CN113546172A - Vegf抑制剂在制备治疗缺氧相关疾病药物中的应用 - Google Patents
Vegf抑制剂在制备治疗缺氧相关疾病药物中的应用 Download PDFInfo
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Abstract
本发明提供了VEGF抑制剂在制备治疗缺氧相关疾病的药物中的应用。VEGF抑制剂通过作用有VEGF与VEGF受体的结合通路,可显著抑制缺氧导致的VEGF应激表达,用于治疗缺氧及其他相关的疾病,能显著改善患者的氧合指数,缓解肺部及其他器官组织的缺氧状态,起到良好的治疗效果。
Description
技术领域
本发明属于医药领域,涉及VEGF抑制剂的应用,尤其涉及VEGF抑制剂在制备治疗缺氧相关疾病的药物中的应用。
背景技术
缺氧是一种组织、细胞缺乏足够的氧供应的病理状态。缺氧在人和其它哺乳动物中引发多种生理学上的反应,例如细胞中的正常生物过程常常因为缺氧而受损,缺氧还导致与诸如血管形成、糖代谢的许多生理过程相关基因的上调。缺氧可发生在整个生物体水平,例如呼吸困难或者通气中断、氧利用率较低时均会发生缺氧。
呼吸困难(呼吸窘迫)是引起个体缺氧的常见因素,任何引起肺部弥漫性损伤的因素例如创伤、败血症、病毒性肺炎或细菌性肺炎等均能导致呼吸困难,进而导致组织细胞缺氧或者低血氧症,引起多种缺氧并发症,例如心脏、肝脏、肾脏的损伤。
现有研究已经表明,在许多致病因素作用下肺泡单核巨噬细胞和中性粒细胞最早产生补体C5a、肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)启动了炎症的级联反应,再刺激肺内多种细胞因子,例如血管内皮生长因子(vascular endothelial growth factor,VEGF),缺氧诱导因子-1(hypoxia-inducible factor,HIF-1α)。大量炎症介质和细胞因子的释放,导致呼吸困难(孙中吉等,急性呼吸窘迫综合征发病中的细胞因子和炎性介质,中国危重病急救医学2003年3月第15卷第3期,第186-189页),其中VEGF参与多种病理过程,例如引起肺部血管功能异常,参与肺部炎症反应,肺水肿,出血,脓毒血症等等。
呼吸困难导致的缺氧是目前大范围爆发的由新型冠状病毒SARS-CoV-2引起的新型冠状病毒疾病COVID-19(Corona Virus Disease 2019)的主要症状之一。该病毒感染肺上皮细胞后,常见非心源性肺水肿和透明膜形成,患者表现为增殖期或组织期的弥漫性肺泡损伤,伴随严重的呼吸困难,是导致患者病程漫长、预后不良的关键因素之一,严重的呼吸衰竭和难以纠正的低血氧症导致患者严重缺氧,进而多器官衰竭是该病毒致死的主要原因。已有研究发现,和健康人相比,新型冠状病毒感染患者血液中多种细胞因子的表达水平存在明显区别(Huang C,Wang Y,Li X,et al.Clinical features of patients infectedwith 2019 novel coronavirus in Wuhan,China.Lancet 2020,published online Jan24.)。但是目前尚未见通过相关调节细胞因子水平治疗或缓解缺氧的报道。
发明内容
本发明提供VEGF(血管内皮生长因子)抑制剂在治疗疾病或病征中的应用,其中所述疾病或病征选自缺氧相关的疾病。
根据本发明,所述缺氧相关疾病没有特别的限定,包括导致受试者机体缺氧或者氧气摄入不足的症状,或者因受试者细胞、组织或器官氧气供应不足导致的病变或损伤。根据本发明,所述缺氧相关疾病为呼吸窘迫综合征、肺炎、肺水肿、急性肺损伤、呼吸机导致的肺损伤、吸烟导致的肺损伤、肺癌、病理性呼吸暂停、缺血性心脏病、急性心肌梗塞(AMI)、缺血性脑病症、缺血性中风、眼部缺血性疾病、缺血性视神经病、炎症、败血症、肾衰竭、组织纤维化、支气管发育不良、胎儿窘迫、手术后缺氧、贫血、血容量不足、类风湿性关节炎、中毒(例如一氧化碳中毒、重金属中毒)、缺血再灌注损伤(例如肢体、肠、肾局部缺血)、窒息、脉管栓塞中的至少一种。例如所述缺氧相关疾病是缺氧导致的肺部疾病,包括但不限于呼吸窘迫综合征、肺炎、肺水肿、急性肺损伤。再例如所述缺氧相关疾病是呼吸道感染、急性肺损伤、外伤或者中毒导致的呼吸窘迫综合征或其并发症,所述并发症包括肺水肿、炎症反应或炎症因子风暴、脓毒血症、器官衰竭中的至少一种。
根据本发明,所述呼吸道感染包括病毒性肺炎、细菌性肺炎或真菌感染。在一个实施方案中,所述病毒性肺炎是冠状病毒SARS-CoV-2、SARS-Cov或MERS-Cov中任一种或多种病毒感染引起的重型或危重型肺炎。
进一步地,本发明还提供VEGF抑制剂在治疗肺水肿中的应用。
进一步地,本发明还提供VEGF抑制剂在缓解炎症反应或炎症因子风暴中的应用。
进一步地,本发明还提供VEGF抑制剂在治疗脓毒血症中的应用。
进一步地,本发明还提供VEGF抑制剂在治疗冠状病毒疾病COVID-19或其引起的病征中的应用。在一个实施方案中,所述VEGF抑制剂用于治疗COVID-19引起的肺炎或呼吸窘迫。在又一实施方案中,所述VEGF抑制剂用于治疗COVID-19感染引起的肺水肿。在又一实施方案中,所述VEGF抑制剂用于治疗COVID-19引起的炎症反应或炎症因子风暴。在又一实施方案中,所述VEGF抑制剂用于治疗COVID-19引起的肺部渗出性病变,提高对象的氧合指数。
本发明还提供一种包含VEGF抑制剂的药物组合物在治疗上述疾病或病征中的应用。在一个实施方案中,所述药物组合物还包括至少一种治疗剂,所述治疗剂是对于上述疾病具有活性的其他治疗剂。
本发明还提供一种治疗上述疾病的方法,包括将VEGF抑制剂施用于患有上述疾病或病征的患者。
本发明还提供一种VEGF抑制剂或包含VEGF抑制剂的药物组合物,其用于治疗上述疾病或病征。
本发明还提供VEGF抑制剂在制备药物中的应用,所述药物用于治疗缺氧相关疾病。
根据本发明,所述缺氧相关疾病呼吸窘迫综合征、肺炎、肺水肿、急性肺损伤、呼吸机导致的肺损伤、吸烟导致的肺损伤、肺癌、病理性呼吸暂停、缺血性心脏病、急性心肌梗塞(AMI)、缺血性脑病症、缺血性中风、眼部缺血性疾病、缺血性视神经病、炎症、败血症、肾衰竭、组织纤维化、支气管发育不良、胎儿窘迫、手术后缺氧、贫血、血容量不足、类风湿性关节炎、中毒(例如一氧化碳中毒、重金属中毒)、缺血再灌注损伤(例如肢体、肠、肾局部缺血)、窒息、脉管栓塞中的至少一种。例如所述缺氧相关疾病是缺氧导致的肺部疾病,包括但不限于呼吸窘迫综合征、肺炎、肺水肿、急性肺损伤。再例如所述缺氧相关疾病是呼吸道感染、急性肺损伤、外伤或者中毒导致的呼吸窘迫综合征或其并发症,所述并发症包括肺水肿、炎症反应或炎症因子风暴、脓毒血症、器官衰竭中的至少一种。
根据本发明,所述呼吸道感染包括病毒性肺炎、细菌性肺炎、或真菌感染。在一个实施方案中,所述病毒性肺炎是冠状病毒SARS-CoV-2、SARS-Cov或MERS-Cov中任一种或多种病毒感染引起的重型或危重型肺炎。
进一步地,本发明还提供VEGF抑制剂在制备治疗肺水肿药物中的应用。
进一步地,本发明还提供VEGF抑制剂在制备缓解炎症反应或炎症因子风暴药物中的应用。
进一步地,本发明还提供VEGF抑制剂在制备治疗脓毒血症药物中的应用。
进一步地,本发明还提供VEGF抑制剂在制备治疗冠状病毒疾病COVID-19或其引起的症状的药物中的应用。在一个实施方案中,所述药物用于治疗COVID-19引起的重型或危重型肺炎。在又一实施方案中,所述药物用于治疗COVID-19感染引起的呼吸窘迫。在又一实施方案中,所述药物用于治疗COVID-19感染引起的肺水肿。在又一实施方案中,所述药物用于缓解或降低COVID-19感染引起的炎症反应或炎症因子风暴。在又一实施方案中,所述药物用于减小COVID-19感染引起渗出性病变,提高受试者的氧合指数。
本发明中“缺氧”是指氧缺乏或低于生理水平的氧供应不足的环境。包括慢性缺氧或急性缺氧。在一个实施方案中,所述缺氧是指受试者氧合指数(PaO2/FiO2,mmHg)≤300mmHg,和/或在静息状态、无吸氧时指脉氧饱和度≤96%,例如≤90%,再例如≤85%,再例如≤80%。
在一个实施方案中,通过施用VEGF抑制剂,使得受试者的氧合指数(PaO2/FiO2,mmHg)≥300mmHg,例如≥330mmHg,再例如≥360mmHg。在一个实施方案中,通过施用VEGF抑制剂,使受试者在静息状态、无吸氧时指脉氧饱和度≥96%,例如≥98%,再例如≥99%,再例如=100%。
本发明中“缺氧相关疾病”包括由于患者呼吸障碍,难以摄入足够的氧气,导致血氧含量降低,或者由于通往器官的血流减少导致器官或组织、细胞中氧水平低于到正常生理活动所需的水平或范围以下。缺氧可能是一种症状,或在疾病、病症或状况的病因、发展、进程、改善或治愈中起作用。在一个实施方案中,所述缺氧是由肺部减少氧的摄取引起的,包括肺部病变或外伤、呼吸道病变或外伤、过敏导致的呼吸困难,外在因素导致的窒息或呼吸障碍,例如溺水、中毒等。在一个实施方案中,缺氧是由肺部病变引起的,例如呼吸窘迫综合征、慢性阻塞性肺部疾病、肺气肿、支气管炎、肺水肿、肺炎、急性肺损伤、呼吸机导致的肺损伤、吸烟导致的肺损伤、肺癌、病理性呼吸暂停等。在一个实施方案中,所述缺氧由通往器官的血流减少的原因,例如脉管栓塞,血管破损,外伤,炎症等。缺氧相关的疾病包括但不限于:呼吸窘迫综合征、肺炎、肺水肿、急性肺损伤、呼吸机导致的肺损伤、吸烟导致的肺损伤、肺癌、病理性呼吸暂停、缺血性心脏病、急性心肌梗塞(AMI)、缺血性脑病症、缺血性中风、眼部缺血性疾病、缺血性视神经病、炎症、败血症、肾衰竭、组织纤维化、支气管发育不良、胎儿窘迫、手术后缺氧、贫血、血容量不足、类风湿性关节炎、中毒(例如一氧化碳中毒、重金属中毒)、缺血再灌注损伤(例如肢体、肠、肾局部缺血)、窒息、脉管栓塞等。
呼吸窘迫或呼吸困难在临床症状上表现为呼吸增快,困难,胸骨上下窝吸气性凹陷,鼻翼扇动,肺不张范围和呼吸衰竭的严重程度逐渐加重。呼吸窘迫可以是各种原因引起的肺部血管组织气体液体交换功能紊乱,导致严重低氧血症和呼吸困难。本发明的呼吸窘迫综合征可以由任何严重的肺损伤引起,包括但不限于各种病原体感染、外伤或者中毒所导致引起的呼吸困难或呼吸衰竭,例如各种真菌、细菌或病毒感染所引起的肺炎、吸入有毒化学物质、脓毒性休克、呕吐物吸入等。在一个实施方案中,本发明的呼吸窘迫综合征是肺部感染所导致的呼吸困难,本发明的肺部感染包括但不限于冠状病毒SARS-Cov-2、SARS-Cov或SARS病毒、MERS-Cov、各种流感病毒(例如H1N1、H7N9或其他流感病毒)、细菌感染、真菌感染等。本发明的冠状病毒SARS-Cov-2属于β属冠状病毒,包括通过基因测序确定其基因序列为MN908947(Genebank ID)或者与之具有较高同源性例如同源性达到98%以上的冠状病毒。COVID-19及其引起的病征是指因感染新型冠状病毒SARS-Cov-2引起的疾病或病变,包括各种程度的肺损伤、呼吸窘迫综合征和脓毒血症等,COVID-19可以通过样本RT-PCR病原学核酸检测、血清特异性抗体检测和/或肺部CT影像学诊断确诊。病原学检测的样本包括但不限于上呼吸道样本、下呼吸道样本、消化道样本、体液样本等,例如鼻咽拭子、痰液、粪便、尿液、血液、眼泪、汗液、唾液等。
本发明的“对象”和“患者”、“受试者”具有相同含义,指具有人或其他温血哺乳动物。本发明作为“对象”的人包括成人和婴幼儿、儿童,其他温血哺乳动物包括但不限于非人类的灵长类动物、例如黑猩猩、其他类人猿或猴,以及其他动物园动物、家养哺乳动物或实验室动物,例如猫、猪、狗、牛、羊、小鼠、大鼠和豚鼠等。优选地,本发明的“对象”为人。
本发明的一个重要方面在于缺氧伴随VEGF表达水平上调,当患者呼吸困难或者缺血时,造成细胞缺氧,缺氧诱导因子HIF-1α转录因子会大幅度的增加。VEGF基因是HIF的转录靶基因,HIF-1α升高进而诱导VEGF的大量合成,从而刺激血管形成代偿组织缺氧,进而维持和改善组织功能。VEGF与内皮细胞上的VEGF受体结合,触发酪氨酸激酶途径诱导血管生成。本发明通过VEGF抑制剂阻断缺氧导致的VEGF应激反应和表达,进而对缺氧相关疾病起到有益效果,有效治疗缺氧导致的各种疾病。
新型冠状病毒感染的重症和危重症病人出现呼吸困难,造成严重缺氧,从而上调VEGF,增加血管通透性,诱导肺水肿。因此,对于呼吸窘迫综合征的治疗包括但不限于抑制VEGF与VEGF受体的结合,或者降低VEGF表达水平,通过抑制肺水肿、减少组织间液渗出、提高氧合指数、降低炎症反应或炎症因子风暴等途径缓解呼吸窘迫。
本发明中,“重型肺炎”表示患者符合如下任何一条:
1.呼吸窘迫,呼吸频率(RR)≥30次/分;
2.静息状态、无吸氧时指脉氧饱和度≤93%;
3.动脉血氧分压(PaO2)/吸氧浓度(FiO2)≤300mmHg;
4.符合以上任何一条,按照重型管理;或者,虽然尚未达到上述重型诊断标准,亦按重型管理病例:肺部影像学显示24-48小时内病灶明显进展>50%者;年龄>60岁、合并严重慢性疾病包括高血压、糖尿病、冠心病、恶性肿瘤、结构性肺病,肺心病以及免疫抑制人群等。
“危重型肺炎”表示患者符合如下任何一条:
1.出现呼吸衰竭,且需要机械通气;
2.出现休克;
3.合并其他器官功能衰竭需收入ICU治疗。
本发明的VEGF抑制剂没有特别的限定,任何可以抑制VEGF表达或者对于VEGF信号通路上游或下游有抑制作用的物质对于本发明所述的缺氧相关疾病均有效,包括但不限于作用于哺乳动物雷帕霉素靶蛋白(mTOR)信号通路的物质,或者作用于缺氧诱导因子HIF-1α通路的物质,或者直接作用于血管内皮生长因子VEGF通路的物质,或者作用于其他与VEGF信号通路相关的细胞生物过程的物质。所述VEGF抑制剂可以是大分子药物,例如单克隆抗体、多肽,或者是基因治疗药物,例如克隆载体,也可以是小分子化合物。
在一个实施方案中,所述VEGF抑制剂是靶向VEGF和VEGFr(血管内皮生长因子受体)之间的相互作用的物质。本发明的VEGF抑制剂是指能够抑制VEGF的一种或多种生物活性,例如其促分裂或血管生成活性。VEGF抑制剂通过干扰VEGF与细胞受体的结合、通过阻断VEGF受体激活后信号传导、通过使被VEGF激活的细胞失去功能或被杀灭、或通过干扰VEGF结合细胞受体后血管内皮细胞的激活过程而起作用。在一个实施方案中,本发明所述VEGF抑制剂可以是抗VEGF药物或抗VEGF受体的药物。在一个实施方案中,所述VEGF抑制剂是抗VEGF抗体(例如贝伐珠单抗)或抗体衍生物(例如兰尼单抗Lucentis)或抗VEGF肽;在一个实施方案中,所述VEGF抑制剂可以是基因治疗药物,例如表达VEGF抗体的微生物克隆载体或者抑制VEGF表达的基因治疗药物;在一个实施方案中,所述VEGF抑制剂是小分子VEGF受体抑制剂,例如拉帕替尼、舒尼替尼、索拉非尼、阿昔替尼和帕唑帕尼等。
在一个实施方案中,所述VEGF抑制剂为mTOR抑制物,可以作用于mTOR信号通路,并影响下游细胞因子HIF-1α或VEGF的表达,实现对VEGF的调控。所述mTOR抑制物可以选自本领域已知的各种作用于mTOR信号通路的大分子药物、基因治疗药物或小分子化合物,例如mTOR抑制物为雷帕霉素、依维莫司中的至少一种。
在一个实施方案中,所述VEGF抑制剂为HIF-1α抑制物。缺氧条件下,HIF-1α降解受阻,与HIF-1β结合成HIF-1分子,HIF-1α表达增加后至VEGF表达上调从而明显加快血管生长,HIF-1α抑制物可以起到抑制VEGF表达上调的作用。HIF-1α抑制剂包括但不限于抑制HIF-1α的表达,加速HIF-1α的降解,影响HIF-1α细胞核聚集,阻断HIF-1α与HIF-1β结合等;例如所述HIF-1α抑制物包括但不限于坦西莫司,拓扑替康,喜树碱等。
在一个实施方案中,本发明的VEGF抑制剂优选贝伐珠单抗。本发明的贝伐珠单抗与本领域“贝伐单抗”含义相同,在美国专利US6884879中已有描述,该专利中有关贝伐珠单抗的全部内容通过引用结合至本文中。本发明的贝伐珠单抗包括但不限于本领域已知的商品化或非商品化的贝伐珠单抗(Bevacizumab)制剂(例如商品化的阿瓦斯汀Avastin)、具有生物等效性和一致性的贝伐珠单抗生物类似药(例如安可达),或者贝伐珠单抗衍生物。
可以向受试者施用治疗有效量的VEGF抑制剂来实现缺氧相关疾病的治疗效果。“治疗有效量”可以根据本领域具有临床执业资格的医生所掌握的方法确定。确定治疗有效剂量是本领域临床医生或研究人员力所能及的,例如,可根据US6884879中所记载的剂量,结合商品化贝伐珠单抗的剂量,根据受治疗的对象的具体情况确定贝伐珠单抗的施用剂量。在一个实施方案中,贝伐珠单抗对于成人以每天1-100mg/kg剂量施用,例如每天10-50mg/kg、每天12-15mg/kg,根据患者的个体独特因素以及症状严重程度可以单次或多次给药。患者的个体独特因素通常包括年龄、体重、一般健康状况及其他影响疗效的因素,其他影响疗效的因素例如药物过敏史。
本发明所述VEGF抑制剂可以通过本领域已知的给药途径实现给药,包括但不限于静脉注射、肌肉注射、皮下注射、口服、肺吸入等给药途径。本领域技术人员可以根据患者情况选择给药途径。相应地,本发明所述VEGF抑制剂或包括其的药物组合物根据给药途经可以配制成各种合适的剂型,包括片剂、胶囊、丸剂、粉末等等。在一个实施方式中,所述药物通过静脉注射施用。
所述VEGF抑制剂可以与其他缓解缺氧或缺氧相关疾病的治疗手段或者药物共同施用,例如向患者施用治疗有效量的VEGF抑制剂,同时采取机械通气等治疗手段;或者向患者施用VEGF抑制剂,同时施用对相应疾病有效的其他药物,例如与抗真菌剂、抗细菌剂、抗病毒药物、抗血栓药物、免疫调节药物、滴眼液、泌尿系药物、激素类药物、抗感染药物、抗炎症药物等中的至少以一种联合施用。在一个实施方案中,联合给药或共同给药的两种或更多种药物活性成分包含在一种药物组合物当中。在另一实施方案中,不必要求使用单一的药物组合物,可以分别包括在不同的药物组合物当中,也不必要求使用相同的剂型或相同的给药途径、相同的时间来给予本发明的VEGF抑制剂或共同施用的其他药物。但是,出于给药便利性,可以将联合施用的两种或多种药物活性成分制备成相同剂型,在基本相同的给药时间完成给药。
本发明的“治疗”是指当涉及疾病或病症时,通过对对象实施的医疗行为预防或阻止该疾病或病征的恶化,至少维持现状或缓和、更优选地全面治愈和解决所述疾病或病征。具体来说,本发明的“治疗”包括通过施用药物或者结合其他治疗手段,缓解或消除患者因缺氧导致的相关病征。在一个实施方案中,所述“治疗”是指缓解或消除呼吸窘迫症状,稳定呼吸指标,包括提高患者的氧合指数、血氧饱和度,改善组织氧合状态;还可以包括减少肺部渗出性病变,促进肺部病变明显吸收,减小肺部病变总体积。
有益效果
本发明将VEGF抑制剂通过作用有VEGF与VEGF受体的结合通路,可显著抑制缺氧导致的VEGF应激表达,用于治疗缺氧及其他相关的疾病,能显著改善患者的氧合指数,缓解肺部及其他器官组织的缺氧状态,改善其呼吸状态和缺血症状。尤其是贝伐珠单抗用于新型冠状病毒COVID-19引起的病征,可提升患者氧合指数,还能显著减小肺部病变体积,促进肺部病变吸收,改善患者的免疫能力,抑制炎症因子风暴,促进组织恢复,具有良好的效果。
附图说明
图1:试验组受试者在贝伐珠单抗治疗前和治疗后1天、治疗后7天氧合指数变化曲线和统计图;
图2:不同受试者在用药前后肺部CT影像学表现对比;
图3:试验组受试者在贝伐珠单抗治疗前和治疗后3天淋巴细胞计数变化曲线和统计图;
图4:试验组受试者在贝伐珠单抗治疗前和治疗后3天hs-CRP和CRP水平变化曲线;
图5:试验组受试者在贝伐珠单抗治疗前和治疗后3天乳酸脱氢酶水平变化曲线和统计图。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述材料如无特别说明均能从公开途径得到。
本发明实施例所用贝伐珠单抗Bevacizumab为已上市药品Avastin。
实验方案:
本实验经由山东大学齐鲁医院经反复论证、伦理审查、规范注册(NCT04275414)后开展。
受试者(P):新型冠状病毒疾病COVID-19的重型、危重型患者,肺部影像示渗出病变;干预(I):贝伐珠单抗500mg+0.9%氯化钠溶液100ml配置,静脉滴注时间不小于90min,单次给药,同时给予常规治疗;比较(C):贝伐珠单抗干预前后比较、与外部对照比较;主要结局指标(O):氧合指数、肺部病变定量值(通过影像软件计算)。
可能患有新型冠状病毒疾病COVID-19的受试者通过鼻咽拭子RT-PCR检测COVID-19病毒核酸,结合血清特异性IgM抗体、IgG抗体检测和肺部CT影像学检查确诊。受试者重症、危重症分型根据国家卫生健康委员会《新型冠状病毒感染的肺炎诊疗方案(试行第五版修正版)》中重型、危重型分型诊断标准进行分型:
(一)重型
符合如下任何一条:
1.呼吸窘迫,呼吸频率(RR)≥30次/分;
2.静息状态、无吸氧时指脉氧饱和度≤93%;
3.动脉血氧分压(PaO2)/吸氧浓度(FiO2)≤300mmHg;
4.符合以上任何一条,按照重型管理;或者,虽然尚未达到上述重型诊断标准,亦按重型管理病例:肺部影像学显示24-48小时内病灶明显进展>50%者;年龄>60岁、合并严重慢性疾病包括高血压、糖尿病、冠心病、恶性肿瘤、结构性肺病,肺心病以及免疫抑制人群等。
(二)危重型
符合如下任何一条:
1.出现呼吸衰竭,且需要机械通气;
2.出现休克;
3.合并其他器官功能衰竭需收入ICU治疗。
受试者实验组总人数11例。实验组和对照组患者基本信息和基线特征如表1所示。
表1实验组和对照组患者基线特征
(1)氧合指数
贝伐珠单抗治疗后1天、7天,受试者组织氧合状态显著改善(结果如表2和图1所示),氧合指数(PaO2/FiO2)较治疗前明显提升(P<0.001)。
表2试验组受试者在贝伐珠单抗治疗前后呼吸指标变化
(2)肺部CT定量分析及影像表现
以用药前CT影片为初始点,与贝伐珠单抗干预后7天CT比对分析。肺部CT定量分析显示,在7天时间段内,贝伐珠单抗治疗促进肺部病变明显吸收。贝伐珠单抗干预后,斑片状病变数量显著减少(P=0.024),经吸收向较轻的磨玻璃样病变转变(P=0.007),病变总体积显著缩小(P=0.028),左(右)肺的病变占比有减小趋势(表3)。肺部影像图可直观观察到上述定量分析反映出的变化,提示疗效较为显著(图2)。
表3试验组受试者在贝伐珠单抗治疗前后肺部CT定量分析
(3)免疫功能
受试者淋巴细胞水平在贝伐珠单抗治疗后3天显著提高(P=0.013),提示患者免疫状态改善(结果如表4和图3所示)。
表4试验组受试者在贝伐珠单抗治疗前后血常规检验指标对比
(4)炎症因子
在贝伐珠单抗治疗后3天,受试者hs-CRP与治疗前相比水平显著下降(P=0.036);CRP也呈现下降趋势(结果如表5和图4所示)。
表5试验组受试者在贝伐珠单抗治疗前后hs-CRP和CRP水平变化
(5)乳酸脱氢酶(LDH)水平
贝伐珠单抗治疗后3天,LDH水平较前降低明显(P=0.032),提示组织损伤有恢复趋势(结果如表6和图5所示)。
表6试验组受试者在贝伐珠单抗治疗前后LDH水平变化
以上结果显示,对于COVID-19的重症、危重症患者,贝伐珠单抗治疗后,患者氧合指数显著改善,肺部CT定量分析显示肺病变体积显著缩小、病变占比显著减小、斑片状阴影转为较轻的磨玻璃样阴影,淋巴细胞计数(L)增多提示免疫功能改善,多项重要指标包括高敏C反应蛋白(hs-CRP)、乳酸脱氢酶(LDH)均显著改善,且所有患者在试验期间均未出现药物过敏、咯血、消化道出血、中性粒细胞减少等不良反应。
(6)试验组与对照组的匹配分析
试验组和对照组在年龄、最高体温、发病至入院天数、性别、心脏病史、高血压病史、糖尿病史、慢阻肺病史及发热、乏力、干咳等症状方面的差异均无统计学意义(P>0.05),两组在受试者基线资料方面均衡可比(如表1所示)。试验组与对照组重要指标方面,施用贝伐珠单抗的试验组氧合指数显著改善(提升100mmHg)的比例、hs-CRP和淋巴细胞计数改善程度均高于对照组,其他指标未见明显差异(表7)。
表7试验组与对照组重要指标改善程度对比
以上结果表明,对于COVID-19的重症、危重症患者,施用贝伐珠单抗的试验组与对照组先比,可显著改善氧合指数,明显缓解患者呼吸衰竭症状。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (30)
1.VEGF(血管内皮生长因子)抑制剂在治疗疾病或病征中的应用,其中所述疾病或病征选自缺氧相关的疾病。
2.根据权利要求1所述的应用,所述缺氧相关疾病包括导致受试者机体缺氧或者肺部氧气摄入不足的肺部损伤或症状,或者因受试者细胞、组织或器官氧气供应不足导致的病变或损伤;例如,所述缺氧相关疾病包括缺氧造成的肺部疾病。
3.根据权利要求1或2所述的应用,所述缺氧相关疾病选自以下疾病组成的组:呼吸窘迫综合征、肺炎、肺水肿、急性肺损伤、呼吸机导致的肺损伤、吸烟导致的肺损伤、肺癌、病理性呼吸暂停、窒息中的至少一种。
4.根据权利要求1-2所述的应用,所述缺氧相关疾病是缺血性心脏病、急性心肌梗塞(AMI)、缺血性脑病症、缺血性中风、眼部缺血性疾病、缺血性视神经病、炎症、败血症、肾衰竭、组织纤维化、支气管发育不良、胎儿窘迫、手术后缺氧、贫血、血容量不足、类风湿性关节炎、中毒(例如一氧化碳中毒、重金属中毒)、缺血再灌注损伤(例如肢体、肠、肾局部缺血)、脉管栓塞中的至少一种。
5.根据权利要求1-3所述的应用,所述缺氧相关疾病是呼吸道感染、急性肺损伤、外伤或者中毒导致的呼吸窘迫综合征或其并发症。
6.根据权利要求5所述的应用,所述并发症包括肺水肿、炎症反应或炎症因子风暴、脓毒血症、器官衰竭中的至少一种。
7.根据权利要求5所述的应用,所述呼吸道感染包括病毒性肺炎、细菌性肺炎或肺部真菌感染中的至少一种。
8.根据权利要求7所述的应用,所述病毒性肺炎是冠状病毒SARS-CoV-2、SARS-Cov或MERS-Cov中任一种或多种病毒感染引起的重型或危重型肺炎。
9.根据权利要求1-8任一项所述的应用,所述VEGF抑制剂为能够抑制VEGF表达或其作用通路的物质;优选地,所述VEGF抑制剂是靶向VEGF和VEGFr(血管内皮生长因子受体)之间的相互作用的物质;
优选地,所述VEGF抑制剂为mTOR抑制物,例如mTOR信号通路的大分子药物、基因治疗药物或小分子化合物,再例如mTOR抑制物选自雷帕霉素、依维莫司的至少一种;
优选地,所述VEGF抑制剂为HIF-1α抑制物;例如所述HIF-1α抑制物选自坦西莫司,拓扑替康,喜树碱的至少一种。
10.根据权利要求1-9任一项所述的应用,所述VEGF抑制剂为抗VEGF抗体、抗体衍生物或抗VEGF肽,例如所述VEGF抑制剂是贝伐珠单抗或兰尼单抗)。
11.根据权利要求1-9任一项所述的应用,所述VEGF抑制剂为基因类药物,例如所述VEGF抑制剂是表达VEGF抗体的微生物克隆载体或者抑制VEGF表达的基因药物。
12.根据权利要求1-9任一项所述的应用,所述VEGF抑制剂是小分子VEGF受体抑制剂化合物,例如所述VEGF抑制剂是拉帕替尼、舒尼替尼、索拉非尼、阿昔替尼或帕唑帕尼中的任一种。
13.根据权利要求1-12任一项所述的应用,所述缺氧包括慢性缺氧或急性缺氧。
14.根据权利要求1-13任一项所述的应用,所述缺氧相关疾病的受试者氧合指数(PaO2/FiO2,mmHg)≤300mmHg,和/或在静息状态、无吸氧时指脉氧饱和度≤96%,例如≤90%,再例如≤85%,再例如≤80%。
15.根据权利要求1-14任一项所述的应用,施用VEGF抑制剂使得受试者的氧合指数(PaO2/FiO2,mmHg)≥300mmHg,例如≥330mmHg,再例如≥360mmHg。
16.根据权利要求1-15任一项所述的应用,施用VEGF抑制剂使得受试者在静息状态、无吸氧时指脉氧饱和度≥96%,例如≥98%,再例如≥99%,再例如=100%。
17.VEGF抑制剂在治疗肺水肿中的应用。
18.VEGF抑制剂在缓解炎症反应或炎症因子风暴中的应用。
19.VEGF抑制剂在治疗脓毒血症中的应用。
20.VEGF抑制剂在治疗冠状病毒疾病COVID-19或其引起的病征中的应用。
21.根据权利要求20所述的应用,所述VEGF抑制剂用于治疗COVID-19引起的缺氧相关疾病。
22.根据权利要求20所述的应用,所述VEGF抑制剂用于治疗COVID-19引起的肺炎或呼吸窘迫、肺水肿、炎症反应或炎症因子风暴、器官衰竭。
23.根据权利要求20所述的应用,所述VEGF抑制剂用于治疗COVID-19引起的肺部渗出性病变。
24.根据权利要求17-23任一项所述的应用,所述VEGF抑制剂为能够抑制VEGF表达或其作用通路的物质;优选地,所述VEGF抑制剂是靶向VEGF和VEGFr(血管内皮生长因子受体)之间的相互作用的物质;
优选地,所述VEGF抑制剂为抗VEGF抗体、抗体衍生物或抗VEGF肽,例如所述VEGF抑制剂是贝伐珠单抗或兰尼单抗;
优选地,所述VEGF抑制剂为基因类药物,例如所述VEGF抑制剂是表达VEGF抗体的微生物克隆载体或者抑制VEGF表达的基因药物;
优选地,所述VEGF抑制剂是小分子VEGF受体抑制剂化合物,例如所述VEGF抑制剂是拉帕替尼、舒尼替尼、索拉非尼、阿昔替尼或帕唑帕尼中的任一种;
优选地,所述VEGF抑制剂为mTOR抑制物,例如mTOR信号通路的大分子药物、基因治疗药物或小分子化合物,再例如mTOR抑制物选自雷帕霉素、依维莫司的至少一种;
优选地,所述VEGF抑制剂为HIF-1α抑制物;例如所述HIF-1α抑制物选自坦西莫司,拓扑替康,喜树碱的至少一种。
25.包含VEGF抑制剂的药物组合物在治疗权利要求1-24任一项所述疾病或病征中的应用。
26.根据权利要求25所述的应用,所述VEGF抑制剂为贝伐珠单抗。
27.根据权利要求25或26所述的应用,所述药物组合物还包括至少一种治疗剂,所述治疗剂是对于所述疾病或病征具有活性的其他治疗剂,例如所述其他治疗剂是抗真菌剂、抗细菌剂、抗病毒药物、抗血栓药物、免疫调节药物、滴眼液、泌尿系药物、激素类药物、抗感染药物、抗炎症药物中的至少一种。
28.一种VEGF抑制剂或包含VEGF抑制剂的药物组合物,其用于治疗权利要求1-24任一项所述的疾病或病征。
29.根据权利要求28所述的VEGF抑制剂或包含VEGF抑制剂的药物组合物,所述VEGF抑制剂为贝伐珠单抗。
30.根据权利要求28或29所述的药物组合物,其包含VEGF抑制剂,以及至少一种其他治疗剂,所述其他治疗剂是对于所述疾病或病征具有活性的治疗剂,例如所述其他治疗剂是抗真菌剂、抗细菌剂、抗病毒药物、抗血栓药物、免疫调节药物、滴眼液、泌尿系药物、激素类药物、抗感染药物、抗炎症药物中的至少一种。
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