类或动物患者。术语“患者”是指在临床医生(例如医生或兽医)以及其他联合健康专业人员(包括护士、医生助理和药剂师)的治疗下的受试者。
术语“治疗有效”是指所用组合物的量足以改善疾病或病症的一个或多个原因、症状和/或临床症状。这种改善只需要减少或改变,不一定要消除。
术语“药学上可接受”是指在合理的医学判断范围内适用于与人和动物组织接触,而没有过多毒性、刺激性、过敏反应,或与合理的利益/风险比相称的其他问题或并发症的那些化合物、材料、组合物和/或剂型。
术语“载体”是指当与化合物或组合物组合时,有助于或促进于化合物或组合物的制备、储存、施用、递送、有效性、选择性或任何其他特征以用于其预期用途或目的的化合物、组合物、物质或结构。例如,载体可以被选择为使活性成分的任何降解最小化,并且使受试者中的任何不良副作用最小化。
术语“治疗”是指患者的医学管理,其旨在治愈、改善、稳定或预防疾病、病理状况或病症。这术语包括积极治疗(active treatment),即专门针对改善疾病、病理状况或病症的治疗,还包括因果治疗(casual treatment),即针对消除相关疾病、病理状况或病症的原因的治疗。此外,这术语包括:姑息治疗(palliative treatment),即用于缓解症状和/或临床症状而不是治愈疾病、病理状况或病症的治疗;预防性治疗,即旨在最小化或部分地或完全地抑制相关疾病、病理状况或病症发展的治疗;以及支持性治疗,即用于补充针对相关疾病、病理状况或病症的改善的另一种特定疗法的治疗。
所公开的方法可用于预防或治疗任何形式的ARDS,其可以由直接肺损伤(感染、有毒气体吸入、癌症、酸吸入、胸部创伤等)引起,或者作为其他身体部位的创伤、脓毒症、缺血/再灌注或手术的间接结果。在一些情况下,ARDS是由流感或其他呼吸道病毒、细菌或真菌感染引起的。
在一些实施例中,所公开的方法可以用于治疗心源性肺水肿、肺创伤和/或出血、肺缺血或肺栓塞。表1描述了其他主要ARDS适应症和非ARDS用途。
所公开方法的ARDS相关癌症可以是受试者中经历直接或间接导致某形式的ARDS的不受调节生长、侵袭或转移的任何细胞。在一些情况下,癌症是肺部的原发性或继发性癌症。在一些情况下,癌症不存在于肺部,但癌症或癌症治疗会导致肺部损伤。
在一些方面,癌症可以是目前针对其使用放射疗法的任何新生物(neoplasm)或肿瘤。替代地,癌症可以是对使用标准方法的放射疗法不够敏感的新生物或肿瘤。因此,癌症可以是肉瘤、淋巴瘤、白血病、癌(carcinoma)、母细胞瘤或生殖细胞肿瘤。可使用所公开的组合物治疗的代表性但非限制性的癌症列表包括:淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、蕈样真菌病、霍奇金病、骨髓性白血病、膀胱癌、脑癌、神经系统癌症、头和颈癌、头颈部鳞状细胞癌、肾癌、小细胞肺癌和非小细胞肺癌等肺癌、神经母细胞瘤/胶质母细胞瘤、卵巢癌、胰腺癌、前列腺癌、皮肤癌、肝癌、黑色素瘤、口腔、咽喉、喉和肺的鳞状细胞癌、结肠癌、宫颈癌症(cervical cancer)、宫颈癌(cervical carcinoma)、乳腺癌、上皮癌、肾癌、泌尿生殖系统癌、肺癌、食道癌、头颈癌、大肠癌、造血癌症;睾丸癌;结肠癌和直肠癌、前列腺癌和胰腺癌。
二磷酸胞苷-胆碱(CDP-胆碱)是天然存在的化合物,由胞苷-5′-三磷酸和磷酸胆碱合成,伴随着由酶CTP-磷酸胆碱胞苷酰基转移酶-α(pcytla)催化的可逆反应产生无机焦磷酸。CDP-乙醇胺由胞苷-5′-三磷酸和磷酸乙醇胺合成,伴随着由酶CTP-磷酸乙醇胺胞苷酰基转移酶(pcyt2)的可逆反应生成无机焦磷酸。
CDP-胆碱的分子结构如下。
CDP-乙醇胺的分子结构如下。
CDP-DAG的分子结构如下。
在这些结构中,R表示各种长度酰基链与CDP-DAG的甘油部分的连接点。
所公开的组合物可以在治疗上与药学上可接受的载体组合使用。“药学上可接受”是指不在生物学上或其他方面不期望的材料,即,该材料可以与核酸或载体一起施用于受试者,而不会引起任何不期望的生物学作用或以任何有害的方式与包含其的药物组合物的其他组分的任何物质相互作用。如本领域技术人员所熟知的,载体会被自然地选择为使活性成分的任何降解最小化,并使受试者中的任何不良副作用最小化。
药物载体是本领域技术人员已知的。这些通常是用于向人类或动物施用药物的标准载体,包括诸如无菌水、盐水和生理pH的缓冲溶液的溶液。组合物可以肌肉内或皮下施用。其他化合物将根据本领域技术人员使用的标准程序施用。
除了所选择的分子之外,药物组合物还可包括载体、增稠剂、稀释剂、缓冲剂、防腐剂、表面活性剂等。药物组合物还可包含一种或多种活性成分,例如抗微生物剂、抗炎剂、麻醉剂、疫苗抗原、佐剂和DAMP。
肠内和/或肠胃外施用的制剂包括无菌水溶或非水溶液、悬浮液和乳液。非水溶剂的示例是丙二醇、聚乙二醇、诸如橄榄油的植物油,以及诸如油酸乙酯的可注射有机酯。水溶载体包括水、醇/水溶液、乳液或悬浮液,包括盐水和缓冲介质。肠内和肠胃外载体包括氯化钠溶液、林格氏葡萄糖、葡萄糖和氯化钠、乳酸林格氏液、葡萄糖或固定油。静脉内载体包括液体和营养补充剂、电解质补充剂(例如基于林格氏葡萄糖的补充剂)等。粘膜载体包括无菌水溶液或非水溶液、悬浮液和乳液。示例包括氯化钠溶液、林格氏葡萄糖、葡萄糖和氯化钠、乳酸林格氏液、葡萄糖、固定油、丙二醇等。还可以存在防腐剂和其他添加剂,例如抗微生物剂、抗氧化剂、螫合剂和惰性气体。
一些组合物可以作为药学上可接受的酸加成盐或碱加成盐施用,通过与诸如盐酸、氢溴酸、高氯酸、硝酸、硫氰酸、硫酸和磷酸等无机酸和诸如甲酸、乙酸、丙酸、乙醇酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、马来酸和富马酸等有机酸反应形成,或与诸如氢氧化钠、氢氧化铵、氢氧化钾等无机碱和诸如单、二、三烷基和芳基胺和取代的乙醇胺等有机碱反应形成。
本文公开的组合物,包括药物组合物,可以以多种方式施用,这取决于所需治疗是预防性的,用于预防流感感染和/或其他高危人士中的ARDS发展,还是用于ARDS患者的急性治疗。例如,所公开的组合物可以粉末或片剂形式口服施用以预防或防止ARDS,或者静脉内、腹膜内、肌肉内、皮下、腔内或透皮施用以治疗ARDS。药物级组合物可以作为复合片剂口服施用,所述复合片剂包括适当剂量的活性成分、赋形剂和包衣以便于吞咽,和/或控制活性成分的释放速率,以及延长保质期。药物级组合物可以作为液体悬浮液或乳液口服施用。药物级组合物可以通过以下方式施用:胃肠外(例如以适当的载体和稳定剂静脉内施用)、肌内注射、腹膜内注射、透皮、体外、眼用、经阴道、经直肠、鼻内、局部施用等,包括局部鼻内施用或通过吸入施用。
在一个实施例中,所公开的组合物以相当于肠胃外施用的剂量施用,即每kg体重大约0.1ng至大约100g,每kg体重大约10ng至大约50g,每kg体重大约100ng至大约1g,每kg体重大约1μg至大约100mg,每kg体重大约1μg至大约50mg,每kg体重大约1mg至大约500mg;以及每kg体重大约1mg至大约50mg。替代地,为达到治疗有效的剂量,所公开组合物施用的量为每kg体重0.1ng、1ng、10ng、100ng、1μg、10μg、100μg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、500mg或更多。
已经描述了本发明的许多实施例。然而,应该理解,在不脱离本发明的精神和范围的情况下,可以进行各种修改。因此,其他实施例在以下权利要求的范围内。
示例
示例1:
图1是示出感染对ATII细胞DPPC(16∶0/16∶0)表面活性剂的影响的图。#=P<0.001。
图2是显示感染对ATII细胞DPPG(16∶0/16∶0)表面活性剂的影响的图。*=P<0.05,#=P<0.001。
图3是显示感染对ATII细胞PE(16∶0/18∶2)表面活性剂的影响的图。#=P<0.001。
图4是显示感染对BALF磷脂甘油的影响的图。#=P<0.001。
图5是显示CDP-胆碱(Kennedy)途径的DPPC合成的示意图。
图6是显示感染对ATII细胞DAG(18∶1/18∶2)的影响的图。*=P<0.05,#=P<0.001。
图7是显示感染对ATII细胞胆碱-P(18∶1/18∶2)的影响的图。
图8是显示感染对ATII细胞CDP-胆碱的影响的图。
图9是显示治疗方法的示意图。
图10是显示随着时间(感染后的日数)CDP-胆碱治疗(▲)对小鼠O2SATS的影响的图。#=P<0.001。
图11是显示随着时间(感染后的日数)CDP-胆碱治疗(▲)对小鼠活动(rmp/小鼠)的影响的图。*=P<0.05,#=P<0.001。
图12是柱状图,显示仅第5天CDP-胆碱治疗对小鼠O2SATS的影响。*=P<0.05,#=P<0.001。
CDP-胆碱改善了氧合作用。SaO2从大约85%上升至大约96%。这相当于PaO2从大约65mmHg上升至大约85mmHg。也相当于血液的O2携带能力(CaO2)从正常的大约88%上升至97%。具有96%的SaO2和96%的PaO2的患者不需要额外的治疗。
CDP-胆碱改善了心脏功能,导致更好的肺功能和减少了肺水肿。在感染后期单剂量治疗的效果与整个感染过程中每天治疗的效果一样好。
示例2:
表2显示了CDP共轭的前体组合的效果。
示例3:
图14是一组三张透射电子显微照片,显示CDP-胆碱治疗对ATII细胞层状体(由表面活性剂脂质和蛋白质组成)的超微结构的影响。相对于模拟感染的对照,来自甲型流感/WSN/33(H1N1)感染的小鼠的ATII细胞中的层状体较小,并且具有不正常的薄层。CDP-胆碱治疗改善了层状体形态。来自CDP-胆碱治疗的小鼠的ATII细胞中的Mi也更具电子密度和具有更多正常的嵴(cristae)。
示例4:
图15是一组三张透射电子显微照片,显示流感感染对ATII细胞线粒体(Mi)的超微结构的影响。相对于模拟感染的对照(左),来自甲型流感/WSN/33(H1N1)感染的小鼠(中心)的ATII细胞中的Mi数量较少,电子密度较小,并且具有不正常的膜和嵴。来自用CDP-胆碱治疗的甲型流感/WSN/33(H1N1)感染小鼠的ATII细胞中的Mi显示正常形态。
示例5:
表3显示了流感感染和口服脂核苷酸治疗对肺功能的影响。
表4显示了流感感染和CDP-胆碱治疗对ATII细胞超微结构的影响。
表5显示了流感感染和CDP-胆碱治疗对肺部炎症的影响。
表6显示了流感感染和CDP-胆碱治疗对线粒体功能的影响。
除非另外定义,否则本文使用的所有技术和科学术语具有与所公开发明所属领域的技术人员通常理解的含义相同的含义。本文引用的出版物和引用它们的材料通过引用明确地并入本文。
本领域技术人员将认识到或能够使用不超过常规的实验确定本文所述的发明的具体实施例的许多等同物。这些等同物旨在由以下权利要求涵盖。
Claims (20)
1.一种组合物,包括在药学上可接受的载体中的两种或更多种二磷酸胞苷(CDP)共轭的前体,其选自由CDP-胆碱、CDP-乙醇胺和CDP-甘油二酯(CDP-DAG)组成的组。
2.如权利要求1所述的组合物,包括在药学上可接受的载体中的CDP-胆碱和CDP-DAG。
3.如权利要求1所述的组合物,基本上由药学上可接受的载体中的CDP-胆碱和CDP-DAG组成。
4.如权利要求2或3所述的组合物,其中CDP-胆碱和CDP-DAG以相同的浓度存在。
5.如权利要求1所述的组合物,包括在药学上可接受的载体中的CDP-胆碱、CDP-乙醇胺和CDP-DAG。
6.如权利要求5所述的组合物,其中CDP-胆碱、CDP-乙醇胺和CDP-DAG以相同的浓度存在。
7.如权利要求1至6中任一项所述的组合物,其中所述CDP共轭的前体以每kg体重至少0.1ng的浓度共同存在。
8.如权利要求1至7中任一项所述的组合物,其中所述CDP共轭的前体包括一种或多种化学修饰,其选自由甲基化、酯化、酰胺化、硝化、亚硝基化、氧化、硫酸化、乙酰化、醇解、酸解、生物素化和萤光团共轭组成的组。
9.一种治疗受试者的急性呼吸窘迫综合症(ARDS)的方法,包括向受试者施用有效量的组合物,所述组合物包括一种或多种二磷酸胞苷(CDP)共轭的前体,其选自由CDP-胆碱、CDP-乙醇胺、CDP-甘油二酯(CDP-DAG),以及其组合组成的组。
10.如权利要求9所述的方法,其中所述组合物包括权利要求1至8中任一项所述的组合物。
11.如权利要求9或10所述的方法,其中所述组合物通过静脉内、口服或吸入施用。
12.如权利要求9至11中任一项所述的方法,其中所述ARDS由直接肺损伤引起。
13.如权利要求12所述的方法,其中所述直接肺损伤选自由病毒、细菌或真菌感染;有毒气体吸入;肺癌;化疗;酸吸入;以及胸部创伤组成的组。
14.如权利要求13所述的方法,其中所述感染包括流感。
15.如权利要求9至14中任一项所述的方法,其中所述ARDS由其他身体部位的创伤的间接结果引起。
16.如权利要求15所述的方法,其中所述创伤选自由脓毒症、缺血/再灌注和手术组成的组。
17.如权利要求9至16中任一项所述的方法,还包括使用表面活性剂疗法治疗受试者。
18.如权利要求9至17中任一项所述的方法,其中在感染一种或多种流感病毒株之前向受试者施用所述组合物。
19.如权利要求9至17中任一项所述的方法,其中在受试者已感染一种或多种流感病毒株之前但在所述受试者已发展ARDS之前施用所述组合物。
20.如权利要求9至17中任一项所述的方法,其中在受试者已发展ARDS之后施用所述组合物。
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EP3474853A1 (en) | 2019-05-01 |
SG11201811595SA (en) | 2019-01-30 |
EP4292651A2 (en) | 2023-12-20 |
WO2018005527A1 (en) | 2018-01-04 |
US20190134074A1 (en) | 2019-05-09 |
KR20190022682A (ko) | 2019-03-06 |
JP2019518798A (ja) | 2019-07-04 |
AU2017289278A1 (en) | 2019-01-17 |
US10874684B2 (en) | 2020-12-29 |
EP4292651A3 (en) | 2024-03-13 |
CA3029005A1 (en) | 2018-01-04 |
EP3474853A4 (en) | 2020-02-19 |
US20210069225A1 (en) | 2021-03-11 |
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