CN116440117A - 甲磺酸萘莫司他在制备治疗肾损伤或肾功能不全药物中的应用 - Google Patents
甲磺酸萘莫司他在制备治疗肾损伤或肾功能不全药物中的应用 Download PDFInfo
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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Abstract
本发明公开了甲磺酸萘莫司他在制备治疗肾损伤或肾功能不全药物中的应用,涉及肾损伤治疗技术领域。首次提出了甲磺酸萘莫司他以非抗凝剂的形式直接用于制备肾损伤或肾功能不全药物。发明人研究发现甲磺酸萘莫司他在缺氧而后复氧的条件下对肾小管上皮细胞具有一定的保护作用,且甲磺酸萘莫司他可改善缺小鼠肾缺血再灌注损伤,提示甲磺酸萘莫司他在患有肾损伤或肾功能不全疾病的患者中对肾小管上皮细胞具有保护作用,可治疗肾损伤或肾功能不全。本发明的提出,为急性肾损伤、慢性肾脏病或终末期肾病的防治带来了新的药物选择。
Description
技术领域
本发明涉及肾损伤治疗技术领域,具体而言,涉及甲磺酸萘莫司他在制备治疗肾损伤或肾功能不全药物中的应用。
背景技术
急性肾损伤(Acute kidney injury,AKI)是临床常见的危重病之一,其诊断标准以血肌酐(serum creatinine,Scr)和尿量等指标为主,而这些指标常出现在病情进展期,可能延误对早期病变进程监控,进而使其进展为慢性肾脏病(Chronic kidney diseases,CKD),最后导致终末期肾病(End stage renal diseases,ESRD),从而给患者自身健康、家庭及社会造成巨大危害。近年来,该病的发病率和致死率不断增高,但其发病机制复杂,尤其缺乏有效的早期干预手段,给该病的防治均带来了巨大的困难。
对于AKI发病机制的研究多聚焦于损伤后的效应阶段,而对启动机制研究尚少,因此,深入探讨AKI发病的始动机制是亟待解决的问题,也是早期防治AKI并延缓CKD发生发展的前提和关键。AKI病理特征主要表现为肾小管上皮细胞损伤和死亡。肾小管上皮细胞极易发生凋亡进而促进肾小管损伤,而肾小管损伤是导致肾脏衰竭最重要的病理生理过程。在AKI早期,缺血再灌注损伤(Ischemia reperfusion injury,IRI)和肾毒性物质(如顺铂等)诱导的肾小管上皮细胞损伤主要以凋亡为主。肾小管上皮细胞凋亡与肾小管上皮细胞损伤、肾组织损害和肾功能丧失密切相关。AKI中受损的肾脏分泌到外周循环中的因子还会进一步诱导心、肺、肝脏和大脑中细胞凋亡和炎症的发生,进一步提高AKI的致死率,因此肾小管上皮细胞凋亡是AKI发生发展的关键环节。
最新研究发现如PIPK3,PTEN/Akt等信号分子或通路可介导AKI中肾小管上皮细胞凋亡。由此可见,针对多种细胞死亡途径的联合治疗可能潜在增加AKI患者的临床获益,但目前尚缺乏关键靶标,因此,既无切实有效的特异方法用于临床防治肾小管上皮凋亡,也缺乏相应检测技术用于AKI早期诊断。为此本发明拟获取AKI进程早期关键靶标分子,探讨其作用机制,进而设计AKI早期诊断体系用于AKI筛查、监测和诊断。
甲磺酸萘莫司他(Nafamostat mesilate)(又叫FUT-175) 是合成的丝氨酸蛋白酶抑制剂,在血液透析中通常被用作是一种抗凝血剂。甲磺酸萘莫司他可抑制SARS-CoV-2的激活,并用于COVID-19的治疗选择的研究中。甲磺酸萘莫司他可减弱炎症。然而尚无报道其具有治疗肾损伤或肾功能不全的功效。
鉴于此,特提出本发明。
发明内容
本发明的目的在于提供甲磺酸萘莫司他在制备治疗肾损伤或肾功能不全药物中的一种新应用。
本发明是这样实现的:
本发明提供了一种甲磺酸萘莫司他在制备预防或治疗肾损伤或肾功能不全药物中的应用。
本发明首次提出了甲磺酸萘莫司他以非抗凝剂的形式直接用于制备肾损伤或肾功能不全药物。发明人研究发现甲磺酸萘莫司他在缺氧而后复氧的条件下对肾小管上皮细胞具有一定的保护作用,且甲磺酸萘莫司他可改善缺小鼠肾缺血再灌注损伤,提示甲磺酸萘莫司他在患有肾损伤或肾功能不全疾病的患者中对肾小管上皮细胞具有保护作用,可治疗肾损伤或肾功能不全。
在本发明应用较佳的实施方式中,上述药物具有如下至少一种作用:改善肾缺血再灌注损伤和在缺氧而后复氧的条件下保护肾上皮细胞。
在一种可选的实施方式中,缺氧而后复氧是指缺氧15min-24h复氧24h-48h。在一种可选的实施方式中,缺氧而后复氧是指缺氧45min后复氧24h。
在本发明应用较佳的实施方式中,上述改善肾缺血再灌注损伤是指改善肾缺血再灌注损伤所导致的肾功能失衡和肾脏组织损伤。肾功能失衡表现为如下至少一种情形:血清肌酐水平升高和尿素氮水平显著升高;肾脏组织损伤表现为如下至少一种情形:肾小管上皮细胞发生空泡变性、凋亡和脱落。
在本发明应用较佳的实施方式中,上述肾损伤为急性肾损伤或慢性肾损伤。
在本发明应用较佳的实施方式中,上述的急性肾损伤或慢性肾损伤选自如下至少一种:缺血再灌注所致的急性肾损伤或慢性肾损伤、药物毒性致急性或慢性肾损伤、病菌感染致急性或慢性肾损伤、免疫应激引起的急性或慢性肾损伤。
在本发明应用较佳的实施方式中,上述药物毒性致急性或慢性肾损伤为肾毒性物质导致的急性或慢性肾损伤。
肾毒性物质可列举农药或药物、造影剂、抗生剂等,通过这些物质而肾单位被伤害,从而肾功能丧失。肾毒性物质例如选自铂。
在本发明应用较佳的实施方式中,上述的病菌感染致急性或慢性肾损伤为病菌的内毒素脂多糖导致的急性或慢性肾损伤。
在本发明应用较佳的实施方式中,上述肾损伤或肾功能不全选自糖尿病肾病、高血压肾病或终末期肾病。
在本发明应用较佳的实施方式中,上述药物以口服或注射的途径给予患者。注射包括不限于:皮内、肌肉、皮下或静脉注射的途径给予患者。
在本发明应用较佳的实施方式中,上述药物的剂型选自片剂、胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、霜剂、喷雾剂、滴剂和贴剂。
膏剂例如选自软膏剂或硬膏剂。胶囊剂例如选自硬胶囊剂或软胶囊剂。片剂例如选自糖衣片剂、薄膜衣片剂或肠溶衣片剂。
本发明具有以下有益效果:
本发明首次提出了甲磺酸萘莫司他以非抗凝剂的形式直接用于制备肾损伤或肾功能不全药物。发明人研究发现甲磺酸萘莫司他在缺氧而后复氧的条件下对肾小管上皮细胞具有一定的保护作用,且甲磺酸萘莫司他可改善缺小鼠肾缺血再灌注损伤,提示甲磺酸萘莫司他在患有肾损伤或肾功能不全疾病的患者中对肾小管上皮细胞具有保护作用,可治疗肾损伤或肾功能不全。本发明的提出,为急性肾损伤、慢性肾脏病或终末期肾病的防治带来了新的药物选择。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,应当理解,以下附图仅示出了本发明的某些实施例,因此不应被看作是对范围的限定,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相关的附图。
图1为CCK-8检测结果统计图;
图2为不同浓度的甲磺酸萘莫司他给药缺血再灌注损伤小鼠模型后的血清肌酐(A)和尿素氮(B)水平统计图;
图3为不同浓度的甲磺酸萘莫司他给药缺血再灌注损伤小鼠模型后的肾脏组织切片后分别进行HE和PAS染色后的显微图;
图4为不同浓度的甲磺酸萘莫司他给药缺血再灌注损伤小鼠模型后的肾脏组织切片后进行TUNEL染色后的显微图。
具体实施方式
现将详细地提供本发明实施方式的参考,其一个或多个实例描述于下文。提供每一实例作为解释而非限制本发明。实际上,对本领域技术人员而言,显而易见的是,可以对本发明进行多种修改和变化而不背离本发明的范围或精神。例如,作为一个实施方式的部分而说明或描述的特征可以用于另一实施方式中,来产生更进一步的实施方式。
除非另外指明,否则实践本发明将采用细胞生物学、分子生物学(包含重组技术)、微生物学、生物化学和免疫学的常规技术,所述常规技术在本领域技术人员的能力范围内。文献中充分解释了这种技术,如《分子克隆:实验室手册(Molecular Cloning:ALaboratory Manual)》,第二版(Sambrook等人,1989);《寡核苷酸合成(OligonucleotideSynthesis)》(M.J.Gait编,1984);《动物细胞培养(Animal Cell Culture)》(R.I.Freshney编,1987);《酶学方法(Methods in Enzymology)》(学术出版社有限公司(Academic Press,Inc.);《实验免疫学手册(Handbook of Experimental Immunology)》(D.M.Weir和C.C.Blackwell编);《哺乳动物细胞用基因转移载体(Gene Transfer Vectors forMammalian Cells)》(J.M.Miller和M.P.Calos编,1987);《当代分子生物学方法(CurrentProtocols inMolecular Biology)》(F.M.Ausubel等人编,1987);《PCR:聚合酶链反应(PCR:The Polymerase Chain Reaction)》(Mullis等人编,1994);以及《当代免疫学方法(Current Protocols in Immunology)》(J.E.Coligan等人编,1991),所述文献中的每个文献均通过引用明确并入本文中。
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
人肾皮质近曲小管上皮细胞(human renal tubular epithelial cell line,HK2)购买于中国科学院细胞典藏库,经细胞系STR鉴定合格。培养于含10 % FBS、1 %抗链霉素-青霉素和DMEM-F12培养基中,置于5% CO2,37℃培养箱中进行培养。完全培养基含10 %FBS、1 %抗链霉素-青霉素和DMEM-F12培养基。
CCK-8检测:人肾小管上皮细胞系HK2细胞按2*104个/孔铺在96孔板中,待细胞过夜贴壁以后,分别用0.15625、0.3125、0.625、1.25、2.5、5、10、20、40、80、160、320的甲磺酸萘莫司他(Nafamostat mesilate,溶剂为完全培养基)处理HK2细胞24小时,然后再用Billupus缺氧模块化系统对相应的细胞进行缺氧/复氧处理,缺氧45 min以后再复氧24 h,CCK-8检测每组细胞活力。Ctrl是指正常HK2细胞,没有经过任何处理;“-”为负对照,含有1‰DMSO的完全培养基。
细胞存活率参照图1所示,结果可见:与单纯缺氧45 min/复氧 24 h处理组的细胞比较,0.15625、0.3125、0.625、1.25的甲磺酸萘莫司他可在缺氧45 min/复氧 24h后能显著改善人肾小管上皮细胞系HK2细胞的存活情况。相比于负对照(含有1‰DMSO的完全培养基),甲磺酸萘莫司他的浓度超过2.5/>后细胞存活率有所下降。原因在于甲磺酸萘莫司他的浓度超过2.5/>后可能会产生一定的细胞毒性诱导细胞死亡,该结果提示2.5可能是一个临界点。
实施例2
40只野生型雄性Balb/C小鼠,4-6周,体重为14-16g,购买于成都达硕试验动物有限公司。将小鼠随机分为五个组(n=8):假手术组(sham组),模型组(缺血再灌注损伤(IRI)组),25 mg/kg甲磺酸萘莫司他治疗组(IRI+25 mg/kg甲磺酸萘莫司他组),50 mg/kg甲磺酸萘莫司他治疗组(IRI+50 mg/kg甲磺酸萘莫司他组),50 mg/kg甲磺酸萘莫司他单独给药组(50 mg/kg甲磺酸萘莫司他组)。需要造模的小鼠麻醉后,仰卧位固定腹部正中切开。游离双侧肾的动静脉并夹闭45min后解除夹闭,肾脏由暗红色变为鲜红色时显示肾脏血液再灌注成功,解除夹闭血流再灌注24h后,麻醉安乐死小鼠后收集血液、肾脏组织等样品。在造模前半小时分别给对应组小鼠灌胃25 mg/kg或50 mg/kg甲磺酸萘莫司他。甲磺酸萘莫司他用注射用生理盐水配制。同时分别给与假手术组和模型组小鼠等量的生理盐水。
动物血清肌酐的测定方法如下:
(1)根据实验设计,提前设计好空白、标准品和待测孔。在每个孔中加入180μl酶溶液A,在空白孔中加入双蒸水6μl,标准品孔中加入标准品6μl,待测孔中加入血清样本6μl,放入37℃培养箱中孵育5min,在546nm波长下测定吸光度值A1;
(2)在每个孔中加入酶溶液B各60μl,放入37℃培养箱中孵育5min,在546nm波长下测定吸光度值A2;
(3)根据如下公式计算样品肌酐值:
肌酐含量(μmol/L)=[(测定A2–K×测定A1)–(空白A2–K×空白A1)]/[(标准A2–K×标准A1)–(空白A2–K×空白A1)]×标准品浓度
注:标准品浓度为442μmol/L
稀释因子K=(加样量+酶溶液A体积)/(加样量+酶溶液A体积+酶溶液B体积)=186/246
动物血清尿素氮的测定方法如下:
(1)缓冲酶液需现配现用,按酶储备液:酶稀释液=3:1000配成缓冲酶液;
(2)根据实验设计,提前设计好空白、标准和待测管。在5ml EP管中加入250μl缓冲酶液,在空白管中加入双蒸水20μl,标准品孔中加入10mmol/L标准品20μl,待测孔中加入血清样本20μl,置于37℃水浴锅中10min;
(3)在每个管中加入酚显色剂和碱性次氯酸钠各1ml,置于37℃水浴锅中10min;
(4)在每个管中取200μl于96孔板中,在640nm波长下测定空白、标准和待测管的吸光度OD值,根据如下公式计算样品尿素氮值:
(mmol/L)=(测定OD值–空白OD值)/(标准OD值–空白OD值)×标准品浓度×待测样本稀释倍数
小鼠血清肌酐(A)和尿素氮(B)结果参照图2所示:结果表明:与sham组小鼠比较,IRI组小鼠血清肌酐和尿素氮水平显著升高,提示肾功能损害增强;而25 mg/kg或50 mg/kg甲磺酸萘莫司他治疗肾IRI组小鼠的血清肌酐和尿素氮水平均显著降低且呈一定的剂量性,提示甲磺酸萘莫司他可改善IRI所致的小鼠肾功能失衡。与sham组比较,未见50 mg/kg甲磺酸萘莫司他单独给药组小鼠血清肌酐和尿素氮水平升高,提示甲磺酸萘莫司他不会导致小鼠肾功能失衡。
实施例3
40只野生型雄性Balb/C小鼠,4-6周,体重为14-16g,购买于成都达硕试验动物有限公司。将小鼠随机分为五个组(n=8):假手术组(sham组),模型组(IRI组),25 mg/kg甲磺酸萘莫司他治疗组(IRI+25 mg/kg甲磺酸萘莫司他组),50 mg/kg甲磺酸萘莫司他治疗组(IRI+50 mg/kg甲磺酸萘莫司他组),50 mg/kg甲磺酸萘莫司他单独给药组(50 mg/kg甲磺酸萘莫司他组)。需要造模的小鼠麻醉后,仰卧位固定腹部正中切开。游离双侧肾的动静脉并夹闭45min后解除夹闭,肾脏由暗红色变为鲜红色时显示肾脏血液再灌注成功,解除夹闭血流再灌注24h后,麻醉安乐死小鼠后收集血液、肾脏组织等样品。在造模前半小时分别给对应组小鼠灌胃25 mg/kg或50 mg/kg甲磺酸萘莫司他。甲磺酸萘莫司他用注射用生理盐水配制。同时分别给与假手术组和模型组小鼠等量的生理盐水。
组织标本脱水、包埋和切片
(1)取新鲜组织厚度不超过5mm,4%多聚甲醛固定超过24小时;
(2)冲水12-24小时后梯度酒精脱水和二甲苯透明,具体如下:
75%酒精,1次,1小时;
85%酒精,1次,1小时;
95%酒精,3次,1小时;
100%酒精,3次,1小时;
二甲苯,2次,1小时;
石蜡浸泡,3次,2小时;
(3)52℃-54℃石蜡包埋;
(4)切片:切片前将蜡块置于冰上10min,然后将蜡块固定至切片机。先对蜡块组织进行修整,使之平滑且切面完整。切片后,将组织片放入42℃的恒温水浴槽,待组织片展开后,用载玻片将组织片快速捞出,尽量甩干玻片上的水,并置于72℃的烤片机上,待玻片干燥后放回至切片盒,进行染色前将片子于60℃烘干箱放置1h。切片厚度为2μm。
HE染色
(1)烤片:将切片放入60°C恒温烤箱烤片至少1h;
(2)脱蜡:二甲苯I、二甲苯II、二甲苯III各10min,溶解切片上石蜡,95%乙醇I、95%乙醇II、80%乙醇、75%乙醇各2min,洗去切片上的二甲苯;放入流水中冲洗10min;
(3)染色:将切片置于苏木素中染色5min,蒸馏水冲洗干净;
(4)分化:切片放入1%盐酸中1min,蒸馏水冲洗15min;
(5)染核:切片放入伊红溶液中染色1min。蒸馏水冲洗干净;
(6)脱水:依次放入80%乙醇、95%乙醇I、95%乙醇II、无水乙醇I、无水乙醇II各2min;
(7)透明:二甲苯I、二甲苯II中各5min;
(8)封片:中性树胶封片。
PAS染色
(1)烤片:将切片放入60℃恒温烤箱烤片至少1h;
(2)脱蜡:二甲苯I、二甲苯II、二甲苯III各10min,溶解切片上的石蜡,95%乙醇I、95%乙醇II、80%乙醇、75%乙醇各2min,洗去切片上的二甲苯;放入流水中冲洗10min;
(3)置玻片于 Periodic Acid溶液中室温浸泡 5分钟。蒸馏水漂洗干净;
(4)置玻片于Schiff’s Reagent中室温浸泡15分钟,自来水冲洗玻片5分钟,避免直接冲击组织;
(5)将苏木素滴于玻片上30秒,自来水冲洗干净;
(6)脱水:依次放入80%乙醇、95%乙醇I、95%乙醇II、无水乙醇I、无水乙醇II各2min;
(7)透明:二甲苯I、二甲苯II中各5min;
(8)封片:中性树胶封片
HE和PAS染色结果参照图3所示,图3中:IRI:缺血再灌注损伤;25NM:25 mg/kg甲磺酸萘莫司他;50NM:50 mg/kg甲磺酸萘莫司他。结果表明与sham组小鼠比较,IRI组小鼠肾脏组织中肾小管刷状缘减少,肾小管上皮细胞发生空泡变性、死亡并脱落,提示肾组织损害增强;而25 mg/kg或50 mg/kg甲磺酸萘莫司他治疗肾IRI组小鼠肾脏组织中肾小管刷状缘维持良好,少量肾小管上皮细胞发生空泡变性、死亡与脱落,该情况且呈一定的剂量性,提示甲磺酸萘莫司他可改善IRI所致的小鼠肾脏组织损伤。与sham组比较,未见50 mg/kg甲磺酸萘莫司他单独给药组小鼠肾脏组织损害,提示甲磺酸萘莫司他不会导致小鼠肾组织损伤。
实施例4
40只野生型雄性Balb/C小鼠,4-6周,体重为14-16g,购买于成都达硕试验动物有限公司。小鼠随机分为五个组(n=8):假手术组(sham组),模型组(IRI组),25 mg/kg甲磺酸萘莫司他治疗组(IRI+25 mg/kg甲磺酸萘莫司他组),50 mg/kg甲磺酸萘莫司他治疗组(IRI+50 mg/kg甲磺酸萘莫司他组),50 mg/kg甲磺酸萘莫司他单独给药组(50 mg/kg甲磺酸萘莫司他组)。需要造模的小鼠麻醉后,仰卧位固定腹部正中切开。游离双侧肾的动静脉并夹闭45min后解除夹闭,肾脏由暗红色变为鲜红色时显示肾脏血液再灌注成功,解除夹闭血流再灌注24h后,麻醉安乐死小鼠后收集血液、肾脏组织等样品。在造模前半小时分别给对应组小鼠灌胃25 mg/kg或50 mg/kg甲磺酸萘莫司他。甲磺酸萘莫司他用注射用生理盐水配制。同时分别给与假手术组和模型组小鼠等量的生理盐水。
组织标本脱水、包埋和切片步骤如下:
(1)取新鲜组织厚度不超过5mm,4%多聚甲醛固定超过24小时;
(2)冲水12-24小时后梯度酒精脱水和二甲苯透明,具体如下:
75%酒精,1次,1小时;
85%酒精,1次,1小时;
95%酒精,3次,1小时;
100%酒精,3次,1小时;
二甲苯,2次,1小时;
石蜡浸泡,3次,2小时;
(3)52℃-54℃石蜡包埋;
(4)切片:切片前将蜡块置于冰上10min,然后将蜡块固定至切片机。先对蜡块组织进行修整,使之平滑且切面完整。切片后,将组织片放入42℃的恒温水浴槽,待组织片展开后,用载玻片将组织片快速捞出,尽量甩干玻片上的水,并置于72℃的烤片机上,待玻片干燥后放回至切片盒,进行染色前将片子于60℃烘干箱放置1h。切片厚度为2μm。
动物肾组织TUNEL染色步骤如下:
(1)石蜡切片脱蜡,复水同上;
(2)组织渗透:用PBS稀释蛋白酶K储液,配成20μg/ml溶液。在载玻片上滴加稀释的蛋白酶K溶液以覆盖组织切片,室温孵育载玻片15min;
(3)PBS洗3次,每次3min;
(4)加100μl 平衡缓冲液,室温下5-10min;
(5)吸去平衡缓冲液,滴加TUNEL反应混合液(平衡缓冲液:核苷酸 Mix:rTdT 酶 =45:5:1),加盖Plastic Cover Slips,37℃避光孵育60min;
(6)移去Plastic Cover Slips(暗盒的盖子),将切片室温下孵育15min;
(7)PBS洗3次,每次3min;
(8)DAPI室温下避光复染5min;
(9)PBS洗3次,每次3min;
(10)甘油封片,激光共聚焦下观察。
TUNEL染色参照图4所示,DAPI为一种是一种能够与DNA强力结合的荧光染料,常用于荧光显微镜观测,Merge为TUNEL的绿色荧光与DAPI的蓝色荧光的叠加图;图4中,IRI:缺血再灌注损伤;25NM:25 mg/kg甲磺酸萘莫司他;50NM:50 mg/kg甲磺酸萘莫司他。结果显示,与sham组相比,IRI模型组小鼠肾脏组织中大量肾小管上皮细胞明显发生凋亡,提示肾组织中肾小管损害增强;而25 mg/kg或50 mg/kg甲磺酸萘莫司他治疗肾IRI组小鼠肾脏组织中少量肾小管上皮细胞发生凋亡且呈一定的剂量性,提示甲磺酸萘莫司他可改善IRI所致的小鼠肾脏组织中肾小管损害。与sham组比较,未见50 mg/kg甲磺酸萘莫司他单独给药组小鼠肾脏组织中肾小管上皮细胞发生凋亡,提示甲磺酸萘莫司他不会导致小鼠肾小管损害。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.甲磺酸萘莫司他在制备预防或治疗肾损伤或肾功能不全药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述药物具有如下至少一种作用:改善肾缺血再灌注损伤和在缺氧而后复氧的条件下保护肾上皮细胞;
所述缺氧而后复氧是指缺氧15min-24h复氧24h-48h。
3.根据权利要求2所述的应用,其特征在于,所述改善肾缺血再灌注损伤是指改善肾缺血再灌注损伤所导致的肾功能失衡和肾脏组织损伤;所述肾功能失衡表现为如下至少一种情形:血清肌酐水平升高和尿素氮水平升高;所述肾脏组织损伤表现为如下至少一种情形:肾小管上皮细胞发生空泡变性、凋亡和脱落。
4.根据权利要求1所述的应用,其特征在于,所述肾损伤为急性肾损伤或慢性肾损伤。
5.根据权利要求4所述的应用,其特征在于,所述的急性肾损伤或慢性肾损伤选自如下至少一种:缺血再灌注所致的急性肾损伤或慢性肾损伤、药物毒性致急性或慢性肾损伤、病菌感染致急性或慢性肾损伤、免疫应激引起的急性或慢性肾损伤。
6.根据权利要求5所述的应用,其特征在于,所述药物毒性致急性或慢性肾损伤为肾毒性物质导致的急性或慢性肾损伤。
7.根据权利要求5所述的应用,其特征在于,所述的病菌感染致急性或慢性肾损伤为病菌的内毒素脂多糖导致的急性或慢性肾损伤。
8. 根据权利要求1所述的应用,其特征在于,所述肾损伤或肾功能不全选自糖尿病肾病、 高血压肾病或终末期肾病。
9.根据权利要求1-8任一项所述的应用,其特征在于,所述药物以口服或注射的途径给予患者。
10.根据权利要求1-8任一项所述的应用,其特征在于,所述药物的剂型选自片剂、胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、霜剂、喷雾剂、滴剂和贴剂。
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