CN114796227B - Ponatinib在制备预防或治疗血管退行性疾病药物中的应用及该药物 - Google Patents
Ponatinib在制备预防或治疗血管退行性疾病药物中的应用及该药物 Download PDFInfo
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Abstract
本发明公开了Ponatinib在制备预防或治疗血管退行性疾病药物中的应用及该药物,涉及生物医药领域。本申请发现低剂量的Ponatinib对小鼠血管有显著的修复作用,对主动脉夹层有明显的治疗效果,在主动脉夹层血管瘤小鼠模型试验中,B超图像结果可知ApoE‑/‑小鼠在给予Ponatinib后,其因高血压诱导的主动脉中层结构空洞及破裂得到明显抑制,主动脉弓扩张程度减小,腹主动脉管壁连贯清晰,血管病变显著减轻,说明Ponatinib可明显抑制小鼠主动脉夹层的形成,为主动脉夹层的治疗提供一种新的治疗药物。
Description
技术领域
本发明涉及生物医药领域,尤其涉及Ponatinib在制备预防或治疗血管退行性疾病药物中的应用及该药物。
背景技术
主动脉瘤和主动脉夹层为不完全相同但有相似性的疾病,均属于血管退行性病变疾病。主动脉瘤多表现为主动脉血管壁内形成梭状或囊状的动脉瘤增宽,主动脉瘤壁的内面常覆有层状血栓。动脉粥样硬化为主动脉动脉瘤最常见的病因,它可使主动脉壁变弱,使其扩张。主动脉夹层主要表现为主动脉血管壁退行性病变,血液冲破内膜进入有缺陷的血管中层,撕裂动脉壁形成真假两腔分离状态。主动脉夹层在早期可能会形成血管壁血肿,随着血液的冲击,血管损伤部位会进一步扩大,有部分主动脉夹层在破裂前亦呈瘤状,称为夹层动脉瘤。
高血压是主动脉夹层破裂的主要诱发因素,一旦发生血管破裂,一周内患者死亡率可高达91%,因此主动脉夹层的早期发现和治疗尤为重要。然而目前临床治疗主动脉夹层仅能通过手术置换人工血管,置换面临着严重的手术风险,并且术后血管会进一步退行性病变,面临二次手术和破裂的风险以防主动脉破裂。
目前,临床上并无可以直接修复血管结构治疗主动脉夹层的药物,这是当下控制主动脉夹层的关键难点与突破口,因此急需开发防治主动脉夹层的临床药物。
发明内容
本发明提供了Ponatinib在制备预防或治疗血管退行性疾病药物中的应用及该药物,以提供一种新的主动脉夹层治疗药物。
为了解决上述技术问题,本发明目的之一提供了Ponatinib、其同分异构体、化学衍生物或药学上可接受的盐在制备预防或治疗血管退行性疾病药物中的应用。
作为优选方案,所述血管退行性疾病为主动脉瘤或主动脉夹层。
为了解决上述技术问题,本发明目的之二提供了一种预防或治疗血管退行性疾病的药物,其特征在于,包括Ponatinib、其同分异构体、化学衍生物或药学上可接受的盐。
作为优选方案,所述血管退行性疾病为主动脉瘤或主动脉夹层。
作为优选方案,所述Ponatinib的给药剂量为5-25mg/kg/72h,给药对象为小鼠。
作为优选方案,所述药物的给药方式为口服。
作为优选方案,所述Ponatinib、其同分异构体、化学衍生物或药学上可接受的盐作为药物活性成分,制成任何一种药学上可接受的剂型。
作为优选方案,所述剂型为胶囊、酊剂、丸剂、口服液、片剂、颗粒剂类口服给药的剂型。
相比于现有技术,本发明实施例具有如下有益效果:
本申请发现低剂量的Ponatinib对小鼠血管有显著的修复作用,Ponatinib可以通过抑制血管平滑肌细胞的凋亡,维持血管壁结构的完整,对主动脉夹层有明显的治疗效果,在主动脉夹层血管瘤小鼠模型试验中,B超图像结果可知ApoE-/-小鼠在给予Ponatinib后,其因高血压诱导的主动脉中层结构空洞及破裂得到明显抑制,主动脉弓扩张程度减小,腹主动脉管壁连贯清晰,血管病变显著减轻,说明Ponatinib可明显抑制小鼠主动脉夹层的形成,对主动脉夹层的治疗提供一种新的治疗药物。
附图说明
图1:为本发明关于ApoE-/-+Ponatinib组和ApoE-/-+Vehicle组中主动脉弓和腹主动脉的B超图像结果(AoAr-主动脉弓;AbAo-腹主动脉;);
图2:为本发明关于ApoE-/-+Ponatinib组和ApoE-/-+Vehicle组中主动脉弓和腹主动脉的最大内径统计结果(aorticarch-主动脉弓;abdominalaorta-腹主动脉);
图3:为本发明关于ApoE-/-+Ponatinib组和ApoE-/-+Vehicle组中两根主动脉的解剖结果;
图4:为本发明关于ApoE-/-+Ponatinib组和ApoE-/-+Vehicle组中升主动脉的HE染色和EVG染色结果。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
帕纳替尼(Ponatinib)是一种治疗慢性粒细胞白血病的药物,但其它适应症仍未被发现。本研究发明人发现低剂量的Ponatinib对小鼠血管有显著的修复作用,对主动脉夹层有明显的治疗效果。
以下进行Ponatinib对主动脉夹层动脉瘤的影响试验:
1.主动脉夹层/动脉瘤小鼠模型的构建方法:
载脂蛋白E(ApolipoproteinE,ApoE)敲除小鼠(ApoE-/-)加血管紧张素II(AngⅡ)诱导高血压28天,给药量为1.44mg·kg-1·d-1,构建得到主动脉夹层/动脉瘤模型。
2.Ponatinib小鼠给药方式:
将ApoE敲除小鼠分成两组,背部埋置AngⅡ缓释泵,用于释放血管紧张素II,将Ponatinib用配置好的pH为3的柠檬酸缓冲液稀释(浓度为1.5mg/mL),在血管紧张素II诱导开始24小时后,实验组(ApoE-/-小鼠)每只小鼠灌胃给药含有Ponatinib的柠檬酸缓冲液,即ApoE-/-+Ponatinib组;对照组灌胃给药同体积的空白柠檬酸缓冲液,即ApoE-/-+Vehicle组;给药剂量为25mg/kg/只,给药周期为72h/次。
3.B超图像的采集:
在AngⅡ诱导28天后,对小鼠行活体超声检测,小鼠超声检测使用VEVO 3100超声设备(Visual Sonics加拿大多伦多)采集,先将待测小鼠置于麻醉箱内以2%异氟烷麻醉至昏迷,随后固定在载体板上以1%异氟烷持续麻醉,选择合适的***分别采集升主动脉、主动脉弓、胸主动脉及腹主动脉图像,观察整条主动脉结构以及是否形成主动脉瘤,B超图像结果如图1所示,同时测量其最大内径。
4.统计学处理:
数据处理采用SPSS 13.0软件,统计结果以均数±标准误表示,两组数据间的差异采用t检验。当进行多组数据间比较时,采用ANOVA方差分析,并以Bonferroni检验进行进一步分析验证,p<0.05为具有明显差异,p<0.01为具有显著性差异,p<0.001为具有高度显著性差异,分析结果如图2所示。
5.试验结果:Ponatinib可抑制小鼠主动脉夹层发生。
如图1和图2所示,ApoE-/-+Vehicle组可观察到主动脉弓扩张,腹部形成明显夹层动脉瘤,ApoE-/-+Ponatinib组主动脉弓扩张程度减小,腹主动脉管壁连贯清晰,血管病变显著减轻,血管壁结构正常,血管内径相比于ApoE-/-+Vehicle组明显减小。
对两组小鼠的整条主动脉进行解剖处理,如图3所示,解剖后也可以看到ApoE-/-+Vehicle组小鼠仍旧发生了严重的主动脉夹层,但ApoE-/-+Ponatinib组小鼠血管结构正常,主动脉夹层发生率明显降低。
将小鼠主动脉进行组织冰冻切片处理,如图4的HE染色结果显示,ApoE-/-小鼠在给予Ponatinib后,其因高血压诱导的主动脉中层结构空洞及破裂得到明显抑制;同时EVG染色结果显示Ponatinib的治疗恢复了ApoE-/-小鼠主动脉弹力纤维的含量(Fig6 I)。EVG和HE染色显示ponatinib有效抑制了血管壁的损伤和弹力纤维的断裂。
以上结果证明,Ponatinib可明显抑制小鼠主动脉夹层动脉瘤的形成,为主动脉夹层动脉瘤的治疗提供一种新的治疗药物。
以上所述的具体实施例,对本发明的目的、技术方案和有益效果进行了进一步的详细说明,应当理解,以上所述仅为本发明的具体实施例而已,并不用于限定本发明的保护范围。特别指出,对于本领域技术人员来说,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 (5)
1. Ponatinib或其药学上可接受的盐作为唯一活性成分在制备预防或治疗血管退行性疾病药物中的应用,其特征在于,所述血管退行性疾病为主动脉夹层或主动脉夹层动脉瘤。
2.如权利要求1所述的Ponatinib或其药学上可接受的盐作为唯一活性成分在制备预防或治疗血管退行性疾病药物中的应用,其特征在于,所述Ponatinib的给药剂量为5-25mg/kg/72h,给药对象为小鼠。
3.如权利要求1所述的Ponatinib或其药学上可接受的盐作为唯一活性成分在制备预防或治疗血管退行性疾病药物中的应用,其特征在于,所述药物的给药方式为口服。
4.如权利要求1所述的Ponatinib或其药学上可接受的盐作为唯一活性成分在制备预防或治疗血管退行性疾病药物中的应用,其特征在于,所述Ponatinib或其药学上可接受的盐作为药物活性成分,制成任何一种药学上可接受的剂型。
5.如权利要求4所述的Ponatinib或其药学上可接受的盐作为唯一活性成分在制备预防或治疗血管退行性疾病药物中的应用,其特征在于,所述剂型为胶囊、酊剂、丸剂、口服液、片剂、颗粒剂类口服给药的剂型。
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