CN1258354A - 检测流体介质中一氧化氮的方法 - Google Patents
检测流体介质中一氧化氮的方法 Download PDFInfo
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- CN1258354A CN1258354A CN97199504A CN97199504A CN1258354A CN 1258354 A CN1258354 A CN 1258354A CN 97199504 A CN97199504 A CN 97199504A CN 97199504 A CN97199504 A CN 97199504A CN 1258354 A CN1258354 A CN 1258354A
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Abstract
本发明已研究出测量各种流体介质(例如哺乳类动物体液)中NO水平的非侵害性方法。本发明包括一种装有一氧化氮反应物质的半渗透膜袋的使用,以捕获扩散到袋内的NO。选择的半渗透膜渗透一氧化氮但不渗透硝酸盐/亚硝酸盐,使得用于本发明中的半渗透膜袋,即便存在可能的竞争物质(例如硝酸盐和亚硝酸盐)时也能够有选择性地收集NO。本发明的测量流体介质中NO的简单、方便和非侵入性方法有很多用途,例如诊断和检测与许多炎症和感染疾病有关的NO产生过剩或产生不足。
Description
发明领域
本发明涉及检测流体介质(例如哺乳动物的体液)中一氧化氮的方法,以及用于该方法的制品和试剂。一方面,本发明涉及检测体液中一氧化氮的非侵入性方法。另一方面,本发明涉及用于收集和检测各种流体介质中一氧化氮的制品。另一方面,本发明涉及监控病人一氧化氮产生不足或产生过剩的方法。
发明背景
一氧化氮(NO),一种气态自由基,曾被认为是汽车尾气和城市烟雾及香烟烟雾中的主要环境污染物。1987年,该关于一氧化氮的观点有所改变,人们发现人体产生NO(例如参见,Ignarro等,Proc.Natl.Acad.Sci.,美国,84:9265-69(1987),和Palmer等,自然(Nature),327:524-26(1987))。作为第一个被认证的内皮衍生的松弛因子,NO现被认为是一种新的调节许多哺乳动物细胞和组织的细胞信号分子。
NO由L-精氨酸的酶分裂产生,由一氧化氮合酶催化(NOS;参见,例如Rodeberg等,Am.J.Surg.,170:292-303(1995),和Bredt和Snyder,Ann.Rev.Biochem.63:175-95(1994))。三种不同异构形式的NOS已被分离、克隆、序列测定和表达,即内皮细胞衍生的一氧化氮合酶(eNOS)、神经元细胞衍生的一氧化氮合酶(nNOS)和可诱导的一氧化氮合酶(iNOS)。eNOS和nNOS的异构形式在构成上已被表达,并且两种酶的活化均需要在细胞内增加钙。在生理条件下,由eNOS异构体持续地产生NO的低输出,eNOS存在于包括内皮细胞和神经元细胞在内的许多细胞中。该低水平的一氧化氮与许多调节过程有关,例如,血管内环境稳定,神经元传达和免疫系统功能。
另一方面,在病理生理条件下,由可诱导的、不依存钙的NOS异构体(iNOS)产生NO的高输出,这种NOS异构体被细胞因子或内毒素激活,在包括内皮细胞、平滑肌细胞和巨噬细胞在内的许多细胞类型中表达。这些高水平一氧化氮的产生(因细胞因子激活的巨噬细胞而引起)对这些细胞杀死细菌或肿瘤细胞的能力作出部分贡献,因而对宿主的防御起着重要作用。然而,虽然过量的NO有助于破坏侵入微生物,但由于包括内皮细胞、平滑肌细胞、巨噬细胞和肝细胞在内的被细胞因子激活的各种类型的细胞导致的全身性NO产生过剩可以触发连一串事件,导致各种炎症和感染疾病和症状(例如组织损伤、休克、多发性器官衰竭和死亡)。事实上,最近已发现异常高的NO水平与许多炎症和感染疾病或症状有关,例如,败血症性休克、细胞因子的过度表达、糖尿病、同种移植物排斥、肠炎、类风湿性关节炎、中风、多发性硬化等。
类似地,一氧化氮产生不足也能引起各种疾病状态,例如,新生儿持续性肺动脉高血压、先兆子痫、成人呼吸窘迫综合症、血管成型术后再狭窄、阳痿等。
一氧化氮是一种强力的血管舒张药(参见,例如Palmer Arch.Surg.128:396-401(1993)和Radomski&Moncada Thromb.Haemos.,70:36-41(1993))。例如,由内皮产生的NO在血液中各向同性地扩散到各个方向的临近组织中。当NO扩散到血管平滑肌中,它与催化cGMP产生的鸟苷酸环化酶结合,诱导血管舒张(参见,例如Ignarro,L.J.,Ann.Rev.Toxicol,30:535-560(1990);Moncada,S.,Acta PhysiolScand.,145:201-227(1992)和Lowenstein和Snyder;细胞(Cell),70:705-707(1992))。
一氧化氮产生过剩引起血压的极度降低,导致不充分组织灌注和器官衰竭,即与许多疾病和/或症状(例如,败血症性休克、中风、细胞因子的过度表达、同种移植物排斥等)有关的综合症。一氧化氮的产生过剩是由许多刺激物触发的,例如炎症细胞因子的产生过剩(例如白细胞介素-1、干扰素、内毒素等的产生过量)。另外,已发现NO产生过量是细胞因子疗法的主要副作用之一(参见,例如Miles等,Eur.J.Clin.Invest.,24:287-290(1994)和Hibbs等,J.Clin.Invest.,89:867-877(1992))。因此,异常高的一氧化氮水平与许多炎症和感染疾病有关。
体内NO的半寿命只有3-5秒,如此短的寿命,使NO很难被检测和量化。为测量水溶液中NO水平,人们已研究了几种生物物理技术。这些技术包括化学发光测定(参见,例如Downes等,分析者(Analyst).,101:742-748(1976))、氧合血红蛋白测定(参见,例如Kelm和Schrader,Cris.Res.,66:1561-1575(1990))、GC-MS检测(参见,例如Palmer等,自然(Nature)(伦敦),327:524-526(1987)和在液氮温度下用电子顺磁共振(EPR)光谱学检测亚硝酰基-血红蛋白形成(参见,例如Lancaster等,Proc.Natl.Acad.Sci.美国,87:1223-1227(1990))。
由测量NO的终产物NO2 -/NO3 -也能间接地检测NO的产生(参见,例如Palmer等,前引)。然而这些技的现有水平都不能用于检测体内NO的产生。最近,用于检测健康人类志愿者血管内NO水平的一种侵入性电化学微观传感器已有报道(参见,例如Vallance等,Lancet,346:135-154(1995))。
二硫代氨基甲酸酯是一类低分子量含硫化合物,是有效的螯合剂(参见,例如Shinobu等,Acta Pharmacol et Toxical.,54:189-194(1984))。例如二乙基二硫代氨甲酸盐(DETC)临床用于治疗镍中毒。最近,人们发现N-甲基-D-葡糖胺二硫代氨基甲酸盐(MGD)与二价铁离子螯合为2比1的[(MGD)2-Fe]配合物,接着该配合物本身又与NO强烈地相互作用,在水溶液中形成一种稳定的水溶性配合物,即[(MGD)2-Fe-NO](参见,例如Lai和Komarov,FEBS Lett.,345:120-124(1994))。后一种配合物产生giso=2.04的陡三线光谱,亚硝酰基-Fe-二硫代氨基甲酸盐配合物的特征在室温下由EPR光谱学能容易地检测出来。这种快速检测体液中NO的方法最近已被Lai在美国专利第5,358,703号中揭示。
然而,在本领域中仍需要检测流体介质(例如哺乳动物体液)中一氧化氮的更快、更好的非侵入性方法。
发明的简要说明
本发明已研究出测量各种流体介质(例如哺乳类动物体液)中NO水平的非侵入性方法。本发明包括一种含有一氧化氮反应物质(例如[(MGD)2-Fe])的半渗透性膜袋的使用,以及测量袋中[(MGD)2-Fe-NO]水平或其它终产物的简单的物理或化学检测方法。
因为NO是中性气体分子,它能自由地扩散穿过大部分生理相容聚合物膜,例如聚二烷基硅氧烷(硅氧橡胶)、聚异戊二烯和聚丁二烯(参见,例如Robb,Ann.N.Y. Acad.Sciences,146,119-137,1968)。在所有的聚合物膜中,硅氧烷膜对一氧化氮和其它中性气体分子(例如氧和二氧化碳)有很高的渗透性,但它不渗透水溶液中带电分子,如硝酸盐(NO3 -)或者亚硝酸盐(NO2 -)(参见,例如Tamir等,Chem.Res.Toxicol.,6,895-899,1993,)。后两种化合物,即硝酸盐和亚硝酸盐在体液(例如唾液、血液和尿液)中到处存在,并常常干扰测量真实的NO水平。硅氧烷膜对一氧化氮的高渗透性和对硝酸盐/亚硝酸盐的非渗透性的独特性能使之成为本发明实践中设计使用的半渗透膜的优良选择。
尽管早先已有报道NO在人的唾液中是可测的,但NO水平是用Griess反应由测量唾液中硝酸盐/亚硝酸盐水平确定的(参见,例如Bodis和Haregewoin,Biochem.Biophys.Res.Commun.,194,347-350,1993)。众所周知,人类唾液中含有高水平的硝酸盐/亚硝酸盐,并根据不同人的健康水平、饮食和其它因素变化(参见,例如Tannenbaum等,Fd.Cosmet.Toxicol.,14,549-552,1976),因此,唾液中硝酸盐/亚硝酸盐水平的测量值不能推断出人类唾液中真实的NO水平的测量值。相反,根据本发明,使用含有对NO自由渗透(但不渗透硝酸盐/亚硝酸盐)的半渗透膜的容器,阻止例如硝酸盐/亚硝酸盐类的杂质进入本发明容器中,因此,能测量唾液中以及其它体液和其它流体介质中真实的NO水平。
例如用于临床诊断时,可以将含有适量NO捕获剂的本发明容器置于病人舌下,或者通过外科手术皮下置入这种容器。容器内含有的NO捕获剂暴露于含有NO的介质中适当长的时间,捕获介质中含有的NO,然后体外测量。本发明测量流体介质中NO水平的简单、方便和非侵害性方法有各种用途,例如,用于诊断和监测与许多炎症和感染疾病有关的NO产生过剩(和产生不足)。
附图的简要说明
图1表示22℃时[(MGD)2-Fe-NO]配合物EPR光谱。一个包括在同一边有两个由硅氧烷制成的管状开口(长4cm,外径3mm.,内径1mm)的硅氧烷膜袋(尺寸2cm×2cm×0.025cm),其中装有0.5ml的含有20mM MGD和4mM硫酸亚铁的水溶液。
图1A表示将该袋置于志愿者舌下1小时,然后分析袋中的内含物所得出的NO摄取量的结果。
图1B表示将袋置于实验室工作台上1小时,然而分析袋中的内含物所得出的NO摄取量的结果。
图1C表示将袋浸入一装有50ml 1mM亚硝酸盐的100ml烧杯中1小时,然而分析袋中的内含物所得出的NO摄取量的结果。
图1A、1B和1C分别所指的光谱是由EPR光谱仪记录的,光谱仪装有X带微波桥和一个TE102空腔,并在9.5GHz下操作。1小时后,将试样移入石英EPR平面测定池(flat cell)中,在室温测量EPR。设备设定包括200G扫描范围、0.5秒时间恒定值、2.5G调制振幅,100KHz调制频率和100Mw微波功率。
图2表示亚硝酸盐水平和荧光强度之间的线性关系。将0.62N HCl中0.2mg/ml浓度的2,3-二氨基萘(DAN)溶液的等分试样加入到一系列浓度为0至1μM的亚硝酸盐滴定水溶液中。反应在22℃持续30分钟,然后通过加入一等分的1N NaOH溶液终止反应。用荧光检测方法(Fluoro-Tech 2001A model)测量试样的荧光强度。设备设定包括100灵敏度,高阻尼和450V的电压。
发明的详细说明
本发明提供了检测流体介质中一氧化氮的方法。发明方法包括:
将流体介质与包括实际上在容器中含有一氧化氮捕获剂的制品接触,其中容器的内含物能与和该容器接触的流体介质通过半渗透膜沟通,并且其中所述接触是在适合允许该流体介质中一氧化氮扩散穿过半渗透膜的条件下进行的,并且
测定由一氧化氮捕获剂捕获的一氧化氮含量。
根据本发明的另一实施方案,本发明提供了检测诱导一氧化氮产生过剩的疾病状态或症状的方法。这些方法包括:
将来自怀疑患有这种疾病症状的患者的流体介质与本文所述的发明制品接触,其中所述接触是在适合允许该流体介质中一氧化氮扩散穿过半渗透膜的条件下进行的,并且
测定由一氧化氮捕获剂捕获的一氧化氮含量。
与NO产生过剩有关的疾病状态以及本发明计划监测和/或治疗的疾病包括:脓毒性休克、局部缺血、服用细胞因子、细胞因子表达过度、溃疡、炎症性肠疾病(例如溃疡性结肠炎或节段性回肠炎)、糖尿病、关节炎、哮喘、早老性痴呆、帕金森病、多发性硬化、硬变、同种移植物排异、脑脊髓炎、脑膜炎、胰腺炎、腹膜炎、脉容器炎、淋巴细胞性脉络丛脑膜炎、肾小球性肾炎、眼色素层炎、回肠炎、肝炎、肾炎、出血性休克、过敏性休克、发烧、感染(包括细菌、病毒、真菌和寄生虫感染)、血液透析、慢性疲劳综合症、中风、癌症(例如乳腺癌、黑瘤、癌等)、心肺分流术、局部缺血/再灌注损伤、炎症、中毒性休克综合征、胃炎、成人呼吸窘迫综合症、恶病质、心肌炎、自身免疫疾病、湿疹、牛皮癣、心力衰竭、心脏病、动脉粥样硬化、皮炎、荨麻疹、大脑局部缺血、系统性红斑狼疮、艾滋病、艾滋病痴呆、慢性神经变性疾病、慢性疼痛、阴茎异常勃起、囊纤维变性、肌萎缩性侧索硬化、神经分裂症、神经变性疾病、肠胃动力疾病、肥胖、饮食过量、实体瘤(例如成神经细胞瘤)、疟疾、血癌、骨髓纤维变性、肺损伤、移植物-抗-宿主疾病、脑损伤、CNS创伤、肝炎、肾衰竭、肝病(例如慢性丙肝)、药物引起的肺损伤(例如百草枯)、重症肌无力(MG)、眼疾等。
根据本发明的另一实施方案,本发明提供了检测与一氧化氮产生不足有关的疾病症状的方法。这些方法包括:
将来自怀疑患有这种疾病症状的患者的流体介质与本文所述的发明制品接触,其中所述接触是在适合允许该流体介质中一氧化氮扩散穿过半渗透膜的条件下进行的,并且
测定由一氧化氮捕获剂捕获的一氧化氮含量。
与一氧化氮产生不足有关的疾病症状包括新生儿持续性肺动脉高血压、先兆子痫、成人呼吸窘迫综合征、血管成形术后再狭窄、阳痿、动脉粥样硬化及类似病症。
根据本发明的另一个实施方案,本发明提供了一种包括实际上在容器中含有一氧化氮捕获剂的制品,其中该容器的至少一部分包括半渗透膜,并且其中容器中的内含物能够与和该容器接触的流体介质通过半渗透膜沟通。
正如本领域技术人员容易理解的,本发明的制品可以制成不同形状和尺寸。例如,用于本发明制品结构的容器可以包括实际上全部由用于半渗透膜的材料制造的柔性袋。
另一方面,用于本发明制品结构的容器包括一种收容一氧化氮捕获剂的实际上是刚性或半刚性的无孔收容器,其中该收容器至少有一个开口,并且一氧化氮捕获剂由半渗透膜保存在收容器中。
另一方面,用于本发明制品结构的容器包括一种装一氧化氮捕获剂的袋,其中至少有一部分一氧化氮捕获剂通过半渗透膜与和容器接触的流体介质沟通。
正如本领域技术人员容易理解的,本发明的制品可以做成任何形状或尺寸,例如圆形、椭圆形、正方形、长方形、容器状、球形等等。对于一定的制品而言,其具体尺寸的选择由这些参数确定,例如与被分析的流体试样的接触(例如当要分析唾液中NO时,适合置于患者口中),所需一氧化氮捕获剂的容积(可以从约1μl变化到约1ml)等。本发明制品的厚度可以变化很大,一般由这些参数确定,例如为方便试样收集所需的容器柔软性、所需渗透性的程度、试样收集可用的时间等等。典型的制品厚度范围为约0.01cm至约0.2cm。
正如本领域技术人员容易理解的,很多材料可以用于制备用于本发明制品的半渗透膜。能渗透中性气体分子,但不渗透带电分子的任何材料均适合于本发明的应用。满足这些标准的典型材料包括聚双有机硅氧烷、聚烯烃、聚链二烯、聚乙烯基苯、卤代聚烯烃、卤代聚链二烯、聚碳酸酯、聚(乙烯对苯二酸酯)、聚丙烯酸酯、聚氨基甲酸酯等,及它们的任何两种或多种的混合物。
计划用于本发明的合适的聚双有机硅氧烷的实例包括聚二烷基硅氧烷(例如聚二甲基硅氧烷、聚二乙基硅氧烷等)、聚二芳基硅氧烷(例如,聚二苯基硅氧烷、聚二甲苯基硅氧硅等)、聚烷基芳基硅氧烷(例如聚甲基苯基-硅氧烷、聚甲基甲苯基硅氧烷等)、聚二链烯基硅氧烷(例如聚二乙烯基硅氧烷)、聚链烯基烷基硅氧烷(例如,聚乙烯基甲基硅氧烷)、聚链烯基芳基硅氧烷(例如聚乙烯基苯基硅氧烷)等。
计划用于本发明的合适的聚烯烃的实例包括聚丙烯、聚异丁烯、聚(丙烯-CO-乙烯)、聚(异丁烯-CO-异戊二烯)、聚(异丁烯-CO-顺式丁烯二酸)等。
计划用于本发明的合适的聚链二烯的实例包括聚丁二烯、聚(二甲基丁二烯)、聚异戊二烯等。
计划用于本发明的合适的聚乙烯苯的实例包括聚苯乙烯、聚(α-甲基苯乙烯)、聚(丁二烯-苯乙烯)、聚(烯丙醇-苯乙烯)、聚(二乙烯基苯-苯乙烯)、聚(马来酸-苯乙烯)等。
计划用于本发明的合适的卤代聚烯烃或卤代聚链二烯的实例包括聚(氯乙烯)、聚氯丁二烯、聚三氟氯乙烯、聚四氟氯乙烯等。
计划用于本发明的合适的聚丙烯酸酯的实例包括聚丙烯酸、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸甲酯-CO-乙基丙烯酸酯)、聚(甲基丙烯酸甲酯-CO-甲基丙烯酸)等。
在稳定状态条件下溶液中NO向半渗透膜袋中的迁移可以用如下方程式解释(Tamir等,前引)。
NO迁移速率(mol/s)=(πdL/δ)(αDNO)(ΔPNO)f其中:
πdL/δ表示被墙厚度分开的袋表面积,
αDNO表示NO的渗透性(即膜中NO的溶解性(α)和扩散性(DNO)
之乘积),
ΔPNO表示体液和袋之间NO分压之差,和
系数f的值在0-1之间,取决于影响NO迁移穿过膜的边界层的
厚度。假设袋的尺寸为2cm×2cm×0.025cm,NO的渗透性为5×10-12molcm-1s-1cm Hg-1,该渗透性与分子氧的相近,并且f为0.3-1,迁移过膜的NO的量只受液体和袋之间NO的分压差控制。
袋内NO的分压可通过将NO转变成非扩散形式(或转变成加成化合物(例如[(MGD)2-Fe-NO]、或转变成它的终产物(硝酸盐或亚硝酸盐))而显著降低。连续地去除袋内游离NO(因此降低NO分压),将有助于NO迁移至袋中,而不迁移出袋。以二硫代氨基甲酸盐配合物(例如[(MGD)2-Fe-NO]形式捕获的NO能容易地用电子顺磁共振(EPR)分光法测出(参见,例如Lai和Komorov前引),或者转变成硝酸盐/亚硝酸盐的NO能用简单Griess反应方便地测出(Griess,Ber.Dtsch.Chem.Ges.,12,426-428,1879)。
使用本发明方法可以测试不同的流体介质。例如可以测试包括体液、生长或保存介质、工业流体、环境气体等流体介质。
用本发明方法可以测试的体液实例包括唾液、血液、泪液、尿液、滑液、腹膜液等。
用本发明方法可以测试的生长或保存介质的实例包括器官保存介质、组织培养介质、细胞培养介质、再灌注介质等。
用本发明方法可以测试的工业废弃物的实例包括含水和非含水介质,例如城市排弃物、石油提炼厂排弃物、有机合成介质等。
用本发明方法可以测试的环境气体实例包括空气、汽车尾气、工业气体等。
很多一氧化氮捕获剂都适合于本发明。实例包括螯合剂、羧基-2-苯基-4,4,5,5-四甲基咪唑啉-烃氧基-1-烃氧基-3-氧化物、氮羰基、氧、硫羟化合物、生理相容含水介质、非极性氧化溶剂、鸟苷酸环化酶/GTP系统、超氧化物阴离子自由基、过亚硝酸盐、黄嘌呤(次黄嘌呤)/黄嘌呤氧化酶系统、过氧化物、超氧化物歧化酶、抗自由基加成物的抗体、Griess试剂等。
计划用于本发明典型的螯合剂包括含金属离子的二硫代氨基甲酸盐配合物、异羟肟酸载铁体铁草胺B及它的衍生物、二亚乙基三胺五乙酸的含铁离子配合物、血红蛋白、钴胺素(维生素B12)及其衍生物、卟啉、血红素、肌红蛋白、内消旋-2,3-二巯基琥珀酸等。计划用于上述含金属离子配合物的金属离子包括铁离子、铜离子、钴离子、锌离子、镁离子等。
计划用于本发明典型的二硫代氨基甲酸酯包括具有如下结构式的化合物:
(R)2N-C(S)-SH其中各R彼此独立地选自C1-C18烷基、取代的烷基、环烷基、取代的环烷基、杂环、取代的杂环、链烯基、取代的链烯基、链炔基、取代的链炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、烷芳基、取代的烷芳基、芳烷基、取代的芳烷基、芳基链烯基、取代的芳基链烯基、芳基链炔基、取代的芳基链炔基、芳酰基、取代的芳酰基、酰基、或取代的酰基,或者两个R基团可以合在一起形成一个5、6或7员的含有N和这两个R基团的环。
文中所用的“取代的烷基”包括还带有一个或多个取代基的烷基,所述取代基选自羟基、烷氧基(低级烷基的烷氧基)、巯基(低级烷基的巯基)、环烷基、取代的环烷基、杂环、取代的杂环、芳基、取代的芳基、杂芳基、取代的杂芳基、芳氧基、取代的芳氧基、卤素、三氟甲基、氰基、硝基、氮羰基、氨基、酰氨基、-C(O)H、酰基、氧酰基、羧基、氨基甲酸酯、磺酰基、磺酰胺、砜基等。
文中所用的“环烷基”指含有约3-8个碳原子的环状基团,“取代的环烷基”指还带有一个或多个上述取代基的环烷基。
文中所用的“杂环”指含有一个或多个杂原子(例如N、O、S等)作为环结构一部分并且含有3-14个碳原子的环状(即含有环)的基团,“取代的杂环”指还带有一个或多个上述取代基的杂环。
文中所用的“链烯基”指带有至少一个碳-碳双键的并且含有约2-12个碳原子的直链或支链烃基,“取代的链烯基”指还带有一个或多个上述取代基的链烯基。
文中所用的“链炔基”指带有至少一个碳-碳叁键的并且含有约2-12个碳原子的直链或支链烃基,“取代的链炔基”指还带有一个或多个上述取代基的链炔基。
文中所用的“芳基”指含有6-14个碳原子的芳基,“取代的芳基”指还带有一个或多个上述取代基的芳基。
文中所用的“杂芳基”指含有一个或多个杂原子(例如N、O、S等)作为环结构一部分的、含有3-14个碳原子的芳基,“取代的杂芳基”指还带有一个或多个上述取代基的杂芳基。
文中所用的“烷芳基”指烷基取代的芳基,“取代的烷芳基”指还带有一个或多个上述取代基的烷芳基。
文中所用的“芳烷基”指芳基取代的烷基,“取代的芳烷基”指还带有一个或多个上述取代基的芳烷基。
文中所用的“芳基链烯基”指芳基取代的链烯基,“取代的芳基链烯基”指还带有一个或多个上述取代基的芳基链烯基。
文中所用的“芳基链炔基”指芳基取代的链炔基,“取代的芳基链炔基”指还带有一个或多个上述取代基的芳基链炔基。
文中所用的“芳酰基”指芳基羰基如苯甲酰基,“取代的芳酰基”指还带有一个或多个上述取代基的芳酰基。
文中所用的“酰基”指烷基羰基。
文中所用的“卤素”指氟、氯、溴或碘原子。
计划用于本发明的优选的二硫代氨基甲酸酯是具有结构式I的化合物,其中:
R基团之一选自C1-C12烷基、取代的烷基、链烯基、取代的链烯
基、链炔基、取代的链炔基,其中的取代基选自羧基、-C(O)H、
氧酰基、苯酚、苯氧基、吡啶基、吡咯烷基、氨基、酰氨基、
羟基、硝基或砜基,而
另一个R基团选自C1-C4烷基或取代的烷基。
计划用于本发明特别优选的二硫代氨基甲酸酯是具有结构式I的化合物,其中:
R基团之一选自C2-C8烷基或取代的烷基,其中的取代基选自羧
基、乙酰基、吡啶基、吡咯烷基、氨基、酰氨基、羟基或硝
基,而
另一个R基团选自甲基、乙基、丙基或丁基。
计划用于本发明的极为优选的二硫代氨基甲酸酯是具有结构式I的化合物,其中:
R基团之一选自C2-C8烷基或取代的烷基,其中的取代基选自羧
基、乙酰基、酰氨基或羟基,而
另一个R基团选自甲基、乙基、丙基或丁基。
计划用于本发明典型的巯基化合物包括含氨基酸的硫醇(例如半胱氨酸、N-乙酰基半胱氨酸等)、含肽的硫醇、含蛋白质的硫醇(例如清蛋白、胰岛素、血红蛋白、溶菌酶、免疫球蛋白、α-2-巨球蛋白、纤维结合素、玻璃体结合蛋白、纤维蛋白原等)、谷胱苷肽、含碳水化合物的硫醇、含核苷酸的硫醇。
作为一氧化氮捕获剂计划用于本发明合适的生理相容含水介质包括盐水、无菌水、磷酸盐缓冲的盐水,培养介质、平衡盐溶液等。
作为一氧化氮捕获剂计划用于本发明合适的非极性氧化溶剂包括氟化环脂肪族化合物(例如全氟金刚烷、全氟萘烷、全氟己烷等)、氟化芳香族化合物(例如全氟苯、全氟甲苯等)、氟化羧酸(例如全氟十二烷酸)等。
本发明中用作一氧化氮捕获剂的其它试剂包括超氧化物阴离子基、过亚硝酸盐、黄嘌呤(次黄嘌呤)/黄嘌呤氧化酶系统、过氧化物、超氧化物歧化酶、抗自由基加成物的抗体、Griess试剂等。
计划用于本发明的抗自由基加成物的抗体包括抗单亚硝酰基-金属配合物抗体、S-亚硝基蛋白质(例如S-亚硝基清蛋白)、S-亚硝基谷胱苷肽、S-亚硝基-L-半胱氨酸、含硝基酪氨酸蛋白质和含硝基酪氨酸肽及类似物。
发明制品能与流体介质接触,以便以任何方式进行测试。例如可以把制品置于受验者舌下,足以使一氧化氮扩散通过半渗透膜,并由一氧化氮捕获剂收集的时间。因此该实例中使用的制品的尺寸和形状应适合放入受验者舌下。
另外,本发明制品可用外科手术置入受验者体内,以便连续或间断地测试不同体液中的一氧化氮。本发明制品可以方便地置入口患者皮下。
另一方面,本发明制品置入细胞培养皿中的培养介质中,以便允许人们监测所述介质中一氧化氮的产生。
由本发明制品捕获的一氧化氮量能容易地用不同的方法确定,例如电子顺磁共振光谱法、核磁共振法、放射性同位素跟踪、UV-可见光分光光度法、免疫组织化学法、荧光法、免疫学法、气相色谱法、液相色谱法、薄层色谱法、质谱法、液体闪烁计数、红外光谱法等。
现在参照下列非限定性实施例对本发明作更详细的说明。
实施例1
用EPR检测人唾液中的NO产生
将一个充有[(MGD)2-Fe]溶液(40/8mM)的硅氧烷膜袋放入一志愿者舌下。1小时后,用蒸馏水将该袋完全冲洗,并将袋中溶液移入EPR石英平面测定池中。在室温进行X带EPR测量。如图1A所示,得到的EPR光谱包括[(MGD)2-Fe-NO]配合物的两个叠加部分,一个三线部分(实心圆aN=12.5G,giso=2.04)的特征,和强宽信号(空心圆)。强宽信号是[(MGD)2-Cu]配合物EPR光谱的一部分,提示溶液中铜离子的存在。计算出试样中检测的[(MGD)2-Fe-NO]配合物浓度大约为5μM。
相反,当含有[(MGD)2-Fe]配合物的硅氧烷膜袋放在实验室工作台上1小时,没有测出[(MGD)2-Fe-NO]配合物的EPR信号(见图1B)。因此,推断出人唾液中含有的NO(如图1A所示)不是由于大气中存在NO而造成的。另外,当含有[(MGD)2-Fe]配合物的硅氧烷膜袋浸入含1mM亚硝酸盐溶液1小时时,也没有发现[(MGD)2-Fe-NO]配合物的EPR信号,结果表明所用硅氧烷膜袋不渗透亚硝酸盐。结合考查,图1的结果清楚表明由袋内[(MGD)2-Fe]配合物捕获的NO是该受验者唾液中存在的、扩散穿过硅氧烷膜并由[(MGD)2-Fe]配合物捕获的真实的NO。这意味着第一次确切地证明了人唾液中存在NO。
实施例2
荧光测试人唾液中NO的产生
已知2,3-二氨基萘(DAN)与亚硝酸盐反应生成2,3-萘噻唑,即能用荧光光谱法容易地检测和定量的荧光团。图2表示亚硝酸盐水平与荧光强度之间的线性关系,表明该荧光法的灵敏度足以测出亚微摩尔范围内的亚硝酸盐水平。
根据下面的方程式(1),可知水溶液中NO与分子氧反应产生亚硝酸盐。因此,亚硝酸盐水平的测量值应推算出水溶液中NO的化学计算定量。
有趣的是,由EPR方法测出的人唾液中NO水平高出由荧光法测出的约十倍。该差别可能归因于两个不同系统中捕获NO的性质。在[(MGD)2-Fe]捕获方法中,NO扩散至袋中迅速与[(MGD)2-Fe]反应生成非扩散的[(MGD)2-Fe-NO]配合物,由于袋中分压的降低,这种方法更便于NO的迁移。另一方面,在PBS捕获方法中,NO扩散至袋中与溶解氧以106M-2S-1的速度反应,该反应速度相对于NO是第二级,而相对于氧是第一级的。
尽管已参照特定优选实施例详细地说明了本发明,但应理解,改进和变化在所述说明和权利要求的精神和范围内。
Claims (37)
1.一种检测流体介质中一氧化氮的方法,所述方法包括
将流体介质与包括实际上在容器中含有一氧化氮捕获剂的制品接触,其中所述容器的内含物能与和所述容器接触的流体介质通过半渗透膜沟通,并且其中所述接触是在适合允许所述流体介质中一氧化氮扩散穿过所述半渗透膜的条件下进行的,并且
测定由所述一氧化氮捕获剂捕获的一氧化氮含量。
2.根据权利要求1的方法,其中所述流体介质选自体液、生长和保存介质、工业流体或环境气体。
3.根据权利要求2的方法,其中所述流体介质是选自唾液、血液、泪液、尿液、滑液或腹膜液的体液。
4.根据权利要求2的方法,其中所述流体介质是选自器官保存介质、组织培养介质、细胞培养介质或再灌注介质的生长和保存介质。
5.根据权利要求2的方法,其中所述流体介质是含水或不含水工业废弃物。
6.根据权利要求2的方法,其中所述流体介质是选自大气、汽车尾气或工业气体的环境气体。
7.根据权利要求1的方法,其中所述一氧化氮捕获剂选自螯合剂、羧基-2-苯基-4,4,5,5-四甲基咪唑啉-烃氧基-1-烃氧基-3-氧化物、氮羰基、氧、硫羟化合物、生理相容含水介质、非极性氧化溶剂、鸟苷酸环化酶/GTP系统、超氧化物阴离子自由基、过亚硝酸盐、黄嘌呤(次黄嘌呤)/黄嘌呤氧化酶系统、过氧化物、超氧化物歧化酶、抗自由基加成物的抗体或Griess试剂。
8.根据权利要求7的方法,其中所述螯合剂选自含金属离子的二硫代氨基甲酸盐配合物、异羟肟酸载铁体铁草胺B及它的衍生物、二亚乙基三胺五乙酸的含铁离子配合物、血红蛋白、钴胺素(维生素B12)及其衍生物、卟啉、血红素、肌红蛋白或内消旋-2,3-二巯基琥珀酸。
9.根据权利要求8的方法,其中所述金属离子选自铁离子、铜离子、钴离子、锌离子或镁离子。
10.根据权利要求8的方法,其中所述二硫代氨基甲酸酯选自具有如下结构的化合物:
(R)2N-C(S)-SH
其中各R彼此独立地选自C1-C18烷基、取代的烷基、环烷基、取代的环烷基、杂环、取代的杂环、链烯基、取代的链烯基、链炔基、取代的链炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、烷芳基、取代的烷芳基、芳烷基、取代的芳烷基、芳基链烯基、取代的芳基链烯基、芳基链炔基、取代的芳基链炔基、芳酰基、取代的芳酰基、酰基、或取代的酰基,或者两个R基团可以合在一起形成一个5、6或7员的含有N和所述两个R基团的环。
11.根据权利要求7的方法,其中所述巯基化合物是含氨基酸的硫醇、含肽的硫醇、含蛋白质的硫醇、含碳水化合物的硫醇或含核苷酸的硫醇。
12.根据权利要求7的方法,其中所述生理相容含水介质选自盐水、无菌水、磷酸盐缓冲的盐水,培养介质或平衡盐溶液。
13.根据权利要求7的方法,其中所述非极性氧化溶剂是氟化环脂肪族化合物、氟化芳香族化合物或氟化羧酸。
14.根据权利要求7的方法,其中所述一氧化氮捕获剂选自超氧化物阴离子基、过亚硝酸盐、黄嘌呤(次黄嘌呤)/黄嘌呤氧化酶系统、过氧化物或Griess试剂。
15.根据权利要求1的方法,其中所述容器包括:
一种由所述半渗透膜构成的柔性袋;或者
一种装有所述一氧化氮捕获剂的刚性或半刚性的收容器,其中所述收容器至少有一个开口,并且其中所述一氧化氮捕获剂由半渗透膜保存在所述收容器中;或者
一种装有所述一氧化氮捕获剂的袋,其中所述一氧化氮捕获剂的至少一部分通过所述半渗透膜与所述流体介质进行流体沟通。
16.根据权利要求1的方法,其中所述容器适合于置入患者舌下。
17.根据权利要求1的方法,其中所述容器适合于置入患者皮下。
18.根据权利要求17的方法,进一步包括用外科手术将所述容器置入所述患者体内。
19.根据权利要求1的方法,其中所述容器适合于置入细胞培养皿中的培养介质中。
20.根据权利要求1的方法,其中所述半渗透膜渗透中性气体分子,但不渗透带电分子。
21.根据权利要求20的方法,其中所述半渗透膜选自聚双有机硅氧烷、聚烯烃、聚链二烯、聚乙烯苯、卤代聚烯烃、卤代聚链二烯、聚碳酸酯、聚(乙烯对苯二酸酯)、聚丙烯酸酯、聚氨基甲酸酯,及其任何两种或多种混合物。
22.根据权利要求21的方法,其中所述半渗透膜是选自聚二烷基硅氧烷、聚二芳基硅氧烷、聚烷基芳基硅氧烷、聚二链烯基硅氧烷、聚链烯基烷基硅氧烷或聚链烯基芳基硅氧烷的聚双有机硅氧烷。
23.根据权利要求21的方法,其中所述半渗透膜是选自聚丙烯、聚异丁烯、聚(丙烯-CO-乙烯)、聚(异丁烯-CO-异戊二烯)或聚(异丁烯-CO-顺式丁烯二酸)的聚烯烃。
24.根据权利要求21的方法,其中所述半渗透膜是选自聚丁二烯、聚(二甲基丁二烯)或聚异戊二烯的聚链二烯。
25.根据权利要求21的方法,其中所述半渗透膜是选自聚苯乙烯、聚(α-甲基苯乙烯)、聚(丁二烯-苯乙烯)、聚(烯丙醇-苯乙烯)、聚(二乙烯苯-苯乙烯)或聚(马来酸-苯乙烯)的聚乙烯苯。
26.根据权利要求21的方法,其中所述半渗透膜是选自聚(氯乙烯)、聚氯丁二烯、聚三氟氯乙烯或聚四氟氯乙烯的卤代聚烯烃或卤代聚链二烯。
27.根据权利要求21的方法,其中所述半渗透膜是选自聚丙烯酸、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸甲酯-CO-乙基丙烯酸酯)或聚(甲基丙烯酸甲酯-CO-甲基丙烯酸)的丙烯酸酯。
28.根据权利要求1的方法,其中由所述制品捕获的一氧化氮量由电子顺磁共振光谱法、核磁共振法、放射性同位素跟踪、UV-可见光分光光度法、免疫组织化学法、荧光法、免疫学法、气相色谱法、液相色谱法、薄层色谱法、质谱法、液体闪烁计数或红外光谱法确定。
29.一种检测诱导一氧化氮产生过剩的疾病状态或症状的方法,所述方法包括:
将来自怀疑患有这种疾病症状的患者的流体介质与包括容器中实际上含有一氧化氮捕获剂的制品接触,其中所述容器的内含物能与和所述容器接触的流体介质通过半渗透膜沟通,并且其中所述接触是在适合允许流体介质中一氧化氮扩散穿过半渗透膜的条件下进行的,并且
测定由一氧化氮捕获剂捕获的一氧化氮含量。
30.根据权利要求29的方法,其中所述疾病状态或症状是脓毒性休克、局部缺血、服用细胞因子、细胞因子表达过度、溃疡、炎症性肠疾病(例如溃疡性结肠炎或节段性回肠炎)、糖尿病、关节炎、哮喘、早老性痴呆、帕金森病、多发性硬化、硬变、同种移植物排异、脑脊髓炎、脑膜炎、胰腺炎、腹膜炎、脉容器炎、淋巴细胞性脉络丛脑膜炎、肾小球性肾炎、眼色素层炎、回肠炎、肝炎、肾炎、出血性休克、过敏性休克、发烧、感染(包括细菌、病毒、真菌和寄生虫感染)、血液透析、慢性疲劳综合症、中风、癌症(例如乳腺癌、黑瘤、癌等)、心肺分流术、局部缺血/再灌注损伤、炎症、中毒性休克综合征、胃炎、成人呼吸窘迫综合症、恶病质、心肌炎、自身免疫疾病、湿疹、牛皮癣、心力衰竭、心脏病、动脉粥样硬化、皮炎、荨麻疹、大脑局部缺血、系统性红斑狼疮、艾滋病、艾滋病痴呆、慢性神经变性疾病、慢性疼痛、阴茎异常勃起、囊纤维变性、肌萎缩性侧索硬化、神经分裂症、神经变性疾病、肠胃动力疾病、肥胖、饮食过量、实体瘤(例如成神经细胞瘤)、疟疾、血癌、骨髓纤维变性、肺损伤、移植物-抗-宿主疾病、脑损伤、CNS创伤、肝炎、肾衰竭、肝病(例如慢性丙肝)、药物引起的肺损伤(例如百草枯)、重症肌无力(MG)或眼疾。
31.一种与一氧化氮产生不足有关的疾病症状的检测方法,所述方法包括:
将来自怀疑患有这种疾病症状的患者的流体介质与包括容器中实际上含有一氧化氮捕获剂的制品接触,其中所述容器的内含物能与和所述容器接触的流体介质通过半渗透膜沟通,并且其中所述接触是在适合允许所述流体介质中一氧化氮扩散穿过半渗透膜的条件下进行的,并且
测定由一氧化氮捕获剂捕获的一氧化氮含量。
32.根据权利要求31的方法,其中所述疾病症状是新生儿持续性肺动脉高血压、先兆子痫、成人呼吸窘迫综合征、血管成形术后再狭窄、阳痿或动脉粥样硬化。
33.一种包括在容器中实际上含有一氧化氮捕获剂的制品,其中所述容器的至少一部分包括半渗透膜,并且其中所述容器中的内含物能与和所述容器接触的流体介质通过半渗透膜沟通。
34.根据权利要求33的制品,其中所述容器包括由所述半渗透膜构成的柔性袋。
35.根据权利要求33的制品,其中所述容器包括含有所述一氧化氮捕获剂的实际上是刚性或半刚性的无孔收容器,其中所述收容器至少有一个开口,并且其中所述一氧化氮捕获剂由半渗透膜保存在所述收容器中。
36.根据权利要求33的制品,其中所述容器包括一种装有一氧化氮捕获剂的袋,其中所述一氧化氮捕获剂的至少一部分通过半渗透膜与和所述容器接触的流体介质进行流体沟通。
37.根据权利要求33的制品,其中所述容器是圆形、椭圆形、正方形、长方形、容器形或球形。
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- 1997-10-20 JP JP52146698A patent/JP2001507789A/ja active Pending
- 1997-10-20 EP EP97911028A patent/EP1012597A4/en not_active Withdrawn
- 1997-10-20 WO PCT/US1997/019119 patent/WO1998020336A1/en not_active Application Discontinuation
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CN102004100A (zh) * | 2010-11-24 | 2011-04-06 | 武汉大学 | 一种检测硫离子的方法 |
CN105765376A (zh) * | 2013-11-13 | 2016-07-13 | 纳诺努德股份公司 | 用于对水流体中氮的定量测定的方法 |
CN108169372A (zh) * | 2017-12-22 | 2018-06-15 | 上海微谱化工技术服务有限公司 | 电镀废水中络合剂的测定方法 |
CN108169372B (zh) * | 2017-12-22 | 2020-11-10 | 上海微谱化工技术服务有限公司 | 电镀废水中络合剂的测定方法 |
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AU4826597A (en) | 1998-05-29 |
AU722709B2 (en) | 2000-08-10 |
CA2271195A1 (en) | 1998-05-14 |
EP1012597A1 (en) | 2000-06-28 |
JP2001507789A (ja) | 2001-06-12 |
EP1012597A4 (en) | 2002-03-20 |
US6306609B1 (en) | 2001-10-23 |
WO1998020336A1 (en) | 1998-05-14 |
US5885842A (en) | 1999-03-23 |
KR20000053120A (ko) | 2000-08-25 |
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