CN1249349A - 基于四唑鎓化合物的诊断剂 - Google Patents
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Abstract
一种试剂,适用于测量分析物在含血红蛋白的生物体液、例如全血中的浓度。该试剂包含对分析物具有专一性的脱氢酶、NAD、NAD衍生物、吡咯并喹啉醌(PQQ)或PQQ衍生物、四唑鎓染料前体、心肌黄酶或其类似物、和亚硝酸盐。该试剂引起染料形成反应,后者是分析物浓度的量度。亚硝酸盐抑制了血红蛋白以非酶促方法对染料形成反应的干扰。优选该试剂用在干燥试剂条中,用于测量酮体,如β-羟丁酸盐。
Description
本申请是1998年9月28日申请的美国专利申请第09/161876号申请的继续部分。
本发明涉及诊断用组合物,该组合物可以测量分析物在含血红蛋白的生物体液中的浓度。该组合物是基于四唑鎓染料前体的,并可抑制血红蛋白引起的还原反应。
脂肪组织是体内能量储存的最大量形式之一。它将所储存的脂肪酸释放至主要由肝脏代谢的循环系统。在此过程中,消耗脂肪并释放出能量供身体使用。正常情况下,很少消耗脂肪,脂肪酸完全代谢成二氧化碳和水,并且该转化不会扰乱体内敏感的pH平衡。但是,如果由于例如节食而在体内存在不足量的碳水化合物,那么脂肪的消耗和脂肪酸的产生可以增加至可能造成危害的水平。除了节食者以外,胰岛素依赖性患者由于碳水化合物代谢被破坏而容易受到伤害。若使用过量的脂肪酸供应身体能量的需求,则将产生大量的乙酰乙酸盐、丙酮及β-羟丁酸盐。这些中间体称为酮体,这种情形称为酮酸中毒。
只要酮体不是太过量,它通常可经身体再度循环成其他形式,因此这些分析物在健康个体中的蓄积量是可以忽视的。当大量的脂肪在相当短的期间内代谢,或当大部分的能量是来源于脂肪时,将产生大量的酮体。这些脂肪代谢物的过量产生,如果没有及时纠正的话,将会导致某些神经上的疾病。
酮体存在于血液中,如果超过阈值,可经尿液排出,用先进的临床分析仪器是很容易检测出来的。一股来说,β-羟丁酸盐、乙酰乙酸盐和丙酮的百分比分别为78%、20%和2%。由于丙酮具有相对较低的浓度和较高的挥发性,因此很少测量丙酮,而是通过硝普盐反应定量测定乙酰乙酸盐,并通过酶促法定量β-羟丁酸盐。乙酰乙酸盐测试条已经应用了数十年,它是以硝普盐离子与醛及酮的偶合反应为基础制造的。使碱性尿液样本或血清样本与硝普盐反应数分钟,显紫色,颜色的强度显示乙酰乙酸盐的浓度。但是丙酮会干扰该测试,并导致读数偏高。而且当患者从酮酸中毒事件中恢复时,尿液和血液中的乙酰乙酸盐含量升高,因此增加了诊断的难度。
β-羟丁酸盐测试对酮体浓度的监测更为有用,它以β-羟丁酸盐与相应脱氢酶在烟酰胺腺嘌呤二核苷酸(NAD)辅因子存在下的氧化反应为基础(严格说来,只有D-β-羟丁酸盐是天然存在并氧化的,但是我们为了简化起见,在本说明书及附带的权利要求书中省略了“D”)。氧化生成NADH,其浓度可用UV分光光度计直接测量,因此光谱中相应信号的变化与分析物的浓度成正比。不幸的是,NADH的激发是发生在UV区域内的,所以该检测方式只适合于实验室仪器。另一种监测β-羟丁酸盐的方法是用四唑鎓化合物氧化NADH。
四唑鎓化合物通常对强碱和光非常敏感,因此必须特别小心,以确保这些化合物的完整。然而四唑鎓化合物在组织代谢的研究中扮演重要的角色,例如这类化合物曾用于探测细胞中的厌氧性氧化及还原反应,而且普遍用在临床诊断中。这种化合物通常是浅色或无色的化合物,在还原剂的存在下发生还原反应,产生深色的甲。诸如抗坏血酸盐、硫氢化物或各种NADH、NADPH和PQQH2(还原的PQQ-吡咯并喹啉醌)等还原剂能够形成染料。
在临床诊断中发现,这些染料对于监测厌氧反应中从母体化合物NAD(P)+生成NAD(P)H是没有用的(例如参见于1994年11月1日颁给D.Bell等的美国专利第5360595号)。该氧化还原反应迅速,且对氧不敏感,所得染料颜色非常强烈,且在水中的溶解度较低。
原则上,四唑鎓染料前体可用于测量全血中的酮体和葡萄糖。但是如果血红蛋白不是包含在血液的红细胞内,四唑鎓化合物可被血红蛋白(Fe(II))非酶促地还原生成有颜色的甲,因此,游离的血红蛋白会对测量造成严重的干扰。事实上,由于血细胞溶解作用以及相对于分析物来说产生的游离血红蛋白量很大,因此在典型的酮体测量中,来自血红蛋白的干扰信号将超过所要测量的信号。葡萄糖的测量,特别是在正常或更高的浓度下,尚没有什么不利影响。当在高血细胞比容样本中或在高温下进行反应时,血红蛋白更加快速地氧化,对葡萄糖测量的干扰也很明显。因为无法轻易地避免由于红细胞的血细胞溶解作用而导致游离血红蛋白的存在,如果用四唑鎓化合物进行分析时,在测试前必须先除去样本中的红细胞。
从样本中除去红细胞的方法是用膜及滤器过滤、用化学试剂捕集,或两种方法的结合。从全血中分离红细胞的过滤法是昂贵的,且需要相当大的样本体积。使用过滤法从全血样本中除去红细胞的血酮(β-羟丁酸盐)测试法实例是可由GDSDiagnostics,Elkhart,IN得到的KetoSite测试法(见《Tietz临床化学教科书》第2版,C.Burtis等编,W.B.Saunders Co.,Philadelphia,PA出版,1994,P974)。在该测试中使用的“测试卡”有两个过滤层,这使得该卡相当昂贵,且需要大量(25μL)的血液样本,而且血液必须是血细胞未溶解化的。
可由Miles得到的AmesGlucometer EncoreTM血液葡萄糖测试条中使用了过滤与化学捕集的组合,该测试条利用一层过滤材料和一种凝集助剂(马铃薯卵磷脂)来消除红细胞的干扰(见Chu等,1995年2月15日公开的欧洲专利申请0638805A2)。
在系统中加入一种氧化剂,将血红蛋白氧化成高铁血红蛋白,是减少血红蛋白干扰的另一种方法。虽然已知铁氰化物可将血红蛋白转化为高铁血红蛋白,但是它们也会破坏所需的产物NADH。
本发明提供了一种用于测量分析物在含血红蛋白的生物体液中的浓度的试剂。该试剂包含:
a)对分析物具有专一性的脱氢酶,
b)烟酰胺腺嘌呤二核苷酸(NAD)、NAD衍生物、吡咯并喹啉醌(PQQ)或PQQ衍生物,
c)四唑鎓染料前体,
d)心肌黄酶或其类似物,和
e)亚硝酸盐。
该试剂特别适合涂覆在一或多种基质上以形成用于测量分析物的干燥试剂条。特别优选的试剂条包含
a)支撑层,
b)位于支撑层上含有涂层的测试衬垫,该涂层含
i)对分析物具有专一性的脱氢酶,
ii)烟酰胺腺嘌呤二核苷酸(NAD)、NAD衍生物、吡咯并喹啉醌(PQQ)或PQQ衍生物,
iii)四唑鎓染料前体,和
iv)心肌黄酶或其类似物,和
c)位于测试衬垫上,涂覆亚硝酸盐的吸收性顶层。
图1为本发明测试条的透视图。
图2为本发明另一种测试条的分解图。
图3为本发明又一种测试条的分解图。
图4为本发明的酮测试化学法的图形说明。
图5为本发明的葡萄糖测试化学法的图形说明。
图6为亚硝酸盐作为血红蛋白抑制剂对酮测试法所显示的作用图。
图7为亚硝酸盐作为血红蛋白抑制剂对葡萄糖测试法所显示的作用图。
本发明提供了一种用于测量分析物在含血红蛋白的生物体液(例如全血)中浓度的试剂,借助于所产生的辅因子例如NADH、NAD(P)H或PQQH2的还原形式的浓度,用来测量分析物的浓度。在试剂中含有亚硝酸盐可以克服血红蛋白对还原型辅因子浓度测量的干扰,尤其适用于(但不限于)酮体和葡萄糖的测量。
图1说明本发明的典型测试条10,其中包括固定在支撑物14上的测试衬垫12。该支撑物可以是塑料一例如聚苯乙烯、尼龙或聚酯-或金属片,或本领域已知的任意其他适当材料。测试衬垫上涂覆有与分析物反应而引起颜色变化的试剂。测试衬垫优选包含吸收性材料,例如滤纸或聚合物膜。不过既然反应不需要氧,测试衬垫也可以是非吸收性材料,例如塑料膜。试剂含有对分析物具有专一性的酶、氢化物传递剂、四唑鎓染料前体、适当的酶辅因子和血红蛋白抑制剂,可选地还含有缓冲剂或稳定剂,以提供更大的稳定性。
如图2所示,测试条也可以是多层结构,以顶层16覆盖测试衬垫12。在该结构中,试剂可分散在两层之间,例如血红蛋白抑制剂可涂覆在可选的顶层16上,并将其余的试剂涂覆在测试衬垫12上,优选顶层16具有吸收性,既起到扩散层的作用,又起到吸收层的作用,以吸附过量的样本。将样本添加至顶层16,通过顶层到达测试衬垫12,通过测量透过支撑层14的颜色变化来测定分析物浓度,或者当连接反应区域的层14是不透明的情况下,通过测量透过可选的窗口或中空的孔18的颜色变化,来测定分析物的浓度。
在图3所显示的另一种实施方式中,间隔层20将顶层16和测试衬垫12分开。间隔层20优选为非吸收性的塑料膜,在两面都有黏附性涂层(没有显示)。间隔层20中的通道22提供毛细管通道,供样本从开口24流至测试区域26。流动取决于测试衬垫12的表面与连接层之间的空气流通,或者取决于可选的排气口18。测试区域26的颜色变化通过可选的排气口/窗口18进行监测,试剂可以全部在测试衬垫12上,或者分散在测试衬垫以及两个非吸收性层14和16或之一上。据此,第一部分试剂可在测试衬垫上,第二部分试剂可在两个非吸收性层或之一上。当我们称试剂为一个“涂层”或在某层的“上面”时,我们是指也包括试剂被吸附至该层内的可能性,尤其是当该层具有吸收性时。
适用于本发明测试法的酶及相应的分析物为:检测醇的醇脱氢酶、检测甲醛的甲醛脱氢酶、检测葡萄糖的葡萄糖脱氢酶、检测葡萄糖-6-磷酸盐的葡萄糖-6-磷酸盐脱氢酶、检测谷氨酸的谷氨酸盐脱氢酶、检测甘油的甘油脱氢酶、检测β-羟丁酸盐的β-羟丁酸盐脱氢酶、检测类固醇的羟基类固醇脱氢酶、检测L-乳酸盐的L-乳酸盐脱氢酶、检测亮氨酸的亮氨酸脱氢酶、检测苹果酸的苹果酸盐脱氢酶和检测丙酮酸的丙酮酸盐脱氢酶。
需要适当的酶辅因子以活化酶,因酶而异,可以使用的辅因子有:β-烟酰胺腺嘌呤二核苷酸(β-NAD)、β-烟酰胺腺嘌呤二核苷酸磷酸(β-NADP)、硫代烟酰胺腺嘌呤二核苷酸、硫代烟酰胺腺嘌呤二核苷酸磷酸、烟酰胺1,N6-乙烯腺嘌呤二核苷酸、烟酰胺1,N6-乙烯腺嘌呤二核苷酸磷酸和吡咯并喹啉醌(PQQ)。在酶的存在下,辅因子被分析物还原。
染料形成过程的下一步是从还原型辅因子提取氢化物,其可通过心肌黄酶或其类似物来完成,心肌黄酶例如硫辛酸脱氢酶、铁氧化还原蛋白-NADP还原酶、硫辛酰胺脱氢酶,其类似物,例如吩嗪甲基硫酸盐(PMS)或Meldola Blue。反应动力学和稳定性是选择氢化物传递剂或“提取剂”的主要因素,例如,PMS是通用的氢化物提取剂,因为它对于大部分下列四唑鎓化合物具有相当迅速的反应动力。基于这个理由,若辅因子为PQQ,则以PMS为优选。但是PMS对光的敏感性要高于以酶为基础的氢化物提取剂。心肌黄酶较稳定,因此,若辅因子为NAD,则以心肌黄酶为优选。
被捕集的氢化物传递至四唑鎓化合物(染料前体)而生成有色的甲。最适合该装置的四唑鎓化合物为:2-(2’-苯并噻唑基)-5-苯乙烯基-3-(4’-邻苯二甲酰肼基)四唑鎓(BSPT)、2-苯并噻唑基-(2)-3,5-二苯基四唑鎓(BTDP)、2,3-二(4-硝基苯基)四唑鎓(DNP)、2,5-二苯基-3-(4-苯乙烯苯基)四唑鎓(DPSP)、二苯乙烯基硝基蓝四唑鎓(DS-NBT)、3,3’-[3,3’-二甲氧基-(1,1’-联苯基)-4,4’-二基]-双[2-(4-硝基苯基)-5-苯基]-2H-四唑鎓(NBT)、3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2H-四唑鎓(MTT)、2-苯基-3-(4-羧苯基)-5-甲基四唑鎓(PCPM)、四唑鎓蓝(TB)、硫代氨基甲酰基硝基蓝四唑鎓(TCNBT)、四硝基蓝四唑鎓(TNBT)、四唑鎓紫(TV)、2-苯并噻唑并噻唑基-3-(4-羧基-2-甲氧基苯基)5-[4-(2-磺乙基氨基甲酰基)苯基]-2H-四唑鎓(WST-4)和2,2’-二苯并噻唑基-5,5’-双[4-二(2-磺乙基)氨基甲酰基苯基]-3,3’-(3,3’-二甲氧基-4,4’-亚联苯基)二四唑鎓二钠盐(WST-5)。优选为WST-5,因为它在水性介质中容易溶解,与生物样本最相容,而且,所得的甲化合物在紫—蓝区域显示强烈的光谱吸收,从而减少了校正来自血红蛋白的本底信号的需要。
最后,存在于试剂中的血红蛋白抑制剂可减少血红蛋白与四唑鎓化合物之间所不需要的染料形成反应。血红蛋白抑制剂的作用是将血红蛋白氧化成高铁血红蛋白,后者不会与四唑鎓或甲反应。令人惊奇的是,亚硝酸盐,例如亚硝酸钠、亚硝酸钾及其衍生物,对于抑制血红蛋白是非常有效的,同时还不会破坏还原型辅因子(例如NADH或PQQH2),亚硝酸盐在高温和高血细胞比容的样本中都是有效的。优选为亚硝酸钠,因为它具有较高的水溶解度,没有毒性且相对便宜。
尽管本发明试剂可在湿化学模式、例如在比色杯中使用,不过在优选的实施方式中,本发明提供了用于化验全血中的β-羟丁酸盐或葡萄糖的干燥测试条。由膜测试衬垫、优选为尼龙组成的测试条置于支撑物与顶层之间,支撑物优选为聚酯薄片,顶层可以是本领域中已知的任意吸收性材料。优选的材料是经油酰牛磺酸甲酯钠处理过的多孔性聚乙烯,可由Porex Corp.Fairburn,GA得到,我们称之为“Porex”。测试衬垫含有由β-羟丁酸盐脱氢酶(或葡萄糖脱氢酶)、NAD(或PQQ)、心肌黄酶(或PMS)和WST-5组成的试剂(下文表1(或表3)),Porex顶层含有亚硝酸盐试剂(表2)。
在操作中,使用者将一滴全血添加至Porex顶层的上表面,当全血或胞溶的血与Porex接触后,亚硝酸钠再生并与可利用的游离血红蛋白反应,因此使血红蛋白对化验无害。所得事实上不含血红蛋白的样本通过毛细管或重力作用转移至下面的测试衬垫,在测试衬垫上,样本引发级联反应而产生有颜色的染料,其浓度与样本中的分析物浓度成正比,并可直接用光度计测量。图4说明用酶、NAD和心肌黄酶进行的β-羟丁酸盐的反应。图5说明用酶、PQQ和PMS进行的葡萄糖的反应。
图6说明了血样的光密度随时间的变化,全部样本都具有55%的血细胞比容,并含有0至15毫克/分升的β-羟丁酸盐,含有或不含亚硝酸盐。使用NAD系统,且亚硝酸盐的浓度为5克/分升。在没有亚硝酸盐存在的条件下,血红蛋白会还原四唑鎓而使染料浓度连续增加,光密度也相应增加。通过除去血红蛋白(通过氧化反应),亚硝酸盐限制了颜色的形成,使颜色的形成仅仅来自样本中的酮体(也就是β-羟丁酸盐)。下文实施例1描述了测试条的制备方法,该测试条用于得出图中说明的数据。
图7显示亚硝酸盐在葡萄糖/PQQ系统中对颜色形成反应的作用。血样都具有60%的血细胞比容,含有0或100毫克/分升的葡萄糖和0或5克/分升的亚硝酸盐。不含葡萄糖的样本在35℃下操作。图形显示本系统在温度高达35℃、且血细胞比容高达60%的条件下仍然是有效的。所用的测试条的制备方法描述在下文的实施例2中。
下列实施例用来说明本发明的优选实施方式。在实施例1中,分析物为β-羟丁酸盐,酶为β-羟丁酸盐脱氢酶。在实施例2中,分析物为葡萄糖,酶为葡萄糖脱氢酶。可以很容易地对组合物进行改良,以用于前文所列的其他分析物—酶的组合(例如,见《Tietz临床化学教科书》第2版,C.Burtis等编,W.B.SaundersCo.,Philadelphia,PA出版,1994,P976-978及1174-1175)。这些实施例不以任何方式限制本发明。
实施例1
将由Cuno(Meriden,CT,USA)得到的0.8微米尼龙膜浸在表1试剂中直至饱和,用玻璃棒轻轻地将过量的试剂刮除。将所得的膜悬吊在56℃的烘箱中10分钟,使其干燥。将Porex(0.6毫米厚)浸在表2的亚硝酸盐溶液中,然后悬吊在100℃的烘箱中10小时,使其干燥。最后将该膜压在聚酯材料(由ICI America,Wilmington,DE得到的0.4毫米Melenex聚酯)与浸渍了亚硝酸盐的Porex之间。
实施例2
除了用表3试剂作为第一个浸渍液以外,其余重复实施例1的步骤。
表1:用于酮体测试衬垫的试剂
成分 | 量 |
水 | 100ml |
三(羟甲基)氨基甲烷(MW 121,Sigma St.,Louis,MO,USA)(加入6M HCl调pH为8.5) | 1.2gm |
氯化钠(MW 56.44,Sigma,St.,Louis,MO,USA) | 560mg |
氯化镁(MW 203,Sigma,St.,Louis,MO,USA) | 2.5gm |
PSSA,聚苯乙烯磺酸钠盐(MW 70000,Polysciences,Inc.,Warrington,PA,USA) | 3gm |
巴豆毒蛋白(Croda Inc.,Parsippany,NJ,USA) | 3gm |
草氨酸钠盐(MW 111.03,Aldrich Chemicals,Milwaukee,WI,USA) | 250mg |
季胴酸1307(BASF Corporation,Mount Olive,NewJersey,USA) | 2gm |
蔗糖(MW 342.30,Aldrich Chemicals,Milwaukee,WI,USA) | 5gm |
NAD(MW 663.4,N-7004,Sigma,St.Louis,MO,USA) | 450mg |
D-3-羟丁酸盐脱氢酶(来源:假单胞菌属,HBD-301,125U/mg,Toyobo,Japan) | 50000U |
心肌黄酶(来源:嗜热脂肪芽胞杆菌1033U/mg,Toyobo,Japan) | 340890U |
WST-5(MW 1331.37,Dojindo,Japan) | 1.8gm |
表2:亚硝酸盐试剂
成分 | 量 |
10mM磷酸盐缓冲盐水,pH7.4(P-3813,Sigma,St.,Louis,MO,USA) | 70ml |
乙醇 | 30ml |
亚硝酸钠(MW 69,Aldrich Chemicals,Milwaukee,WI,USA) | 5gm |
聚乙烯吡咯烷酮(MW 40000,Sigma,St.,Louis,MO,USA) | 200mg |
草氨酸钠盐(MW 111.03,Aldrich Chemicals,Milwaukee,WI,USA) | 500mg |
表3:用于葡萄糖测试衬垫的试剂
成分 | 量 |
水 | 100ml |
三(羟甲基)氨基甲烷(MW 121,Sigma,St.,Louis,MO,USA) | 1.2gm |
加入6M HCl调pH为7.4 | |
氯化钠(MW 56.44,Sigma,St.,Louis,MO,USA) | 560mg |
氯化镁(MW 203,Sigma,St.,Louis,MO,USA) | 2.5gm |
PSSA,聚苯乙烯磺酸钠盐(MW 70000,Polysciences,Inc.,Warrington,PA,USA) | 3gm |
巴豆毒蛋白(Croda Inc.,Parsippany,NJ,USA) | 3gm |
草氨酸钠盐(MW 111.03,Aldrich Chemicals,Milwaukee,WI,USA) | 250mg |
季酮酸1307(BASF Corporation,Mount Olive,New Jersey,USA) | 2gm |
蔗糖(MW 342.30,Aldrich Chemicals,Milwaukee,WI,USA) | 5gm |
PQQ(MW 330,64682,Fluka) | 100mg |
葡萄糖脱氢酶(291U/mg,Toyobo,Japan) | 29100U |
吩嗪甲基硫酸盐(MW 306.34) | 4mg |
WST-5(MW 1331.37,Dojindo,Japan) | 3.2gm |
Claims (10)
1、一种用于测量分析物在含血红蛋白的生物体液中的浓度的试剂,该试剂包含:
a)对分析物具有专一性的脱氢酶,
b)烟酰胺腺嘌呤二核苷酸(NAD)、NAD衍生物、吡咯并喹啉醌(PQQ)或PQQ衍生物,
c)四唑鎓染料前体,
d)心肌黄酶或其类似物,和
e)亚硝酸盐。
2、权利要求1的试剂,其中分析物是β-羟丁酸盐,酶是β-羟丁酸盐脱氢酶。
3、权利要求1的试剂,其中分析物是葡萄糖,酶是葡萄糖脱氢酶。
4、一种用于测定分析物在含血红蛋白的生物体液中的存在和含量的干燥试剂条,该试剂条包括一个支撑层,在该支撑层上是具有权利要求1的试剂涂层的测试衬垫。
5、一种用于测定分析物在含血红蛋白的生物体液中的存在和含量的干燥试剂条,该试剂条包括一个支撑层,在该支撑层上是测试衬垫和覆盖该测试衬垫的顶层,其中第一部分的权利要求1试剂在该测试衬垫上,第二部分试剂在该支撑层和/或顶层上。
6、权利要求5的试剂条,进一步在该顶层和测试衬垫之间包括间隔层和通道,以在该顶层和衬垫之间提供毛细管路径。
7、权利要求5的试剂条,其中分析物是β-羟丁酸盐,酶是β-羟丁酸盐脱氢酶。
8、权利要求5的试剂条,其中分析物是葡萄糖,酶是葡萄糖脱氢酶。
9、权利要求5的试剂条,其中四唑鎓染料前体是2,2’-二苯并噻唑基-5,5’-双[4-二(2-磺乙基)氨基甲酰基苯基]-3,3’-(3,3’-二甲氧基-4,4’-亚联苯基)二四唑鎓二钠盐(WST-5)。
10、一种用于测定分析物在含血红蛋白的生物体液中的存在和含量的干燥试剂条,该试剂条包括:
a)支撑层,
b)位于支撑层上含有涂层的测试衬垫,该涂层含
i)对分析物具有专一性的脱氢酶,
ii)烟酰胺腺嘌呤二核苷酸(NAD)、NAD衍生物、吡咯并喹啉醌(PQQ)或PQQ衍生物,
iii)四唑鎓染料前体,和
iv)心肌黄酶或其类似物,和
c)位于测试衬垫上,涂覆亚硝酸盐的吸收性顶层。
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