CN107088202A - 用于维持哺乳动物体内血糖量正常的钒化合物的用途 - Google Patents
用于维持哺乳动物体内血糖量正常的钒化合物的用途 Download PDFInfo
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- CN107088202A CN107088202A CN201611177322.9A CN201611177322A CN107088202A CN 107088202 A CN107088202 A CN 107088202A CN 201611177322 A CN201611177322 A CN 201611177322A CN 107088202 A CN107088202 A CN 107088202A
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Abstract
本发明涉及用于维持哺乳动物体内血糖量正常的钒化合物的用途,以及用于维持在需要其的哺乳动物,优选患有急性应激的危重病人的体内血糖量正常的方法,并且涉及用于预防或者限制哺乳动物,优选患有急性应激的危重病人的体内肾缺血再灌注(I/R)的方法。
Description
本申请是于2012年3月6日提交的发明名称为“用于维持哺乳动物体内血糖量正常的钒化合物的用途”的中国专利申请号201280022288.1的分案申请。
技术领域
本发明涉及用于维持需要其的哺乳动物,优选患有急性应激的危重病人的血糖量正常的方法。本发明进一步涉及用于预防或者限制在需要其的哺乳动物,优选患有急性应激的危重病人体内的肾缺血再灌注(I/R)的方法。本发明还涉及用于在需要其的哺乳动物,优选患有急性应激的危重病人体内预防、限制或者治疗心肾失调的方法。本发明进一步涉及用于维持患有急性应激的危重病人体内的血糖量正常的药物组合物。
背景技术
患有急性应激(例如中风或者心肌梗死)的患者高比例地发展高血糖症,即使这些患者早期未被诊断为糖尿病。这类应激(压力)诱发的高血糖症与在中风和心肌梗死之后的死亡的高风险相关联。此外,应激(压力)诱发的高血糖症可能是脑损伤的风险因素(参见Sarah E.Capes et al.Stroke2001,32,page2426)。
此外,高血糖症和胰岛素耐受性通常在危重病人中是常见的,甚至当血糖动态平衡预先已经正常时(参见US 2005/171503,通过引用结合在此)。
G.Van Berghe等人(N.Engl.J.Med.2001,345,1359-1367)发现甚至在糖尿病患者以及非糖尿病患者危重病人体内适度的高血糖症直接地或者间接地对重要器官和系统有害。强化胰岛素疗法将总的ICU(重病监护室)死亡率从8%减少至4.6%,以及在需要超过五天特护的患者中从20.2%减少至10.6%。强化胰岛素疗法还显著地减少血流感染、延长炎症、急性肾衰竭、危重病多发性神经病以及输血要求。因此,用强化胰岛素疗法严格地维持血糖量正常将减少特护和医院死亡率以及在ICU中的垂危成年患者的发病率。
然而,强化胰岛素疗法需要患者血糖水平的知识,这涉及频繁地获得(毛细管)血样。这需要相当大的护士或者技师时间以及许多患者,尤其是非糖尿病患者,发现不便重复血液取样。此外,间歇性血液样品可能并未足够频繁地进行以给出血糖水平的准确图形。强化胰岛素疗法的其他缺点包括:低血糖症风险(本领域已知的是低血糖症增加心肌梗死和室性心律不齐的风险;参见US 2005/171503,通过引用结合在此)的增加,镇静作用可以掩盖低血糖症以及在当引入胰岛素时的选项方面以及在给予方案的患者方面的差异。
因此,尽管胰岛素疗法对于如上讨论的危重病人具有确定的优势,在本领域中仍需要提供用于控制胰岛素给予危重病人,具体地患有急性应激的危重病人的方法。
急性肾衰竭(ARF)是一种临床综合征,其特征在于在数天内发生的肾功能快速劣化。ARF通常是由急性肾小管坏死(ATN)引起的,其是由局部缺血性损伤和/或肾毒性损伤引起的。通常世界人口,每年每百万人口中出现大约200例严重的ARF。在临床试验中已经研究了数种药物(例如抗氧化剂、钙通道阻滞剂、利尿剂、血管活性物质、生长因子以及抗炎药的功效,但是发现具有很少的临床用途或无临床用途。
US 5.300.496、US 5.527.790、US 5.620.967、US 5.866.563以及US 5.888.993(全部结合以供参考),公开了钒化合物在治疗糖尿病、高血压、肥胖以及与慢性增强的血糖水平相关的类似病症中的用途。
通过引用结合的US 5.885.980公开了用于治疗糖尿病的药物组合物,所述药物组合物包括生成VO2+的化合物以及微粒化的优降糖。US 5.885.980的实施例5公开了使用胰岛素、硫酸氧钒和格列本脲微粉化片剂(glynase)(更通常用于治疗II型糖尿病的磺酰脲类型的抗糖尿病药物)的组合治疗在ICU中住院的I型糖尿病女性病人的慢性高血糖症。然而,格列本脲微粉化片剂可能引起低血糖症,而定义为血糖低于0.3mM/l的低血糖症将增加心肌梗死和室性心律不齐的风险(参见US2005/171503)。
通过引用结合的US 6.287.586公开了特定的钒双胍复合物(络合物)的药物组合物,用于治疗高血糖症以及相关失调。
通过引用结合的US 6.579.540公开了生理学上可接受的钒化合物用于预防性治疗组织的继发性损伤的用途,其中,所述继发性损伤是原发性损伤的结果并且其中所述原发性损伤是由创伤(例如局部缺血(梗死)之后再灌注)引起的。因此US 6.579.540确实并未公开生理学上可接受的钒化合物在治疗危重病人中的高血糖症或者肾缺血再灌注中的用途。
通过引用结合的US 6.852.760公开了磺酰脲类化合物、铬的生物可利用来源以及钒的生物可利用来源的组合用于治疗糖尿病的用途。
因此,使用钒化合物来控制糖尿病患者的高血糖症是本领域已知的。然而,糖尿病是一种慢性病。但是,危重病人住院时间相对较短,具体地,一至数天,并且具体地,在重病监护室(ICU)。因此,糖尿病患者与危重病人相比是不同类型的患者。
P.A.McCullough,Int.J.Nephrol.,2011卷,文章ID 762590(doi:10.4061/2011/762590)提出在心脏血管失调和肾脏失调之间存在相互关系。这种关系称为心肾失调。
当前,造影剂诱发的肾病,优选放射性造影剂诱发的肾病使用N-乙酰半胱氨酸进行治疗。
发明内容
本发明涉及用于维持需要其的哺乳动物,优选患有急性应激的危重病人的血糖量正常的方法,其中给予所述哺乳动物包括生理学上可接受的有机和/或无机钒化合物或者复合物(络合物)的药物组合物。
本发明还涉及用于预防或者限制需要其的哺乳动物,优选患有急性应激的危重病人的肾缺血再灌注(I/R)的方法,其中给予所述哺乳动物包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物。
本发明还涉及用于预防、限制或者治疗需要其的哺乳动物,优选患有急性应激的危重病人的心肾失调的方法,其中给予所述哺乳动物包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物。
本发明进一步涉及用于维持患有急性应激的危重病人的血糖量正常的药物组合物。
本发明进一步涉及包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物,用于预防或者限制患有急性应激的危重病人的肾缺血再灌注(I/R)。
本发明进一步涉及包括生理学上可接受的有机钒化合物或者复合物、药学上可接受的载体、以及第二组分的药物组合物,所述第二组分选自下组:镁、鱼油、钾、铜、硒、维生素D、维生素E、铬、以及它们的混合物。
本发明还涉及包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物,用于预防或者治疗需要其的哺乳动物的造影剂诱发的肾病。
本发明进一步涉及包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物,用于预防、限制或者治疗需要其的哺乳动物的心肾失调。
附图说明
图1示出了在基线(BSLN)时以及在局部缺血30min和再灌注90min(R90min)之后的平均动脉(art.)压力。
图2示出了在基线(BSLN)时以及在局部缺血30min和再灌注90min(R90min)后肾血管阻力(vasc.res.)(上列),肾血流量(中间列),以及肾氧气运送(下列)。
图3示出了在基线(BSLN)时以及在局部缺血30min和再灌注90min(R90min)后皮质(上列)和髓质(下列)中的肾微血管氧张力(μPO2)。
图4示出了在基线(BSLN)时以及在局部缺血30min和再灌注90min(R90min)后肾的氧消耗(上列),钠再吸收所需的氧气量(VO2/Tna+)(中间列),以及肌酐清除率(creat.clear.)(下列)。
图5示出了在基线(BSLN)时以及在局部缺血30min和再灌注90min(R90min)之后的尿液输出量。
图6示出了在局部缺血30min和再灌注90min(R90min)之后IL-6和iNOS表达(上列)以及MPO-染色的白细胞外观(下列)。
图7示出了在局部缺血30min和再灌注90min(R90min)之后IL-6和iNOS表达(上列)以及MPO-染色的白细胞外观(下列)。
具体实施方式
定义
如在本说明书中和权利要求中以及其结合中使用的动词“包括”以其非限制性含义使用,是指包括该词语后面的事项,但是并未排除并未具体提及的事项。另外,通过不定冠词“一个”或者“一种”提及元件并不排除存在超过一个元件的可能性,除非上下文明确地要求存在一个且仅一个元件。因此,不定冠词“一个”或者“一种”通常是指“至少一个”。
在本文件中,术语“危重病人”是指在重病监护室(ICU)中相应短期(特别地是一至数天,更特别地是一至七天)住院的患者组。优选地,术语“危重病人”是指患有急性应激(特别地是急性肾衰竭(ARF)、急性肾功能不全(ACI)或者两者)的患者组。建议的是针对肾脏的肾缺血再灌注(I/R)(其可以作为以下各项的结果发生或者可以在以下各项的期间发生:例如心脏或者血管手术、肾脏移植、选择性主动脉瘤修复和休克(例如心原性休克、出血性休克或者脓毒性休克))影响肾脏微循环,这可以防止正常的组织再灌注。这可能导致不希望的效应,例如肾缺氧、氧化应激以及具有器官衰竭的不可恢复的损害。
术语“心肾失调”限定为如心脏和肾脏的器官失调,由此,在一个器官中的急性或者慢性功能障碍可以引起在其他器官中的急性或者慢性功能障碍。已经提出了每种失调的数种可能的病理生理学机制。
因此,本发明涉及用于维持需要其的哺乳动物,优选患有急性应激的危重病人的血糖量正常的方法,其中给予所述哺乳动物包括生理学上可接受的有机和/或无机钒化合物或者复合物(络合物)的药物组合物。
本发明进一步涉及用于预防或者限制需要其的哺乳动物,优选患有急性应激的危重病人的肾缺血再灌注(I/R)的方法,其中给予所述哺乳动物包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物。更具体地,本发明进一步涉及用于预防或者限制需要其的哺乳动物,优选患有急性应激的危重病人的肾脏的肾缺血再灌注(I/R)的方法,其中给予所述哺乳动物包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物。
出人意料地发现根据本发明的药物组合物显著地增加需要其的哺乳动物,优选危重病人的肾皮质和髓质中的微血管氧化,其中这种微血管氧化通过I/R损伤在早期被降低。
还出人意料地发现根据本发明的药物组合物增加需要其的哺乳动物,优选危重病人的肾脏氧利用效率,其通过I/R损伤在早期被降低。
另外,出人意料地发现根据本发明的药物组合物显著地降低需要其的哺乳动物,优选危重病人的由早期I/R损伤引起的炎症激活。
另外,出人意料地发现根据本发明的药物组合物显著地降低需要其的哺乳动物,优选危重病人的由早期I/R损伤引起的肾损伤。
本发明进一步涉及在需要其的哺乳动物中用于预防或者治疗造影剂引起肾病,优选放射性造影剂引起肾病(其是急性肾衰竭(ARF)的形式)的方法,其中给予所述哺乳动物包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物。
根据本发明的一个实施方式,危重病人是非糖尿病患者。
根据本发明,优选的是通过以下诱发的急性应激:损害、损伤、创伤、医学处理、感染、中风、血管或者冠状动脉架桥术外科手术、休克(优选心原性休克、出血性休克或者脓毒性休克)、或者心肌梗死的处理。
优选地,在哺乳动物,优选危重病人体内维持血糖水平,在约80mg/dl至约110mg/dl之间(约4.4至约6.1mmol/l)。优选地,血糖水平维持在约85mg/dl至约100mg/dl之间。
根据一个实施方式,肠胃外给予根据本发明的药物组合物,其包括生理学上可接受的有机和/或无机钒化合物或者复合物。根据本发明的另一实施方式,静脉内给予药物组合物。
因为危重病人在重病监护室(ICU)住院,根据本发明的方法执行一至七天,优选一至六天,更优选一至五天,甚至更优选一至四天,又甚至更优选一至三天,又甚至更优选一至两天并且特别地仅一天。
根据本发明的一个实施方式,优选将胰岛素或者胰岛素类似物共同给予哺乳动物,优选危重病人。
根据本发明的另一实施方式,将抗心律不齐药物共同给予哺乳动物,优选危重病人。
根据本发明的又另一实施方式,将营养补充剂共同给予哺乳动物,优选危重病人。在此,优选的是所述营养补充剂选自下组:镁、鱼油、钾、铜、硒、维生素D、维生素E、以及它们的混合物。
根据本发明的优选实施方式,生理学上可接受的有机和/或无机钒化合物或者复合物(络合物)是双(麦芽醇)氧钒(IV)(也称为BMOV)。BMOV及其合成是本领域已知的(CAS38213-69-3)。
因此本发明还涉及包括生理学上可接受的有机和/或无机钒化合物或者复合物、药学上可接受的载体、以及第二组分的药物组合物,所述第二组分选自下组:镁、鱼油、钾、铜、硒、维生素D、以及它们的混合物。
本发明进一步涉及包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物,用于维持患有急性应激的危重病人的血糖量正常。
如上所述,优选危重病人是非糖尿病患者。
优选地,急性应激是由损害、损伤、创伤、医学处理、感染、中风、冠状动脉架桥术外科手术或者心肌梗死的处理诱发的。
根据本发明,优选以足够的量给予药物组合物使得血糖水平维持在约80mg/dl至约110mg/dl之间(约4.4至约6.1mmol/l),优选约85mg/dl至约100mg/dl之间。
优选地,肠胃外或者静脉内给予根据本发明的药物组合物。
优选地,根据本发明的药物组合物给予一至七天,优选一至六天,更优选一至五天,甚至更优选一至四天,又甚至更优选一至三天,又甚至更优选一至两天并且特别地仅一天。
根据本发明的药物组合物可以进一步包括胰岛素或者胰岛素类似物、抗心律不齐药物、营养补充剂、或者它们的组合。优选地,营养补充剂选自下组:镁、鱼油、钾、铜、硒、维生素D、维生素E、铬以及它们的混合物。
本发明进一步涉及包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物,用于预防或者限制患有急性应激的危重病人的肾缺血再灌注(I/R)。
本发明进一步涉及包括生理学上可接受的有机钒化合物或者复合物、药学上可接受的载体、以及第二组分的药物组合物,所述第二组分选自下组:镁、鱼油、钾、铜、硒、维生素D、维生素E、铬、以及它们的混合物。
本发明还涉及包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物,用于预防或者治疗需要其的哺乳动物的造影剂诱发的肾病。优选地,哺乳动物是患有急性应激的危重病人。
本发明进一步涉及包括生理学上可接受的有机和/或无机钒化合物或者复合物的药物组合物,用于预防、限制或者治疗需要其的哺乳动物的心肾失调。优选地,哺乳动物是患有急性应激的危重病人。
实例
材料和方法
动物
本研究方案通过了阿姆斯特丹大学学术医学中心动物实验管理委员会的审查和批准。动物的处理和关照遵守实验室动物研究所的关照和使用实验室动物的指南。
将具有平均体重280±30克的三十二只雄性维斯塔大鼠(Wistar rat)(HarlanNetherlands BV,Horst,The Netherlands)用于本项研究。在开始研究之前将动物隔离一周,以便允许适应它们的新环境并且在保持温度在22±1℃具有相对湿度为55±10%的灯光控制室中在常规笼子中使动物成对地居住。全部动物都接收标准实验室的大鼠食物和水用于无限制地消耗。
手术准备
最初使用克他命(Nimatek,Eurovet Animal Health BV,Bladel,荷兰;90mg/kg)、右旋美托咪啶(Dexdomitor,Pfizer Animal Health BV,Capelle aan den IJssel,荷兰;0.5mg/kg)、硫酸阿托品(CentrafarmBV,Etten-Leur,荷兰;0.05mg/kg)的混合物通过腹膜内注射来麻醉所有动物。一旦麻醉,在开始外科手术之前将胸骨柄(thoracic manubrium)和下巴之间的区域以及覆盖左侧肾脏的左侧肋部剃毛并且清洁。在外科手术准备过程和实验过程的剩余时间期间,通过气管切开术和具有0.4的吸入氧气分数(FiO2)的机械通气装置来维持麻醉。在整个实验期间维持体温在37±0.5℃。调整通气装置的设置以保持动脉pCO2在35至40mmHg之间。
为了药物以及流体管理和血液动力学监测,三个容器插有聚乙烯导管(外径=0.9mm;Braun,Melsungen,德国)。右颈动脉中的导管连接到压力传感器以监测动脉血压和心率。为了以15ml/kg/hr的速率连续灌输林格乳酸盐(Baxter,Utrecht,荷兰)将导管插入右颈静脉。为了取出血样进行血液气体分析,将导管插入股动脉。在全部实验期间,动物保持在全身麻醉下并且接收连续的静脉内稀释的克他命或者镇痛药输注。通过在左侧肋部上约~4cm的切口将左侧肾脏暴露,去被膜,以及固定在路赛特(Lucite)(即聚(甲基丙烯酸甲酯);PMMA)定制的肾杯中。肾动脉和静脉被仔细地分离以保护周围的神经和肾上腺。血管周围超声瞬时流量探针(型号0.7RB;Transonic Systems,伊萨卡岛,纽约,美国)放置在左侧肾动脉周围并且连接至流量计(T206;Transonic Systems,伊萨卡岛,纽约,美国)以允许肾血流量(RBF)的连续测量。分离、结扎左侧输尿管,并且用聚乙烯导管进行插管(外径=0.9mm;Braun,梅尔松根,德国),用于收集尿液。将一小片铝箔(10x10mm)放置在肾静脉的背面部位上以防止并列组织和下部组织促进在静脉pO2测量中干扰磷光信号。在外科手术方案(~60min)之后,将一根光纤放置在去被膜肾脏上方1mm并且将另一光纤放置在肾静脉上方1mm从而使用磷光寿命技术(20)来测量氧化。随后静脉内注入带氧体G2(Oxyphor G2)(Oxygen Enterprises,费城,宾夕法尼亚州,美国;6mg/kg)5min,接下来是30min稳定时间。
手术区域贯穿整个实验都覆盖有湿润的纱网敷布用于防止外科手术区域中暴露组织的干燥。磷光寿命测量已经更详细地在别处(20)描述。通过灌输1ml 3M氯化钾来终止实验。最终,移除肾脏、称量并且处理用于组织学评估。还在事后检查导管的正确位置。
实验方案
在外科手术准备完成之后,接着是30min的稳定时间,每只动物被随机分配到以下组中:BMOV 7mg/kg(n=6);BMOV 15mg/kg;(n=6),I/R对照(n=8),以及时间对照(n=3)。在30分钟局部缺血期之前开始15分钟BMOV灌输并且贯穿整个实验连续地进行灌输。
血液动力学和血液气体参数
从右颈总动脉连续地监控平均动脉压(MAP)。此外,使用瞬时超声流量探针(trans-time ultrasound flow probe)(型号0.7RB;Transonic Systems Inc,伊萨卡岛,纽约)连续地记录肾动脉血流量[RBF;ml/min]。在基线(BSLN)时以及在局部缺血之后90min(R90min)从颈动脉取动脉血样(0.5ml)。用相同体积的HES130/0.4(6%HES130/0.4;Fresenius Kabi Nederland B.V.,Schelle,比利时)替代血样。样品用来确定血液气体值(ABL505血液气体分析器;Radiometer,哥本哈根,丹麦),以及用于确定血红蛋白浓度、血红蛋白氧饱和度、以及钠和钾浓度(OSM3;Radiometer)。
肾微脉管以及静脉pO2
全身性注入白蛋白靶向的(并且因此限定循环)磷光染料(带氧体G2;OxygenEnterprises,Ltd.,费城,宾夕法尼亚州,美国)的氧气淬灭的磷光寿命使用双波长时域磷光计测量,并且用于检测微血管和静脉pO2(μpO2)中的变化。带氧体G2(四-(4-羧基-苯基)苯并卟啉的双层谷氨酸酯树枝状化合物)具有两个激发峰(λ激发1=440nm,λ激发2=632nm)和一个发射峰(λ发射=800nm),由于激发光的不同光学穿透深度其允许在肾皮质和外部髓质中同时进行寿命测量。为了测量肾静脉pO2(PrvO2)使用单波长频率域磷光计。测量的寿命和pO2值之间的相互关系通过斯特恩-沃尔默关系(Stern-Volmer relation)给出:1/τ=(1/τ0)+kq[O2],其中τ是测量的寿命,τ0是在0mmHg的氧浓度下的寿命并且kq是已知的淬灭常数。
肾功能
收集来自左侧输尿管的尿液样品进行尿液体积和肌酸酐浓度的分析。在每个尿液收集期间的中点处获得用于分析肌酸酐浓度的血浆样品。通过比色法确定尿液和血浆中肌酸酐的浓度。肌酐清除率(Clearcrea[ml/min])评估为肾小球滤过率的指数。
使用标准公式完成清除率的计算:
Clearcrea=(Ucrea×V)/Pcrea,
其中Ucrea是尿液中肌酸酐的浓度,V是每单位时间尿液体积,而Pcrea是血浆中肌酸酐的浓度。
此外,分析了全部尿液样品的钠(Na+)浓度。Na+(EFNa+[%])的排出分数用做肾小管功能的标志并且计算如下:
EFNa+=(UNa+×Pcrea)/(PNa+×Ucrea)×100,
其中UNa+是尿液中Na+浓度,而PNa+是血浆中Na+的浓度。Clearcrea以及EFNa+在基线时和再灌注之后进行确定。
免疫组织化学分析
将肾脏组织固定在4%福尔马林中并且包埋在石蜡中。肾脏切片(5μm)用二甲苯脱石蜡并且用逐渐减少百分比的乙醇并且最终用水进行再水化。通过在柠檬酸盐缓冲液(pH6.0)(Thermo Scientific,AP-9003-500)中微波载玻片10min来完成抗原恢复。在室温下,将载玻片放置冷却20分钟,然后用蒸馏水漂洗。切片的周围用PAP笔标记。在室温下使用3%H2O2封闭内源性过氧化物酶活性10min并且随后使用蒸馏水和PBS漂洗。将封闭试剂(LabVision,TA-125-UB)施加于每个载玻片,随后在室温下在潮湿小室内孵育5min。在4℃下使用兔多克隆iNOS抗体(iNOS Ab-1,兔PAb,RB-1605-P,NeoMarkers Fremont,CA)和IL-6(Abcam,6672)孵育肾脏切片过夜,并且在室温下用抗髓过氧化物酶(MPO)抗体(髓过氧化物酶Ab-1,RB-373-A,NeoMarkers Fremont,CA)、脂钙蛋白2抗体(NGAL)(abcam41105)、针对大鼠L-FABP的多克隆抗体(Hycult Biotect HP8010)孵育1小时。在大量UltrAb Diluent(UltrAb稀释剂)(Thermo Scientific,TA-125-UD)中稀释抗体。在PBS中洗涤切片三次,每次5min,然后在室温下使用生物素化的山羊抗兔抗体(LabVision,TP-125-BN)孵育30min。在PBS中洗涤载玻片之后,在潮湿的小室中在室温下施加链霉亲和素过氧化物酶标签试剂(LabVision,TS-125-HR)30min。通过与AEC一起孵育将带颜色产物显色。使用迈尔(Mayer)氏苏木精(LabVision,TA-125-MH)复染载玻片并且安装在视觉支架(vision mount)中(LabVision,TA-060-UG),然后在蒸馏水中洗涤。对iNOS、IL-6、L-FABP、NGAL以及MPO染色强度和分布两者进行评分。对于每个样品,通过将在每个强度下染色的细胞的百分比乘以染色的加权强度求和来得到组织学评分(HSCORE)值[HSCORE=SPi(i+1),其中i是强度评分而Pi是细胞的相应百分比](Senturk et.al.,1999)。在放大倍数X 400下在光学显微镜下在来自240个选择的肾小球中的各个肾小球中以及在240个选择的肾小管周围区域中,我们评估MPO反应。如果在肾小球中可以看见白细胞,我们评分为1,而如果看不见则评分为0(Demirci et.al.,2006;Legrand et.al;2009)。
统计分析
使用GraphPad Prism版本5.0(用于视窗系统)(GraphPad软件公司,拉乔拉市,加利福尼亚州,美国)进行数据分析。全部数据都表示为平均数±SD。使用Bonferroni事后检验通过双向方差分析(ANOVA)进行组和时间点之间的参数比较分析。具有小于0.05P值的之间的差值被认为是统计显著的。表1示出时间对照结果。这些结果示出通过I/R损伤降低了平均动脉压,BMOV不影响平均动脉压而且BMOV的作用不是剂量依赖性的。
表1
BSLN | R 90(min) | p-值 | |
平均动脉压 | 103.5±4.2 | 98.5±4.5 | >0.05 |
肾血管阻力 | 22±2 | 22±2 | >0.05 |
肾血流量 | 4.7±0.6 | 4.6±0.5 | >0.05 |
肾DO2 | 1.2±0.2 | 1.2±0.1 | >0.05 |
CμPO2 | 65±7 | 60±6 | >0.05 |
MμPO2 | 52±6 | 49±7 | >0.05 |
肾VO2 | 0.13±0.07 | 0.19±0.06 | >0.05 |
尿液量 | 0.0022±0.0007 | 0.0020±0.0007 | >0.05 |
平均动脉压
如图1所示,BMOV不影响平均动脉压(图1示出在基线(BSLN)时以及在局部缺血30min和再灌输90min(R90min)之后的平均动脉(art.)压。nsp>0.05(不显著),*p<0.05,**p<0.01,以及***p<0.001相对于BSLN)。
肾脏血液动力学以及氧气递送
数据示出肾血管阻力不受I/R损伤影响,但是显著地降低肾血流量和氧气运送。该数据还示出BMOV不影响肾血流量和氧气运送而且该BMOV的作用不是剂量依赖性的。
如图2所示,BMOV不影响肾血液动力学和氧气运送(图2示出了在基线(BSLN)时以及在局部缺血30min和再灌注90min(R90min)后肾血管阻力(vasc.res.)(上列),肾血流量(中间列),以及肾氧气运送(下列)。nsp>0.05(不显著),*p<0.05,**p<0.01,以及***p<0.001相对于BSLN)。
肾微血管氧化
该数据表明在肾皮质和髓质中微血管氧化通过I/R损伤显著地降低。该数据还示出BMOV显著地增加在肾皮质和髓质中的微血管氧化而且该BMOV作用不是剂量依赖性的。
如图3所示,BMOV显著地增加微血管氧化(图3示出在基线(BSLN)时以及在局部缺血30min和再灌注90min(R90min)后在皮质(上列)和髓质(下列)中的肾微血管氧张力(μPO2)。nsp>0.05(不显著),*p<0.05,**p<0.01,以及***p<0.001相对于BSLN)。
肾功能
该数据表示肾氧消耗和肌酐清除率不受I/R损伤影响,但是钠再吸收所需氧气量(VO2/Tna+)增加,表示降低的肾脏氧气利用效率。该数据还示出BMOV增加肾脏氧气利用效率而且BMOV的作用不是剂量依赖性的。
图4示出了BMOV增加肾脏氧气利用效率(图4示出了在基线(BSLN)时以及在局部缺血30min和再灌注90min(R90min)后肾脏氧气消耗(上列),钠再吸收所需的氧气量(VO2/Tna+)(中间列),以及肌酐清除率(creat.clear.)(下列)。nsp>0.05(不显著),*p<0.05,**p<0.01,以及***p<0.001相对于BSLN)。
图5示出了在基线(BSLN)时以及在局部缺血30min和再灌注90min(R90min)之后的尿液输出量。nsp>0.05(不显著)。
炎症激活的生物标志物
该数据还示出I/R损伤导致炎症激活。该数据进一步表明BMOV显著地降低炎症激活而且BMOV的作用是剂量依赖性的,即,与使用低剂量治疗的组中的水平相比较,在使用高剂量BMOV治疗的组中iNOS表达显著更低。
如图6所示,BMOV显著地降低炎症激活(图6示出了在局部缺血30min和再灌注90min(R90min)之后的IL-6和iNOS表达(上列)以及MPO-染色的白细胞外观)(下列)。nsp>0.05(不显著),*p<0.05,**p<0.01,以及***p<0.001相对于I/R对照)。
肾损伤的生物标志物
该数据示出I/R导致肾损伤。该数据还示出BMOV显著地降低肾损伤而且BMOV的作用是剂量依赖性的,即,与用低剂量治疗的组中的水平相比较,在用高剂量BMOV治疗的组中NGAL水平显著更低。
如图7所示,BMOV显著地降低肾损伤(图7示出了在局部缺血30min和再灌注90min(R90min)之后的IL-6和iNOS表达(上行)以及MPO-染色的白细胞外观)(下行)。nsp>0.05(不显著),*p<0.05,**p<0.01,以及***p<0.001相对于I/R对照,以及+p<0.05相对于BMOV 7mg/kg)。
结论
肾I/R导致:
1)降低平均动脉压;
2)降低肾血流量和氧气递送;
3)降低在肾皮质和髓质中的微血管氧化;
4)降低肾脏氧利用效率;
5)炎症激活;以及
6)肾损伤。
BMOV不影响:
1)平均动脉压;以及
2)肾脏血液动力学以及氧气递送。
BMOV引起
1)增加微血管氧化;
2)增加肾脏氧利用效率;
3)减少炎症激活;以及
4)减少肾损伤。
Claims (13)
1.一种药物组合物,包括生理学上可接受的有机和/或无机钒化合物或者复合物,用于维持患有急性应激的危重病人体内的血糖量正常。
2.根据权利要求1所述的药物组合物,其中所述危重病人是非糖尿病患者。
3.根据权利要求1或者2所述的药物组合物,其中,所述急性应激由以下诱发:损害、损伤、创伤、医学处理、感染、中风、冠状动脉架桥术外科手术或者心肌梗死的处理。
4.根据权利要求1-3中任一项所述的药物组合物,其中,血糖水平维持在80mg/dl至110mg/dl之间(4.4至6.1mmol/l)。
5.根据权利要求1-4中任一项所述的药物组合物,其中,所述药物组合物肠胃外或者静脉内给予。
6.根据权利要求1-5中任一项所述的药物组合物,其中,所述药物组合物给予一至七天。
7.根据权利要求6所述的药物组合物,其中,所述危重病人在重病监护室(ICU)中住院治疗。
8.根据权利要求1-7中任一项所述的药物组合物,进一步包括胰岛素或者胰岛素类似物。
9.根据权利要求1-8中任一项所述的药物组合物,进一步包括抗心律不齐药物。
10.根据权利要求1-9中任一项所述的药物组合物,进一步包括营养补充剂。
11.根据权利要求10所述的药物组合物,其中,所述营养补充剂选自由以下组成的组中:镁、鱼油、钾、铜、硒、维生素D、维生素E、铬以及它们的混合物。
12.根据权利要求1-11中任一项所述的药物组合物,其中,所述急性应激是急性肾衰竭(ARF)、急性肾功能不全(ACI)或者两者。
13.根据权利要求1-12中任一项所述的药物组合物,其中,所述生理学上可接受的有机和/或无机钒化合物或者复合物是双(麦芽醇)氧钒(IV)(BMOV)。
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