CN113588501A - 降低红细胞沉降速率 - Google Patents
降低红细胞沉降速率 Download PDFInfo
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- CN113588501A CN113588501A CN202110760446.4A CN202110760446A CN113588501A CN 113588501 A CN113588501 A CN 113588501A CN 202110760446 A CN202110760446 A CN 202110760446A CN 113588501 A CN113588501 A CN 113588501A
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- Prior art keywords
- sucralose
- blood sample
- blood
- formulation
- anticoagulant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 210000003743 erythrocyte Anatomy 0.000 title claims abstract description 91
- 238000004062 sedimentation Methods 0.000 title claims abstract description 83
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- 239000000203 mixture Substances 0.000 claims abstract description 128
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- 239000004376 Sucralose Substances 0.000 claims description 347
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- IJRKANNOPXMZSG-SSPAHAAFSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC(=O)CC(O)(C(O)=O)CC(O)=O IJRKANNOPXMZSG-SSPAHAAFSA-N 0.000 claims description 24
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Images
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
- G01N33/49—Blood
- G01N33/491—Blood by separating the blood components
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/80—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood groups or blood types or red blood cells
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- G01N2015/012—
Abstract
本发明涉及降低血液样品中的红细胞沉降速率。具体而言,提供了用于降低血液样品中的红细胞沉降速率的制剂、组合物、制品、试剂盒和方法。
Description
本申请是基于申请日为2016年12月6日,优先权日为2015年12月8日,申请号为201680081392.6,发明名称为:“降低红细胞沉降速率”的专利申请的分案申请。
交叉引用
本申请要求于2015年12月8日提交的美国临时申请第62/264,786号的权益,该临时申请通过引用以其全文并入本文。
发明背景
出于研究、诊断和治疗目的,存在对改进制剂和方法的需求,用于将血液沉降的速率降低一段时间,以足以供储存、运输和装运之用。本发明大体上涉及降低血液样品中的一个或多个红细胞的沉降速率。具体而言,本发明涉及用于降低血液样品中的红细胞沉降速率的制剂、组合物、制品、试剂盒和方法。
发明内容
在一些实施方案中,本文描述了用于降低血液样品中的红细胞沉降速率的体外方法,该方法包括:将血液样品与一定量的包含三氯蔗糖的制剂合并,其中所述量足以产生具有至少约5mM三氯蔗糖的三氯蔗糖浓度的经处理的血液样品,由此使所述红细胞沉降速率与未经处理的血液样品中的红细胞沉降速率相比降低。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约100mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约10mM三氯蔗糖至约100mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约20mM三氯蔗糖至约100mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约24mM三氯蔗糖至约100mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约15mM三氯蔗糖至约50mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约50mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约40mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约10mM三氯蔗糖至约35mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约10mM三氯蔗糖至约30mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约25mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖直至但不包括25mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约20mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约15mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约10mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约24mM的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约25mM的三氯蔗糖浓度。在一些实施方案中,红细胞沉降速率降低达所述未经处理的血液样品的红细胞沉降速率的至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%。在一些实施方案中,所述制剂为粉末、固体、冻干形式、溶液或水溶液的形式。在一些实施方案中,该制剂为粉末。在一些实施方案中,该制剂为固体。在一些实施方案中,该制剂是冻干的。在一些实施方案中,该制剂为溶液。在一些实施方案中,该溶液为水溶液。在一些实施方案中,该制剂由三氯蔗糖组成。在一些实施方案中,该制剂进一步包含抗凝剂。在一些实施方案中,该抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。在一些实施方案中,该抗凝剂为酸柠檬酸葡萄糖溶液(ACD)。在一些实施方案中,该抗凝剂为肝素钠。在一些实施方案中,该抗凝剂为氟化钠。在一些实施方案中,该抗凝剂为肝素锂。在一些实施方案中,该抗凝剂为乙二胺四乙酸三钾(K3EDTA)。在一些实施方案中,该抗凝剂为乙二胺四乙酸二钾(K2EDTA)。在一些实施方案中,该抗凝剂为蛭素。在一些实施方案中,该抗凝剂为聚茴香脑磺酸钠(SPS)。在一些实施方案中,所述制剂容纳在采血管内,并且所述合并步骤发生在该采血管内。在一些实施方案中,该采血管为抽空的采血管。在一些实施方案中,所述血液从受试者采集。在一些实施方案中,该受试者为哺乳动物。在一些实施方案中,该受试者为人。
在一些实施方案中,本文描述了用于使一个或多个红细胞在血液样品中保持悬浮的体外方法,该方法包括:将血液样品与一定量的包含三氯蔗糖的制剂合并,其中所述量足以产生具有至少约5mM三氯蔗糖的三氯蔗糖浓度的经处理的血液样品,由此与未经处理的血液样品相比,所述一个或多个红细胞保持悬浮至少30分钟的时间。在一些实施方案中,所述一个或多个红细胞保持悬浮至少10分钟、至少20分钟、至少30分钟、至少40分钟、至少50分钟、至少60分钟、至少90分钟、至少2小时、至少3小时、至少4小时、至少5小时、至少6小时、至少7小时、至少8小时、至少10小时、至少12小时、至少24小时或至少48小时的时间。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约100mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约10mM三氯蔗糖至约100mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约20mM三氯蔗糖至约100mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约24mM三氯蔗糖至约100mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约15mM三氯蔗糖至约50mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约50mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约40mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约10mM三氯蔗糖至约35mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约10mM三氯蔗糖至约30mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约25mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖直至但不包括25mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约20mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约15mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约10mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约24mM的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约25mM的三氯蔗糖浓度。在一些实施方案中,与未经处理的血液样品相比,经处理的血液样品中至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%的所述一个或多个红细胞保持悬浮。在一些实施方案中,该制剂为粉末。在一些实施方案中,该制剂为固体。在一些实施方案中,该制剂是冻干的。在一些实施方案中,该制剂为溶液。在一些实施方案中,该溶液为水溶液。在一些实施方案中,该制剂由三氯蔗糖组成。在一些实施方案中,该制剂进一步包含抗凝剂。在一些实施方案中,该抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。在一些实施方案中,该抗凝剂为酸柠檬酸葡萄糖溶液(ACD)。在一些实施方案中,该抗凝剂为肝素钠。在一些实施方案中,该抗凝剂为氟化钠。在一些实施方案中,该抗凝剂为肝素锂。在一些实施方案中,该抗凝剂为乙二胺四乙酸三钾(K3EDTA)。在一些实施方案中,该抗凝剂为乙二胺四乙酸二钾(K2EDTA)。在一些实施方案中,该抗凝剂为蛭素。在一些实施方案中,该抗凝剂为聚茴香脑磺酸钠(SPS)。在一些实施方案中,所述制剂容纳在采血管内,并且所述合并步骤发生在该采血管内。在一些实施方案中,该采血管为抽空的采血管。在一些实施方案中,所述血液样品从受试者采集。在一些实施方案中,该受试者为哺乳动物。在一些实施方案中,该受试者为人。
在一些实施方案中,本文描述了包含血液样品和三氯蔗糖的组合物,其中该三氯蔗糖的浓度为约5mM三氯蔗糖直至约100mM三氯蔗糖。在一些实施方案中,该三氯蔗糖的浓度为约10mM三氯蔗糖至约100mM三氯蔗糖。在一些实施方案中,该三氯蔗糖的浓度为约20mM三氯蔗糖至约100mM三氯蔗糖。在一些实施方案中,该三氯蔗糖的浓度为约24mM三氯蔗糖至约100mM三氯蔗糖。在一些实施方案中,该三氯蔗糖的浓度为约15mM三氯蔗糖至约50mM三氯蔗糖。在一些实施方案中,该三氯蔗糖的浓度为约5mM三氯蔗糖至约50mM三氯蔗糖。在一些实施方案中,该三氯蔗糖的浓度为约5mM三氯蔗糖至约40mM三氯蔗糖。在一些实施方案中,所述经处理的血液样品具有约10mM三氯蔗糖至约35mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,所述经处理的血液样品具有约10mM三氯蔗糖至约30mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该三氯蔗糖的浓度为约5mM三氯蔗糖直至但不包括25mM三氯蔗糖。在一些实施方案中,该三氯蔗糖的浓度为约5mM三氯蔗糖至约20mM三氯蔗糖。在一些实施方案中,该三氯蔗糖的浓度为约5mM三氯蔗糖至约15mM三氯蔗糖。在一些实施方案中,该三氯蔗糖的浓度为约5mM三氯蔗糖至约10mM三氯蔗糖。在一些实施方案中,所述经处理的血液样品具有约24mM的三氯蔗糖浓度。在一些实施方案中,所述经处理的血液样品具有约25mM的三氯蔗糖浓度。在一些实施方案中,所述组合物进一步包含抗凝剂。在一些实施方案中,该抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。在一些实施方案中,该抗凝剂为酸柠檬酸葡萄糖溶液(ACD)。在一些实施方案中,该抗凝剂为肝素钠。在一些实施方案中,该抗凝剂为氟化钠。在一些实施方案中,该抗凝剂为肝素锂。在一些实施方案中,该抗凝剂为乙二胺四乙酸三钾(K3EDTA)。在一些实施方案中,该抗凝剂为乙二胺四乙酸二钾(K2EDTA)。在一些实施方案中,该抗凝剂为蛭素。在一些实施方案中,该抗凝剂为聚茴香脑磺酸钠(SPS)。在一些实施方案中,所述组合物容纳在采血管内。在一些实施方案中,该采血管为抽空的采血管。在一些实施方案中,所述血液从受试者采集。在一些实施方案中,该受试者为哺乳动物。在一些实施方案中,该受试者为人。
在一些实施方案中,本文描述了包含容纳在采血管内的三氯蔗糖的制品,其中该三氯蔗糖的量足以在血液样品中产生约5mM三氯蔗糖至约100mM三氯蔗糖的最终浓度。在一些实施方案中,该三氯蔗糖的量足以产生约10mM三氯蔗糖至约100mM三氯蔗糖的最终浓度。在一些实施方案中,该三氯蔗糖的量足以产生约20mM三氯蔗糖至约100mM三氯蔗糖的最终浓度。在一些实施方案中,该三氯蔗糖的量足以产生约24mM三氯蔗糖至约100mM三氯蔗糖的最终浓度。在一些实施方案中,该三氯蔗糖的量足以产生约15mM三氯蔗糖至约50mM三氯蔗糖的最终浓度。在一些实施方案中,该三氯蔗糖的量足以在血液样品中产生约5mM三氯蔗糖至约50mM三氯蔗糖的最终浓度。在一些实施方案中,该三氯蔗糖的量足以在血液样品中产生约5mM三氯蔗糖至约40mM三氯蔗糖的最终浓度。在一些实施方案中,所述经处理的血液样品具有约10mM三氯蔗糖至约35mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,所述经处理的血液样品具有约10mM三氯蔗糖至约30mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该三氯蔗糖的量足以在血液样品中产生约5mM三氯蔗糖直至但不包括25mM三氯蔗糖的最终浓度。在一些实施方案中,该三氯蔗糖的量足以在血液样品中产生约5mM三氯蔗糖至约20mM三氯蔗糖的最终浓度。在一些实施方案中,该三氯蔗糖的量足以在血液样品中产生约5mM三氯蔗糖至约15mM三氯蔗糖的最终浓度。在一些实施方案中,该三氯蔗糖的量足以在血液样品中产生约5mM三氯蔗糖至约10mM三氯蔗糖的最终浓度。在一些实施方案中,所述经处理的血液样品具有约24mM的三氯蔗糖浓度。在一些实施方案中,所述经处理的血液样品具有约25mM的三氯蔗糖浓度。在一些实施方案中,该三氯蔗糖为粉末。在一些实施方案中,该三氯蔗糖为固体。在一些实施方案中,该三氯蔗糖是冻干的。在一些实施方案中,该三氯蔗糖在溶液中。在一些实施方案中,该三氯蔗糖溶液为水溶液。在一些实施方案中,所述采血管为抽空的采血管。在一些实施方案中,所述制品进一步包含抗凝剂。在一些实施方案中,该抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。在一些实施方案中,该抗凝剂为酸柠檬酸葡萄糖溶液(ACD)。在一些实施方案中,该抗凝剂为肝素钠。在一些实施方案中,该抗凝剂为氟化钠。在一些实施方案中,该抗凝剂为肝素锂。在一些实施方案中,该抗凝剂为乙二胺四乙酸三钾(K3EDTA)。在一些实施方案中,该抗凝剂为乙二胺四乙酸二钾(K2EDTA)。在一些实施方案中,该抗凝剂为蛭素。在一些实施方案中,该抗凝剂为聚茴香脑磺酸钠(SPS)。
在一些实施方案中,本文描述了包含本文提供的制品和包装插页的试剂盒。
本申请包括以下实施方案:
实施方案1.一种用于降低血液样品中的红细胞沉降速率的体外方法,其包括:将血液样品与一定量的包含三氯蔗糖的制剂合并,所述量足以产生具有约5mM至约50mM三氯蔗糖的三氯蔗糖浓度的经处理的血液样品,由此使所述红细胞沉降速率与未经处理的血液样品中的红细胞沉降速率相比降低。
实施方案2.根据实施方案1所述的方法,其中所述经处理的血液样品具有约5mM直至25mM三氯蔗糖的三氯蔗糖浓度。
实施方案3.根据实施方案1-2中任一项所述的方法,其中红细胞沉降速率降低达所述未经处理的血液样品的红细胞沉降速率的至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%。
实施方案4.根据实施方案1-3中任一项所述的方法,其中所述制剂为粉末、固体、冻干形式、溶液或水溶液的形式。
实施方案5.根据实施方案1-4中任一项所述的方法,其中所述制剂由三氯蔗糖组成。
实施方案6.根据实施方案1-4中任一项所述的方法,其中所述制剂进一步包含抗凝剂。
实施方案7.根据实施方案6所述的方法,其中所述抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。
实施方案8.根据实施方案1-7中任一项所述的方法,其中所述制剂容纳在采血管内,并且所述合并步骤发生在所述采血管内。
实施方案9.根据实施方案8所述的方法,其中所述采血管为抽空的采血管。
实施方案10.一种用于使一个或多个红细胞在血液样品中保持悬浮的体外方法,其包括:将血液样品与一定量的包含三氯蔗糖的制剂合并,所述量足以产生具有约5mM至约50mM的三氯蔗糖浓度的经处理的血液样品,由此与未经处理的血液样品相比,所述一个或多个红细胞保持悬浮至少30分钟的时间。
实施方案11.根据实施方案10所述的方法,其中所述经处理的血液样品具有约5mM直至25mM三氯蔗糖的三氯蔗糖浓度。
实施方案12.根据实施方案10-11中任一项所述的方法,其中所述一个或多个红细胞保持悬浮至少10分钟、至少20分钟、至少30分钟、至少40分钟、至少50分钟、至少1小时、至少2小时、至少3小时、至少4小时、至少5小时、至少6小时、至少7小时、至少8小时、至少10小时、至少12小时、至少24小时或至少48小时的时间。
实施方案13.根据实施方案10-12中任一项所述的方法,其中所述经处理的血液样品具有约5mM三氯蔗糖至约50mM三氯蔗糖的三氯蔗糖浓度。
实施方案14.根据实施方案10-13中任一项所述的方法,其中与所述未经处理的血液样品相比,所述经处理的血液样品中至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%的所述一个或多个红细胞保持悬浮。
实施方案15.根据实施方案10-14中任一项所述的方法,其中所述制剂为粉末、固体、冻干形式、溶液或水溶液的形式。
实施方案16.根据实施方案10-15中任一项所述的方法,其中所述制剂由三氯蔗糖组成。
实施方案17.根据实施方案10-15中任一项所述的方法,其中所述制剂进一步包含抗凝剂。
实施方案18.根据实施方案17所述的方法,其中所述抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。
实施方案19.根据实施方案10-18中任一项所述的方法,其中所述制剂容纳在采血管内,并且所述合并步骤发生在所述采血管内。
实施方案20.根据实施方案19所述的方法,其中所述采血管为抽空的采血管。
实施方案21.一种包含血液样品和三氯蔗糖的组合物,其中所述三氯蔗糖的浓度为约5mM三氯蔗糖直至但不包括50mM三氯蔗糖。
实施方案22.根据实施方案21所述的组合物,其中所述三氯蔗糖的浓度为约5mM三氯蔗糖直至但不包括25mM三氯蔗糖。
实施方案23.根据实施方案21所述的组合物,其进一步包含抗凝剂。
实施方案24.根据实施方案23所述的组合物,其中所述抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。
实施方案25.根据实施方案21所述的组合物,其中所述血液为人血液。
实施方案26.一种制品,其包含采血管,所述采血管包含三氯蔗糖,该三氯蔗糖的量足以在血液样品中产生约5mM三氯蔗糖至约50mM三氯蔗糖的最终浓度。
实施方案27.根据实施方案26所述的制品,其中所述采血管为抽空的采血管。
实施方案28.根据实施方案26-27中任一项所述的制品,其中所述采血管进一步包含抗凝剂。
实施方案29.根据实施方案28所述的制品,其中所述抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)
援引并入
本说明书中所提及的所有出版物、专利和专利申请均通过引用而并入本文,其程度如同特别地且单独地指出每个单独的出版物、专利或专利申请均通过引用而并入。
附图说明
在所附权利要求书中具体阐述了本发明的新颖特征。通过参考以下对利用了本发明原理的说明性实施方案加以阐述的详细描述以及附图,将会获得对本发明的特征和优点的更好理解,在附图中:
图1A-1C图示了在添加0.5M三氯蔗糖、PBS或盐水之后,全血中红细胞沉降速率的降低。储存持续0小时(图1A)、6小时(图1B)和24小时(图1C)。NF=无制剂对照。
图2图示了在添加指定的三氯蔗糖溶液、指定的糖类、PBS或盐水之后,全血中红细胞的沉降速率。储存达1小时(上图)和6小时(中图)。下图中图示了通过在储存7小时后进行离心来降低沉降速率而导致的溶血缺乏。
图3图示了在将粉末形式的三氯蔗糖添加至指定的最终浓度之后,红细胞的沉降速率。储存样品达1小时(上图)和6小时(下图)。NF=无制剂对照。
图4图示了不同抗凝剂对从全血采集的红细胞的沉降速率的影响。样品被采集到含有指定抗凝剂的采血管中。在添加0.5M三氯蔗糖溶液或PBS之后,储存样品达2小时(上图)和8小时(下图)。NF=无制剂对照。
图5图示了与PBS、指定的多元醇和指定的卤化多元醇相比,0.5M三氯蔗糖溶液对全血中红细胞的沉降速率的影响。储存样品达2小时。NF=无制剂对照。
具体实施方式
本发明涉及用于降低血液样品中的一个或多个红细胞的沉降速率的制剂、组合物、制品、试剂盒和方法。
在一些实施方案中,本文提供的制剂、方法和组合物提供了降低的沉降速率,并因此提供了血液样品中的一个或多个红细胞在微流体装置的注射部位的储存。降低血液样品中的一个或多个红细胞的沉降速率允许将一个或多个红细胞缓慢注射至显微注射装置中而无需预先的样品混合。
红细胞沉降速率被用作诸如多发性骨髓瘤、颞动脉炎、风湿性多肌痛、系统性红斑狼疮和类风湿性关节炎等疾病的预后的参数。因此,在一些实施方案中,本文提供的用于降低血液样品中的红细胞沉降速率的制剂、方法和组合物可以使患有与红细胞沉降速率增加相关的疾病的患者受益。
定义
除非上下文中另有明确规定,否则如本说明书及随附的权利要求书中所用的,单数形式“一个”、“一种”和“该”包括其复数个指代物。因此,例如,提及“该方法”包括本领域技术人员在阅读此公开内容等之后将会明白的一种或多种方法和/或本文所述类型的步骤。
如本文所使用的,“约”在提及可测值如量、时距等时,意在包括指定值的±20%或±10%或±5%或甚至±1%的偏差,因为此类偏差对于所公开的组合物或实施所公开的方法是合适的。
除非另有定义,否则本文中所采用的所有技术和科学术语具有与本发明所属领域的技术人员所普遍理解的相同的含义。
如本文中所使用的,术语“环境温度”是指平常的室内室温。在一些实施方案中,环境温度为15℃到32℃。在一些实施方案中,环境温度为20℃到27℃。
如本文所使用的,术语“降低的沉降速率”、“降低沉降速率”和“沉降速率降低”是指材料降低血液样品中红细胞的沉降速率的能力。在一些实施方案中,红细胞沉降速率降低达未经处理的血液样品的红细胞沉降速率的至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%。在一些实施方案中,沉降速率的降低是指材料防止血液样品中的一个或多个红细胞由于重力而从悬浮中沉降的能力。在一些实施方案中,一个或多个红细胞保持悬浮至少30分钟。在一些实施方案中,与未经处理的血液样品相比,经处理的血液样品中至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%的一个或多个红细胞保持悬浮。在一些实施方案中,一个或多个红细胞保持悬浮至少10分钟、至少20分钟、至少30分钟、至少40分钟、至少50分钟、至少60分钟、至少90分钟、至少2小时、至少3小时、至少4小时、至少5小时、至少6小时、至少7小时、至少8小时、至少10小时、至少12小时、至少24小时或至少48小时。
配制试剂
pH缓冲液
根据某些实施方案,本文描述的用于降低血液样品中一个或多个红细胞的沉降速率的制剂和组合物包括一种或多种pH缓冲液。在一些实施方案中,该pH缓冲液是因其对抗溶液(如在存在pH缓冲液的水溶液中)的pH变化的能力而为本领域所知的大量化合物中的任意化合物。用于包含在稳定储存组合物中的一种或多种具体pH缓冲液的选择可基于本公开内容以及根据本领域的常规实践来进行,并且可受到多种因素的影响,包括须维持的pH、生物样品的性质、将采用的溶剂条件、将采用的制剂的其它组分以及其它条件。例如,一般而言,pH缓冲液以在质子解离常数(pKa)的约0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9或1.0个pH单位以内的pH使用,质子解离常数为缓冲液的一个特征。
pH缓冲液的非限制性实例包括柠檬酸、酒石酸、苹果酸、磺基水杨酸、磺基间苯二甲酸、草酸、硼酸盐、CAPS(3-(环己基氨基)-1-丙磺酸)、CAPSO(3-(环己基氨基)-2-羟基-1-丙磺酸)、EPPS(4-(2-羟乙基)-1-哌嗪丙磺酸)、HEPES(4-(2-羟乙基)哌嗪-1-乙磺酸)、MES(2-(N-吗啉基)乙磺酸)、MOPS(3-(N-吗啉基)丙磺酸)、MOPSO(3-吗啉基-2-羟基丙磺酸)、PIPES(1,4-哌嗪二乙磺酸)、TAPS(N-[三(羟甲基)甲基]-3-氨基丙磺酸)、TAPSO(2-羟基-3-[三(羟甲基)甲基氨基]-1-丙磺酸)、TES(N-[三(羟甲基)甲基]-2-氨基乙磺酸)、bicine(N,N-二(2-羟乙基)甘氨酸)、tricine(N-[三(羟甲基)甲基]甘氨酸)、tris(三(羟甲基)氨基甲烷)以及bis-tris(2-[二(2-羟乙基)氨基]-2-(羟甲基)-1,3-丙二醇)。在一些实施方案中,所述制剂具有约4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9或9.0的pH。
二糖衍生物
在某些实施方案中,用于降低血液样品中红细胞的沉降速率的制剂或组合物包含至少一种卤化二糖衍生物。在一些实施方案中,该卤化二糖衍生物是二氯化二糖或三氯化二糖。在一些实施方案中,出乎意料地,此类二氯化二糖或三氯化二糖能够单独地或在仅缓冲液的存在下降低血液样品中红细胞的沉降速率。卤化二糖衍生物是已知的,例如,参见美国专利公开第2014/0065062号,并且包括三氯蔗糖(1,6-二氯-1,6-二脱氧-β-D-呋喃果糖基-4-氯-4-脱氧-α-D-吡喃半乳糖苷)、三氯化麦芽糖、1,6-二氯-1,6-二脱氧-β-D-呋喃果糖基-4-氯-4-脱氧-6-O-单十二烷酸酯-α-D-吡喃半乳糖苷和1,6-二氯-1,6-二脱氧-β-D-呋喃果糖基-4-氯-4-脱氧-6-O-单十四烷酸酯-α-D-吡喃半乳糖苷。为了包含在用于降低血液样品中红细胞的沉降速率的制剂或组合物中而做出的对一种或多种特定的卤化二糖衍生物的选择可以基于本公开内容以及根据本领域的常规实践来进行,并且可能受到包括其它制剂组分在内的多种因素的影响。
在一些实施方案中,所述卤化二糖衍生物为三氯蔗糖。在一些实施方案中,该三氯蔗糖作为用于与血液样品混合的制剂以溶液提供。在一些实施方案中,该溶液为水溶液。在一些实施方案中,该三氯蔗糖在制剂中以约5-500mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约10-500mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约50-500mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约100-500mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约250-500mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约5-630mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约5-750mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约10-750mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约50-750mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约100-750mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约250-750mM存在。在一些实施方案中,该制剂是水和三氯蔗糖的混合物。
在一些实施方案中,所述制剂以在与血液样品混合时足以产生约5至约25mM的三氯蔗糖最终浓度的量提供。在一些实施方案中,该三氯蔗糖在制剂中以约500mM存在,并以1∶20(v/v)(制剂比血液)的比例与血液样品混合。在一些实施方案中,该三氯蔗糖在制剂中以大于25mM直至100mM存在。在一些实施方案中,该三氯蔗糖在制剂中以约13-24mM存在。在一些实施方案中,该三氯蔗糖作为用于与血液样品混合的制剂以粉末形式提供。在一些实施方案中,该三氯蔗糖粉末以在与血液样品混合时足以产生约5至约25mM的三氯蔗糖最终浓度的量提供。
在一些实施方案中,当与血液样品混合时,所述三氯蔗糖以约5-100mM的最终浓度存在。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约5-50mM的最终浓度存在。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约5-25mM的最终浓度存在。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约5mM直至但不包括25mM的最终浓度存在。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约5-20mM的最终浓度存在。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约5-15mM的最终浓度存在。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约10-20mM的最终浓度存在。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约10-15mM的最终浓度存在。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约5-10mM的最终浓度存在。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约25mM的最终浓度存在。
抗凝剂
在一些实施方案中,在本文描述的制剂和组合物中包含抗凝剂。此类抗凝剂在本领域中是已知的。示例性的抗凝剂包括酸柠檬酸葡萄糖溶液(ACD)、乙二胺四乙酸(EDTA)、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、肝素、肝素钠、氟化钠、肝素锂、柠檬酸钠、蛭素和聚茴香脑磺酸钠(SPS)。在一些实施方案中,该抗凝剂被容纳在采血管内。
用于降低血液样品中的红细胞沉降速率的示例性制剂
在一些实施方案中,本文描述了包含三氯蔗糖的制剂。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约5mM三氯蔗糖至约50mM三氯蔗糖的最终浓度存在。在一些实施方案中,当与血液样品混合时,该三氯蔗糖以约5mM三氯蔗糖至约25mM三氯蔗糖的最终浓度存在。在一些实施方案中,该三氯蔗糖以约5mM三氯蔗糖直至但不包括25mM三氯蔗糖的最终浓度存在。在一些实施方案中,该三氯蔗糖以约5mM三氯蔗糖至约20mM三氯蔗糖的最终浓度存在。在一些实施方案中,该三氯蔗糖以约5mM三氯蔗糖至约15mM三氯蔗糖的最终浓度存在。在一些实施方案中,该三氯蔗糖以约5mM三氯蔗糖至约10mM三氯蔗糖的最终浓度存在。在一些实施方案中,该三氯蔗糖作为溶液存在。在一些实施方案中,该溶液为水溶液。在一些实施方案中,该三氯蔗糖作为粉末存在。在一些实施方案中,所述制剂进一步包含抗凝剂。在一些实施方案中,该抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。在一些实施方案中,该抗凝剂为酸柠檬酸葡萄糖溶液(ACD)。在一些实施方案中,该抗凝剂为肝素钠。在一些实施方案中,该抗凝剂为氟化钠。在一些实施方案中,该抗凝剂为肝素锂。在一些实施方案中,该抗凝剂为乙二胺四乙酸三钾(K3EDTA)。在一些实施方案中,该抗凝剂为乙二胺四乙酸二钾(K2EDTA)。在一些实施方案中,该抗凝剂为蛭素。在一些实施方案中,该抗凝剂为聚茴香脑磺酸钠(SPS)。在一些实施方案中,所述制剂被容纳在采血管内。
制备用于降低血液样品中的红细胞沉降速率的制剂的方法
制备用于降低血液样品中的红细胞沉降速率的本文所述制剂的方法采用本领域技术人员所公知的技术并且通常使用商购可得的试剂。在一些实施方案中,将该制剂被制备为制剂试剂的浓缩(例如2倍、5倍、10倍、20倍浓缩等)储备溶液,以便以适当的比例与血液样品混合,从而在血液样品中产生所需的三氯蔗糖最终浓度。
沉降速率降低的红细胞在血液样品中的组合物
在一些实施方案中,本文描述了包含血液样品和三氯蔗糖的组合物,其中该三氯蔗糖的浓度为约5mM三氯蔗糖直至但不包括约25mM三氯蔗糖。在一些实施方案中,所述组合物进一步包含抗凝剂。在一些实施方案中,该抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。在一些实施方案中,该抗凝剂为酸柠檬酸葡萄糖溶液(ACD)。在一些实施方案中,该抗凝剂为酸柠檬酸葡萄糖溶液A(ACD-A)。在一些实施方案中,该抗凝剂是酸柠檬酸葡萄糖溶液B(ACD-B)。在一些实施方案中,该抗凝剂为肝素钠。在一些实施方案中,该抗凝剂为氟化钠。在一些实施方案中,该抗凝剂为肝素锂。在一些实施方案中,该抗凝剂为乙二胺四乙酸三钾(K3EDTA)。在一些实施方案中,该抗凝剂为乙二胺四乙酸二钾(K2EDTA)。在一些实施方案中,该抗凝剂为蛭素。在一些实施方案中,该抗凝剂为聚茴香脑磺酸钠(SPS)。在一些实施方案中,所述组合物被容纳在采血管内。在一些实施方案中,该采血管为抽空的采血管。在一些实施方案中,所述血液从受试者采集。在一些实施方案中,该受试者为哺乳动物。在一些实施方案中,该受试者为人。在一些实施方案中,在分析之前,将沉降速率降低的一个或多个红细胞在血液样品中的组合物在例如微流体装置中的本文所述制剂中储存延长的时间。
制品
在某些实施方案中,提供了制品,其包含本文提供的制剂,该制剂被容纳在合适的采血管、采血容器或采血器皿内以用于采集生物样品。在一些实施方案中,这些制品被用于在生物样品采集时降低血液样品中一个或多个红细胞的沉降速率。在某些实施方案中,该采血管为具有低于大气压的气压的抽空采血管,用于抽取预定体积的全血。在一些实施方案中,该采血管容纳有约28.6mg的三氯蔗糖粉末,并且该采血管的大小被设计用于容纳3.0mL血液的抽血体积,从而在添加3.0mL血液之后产生约24mM的最终三氯蔗糖浓度。在一些实施方案中,该采血管容纳有约33.4mg的三氯蔗糖粉末,并且该采血管的大小被设计用于容纳3.5mL血液的抽血体积。在一些实施方案中,该采血管容纳有约42.9mg的三氯蔗糖粉末,并且该采血管的大小被设计用于容纳4.5mL血液的抽血体积。在一些实施方案中,该采血管含有约52.4mg的三氯蔗糖粉末,并且该采血管的大小被设计用于容纳5.5mL血液的抽血体积。在一些实施方案中,该采血管容纳有约95.4mg的三氯蔗糖粉末,并且该采血管的大小被设计用于容纳10mL血液的抽血体积。在一些实施方案中,这些制品在本文描述的试剂盒及方法中使用。
试剂盒
在某些实施方案中,提供了包含任意本文所述制品和包装插页的试剂盒。在一些实施方案中,试剂盒的组分在容器中提供。在一些实施方案中,该容器为带隔室的塑料包围结构。在一些实施方案中,该容器包括可严密密封的盖子,使得该试剂盒的内容物可以被消毒和密封以供储存。
用于降低血液样品中红细胞的沉降速率的方法
在一些实施方案中,本文描述了用于降低血液样品中的红细胞沉降速率的体外方法,该方法包括:将血液样品与一定量的包含三氯蔗糖的制剂合并,其中所述量足以产生具有至少约5mM三氯蔗糖的三氯蔗糖浓度的经处理的血液样品,由此使红细胞沉降速率与未经处理的血液样品中的红细胞沉降速率相比降低。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约50mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约25mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖直至但不包括25mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,红细胞沉降速率降低未经处理的血液样品的红细胞沉降速率的至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%。在一些实施方案中,该制剂为粉末。在一些实施方案中,该制剂为溶液。在一些实施方案中,该溶液为水溶液。在一些实施方案中,该制剂由三氯蔗糖组成。在一些实施方案中,该制剂进一步包含抗凝剂。在一些实施方案中,该抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。在一些实施方案中,该抗凝剂为酸柠檬酸葡萄糖溶液(ACD)。在一些实施方案中,该抗凝剂为肝素钠。在一些实施方案中,该抗凝剂为氟化钠。在一些实施方案中,该抗凝剂为肝素锂。在一些实施方案中,该抗凝剂为乙二胺四乙酸三钾(K3EDTA)。在一些实施方案中,该抗凝剂为乙二胺四乙酸二钾(K2EDTA)。在一些实施方案中,该抗凝剂为蛭素。在一些实施方案中,该抗凝剂为聚茴香脑磺酸钠(SPS)。在一些实施方案中,所述制剂被容纳在采血管内,并且所述合并步骤发生在该采血管内。在一些实施方案中,该采血管为抽空的采血管。在一些实施方案中,血液从受试者采集。在一些实施方案中,该受试者为哺乳动物。在一些实施方案中,该受试者为人。
在一些实施方案中,本文描述了用于使一个或多个红细胞在血液样品中保持悬浮的方法,该方法包括:将血液样品与一定量的包含三氯蔗糖的制剂合并,其中所述量足以产生具有至少约5mM三氯蔗糖的三氯蔗糖浓度的经处理的血液样品,由此与未经处理的血液样品相比,所述一个或多个红细胞保持悬浮至少30分钟的时间。在一些实施方案中,所述一个或多个红细胞保持悬浮至少10分钟、至少20分钟、至少30分钟、至少40分钟、至少50分钟、至少1小时、至少2小时、至少3小时、至少4小时、至少5小时、至少6小时、至少7小时、至少8小时、至少10小时、至少12小时、至少24小时或至少48小时的时间。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖至约25mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,该经处理的血液样品具有约5mM三氯蔗糖直至但不包括25mM三氯蔗糖的三氯蔗糖浓度。在一些实施方案中,与未经处理的血液样品相比,在经处理的血液样品中至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%的所述一个或多个红细胞保持悬浮。在一些实施方案中,该制剂为粉末。在一些实施方案中,该制剂为溶液。在一些实施方案中,该溶液为水溶液。在一些实施方案中,该制剂由三氯蔗糖组成。在一些实施方案中,该制剂进一步包含抗凝剂。在一些实施方案中,该抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。在一些实施方案中,该抗凝剂为酸柠檬酸葡萄糖溶液(ACD)。在一些实施方案中,该抗凝剂为肝素钠。在一些实施方案中,该抗凝剂为氟化钠。在一些实施方案中,该抗凝剂为肝素锂。在一些实施方案中,该抗凝剂为乙二胺四乙酸三钾(K3EDTA)。在一些实施方案中,该抗凝剂为乙二胺四乙酸二钾(K2EDTA)。在一些实施方案中,该抗凝剂为蛭素。在一些实施方案中,该抗凝剂为聚茴香脑磺酸钠(SPS)。在一些实施方案中,所述制剂被容纳在采血管内,并且所述合并步骤发生在该采血管内。在一些实施方案中,该采血管为抽空的采血管。在一些实施方案中,所述血液样品从受试者采集。在一些实施方案中,该受试者为哺乳动物。在一些实施方案中,该受试者为人。
采血管、采血袋、采血容器和采血器皿是本领域公知的,并且已经被执业医师使用了数十年。可使用本领域技术人员通常采用的任何方法或设备如静脉穿刺或手指针刺来获得为了降低红细胞沉降速率而收集的血液。在一些实施方案中,当通过静脉穿刺采集血液时,在从受试者获得血液样品时,制剂位于采血管内,例如,真空管(采血管、Becton Dickinson或采血管、Greiner Bio-One)内。在一些实施方案中,当通过静脉穿刺采集血液时,在血液抽取后立即或不久向已获得的全血样品添加制剂。
在一些实施方案中,如本文所述的方法采用所公开的制品和试剂盒。
以下实施例以说明而非限制的方式给出。
实施例1
通过添加三氯蔗糖降低全血中的红细胞沉降速率
本实施例描述了通过添加三氯蔗糖降低全血中的红细胞沉降。
将新鲜血液采集到BD K2EDTA 管中并合并。通过将952μL新鲜血液等分至含有48μL制剂的2mL离心管中,将血液与0.5M三氯蔗糖溶液以20∶1的比例混合,得到约24mM的三氯蔗糖的浓度。将48μL PBS和0.9%盐水作为对照。不添加制剂(NF)的血液作为另外的对照。将经填充的离心管轻轻颠倒五次以便混合,并在约25℃下于台面上直立储存。在0小时(图1A)、6小时(图1B)和24小时(图1C)时相对于白色背景对管进行拍照以用于沉降速率的视觉分析。
如图1A-C所示,与仅全血(NF)或添加PBS或盐水后的全血相比,含有三氯蔗糖的K2EDTA管中所采集的全血在等份于环境温度下储存6小时和24小时后具有较低的红细胞沉降速率。
实施例2
三氯蔗糖浓度和其它糖类对降低红细胞沉降速率的影响
本实施例说明了三氯蔗糖浓度和其它糖类对降低全血中的红细胞沉降速率的影响。
将新鲜血液采集到BD K2EDTA 管中并合并。将952μL新鲜血液等分至2mL离心管中,每个离心管含有48μL的图2指定浓度的三氯蔗糖,或指定浓度的指定糖类(ML848、二氯化单糖、或DG783、单氟化单糖)。通过在水中将0.5M三氯蔗糖稀释至10mM来制备不同浓度的三氯蔗糖溶液。除了最高浓度的制剂具有500mOsmol的摩尔渗透压浓度之外,用NaCl将制剂调节至300mOsmol。将48μL PBS和0.9%盐水作为对照。图2中所示的三氯蔗糖或指定糖类的最终浓度如下(从左至右):24mM三氯蔗糖、12mM三氯蔗糖、6.24mM三氯蔗糖、2.88mM三氯蔗糖、1.44mM三氯蔗糖、0.96mM三氯蔗糖、0.48mM三氯蔗糖、24mM蔗糖、2.4mM蔗糖、24mM海藻糖、24mM松三糖、4.8mM ML848和24mM DG783。
将经填充的离心管轻轻颠倒五次以便混合,并在约25℃下于台面上直立储存。在1小时(图2,上图)和6小时(图2,中图)时相对于白色背景对管进行拍照以用于沉降速率的视觉分析。储存7小时后,将管在3000rpm下离心20min,以通过视觉分析确定溶血对沉降速率的影响(图2,下图)。
图2示出了在将等份储存在环境温度下1小时(上图)和6小时(中图)之后,含有高浓度三氯蔗糖的K2EDTA管中所采集的全血具有较低的红细胞沉降速率。在最终三氯蔗糖浓度低于5mM的样品中,或在向全血中添加蔗糖、海藻糖、松三糖、ML848、DG783、PBS或盐水之后的样品中未观察到较低的红细胞沉降速率。
在高浓度三氯蔗糖的存在下全血的均匀性并不是由于红细胞的过度溶血,如通过在储存7小时后离心样品所示(图2,下图)。离心导致血浆的明显分离而没有血浆层的着色,与盐水和PBS样品对照所观察的类似(图2,下图)。在40mM或低于40mM的最终三氯蔗糖浓度下未观察到显著溶血。
实施例3
作为粉末添加的三氯蔗糖对降低红细胞沉降速率的影响
本实施例描述了以粉末形式添加三氯蔗糖对降低全血中的红细胞沉降速率的影响。
将新鲜血液采集到BD K2EDTA 管中并合并。将1mL新鲜血液等分至含有三氯蔗糖粉末的2mL离心管中。三氯蔗糖的最终浓度范围为7.5mM至100mM,对应于每mL血液3.0mg至39.8mg。无制剂(NF)对照样品未接受三氯蔗糖的添加。将管颠倒至少五次,直至管的底部没有可见的未溶解材料。将管在大约25℃下于台面上直立储存。在1小时(图3,上图)和6小时(图3,下图)时相对于白色背景对管进行拍照以用于沉降速率的视觉分析。
图3中的数据显示,红细胞沉降的速率与三氯蔗糖的浓度成反比。在三氯蔗糖浓度为24mM或更高时,观察到在环境温度下储存6小时的全血样品的均匀性,而较低浓度的三氯蔗糖导致红细胞与血浆层分离。
实施例4
血液采集条件对降低红细胞沉降速率的影响
本实施例描述了血液采集时存在的不同抗凝剂对降低全血中的红细胞沉降速率的影响。
为了筛选采集条件,将新鲜血液采集到一系列含有不同抗凝剂的BD或Greiner Bio-One 小体积采血管中,该抗凝剂包括酸柠檬酸葡萄糖溶液B(ACD-B)、乙二胺四乙酸三钾(K3EDTA)、肝素钠(NaHep)、肝素锂(LiHep)、氟化钠(NaF)和聚茴香脑磺酸钠(SPS)。向含有乙二胺四乙酸二钾(K2EDTA)的管中的采集作为对照。将952μL新鲜血液等分至含有48μL的0.5M三氯蔗糖或PBS的2mL离心管中。不添加制剂(NF)作为另外的对照。将经填充的离心管轻轻颠倒五次以便混合,并在约25℃下于台面上直立储存。在2小时(图4,上图)和8小时(图4,下图)时相对于白色背景对管进行拍照以用于沉降速率的视觉分析。如图4所示,对于在血液采集时采血管中存在的每种抗凝剂而言,添加0.5M三氯蔗糖直至经处理的样品中的最终三氯蔗糖浓度为24mM都导致红细胞沉降速率降低。相反,添加PBS对红细胞沉降速率没有影响。
实施例5
三氯蔗糖与多元醇和卤化多元醇相比对降低红细胞沉降速率的影响
本实施例描述了与多元醇和卤化多元醇相比,三氯蔗糖对降低全血中的红细胞沉降速率的影响。
将新鲜血液采集到BD K2EDTA 管中并合并。将952μL新鲜血液等分至含有48μL的0.5M三氯蔗糖、指定多元醇或指定卤化多元醇的溶液的2mL离心管中。用NaCl将0.25M的添加剂调节至300mOsmol。添加PBS且不添加制剂(NF)作为对照。将经填充的离心管轻轻颠倒五次以便混合,并在约25℃下于台面上直立储存。在2小时时相对于白色背景对管进行拍照以用于沉降速率的视觉分析。
图5中的数据显示,添加0.5M三氯蔗糖直至经处理的样品中的最终三氯蔗糖浓度为24mM导致红细胞沉降速率降低。相反,添加指定的多元醇或卤化多元醇对红细胞沉降没有明显影响。
除非上下文另有要求,否则在本说明书和权利要求书通篇中,可与“包括”、“含有”或“特征在于”互换使用的词语“包含”及其变化形式是包含性或开放式语言,并且不排除另外的、未列举的要素或方法步骤。短语“由……组成”排除权利要求中未指明的任何要素、步骤或成分。短语“基本由……组成”将权利要求的范围限制于指明的物质或步骤以及那些实质上不影响所请求保护的发明的基本特性及新特性的物质或步骤。本公开内容涵盖对应于这些短语中每一个的范围的本发明组合物及方法的实施方案。因此,包含所记载的要素或步骤的组合物或方法涵盖其中组合物或方法基本由这些要素或步骤组成或者由这些要素或步骤组成的具体实施方案。
本说明书通篇提及的“一个实施方案”或“实施方案”或“方面”意指与该实施方案相关联地描述的具体特征、结构或特性包含在本发明的至少一个实施方案中。因此,短语“在一个实施方案中”或“在实施方案中”在本说明书全文各处的出现并不一定都指的是同一个实施方案。此外,这些具体特征、结构或特性可以在一个或多个实施方案中以任何合适的方式组合。
以上描述的各种实施方案可进行组合以提供进一步的实施方案。可根据以上详述的说明对实施方案作出这些和其它改变。总之,在所附的权利要求中,所采用的术语不应解释为将权利要求限制于说明书和权利要求书中公开的具体实施方案,而应解释为包括这些权利要求所请求保护的所有可能的实施方案以及等同方案的全部范围。因此,权利要求不受公开内容的限制。
尽管本文中已经示出并描述了本发明的优选实施方案,但对于本领域技术人员显而易见的是这些实施方案仅以示例的方式提供。本领域技术人员在不脱离本发明的情况下现将会想到多种变化、改变和替代。应当理解,本文中所述的本发明实施方案的各种替代方案可用于实施本发明。旨在以下述权利要求限定本发明的范围,并由此涵盖这些权利要求范围内的方法和结构及其等同物。
Claims (10)
1.一种用于降低血液样品中的红细胞沉降速率的体外方法,其包括:将血液样品与一定量的包含三氯蔗糖的制剂合并,所述量足以产生具有约5mM至约50mM三氯蔗糖的三氯蔗糖浓度的经处理的血液样品,由此使所述红细胞沉降速率与未经处理的血液样品中的红细胞沉降速率相比降低。
2.根据权利要求1所述的方法,其中所述经处理的血液样品具有约5mM直至25mM三氯蔗糖的三氯蔗糖浓度。
3.根据权利要求1-2中任一项所述的方法,其中红细胞沉降速率降低达所述未经处理的血液样品的红细胞沉降速率的至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%。
4.根据权利要求1-3中任一项所述的方法,其中所述制剂为粉末、固体、冻干形式、溶液或水溶液的形式。
5.根据权利要求1-4中任一项所述的方法,其中所述制剂由三氯蔗糖组成。
6.根据权利要求1-4中任一项所述的方法,其中所述制剂进一步包含抗凝剂。
7.根据权利要求6所述的方法,其中所述抗凝剂选自酸柠檬酸葡萄糖溶液(ACD)、肝素钠、氟化钠、肝素锂、乙二胺四乙酸三钾(K3EDTA)、乙二胺四乙酸二钾(K2EDTA)、蛭素和聚茴香脑磺酸钠(SPS)。
8.根据权利要求1-7中任一项所述的方法,其中所述制剂容纳在采血管内,并且所述合并步骤发生在所述采血管内。
9.根据权利要求8所述的方法,其中所述采血管为抽空的采血管。
10.一种用于使一个或多个红细胞在血液样品中保持悬浮的体外方法,其包括:将血液样品与一定量的包含三氯蔗糖的制剂合并,所述量足以产生具有约5mM至约50mM的三氯蔗糖浓度的经处理的血液样品,由此与未经处理的血液样品相比,所述一个或多个红细胞保持悬浮至少30分钟的时间。
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