CN113456642B - 一种美氟尼酮在制备治疗急性肾损伤药物中的应用 - Google Patents
一种美氟尼酮在制备治疗急性肾损伤药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种美氟尼酮在制备治疗急性肾损伤药物中的应用。针对缺血再灌注诱导AKI小鼠给予美氟尼酮治疗能减轻肾小管病理损伤和改善肾功能,改善肾功能指标尿素氮、肌酐的水平。说明美氟尼酮对AKI具有治疗作用,也就是说采用美氟尼酮制备的药物适用于治疗AKI。美氟尼酮针对人体的给药剂量为12.8mg/kg。
Description
技术领域
本发明涉及ZHC-116,1-(4-((3-(4-甲基哌嗪-1-基)丙基)氨基)苄基)-5-(三氟甲基)吡啶-2(1H)-酮(简称美氟尼酮)的新医药用途。
背景技术
急性肾损伤(Acute kidney injury,AKI)是一种临床常见的综合征,它的发生常伴随着患者住院时间延长,部分患者预后不良进一步发展为慢性肾脏病。全球每年约1300万人发生AKI(85%的患者生活在发展中国家),约170万人死于AKI及其并发症。AKI可发生于临床多个学科,特别是在ICU中发病率超过50%。在我国,一项大样本多中心流行病学调查数据显示,按照KDIGO AKI的诊断标准和扩展标准,AKI发生率为0.99%和2.03%,而住院病死率高达12.4%。近年来,无论是高收入国家还是低收入国家,AKI的患病率均呈迅速上升趋势,且病死率居高不下,给国家和社会造成了巨大的经济负担。
AKI的病因广泛,传统意义上主要分为肾前性、肾性和肾后性三大类。肾前性因素包括:烧伤、腹泻、呕吐、利尿剂的使用、消化道出血、胰腺炎、烧伤、挤压综合征等,上述因素均通过导致肾脏灌注不足而进一步引起肾脏损伤。肾性因素包括:血管炎、急进性肾炎、间质性肾炎、急性肾小管坏死等。肾后性因素包括:尿道梗阻、前列腺增生/恶性肿瘤、结石等。随着对AKI认识的加深,目前更倾向于按病因将其分为:脓毒症相关AKI、肾毒性药物相关肾损伤、心肾综合征、肝肾综合征以及心脏大手术相关AKI,而缺血再灌注所致肾损伤是上述病因所致AKI发生的重要病理生理机制之一。全球范围内已经开展了大量研究工作以寻找有效的防治AKI的药物,但目前仍没有任何一种药物被批准用于治疗AKI。
目前,AKI的主要治疗手段包括尽早识别并纠正可逆性病因,及时采取干预措施避免肾脏受到进一步损伤,维持水、电解质和酸碱平衡,适当营养支持,积极防治并发症,适时进行个体化RRT。其中纠正可逆性病因的措施包括积极有效地控制感染、停止使用导致肾脏损伤的相关药物、及时解除尿路梗阻和治疗相关的系统性疾病。长期以来临床对于AKI始终沿袭对症支持的治疗原则,静待肾脏病变自身的转归,迄今为止尚无一种可以用于在AKI中减轻肾组织损伤或促进肾脏修复或防止后期肾脏慢性纤维化的治疗药物获批上市。
发明内容
本发明所要解决的技术问题是,提供一种1-(4-((3-(4-甲基哌嗪-1-基)丙基)氨基)苄基)-5-(三氟甲基)吡啶-2(1H)-酮(简称美氟尼酮),或该化合物及药学上可以的辅料在制备治疗急性肾损伤(AKI)药物中的新应用,填补此适应症药物的空白。
为解决上述技术问题,本发明提出的技术方案为:
一种美氟尼酮在制备治疗急性肾损伤药物中的应用。
上述的应用,优选的,所述急性肾损伤为缺血再灌注诱导的急性肾损伤。
优选的,本发明共提供了6个剂量的美氟尼酮在小鼠AKI中的效果,为25mg/kg~125mg/kg,换算成人体给药剂量为3.2mg/kg~16.0mg/kg;更优选的,所述美氟尼酮针对人体的给药剂量为12.8mg/kg。
与现有技术相比,本发明的有益效果为:
美氟尼酮是新研发的抗肾纤维化药物,本发明首次发现美氟尼酮能够减轻缺血再灌注诱导的AKI,降低血清尿素氮、肌酐水平进而在缺血再灌注诱导的AKI中发挥保护肾脏的作用。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1是各组小鼠肾脏HE染色(200×)效果对比。
具体实施方式
为了便于理解本发明,下文将结合说明书附图和较佳的实施例对本发明做更全面、细致地描述,但本发明的保护范围并不限于以下具体实施例。
除非另有定义,下文中所使用的所有专业术语与本领域技术人员通常理解含义相同。本文中所使用的专业术语只是为了描述具体实施例的目的,并不是旨在限制本发明的保护范围。
除非另有特别说明,本发明中用到的各种原材料、试剂、仪器和设备等均可通过市场购买得到或者可通过现有方法制备得到。
实施例:
一种美氟尼酮在制备治疗急性肾损伤药物中的应用。
为证明美氟尼酮在制备治疗急性肾损伤药物中的效果,本实施例提供以下实验观察美氟尼酮治疗缺血再灌注诱导小鼠AKI的疗效:
1.实验方法
制备缺血再灌注诱导AKI实验动物模型,观察美氟尼酮治疗AKI的疗效。
以SPF级C57BL/6小鼠(7-8周龄,雄性,体重20-22g)为实验对象,共分为7组,分别为对照组、模型组、美氟尼酮25mg/kg治疗组、美氟尼酮50mg/kg治疗组、美氟尼酮75mg/kg治疗组、美氟尼酮100mg/kg治疗组及美氟尼酮125mg/kg治疗组。在造模前2天(D1)开始予以美氟尼酮灌胃给药。手术当天(D3),小鼠麻醉后,备皮,在背部脊柱旁切口下暴露双侧肾脏,分离双侧肾蒂周围筋膜,充分暴露双侧肾蒂,使用血管夹夹闭双肾肾蒂30分钟,整个实验过程中使用温度控制加热装置使小鼠体温保持在36.5℃–37℃。30分钟后取下血管夹,分层缝合双侧腹膜、皮肤,再灌注48小时后处死小鼠。对照组小鼠麻醉后,在背部切口下暴露双侧肾脏,分离肾蒂,分层缝合双侧腹膜、皮肤,48小时后处死小鼠。
通过腹主动脉采血法留取小鼠血清。分离双侧肾脏组织,充分灌洗后,留取左肾制作石蜡切片,余下肾脏留取肾脏皮质置于液氮罐中。通过苦味酸两点速率法检测各组小鼠肾功能,石蜡切片行HE染色观察肾小管损伤情况。
肾小管损伤评分标准参考Capasso.等人采用的方法对肾小管病理损伤进行半定量分析。200×镜下随机选取皮髓区10个视野,针对肾小管损伤(小管坏死、管型形成和刷状缘缺失)面积进行评分,具体细则如下:0分:无;1分:1%-25%;2分:26%-50%;3分:51%-75%;4分:76%-100%。0分:无;1分:1%-25%;2分:26%-50%;3分:51%-75%;4分:76%-100%。取平均值为该例样本评分值。
2.统计学方法
3.实验结果
3.1HE染色结果
缺血再灌注损伤后48小时,小鼠肾小管上皮出现了较为明显的细胞肿胀、空泡变性、脱落坏死、管腔扩张,并可见明显裸露的基底膜。与模型组相比,予以美氟尼酮治疗后的小鼠肾脏中,上述病变明显减轻,损伤范围减小(见图1),且肾小管损伤病理评分明显降低(P<0.05)。见表1。
表1各组小鼠肾小管损伤评分(X±S)
*与对照组相比,P<0.05,#与模型组相比,P<0.05。
3.2各组小鼠血肌酐检测结果
与对照组相比,模型组小鼠血肌酐明显升高,模型组小鼠鼠平均值较正常组大鼠升高大于50%,差异有统计学意义(P<0.05);予以美氟尼酮治疗后,小鼠血肌酐明显下降,其中美氟尼酮50mg/kg、75mg/kg、100mg/kg及125mg/kg组与模型组相比差异具有统计学意义(P<0.05)。见表2。
表2各组小鼠血肌酐水平(X±S)
*与对照组相比,P<0.05,#与模型组相比,P<0.05。
3.3各组小鼠血BUN检测结果
与对照组相比,模型组小鼠血BUN明显升高,且差异有统计学意义(P<0.05);予以美氟尼酮治疗后,小鼠血BUN明显下降,其中美氟尼酮75mg/kg、100mg/kg及125mg/kg组与模型组相比差异具有统计学意义(P<0.05)。见表3。
表3各组小鼠血BUN水平(X±S)
*与对照组相比,P<0.05,#与模型组相比,P<0.05。
4.实验结论
美氟尼酮(给药剂量:25mg/kg/天~125mg/kg/天)能有效治疗缺血再灌注诱导的小鼠急性肾损伤。
根据本发明的实施例,按照小鼠体重20g与人体重60kg进行药物剂量换算:小鼠给药剂量为25mg/kg~125mg/kg,对应人体给药剂量为:3.2mg/kg~16.0mg/kg。该转换公式小鼠剂量(mg/kg)=7.8*人用剂量(mg/kg),是本领域技术人员熟知的。本发明显示:美氟尼酮能降低AKI小鼠血肌酐、血尿素氮,减少肾脏损伤评分;其中,血肌酐起效剂量为50mg/kg,血尿素氮起效剂量为75mg/kg,肾脏损伤评分有效剂量为100mg/kg。因此,本发明针对人体提供药物的最佳给药剂量为12.8mg/kg/天。
根据本发明的具体实施方式证明,给予缺血再灌注诱导AKI小鼠美氟尼酮治疗能减轻肾小管病理损伤,改善肾功能指标尿素氮、肌酐的水平。说明该化合物对AKI具有治疗作用,也就是说美氟尼酮制备的药物适用于治疗AKI。
Claims (3)
1.一种美氟尼酮在制备治疗急性肾损伤药物中的应用,其特征在于,所述急性肾损伤为缺血再灌注诱导的急性肾损伤。
2.根据权利要求1所述的应用,其特征在于,所述美氟尼酮针对人体的给药剂量为3.2mg/kg~16.0mg/kg。
3.根据权利要求2所述的应用,其特征在于,所述美氟尼酮针对人体的给药剂量为12.8mg/kg。
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