CN101076728A - 区分含有共同的分析物的血液和对照溶液的方法 - Google Patents
区分含有共同的分析物的血液和对照溶液的方法 Download PDFInfo
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Abstract
鉴于在血液样本中所测到的葡萄糖区别于在用于检验进行这种测量的光学仪器的对照溶液中所测到的葡萄糖。本发明涉及用以区分对对照溶液所做的葡萄糖测量和对血液样本所做的葡萄糖测量的、含有可通过光学仪器识别的标记物质的对照溶液。
Description
技术领域
本发明主要涉及使用光学仪器测量生物液体如全血样本中的分析物。这种仪器通常使用溶液来加以检验,所述的检验溶液模拟平常的生物样本并含有已知量的分析物。本发明涉及对作为检验溶液的样本,即通常被称为对照溶液的鉴别。更特别地,本发明涉及防止光学仪器在它们所保存的测量历史中包括对对照溶液中的分析物所做的测量。也就是说,避免当保存的历史不能准确地报告此前所测量的样本内容时却将用对照溶液得到的结果包括在内时可能发生的错误。
背景技术
对生物液体中的分析物的定量测定在诊断和治疗医学问题方面非常重要,比如测量生物液体中的葡萄糖水平对糖尿病患者来说很重要。本发明描述并被应用于测量血液样本中的葡萄糖。当然,本发明也可以用于可用光学仪器测量的其他分析物。
电化学和光学方法都可以用来测量血液中的葡萄糖含量。本发明涉及光学测量。血液中的葡萄糖发生化学反应而显现的颜色变化能用几种类型的仪器来光学地测量,包括漫反射系数、透射率、吸光度、漫透射率、总透射率测量等。例如,美国专利US5,611,999和US6,181,417所描述的方法中使用了漫反射系数测量。发光二级管(LED)的光射到与血液接触并且显现光学可测性响应的基质上。反射的光射到光电探测器,在其中测量接受到的光的量,并与血液样本中葡萄糖的量相联系。在下面的实施例中使用了光的吸光度。
已有几种类型的化学反应被用于引起可通过光学仪器进行检测的变化。这些反应包括葡萄糖与葡萄糖氧化酶或葡萄糖脱氢酶的反应以显现可指示所检验样本中的葡萄糖的量的颜色。参见例如美国专利US4,689,309。只要对样本中的葡萄糖的响应是光学仪器可检测的,那么本发明不局限于用于测定血液中葡萄糖的量的化学反应的类型。
为了确保准确测量,用含已知量的葡萄糖的对照溶液检验仪器的适当运行。对照溶液组合物已是许多专利和出版物的主题。代表性的是美国专利US 3,920,580、美国专利US 4,572,899、美国专利US4,729,959、美国专利US 5,028,542、美国专利US 5,605,837、WO93/21928、WO95/13535和WO95/13536。使用含血清的对照溶液的同时,最近更多的专利已经关注用无血清的溶液代替基于血清的对照溶液,因为无血清的溶液比含血清的溶液更加一致和稳定。如果要准确地测量葡萄糖,对照溶液应与血液表现方式相似。显然要求组合物必须在使用前冗长的保存期内保持稳定。此外,组合物必须允许葡萄糖与试剂以与含在血液样本中的葡萄糖与试剂反应产生颜色相对应的方式反应。组合物还不应该对用于照亮样本的光产生干扰葡萄糖与试剂反应所显现颜色的读取的响应。因而,改进对照溶液组合物已是本领域相当大的关注点。
尽管有一些对照溶液不加颜色,但是另外有一些对照溶液包括有色添加剂以提供血液的外观。例如,美国专利US 3,920,580建议加红色染料,而且美国专利US 5,605,837提出包括黑色粒子的悬浮液。
某些仪器中出现的问题涉及将血液样本所做的测量与对照溶液所做的测量加以区别的需求,对照溶液经常用于确保检验设备恰当地运行。如果配制成的对照溶液以与全血样本相似的方式进行响应,仪器将不会识别正在检验的是对照溶液而不是血液样本。即,葡萄糖含量与其它样品独立地测定以使对照溶液提供正确的读取。然而,一般这种仪器记录葡萄糖测量并存储下来,因为葡萄糖测量的历史对治疗糖尿病患者非常有用。显然,对照溶液的葡萄糖含量不应被包括在所记录的历史中,除非数据能被鉴别并与血液样本的葡萄糖测量分开。当然,这能通过使用者手工操作进行,但是如果疏忽的话则有可能使葡萄糖历史被歪曲。所以应优选不要求使用者负责对对照溶液和血液样本所做的葡萄糖测量进行分离。
美国专利US5,723,284中讨论了血液中的葡萄糖的电化学测量。专利’284建议改变对照溶液,这样仪表会识别对照溶液正被测量并会采取适当操作以防止结果被包括在血液样本的结果中。本发明包括识别以光学手段来测量葡萄糖或其它分析物的仪器中的对照溶液的存在的方法,下面对此加以详述。
发明内容
本发明对生物液体中的分析物,特别是全血或溶解的血液中的葡萄糖和用于检验光学仪器运行的对照溶液中的分析物进行区别。该对照溶液含有标记物,即在正常生物样本中不会发现的物质,其通过光学仪器来识别从而鉴别对照溶液。在一个实施例中,光学仪器使用与待鉴别物质的特征性波长相对应的从约600至约800nm范围的LED发射光。标记物质优选是染料或是由水溶性染料或当加入表面活性剂时能使之水溶的染料或类似物中的成员。典型地,染料的峰值吸光度在很窄的光谱范围内,其在与对照溶液一起时可被容易地鉴别。
一方面,本发明是区别对血液样本中的葡萄糖所做测量和对照溶液中的葡萄糖所做测量的方法。将标记物质加入到对照溶液中,其作为对照溶液而非血液样本可以通过光学仪器进行识别。
另一方面,本发明是通过光学仪器测量血液样本中的葡萄糖的方法,其中对照溶液用于检验光学仪器的运行,并且对照溶液含有用作标记物的物质,且该物质可通过光学仪器识别从而鉴别对照溶液的存在。
另一个方面,本发明涉及通过葡萄糖与测试条(test strip)的反应来测量全血、溶解的血液、血浆或血清中的葡萄糖的光学仪器。该仪器包括处于用于表征用来检测光学仪器运行的标记对照溶液的物质的波长的LED发射光。用于检测标记物质的LED发射被标记物吸收的波长,其区别于用于检测葡萄糖的LED的波长。
在一个优选实施方案中,光学仪器汇集对全血样本所做的葡萄糖测量,同时排除对照溶液所做的葡萄糖测量。
附图说明
图1是一个实施例所述的WST-4四唑盐的产物甲
和染料吲哚氰绿(indocyanine green)的吸收光谱。
具体实施方式
通过光学方法检测葡萄糖
通过光学方法检测葡萄糖大致可分为使用葡萄糖氧化酶的检测和使用葡萄糖脱氢酶的检测。尽管方法相似,但是它们使用不同的酶、介质和指示剂。
当使用葡萄糖氧化酶时,样本(例如血)中的葡萄糖随着过氧化氢的释放被氧化成葡萄糖酸。所述的过氧化氢氧化指示剂(例如在过氧化物酶存在的条件下)以产生可测的光学响应(例如指示样本中的葡萄糖的量的颜色)。最近一些专利提出葡萄糖首先转化成葡糖酸再转化成葡糖酸内酯,同时其它专利提出首先形成葡糖酸内酯再水解成葡糖酸。不管哪种步骤顺序是正确的,葡萄糖氧化酶已被广泛用于测量血液中葡萄糖含量的干燥测试条。
当使用葡萄糖脱氢酶时,包括辅因子(例如NAD或PQQ)、指示剂和介质例如硫辛酰胺脱氢酶或其类似物。辅因子在酶存在的条件下被还原并且葡萄糖被氧化成如上所述的葡萄糖酸或葡萄糖酸内酯。其后,被还原的辅因子被硫辛酰胺脱氢酶或其类似物氧化。在这个方法中,指示剂例如四唑盐被还原以产生有色的衍生物,其能被测量并与被检验的样本中的葡萄糖的量相关。
本发明可使用这些方法中的任意一种,因为发明涉及对照溶液的使用,通过所述对照溶液检查光学仪器的运行以确保全血中的葡萄糖测量的准确和可靠。
上述方法一般与干燥测试条一起使用,测试条含有能与生物样本或对照溶液中的葡萄糖反应以产生颜色的试剂,颜色能与样本中存在葡萄糖的量相关。当显现的颜色能提供样本中所含葡萄糖的半定量测量时,通过将有色的测试条暴露于光源下、测量通过使用指示剂显现的颜色的程度并将结果与样本的葡萄糖含量联系来获得更准确的结果,例如通过将颜色和颜色与葡萄糖含量的比值表比较。
对照溶液通常是具有几种模拟相关生物样本的基本组分的水基组合物。为了测量血液中的葡萄糖,使之包括一个或多个聚合物以提供具有全血的物理特征的溶液。例子包括,但不局限于,聚乙烯氧化物、聚羟乙基甲丙烯酸酯和聚乙烯吡咯烷酮。典型地,溶液包括约5%至约30%(w/v)的聚合物。第二组分是预定量的葡萄糖,典型地,在约30mg/dL至约500mg/dL的范围内。加入缓冲液以保持适当的pH,典型地,在约5至约8的范围内。例子包括,但不局限于,柠檬酸/柠檬酸钠、磷酸、HEPES-Na和磷酸钠。最后,根据本发明,溶液中含有标记物质,其在暴露于具有在被标记物质峰值吸光度的波长范围的LED光下时产生特征性响应。标记物质具有与用于测定对照溶液中的葡萄糖含量不同范围的响应。用于鉴别对照溶液并将其与血液样本区别开的物质优选是染料或是水溶性染料或当加入表面活性剂时使之为水溶性的染料中的成员。
在一个实施方案中,染料吲哚氰绿加入对照溶液中。如从下述实施例中所见到的,该染料吸收在约780nm的光,从而使之能够容易地辨别染料的存在和进而辨别对照溶液的存在。
在下述的实施例中,具有在700-820nm区域的光的响应达到峰值的染料用于标记被测量的对照溶液。如同所见,一般使用的用于指示葡萄糖的存在的指示剂具有峰值在约500-约650nm范围的响应。峰值的分开足以允许既能有效地鉴别对照溶液,又能有效地测量存在的葡萄糖的量。
当使用指示剂的光学响应测量全血中的葡萄糖时,血红细胞的存在可能干扰对指示剂响应的检测。在对照溶液中,血液并不存在,仅需要确保对照溶液的组分不干扰对指示葡萄糖含量的指示剂和用于指示对照溶液的存在的所加入的标记化合物的检测。
实施例1
使染料吲哚氰绿(Sigma Aldrich)溶解于磷酸盐缓冲溶液中。该溶液的吸收光谱用Hewlett-Packard Model 8453二极管阵列UV可见分光光度计测量,结果标绘在图1中。如图1所示,发现最大吸光度在约780nm。
商用四唑盐WST-4(Dojindo)溶解于pH为约7.5的100毫摩尔的磷酸钾缓冲液中。通过加入抗坏血酸WST-4被还原成等价的甲
染料,进而模拟葡萄糖检验中有色指示剂的产生。测量溶液,测量结果标绘在图1中,与染料吲哚氰绿的吸收光谱作比较。甲
的峰值吸光度在约550-600nm,明显区别于染料的吸光度。
实施例2
用水的低渗溶液溶解全血,再在磷酸盐缓冲液中稀释。溶解的血液的吸光度如实施例1所示进行测量,将结果与图1中的两条吸光度曲线一起标绘在图2中。溶解的血液的最大吸光度在约400nm,波长明显区别于甲
和吲哚氰绿的波长。可以推断出来如果血液溶解是葡萄糖检验的一部分,它将不会对指示对照溶液存在的标记染料造成干扰。
替选实施方案A
一种检验光学仪器的运行的对照溶液,所述光学仪器适于测量与指示剂的光学响应成比例的血液中葡萄糖浓度,该溶液包括鉴别对照溶液的存在的可通过光学仪器所识别的标记物质。
替选实施方案B
替选实施方案A的对照溶液,其中标记物质所具有的对来自光学仪器的发光二极管的激发产生的特征性响应区别于指示剂的响应。
替选实施方案C
替选实施方案A的对照溶液,其中标记物质的具有的光的峰值吸光度区别于指示剂的吸光度。
替选实施方案D
替选实施方案C的对照溶液,其中标记物质是吲哚氰绿。
替选实施方案E
替选实施方案D的对照溶液,其中标记物质区别于四唑盐指示剂。
替选处理F
区别使用光学仪器对血液中葡萄糖的测量和对用于检验光学仪器运行的对照溶液中葡萄糖的测量的方法,该方法包括将可通过光学仪器识别的标记物质加入到对照溶液中。
替选处理G
替选处理F的方法,其中标记物质所具有的对光学仪器的发光二极管的激发产生的特征性响应区别于指示剂的响应。
替选处理H
替选处理F的方法,其中标记物质所具有的光的峰值吸光度区别于指示剂的吸光度。
替选处理I
替选处理F的方法,其中标记物质是吲哚氰绿。
替选处理J
替选处理I的方法,其中标记物质区别于四唑盐指示剂。
替选处理K
通过光学仪器测量血液中葡萄糖的方法,该方法包括检验仪器运行的操作,所述操作通过将含已知量的葡萄糖的对照溶液加入到适合与葡萄糖反应并产生来自指示剂的光学响应的测试条中,然后测量响应,所述对照溶液含有可通过光学仪器识别并区别于指示剂响应的标记物质。
替选处理L
替选处理K的方法,其中标记物质所具有的对光学仪器的发光二极管的激发产生的特征性响应区别于指示剂的响应。
替选处理M
替选处理K的方法,其中标记物质所具有的光的峰值吸光度区别于指示剂的吸光度。
替选处理N
替选处理M的方法,其中标记物质是吲哚氰绿。
替选处理O
替选处理N的方法,其中标记物质区别于四唑盐指示剂。
替选实施方案P
用来将血液样本的葡萄糖含量与光学响应联系起来的光学仪器,所述光学响应获自样本与适合通过与血液样本反应提供光学响应的测试条的接触获,所述光学仪器包括发光二极管,其用于激发用来将对照溶液与血液样本区别开的对照溶液中标记物质的响应。
替选实施方案Q
替选实施方案P的光学仪器,其中光学仪器汇集葡萄糖测量,并排除对照溶液所做的这种测量。
替选实施方案R
替选实施方案P的光学仪器,其中标记物质所具有的光的峰值吸光度区别于用于测量存在的葡萄糖的量的指示剂的峰值吸光度。
替选实施方案S
替选实施方案R的光学仪器,其中标记物质是吲哚氰绿。
替选处理T
区分用于测量生物样本中的分析物的光学仪器中的对照溶液与生物样本的方法,该方法包括向对照溶液中加入可标记对照溶液、并能使光学仪器鉴别该对照溶液以及将该对照溶液与生物样本区分开的物质的操作。
替选处理U
替选处理T的方法,其中标记物质是适合溶解于对照溶液中的染料,该染料的吸收光的波长区别于表征分析物的光的波长。
当发明易受各种改变和替选形式影响时,特殊的实施方案通过图例和详细描述的方式来说明。然而,应理解为不希望将发明局限于所公开的特别形式,然而正相反,发明覆盖落入如所提交权利要求书定义的发明的原则和范围内的所有改变、等效、和替换。
Claims (21)
1.一种用于检验光学仪器运行的对照溶液,所述光学仪器适合测量与指示剂光学响应成比例的血液中的葡萄糖的浓度,所述溶液包括用作鉴别对照溶液的存在的可通过光学仪器识别的标记物质。
2.如权利要求1所述的对照溶液,其中标记物质所具有的对光学仪器的发光二极管的激发产生的特征性响应区别于指示剂的响应。
3.如权利要求1所述的对照溶液,其中标记物质所具有的光的峰值吸光度区别于指示剂的吸光度。
4.如权利要求3所述的对照溶液,其中标记物质是吲哚氰绿。
5.如权利要求4所述的对照溶液,其中标记物质区别于四唑盐指示剂。
6.区分光学仪器对血液中的葡萄糖的测量和对用于检验光学仪器运行的对照溶液中的葡萄糖的测量的方法,该方法包括将可通过光学仪器识别的标记物质加入到对照溶液中。
7.如权利要求6所述的方法,其中标记物质所具有的对光学仪器的发光二极管的激发产生的特征性响应区别于指示剂的响应。
8.如权利要求6所述的方法,其中标记物质所具有的光的峰值吸光度区别于指示剂的吸光度。
9.如权利要求6所述的方法,其中标记物质是吲哚氰绿。
10.如权利要求8所述的方法,其中标记物质区别于四唑盐指示剂。
11.通过光学仪器测量血液中的葡萄糖的方法,该方法包括检验仪器运行的操作,所述操作通过将含有已知量的葡萄糖的对照溶液加入到适合与葡萄糖反应并产生来自指示剂的光学响应的测试条中,然后测量响应,所述对照溶液含有可通过光学仪器识别并区别于指示剂的响应的标记物质。
12.如权利要求11所述的方法,其中标记物质所具有的对光学仪器的发光二极管的激发产生的特征性响应区别于指示剂的响应。
13.如权利要求11所述的方法,其中标记物质所具有的光的峰值吸光度区别于指示剂的吸光度。
14.如权利要求13所述的方法,其中标记物质是吲哚氰绿。
15.如权利要求14所述的方法,其中标记物质区别于四唑盐指示剂。
16.用来将血液样本中的葡萄糖含量与光学响应联系起来的光学仪器,所述的光学响应获自样本与适合通过与血液样本反应以提供光学响应的测试条的接触,所述光学仪器包括发光二极管,其用于激发用来将对照溶液与血液样本区别开的对照溶液中的标记物质产生响应。
17.如权利要求16所述的光学仪器,其中光学仪器汇集对葡萄糖的测量,并排除对对照溶液所做的这种测量。
18.如权利要求16所述的光学仪器,其中标记物质所具有的光的峰值吸光度区别于用于测量存在的葡萄糖的量的指示剂的峰值吸光度。
19.如权利要求18所述的光学仪器,其中标记物质是吲哚氰绿。
20.区分用于测量生物样本中的分析物的光学仪器中的对照溶液与生物样本的方法,该方法包括向对照溶液中加入标记对照溶液、并能使光学仪器鉴别该对照溶液以及将该对照溶液与生物样本区分开的物质的操作。
21.如权利要求20所述的方法,其中标记物质是适合溶解于对照溶液中的染料,该染料的吸收光的波长区别于表征分析物的光的波长。
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2005
- 2005-12-12 CA CA2590363A patent/CA2590363C/en not_active Expired - Fee Related
- 2005-12-12 RU RU2007126675/15A patent/RU2401429C2/ru not_active IP Right Cessation
- 2005-12-12 CN CN200580042776.9A patent/CN101076728A/zh active Pending
- 2005-12-12 EP EP05854032A patent/EP1869457B1/en not_active Not-in-force
- 2005-12-12 AT AT05854032T patent/ATE530906T1/de not_active IP Right Cessation
- 2005-12-12 WO PCT/US2005/045234 patent/WO2006065899A1/en active Application Filing
- 2005-12-12 BR BRPI0518638-2A patent/BRPI0518638A2/pt not_active IP Right Cessation
- 2005-12-12 MX MX2007006884A patent/MX2007006884A/es active IP Right Grant
- 2005-12-12 JP JP2007546856A patent/JP5009808B2/ja active Active
- 2005-12-12 US US11/792,194 patent/US8102517B2/en active Active
- 2005-12-13 TW TW094144094A patent/TW200634306A/zh unknown
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2007
- 2007-07-09 NO NO20073524A patent/NO20073524L/no not_active Application Discontinuation
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2011
- 2011-12-21 US US13/333,008 patent/US8416398B2/en not_active Expired - Fee Related
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2013
- 2013-03-06 US US13/787,305 patent/US8681324B2/en not_active Expired - Fee Related
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JP2008523414A (ja) | 2008-07-03 |
US8416398B2 (en) | 2013-04-09 |
US8102517B2 (en) | 2012-01-24 |
NO20073524L (no) | 2007-07-09 |
US8681324B2 (en) | 2014-03-25 |
EP1869457A1 (en) | 2007-12-26 |
US20120149048A1 (en) | 2012-06-14 |
EP1869457B1 (en) | 2011-10-26 |
US20080145878A1 (en) | 2008-06-19 |
MX2007006884A (es) | 2007-08-03 |
CA2590363C (en) | 2013-04-09 |
US20130183699A1 (en) | 2013-07-18 |
BRPI0518638A2 (pt) | 2008-12-02 |
RU2401429C2 (ru) | 2010-10-10 |
TW200634306A (en) | 2006-10-01 |
CA2590363A1 (en) | 2006-06-22 |
JP5009808B2 (ja) | 2012-08-22 |
US20140154719A1 (en) | 2014-06-05 |
WO2006065899A1 (en) | 2006-06-22 |
ATE530906T1 (de) | 2011-11-15 |
RU2007126675A (ru) | 2009-01-20 |
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