CN102088999A - 用于治疗凝血细胞抑制剂诱导的凝血病的血管假性血友病因子或因子viii和血管假性血友病因子 - Google Patents
用于治疗凝血细胞抑制剂诱导的凝血病的血管假性血友病因子或因子viii和血管假性血友病因子 Download PDFInfo
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Abstract
本发明涉及用于治疗和/或预防与抑制凝血细胞的物质诱导的血小板紊乱相关的出血情况的血管假性血友病因子。此外，本发明涉及治疗和/或预防涉及与抑制凝血细胞的物质诱导的血小板紊乱相关的出血情况的疾病的方法，包含对有此需要的患者给予药学有效量的血管假性血友病因子(vWF)。本发明还涉及包含vWF的组合物和包含FVIII的组合物，其同时、单独或依次用于治疗和/或预防与抑制凝血细胞的物质诱导的血小板紊乱相关的出血情况。
Description
本发明涉及用于治疗和/或预防与抑制凝血细胞的物质诱导的血小板紊乱(thrombopathy)相关的出血情况的血管假性血友病因子(von Willebrand Factor)。此外，本发明涉及治疗和/或预防涉及与抑制凝血细胞的物质诱导的血小板紊乱相关的出血情况的疾病的方法，包含对有此需要的患者给予药学有效量的血管假性血友病因子(vWF)。本发明还涉及包含vWF的组合物和包含FVIII的组合物，其同时、单独或依次用于治疗和/或预防与抑制凝血细胞的物质诱导的血小板紊乱相关的出血情况。
在本说明书中，引述大量对比文件包括专利申请和制造商手册。将这些对比文件公开的内容完整引入本文参考，而不视为涉及本发明的专利性。更具体地说，将全部参考的对比文件引入参考，其引用程度与将每篇对比文件各自特别和分别引入参考的程度相同。
凝固或纤维蛋白溶解系统的成分失衡在临床上分别表现为血栓形成或出血。病理情况可能是威胁生命的。在血栓形成后果发生后，例如在急性心肌梗死过程中，尝试干预实际消散和凝固平衡。例如，给予链激酶(SK)或纤溶酶原激活剂(t-PA，uPA)会支持纤维蛋白溶解系统，以溶解存在的血块。凝血细胞抑制剂抑制或减少凝血细胞活化。由此被血栓封闭的血管会得到再穿通并且防止形成新的血栓。凝血细胞功能抑制剂可以在不同部位起作用。环加氧酶抑制剂(例如乙酰水杨酸)防止血栓烷A2(TXA2)形成，其为凝血细胞功能的有效激活剂。凝血细胞表面上的ADP-受体拮抗剂(例如氯吡格雷(Clopidrogel)、噻氯匹定(Ticlopidin))防止凝血细胞激活剂ADP结合其受体并且防止凝血细胞活化。凝血细胞表面上的纤维蛋白原受体糖蛋白IIb/IIIa(GPIIb/IIIa)在结合其激动剂纤维蛋白原(或vWF)之后诱导凝血细胞聚集。针对GP IIb/IIIa(例如阿昔单抗)或受体拮抗剂如依替巴肽或替罗非班的单克隆抗体也防止凝血细胞聚集。
另一方面，在血管损害后形成凝血球蛋白的一些潜能是在这些位置预防出现出血所必需的。能够在使用凝血细胞抑制剂治疗过程中发生威胁生命的出血的疗法包括中断该疗法和给予凝固促进剂。这种凝固促进剂由部分预活化的凝固因子等组成，其在市场上作为产品(Baxter)或重组凝固因子VIIa(
Novo Nordisk)销售。这些凝固促进剂主要导致凝血细胞抑制的治疗效果下降。Dickneite等人(Dickneite G，Friesen H.-J.，Kumpe G，Reers M，1996 Platelets 7，283-290，Dickneite G，Nicolay U，Friesen H.-J.，Reers M，1998 Thromb Haemost 80，192-8)描述了vWF和
(CSL Behring)作为重组凝血酶抑制剂水蛭素诱导的出血情况过程中的凝固促进剂的应用。
用于临床上抗凝和溶解纤维蛋白作用的定量措施是不同的诊断方法，如凝血弹性描记法、凝血酶生成测定法、激活部分促凝血酶原激酶时间(aPTT)或凝血酶原时间PT)。评价预防实验环境中严重出血的方法是外伤性损伤后的器官出血(Dickneite G，Doerr B，Kaspereit F，2008 Anesth Analg 106，1070-7)。
根据有关血管损害后发生止血的机械学研究，凝血细胞主要通过血管假性血友病因子(vWF)结合内皮下胶原纤维。vWF是在低(例如在静脉区域中)和高剪切速率(例如在动脉、冠状动脉区域或斑块(plaque)诱导的血管狭窄中)下通过结合到暴露的胶原蛋白具有有效结合到凝血细胞的能力的唯一因子(Ruggeri ZM，Seminars in Hematology，1994，31，229-239)。接下来的凝血细胞聚集和随后因凝血酶作用导致的聚集的血小板皱缩和收缩诱导二次止血过程中的止血塞(Hemker HC和Poliwoda H，1993，1-18，Barthels M和Polidowa H，Thieme，Stuttgart，Germany)。
目前，vWF是最大的已知血浆蛋白。它是具有两种生物学特性的多聚化糖蛋白。在局部血管损伤部位，它介导凝血细胞粘着，然后是血栓形成，并且它起促凝因子VIII的载体的作用(Ruggeri ZM，1993Current Opinion in Cell Biology，5，898-906)。发现vWF以确定量以不含因子VIII的形式存在于内皮下细胞中并且以不含因子VIII的形式贮存在凝血细胞的α-颗粒中。凝血细胞具有vWF的两种受体：第一种是在GP Ib-IX-V复合物中的GP Ib且第二种是GP IIb-IIIa(Ruggeri ZM，1994 Seminars in Hematology 31，229-239)。通过其第一种受体，vWF诱导血管损伤侧面上的凝血细胞粘着，然后是vWF和/或纤维蛋白原结合到GP IIb/IIIa受体并且支持随后的凝血细胞聚集。根据这一背景，在文献中讨论使用用于结合vWF的抑制剂作为抗凝药的机理(Alevriadou BR，Moake JL，Turner NA，Ruggeri ZM，Folie BJ，Phillips MD，Schreiber AB，Hrinda ME，Mclntire IV，1993，Blood 81，1263-1276M；Grainick HR，Williams S，McKeown L，Kramer W，Krutzsch H，Gorecki M，Pinet A Garfinkel LI，1992Proc.Natl.Acad.Sci.USA，89，7880-7884)。
对减少或预防给予凝血细胞抑制剂后发生出血的不良情况仍然存在需求。因此，基于本发明的技术问题在于提供成功治疗给予抑制凝血细胞的物质导致的出血情况的方式和方法。
通过提供以权利要求为特征的实施方案解决了本发明的技术问题。
令人意外地发现，在给予血管假性血友病因子(vWF)之后，给予抑制凝血细胞的物质过程中或之后的出血或流血不良情况减少。因此，适当地补充包含vWF的药物组合物可以拮抗抗凝疗法后增强的出血不良情况。抗凝血药或纤溶剂效果的不良反应结果由此得到减少或预防。为了降低患者中的出血风险，可以以预防方式或在抗血小板治疗后给予vWF。
因此，本发明涉及用于治疗和/或预防与抑制凝血细胞的物质诱导的凝血病、尤其是血小板紊乱相关的出血情况的血管假性血友病因子(vWF)。
本发明的术语″血小板紊乱″涉及凝血细胞功能障碍，而凝血细胞数量是正常的或边缘改变。这可以作为血小板减少症、也称作血小板减少的特征性特征观察到，其中在血液中存在相对少的血小板。就血小板紊乱而言，存在大量限制凝血细胞功能的药物，例如乙酰水杨酸、双氯芬酸、肝素、青霉素等。血小板紊乱也称作血小板病，该术语也在本文中使用。
与血浆凝固相关，凝血细胞具有两种重要的特征或功能：一方面，粘着内皮下膜，而另一方面相互聚集。根据本发明，术语″抑制凝血细胞的物质″涉及抑制凝血细胞聚集的物质。这些物质也称作凝血细胞-抑制剂或抗血小板药或血小板聚集抑制剂并且对患者给予以预防尤其是在动脉中的血栓生长，即给予它们以预防例如中风、心肌梗死或另一种相关疾病。
因此，根据本发明，术语″抑制凝血细胞的物质诱导的血小板紊乱″涉及凝血细胞聚集时的功能障碍，而凝血细胞数量是正常的或边缘改变。相反，血小板减少症涉及凝血细胞数量减少。血小板紊乱被一种、两种或多种抑制凝血细胞聚集的物质诱导。优选这些物质抑制环加氧酶和/或ADP受体。
本文所用的术语″血小板紊乱″优选不包括如血小板膜糖蛋白类(GP)IIb/IIIa缺乏导致的血小板无力症(Glanzmann血小板机能不全)或GP Ib缺乏导致的Bernard-Soulier综合征这样的遗传性疾病。血小板无力症是血小板的遗传的不正常性，其特征尤其在于血块凝缩缺陷且通常在于出血时间延长。
本发明还涉及治疗和/或预防涉及与抑制凝血细胞的物质诱导的血小板紊乱相关的出血情况的疾病的方法，包含对有此需要的患者给予药学有效量的血管假性血友病因子(vWF)。
在本发明血管假性血友病因子的应用或方法的优选实施方案中，使用vWF或将其与因子VIII一起作为因子VIII/血管假性血友病因子(FVIII/vWF)组合给予。
优选将vWF或FVIII/vWF组合配制成药物组合物，其任选包含药学可接受的载体、赋形剂和/或稀释剂。
本文所用的术语″药物组合物″涉及对患者、优选人类患者给予的组合物。该药物组合物意指vWF或vWF与FVIII组合的可替代选择混合物。就在组合物中包含一种以上化合物的情况而言，应理解这些化合物中无一对组合物中还包含的其他化合物具有抑制效果。
优选所述药物组合物包含药学可接受的载体、赋形剂和/或稀释剂。适合的药用载体、赋形剂和/或稀释剂的实例是本领域众所周知的并且包括磷酸缓冲盐溶液、水、乳剂例如油/水乳剂、各种类型的湿润剂、无菌溶液等。可以通过众所周知的常规方法配制包含这种载体的组合物。可以以适合的剂量对受试者给予这些药物组合物。例如，可以通过静脉内、腹膜内、皮下或肌内给药，通过不同方式给予适合的组合物。特别优选通过例如注射和/或递送至血流部位进行所述给药。剂量方案可以由主治医师和临床因素确定。正如医学领域众所周知的，用于任一患者的剂量依赖于许多因素，包括患者大小、体表面积、年龄、所给予的具体化合物、给药时间和途径、一般健康状况和同时给予的其他药物。
可以以10-1000单位vWF/kg体重的剂量范围对患者给予本发明的药物组合物。或者，如果使用FVIII/vWF组合，则给予的剂量范围在5-400单位FVIII/kg体重和10-1000单位vWF/kg体重。
优选的剂量范围在30-500单位vWF/kg体重，或就FVIII/vWF而言，给予20-200单位FVIII和30-500单位vWF/kg体重。
作为分别包含本发明使用的vWF或vWF和FVIII的药物组合物，可以使用任意销售的包含vWF或vWF和FVIII的产品，例如
P和
P(CSL Behring)，其包含vWF和FVIII；或其他血浆vWF产品或重组生产的vWF或vWF/FVIII产品。
通过定期评价检测进展。可以通过局部或全身给予本发明的组合物。用于胃肠外给药的制剂包括无菌水或非水溶液、混悬液和乳剂。非水溶剂的实例是丙二醇、聚乙二醇、植物油例如橄榄油和可注射有机酯类例如油酸乙酯。含水载体包括水、醇/水溶液、乳剂或混悬液，包括盐水和缓冲介质。胃肠外介质包括氯化钠溶液、林格葡萄糖、葡萄糖和氯化钠、乳酸林格液或固定油。静脉内介质包括流体和营养物补充剂、电解质补充剂(例如基于林格葡萄糖这样的补充剂)等。还可以存在防腐剂和其他添加剂，例如抗微生物剂、抗氧化剂、螯合剂和惰性气体等。
在本发明血管假性血友病因子的应用或方法的另一个优选的实施方案中，使用或给予vWF以便作为解毒药起作用。
本发明所用的术语″解毒药″涉及提高凝血细胞降低的功能的物质。因此，本发明的解毒药不是典型的激动剂/拮抗剂功能物质，而是改善由抑制凝血细胞的物质降低的凝血细胞功能。
在本发明的一个优选的实施方案中，将vWF或FVIII/vWF作为浓缩物使用或给予。
在另一个优选的实施方案中，vWF或FVIII/vWF分离自人血浆或作为重组蛋白可替代地给予。
在本发明血管假性血友病因子的应用或方法的另一个优选的实施方案中，抑制凝血细胞的物质选自环加氧酶抑制剂、ADP受体抑制剂或其组合。在更优选的实施方案中，环加氧酶抑制剂是乙酰水杨酸，且ADP受体抑制剂是噻吩并吡啶并衍生物(thienopyridino derivative)，优选氯吡格雷或噻氯匹定。在最优选的实施方案中，抑制凝血细胞的物质是乙酰水杨酸、氯吡格雷或乙酰水杨酸与氯吡格雷的组合。
本发明还涉及包含vWF的组合物和包含FVIII的组合物，其同时、单独或依次用于治疗和/或预防因给予抑制凝血细胞的物质导致的出血情况。根据该实施方案，由此以单独的标准剂量使用或给予vWF和FVIII。
附图显示：
图1显示大鼠氯吡格雷模型中总失血量的方框图(与1组(
对照组)相比具有显著性意义)。
图2显示大鼠氯吡格雷模型中总失血量的Kaplan-Meier图。
图3显示
P200U/kg和新鲜大鼠血小板浓缩物(1.6x109PLT/动物)对凝血酶生成的效果/富含血小板的血浆的凝血酶生成(thrombogram)图。
图4显示给予氯吡格雷/
后猪中失血量的方框图。
图5显示给予氯吡格雷/后猪中失血量的Kaplan-Meier图。
图6显示给予氯吡格雷/
对猪中血小板计数的效果。
实施例示例本发明，但不限制本发明。
实施例1：
输注合并有vWF和FVIII浓缩物(
P)的大鼠血小板对大鼠氯吡格雷模型中出血的影响
研究120和200U/kg
P(i.v.)与新鲜制备的大鼠血小板组合的剂量是否可以减少氯吡格雷治疗的大鼠的出血。2组氯吡格雷治疗的大鼠接受
P(120和200U/kg)，不接受血小板。将本研究设计为使用115只大鼠(+60血小板供体)的开放式七-臂试验(open seven-armed trial)。将给药方案概括在表1中。
表1：治疗组
大鼠血小板
通过在深度麻醉下穿刺供体大鼠下腔静脉缓慢取用于制备血小板浓缩物的血液。将3.2mL血液与0.8mL柠檬酸钠混合。收集血样并且以900RPM离心30分钟。将富含血小板的血浆采集入新鲜试管并且以1800-2000RPM离心15-17分钟。将沉淀轻柔混悬于Tyrode HEPES+0.3％BSA。根据血小板收率的不同，动物尾静脉内接受1.6-3x109经洗涤的血小板。
动物模型
在第0天和第1天用2.5mg/kg氯吡格雷
诱导血小板抑制/出血。将片剂溶于等渗盐水并且通过管饲法给予。在第2天，将新鲜制备的大鼠血小板输通过推注(bolus)注入尾静脉。在血小板输注前直接给予
P。给予血小板后15分钟，测定失血量。通过测定存在于用于浸没尾尖部的盐水中的HGB计算总失血体积。在深度麻醉下用解剖刀切割尾尖部，除去约3mm尾尖部。即刻将损害的尾尖部浸入盐水，使用水浴保持在大鼠生理体温下。监测出血的观察期为30min。
出血
将失血量测定为总失血量(t＝0-30min)并且通过双侧确切Wilcoxon检验、方框图和Kaplan-Meier图分析。使用氯吡格雷口服治疗导致总失血量增加(图1和2、表2)。
图1例示出在接受血小板输注的组中总失血量显著减少(统计参见表3)。通过联用血小板输注和P治疗与单独血小板相比不能使总失血量减少。然而，使用
P的单一疗法导致接受200U/kg剂量的组中失血量显著减少。
使用120U/kg未观察到对失血量的影响。
表2：总失血量(μL)
表3：总失血量统计(确切的Wilcoxon检验)
凝血酶生成
使用氯吡格雷治疗导致凝血酶形成迟发和峰值凝血酶下降(图3)。当将
P给予氯吡格雷治疗的大鼠时，观察到凝血酶形成早发，而峰值凝血酶不增加。血小板输注导致凝血酶峰值增加。当联用血小板和
P时，观察到累加乃至协同作用：峰值增加和凝血酶形成发作更快。
实施例2：
氯吡格雷和阿司匹林给药并且还输注vWF和FVIII浓缩物(P)后猪的出血时程
在3天期间内通过管饲法对雄性阉割猪每日口服给予75mg氯吡格雷在第3天，以200mg/kg的剂量静脉内给予乙酰水杨酸
15分钟后，给予静脉内推注的包含FVIII/vWF的浓缩物(60单位/kg FVIII和约150单位/kg vWF)(治疗组，第3组，n＝6)。对照组动物接受适当体积的盐水而不是vWF和FVIII浓缩物(安慰剂组，第2组，n＝4)。5只动物既不接受凝血细胞抑制剂、也不接受
P治疗(第1组，阴性对照)。在本实验过程中，测定血浆中的PT和aPTT，测定全血中的血栓弹力图(thromboelastrography)和凝血细胞聚集。为了凝血酶生成，使用在富含血小板的血浆中的试验。
联合给予氯吡格雷和导致具有受损的血小板聚集和凝血酶生成的血小板病。在脾受伤后，血小板病导致大量出血。相反，血浆凝固(PT，aPTT)不受氯吡格雷/乙酰水杨酸治疗影响。图6显示在给予氯吡格雷/后未观察到血小板计数显著减少，由此未诱导血小板减少症。
在表4和5以及图4和5中，可以观察到在本研究中，使用
P治疗显著减少了失血量。由此显示包含凝固vWF和因子VIII的浓缩物能够部分克服凝血细胞抑制剂诱导的血小板病。
表4：脾损伤后的失血量(ml)
表5：失血量统计(Wilcoxon检验)
Claims (12)
1.用于治疗和/或预防与抑制凝血细胞的物质诱导的血小板紊乱相关的出血情况的血管假性血友病因子(vWF)。
2.用于治疗和/或预防与抑制凝血细胞的物质诱导的血小板紊乱相关的出血情况的疾病的药物的制备方法，其中使用药学有效量的血管假性血友病因子(vWF)。
3.权利要求1的vWF或权利要求2的方法，其中使用vWF或作为因子VIII/血管假性血友病因子(FVIII/vWF)的组合与因子VIII联合给予。
4.权利要求1或3的vWF或权利要求2或3的方法，其中给予vWF或FVIII/vWF以作为解毒药起作用。
5.权利要求1或3-4任一项的vWF或权利要求2或4任一项的方法，其中使用vWF或FVIII/vWF或将vWF或FVIII/vWF作为浓缩物给予。
6.权利要求1或3-5任一项的vWF或权利要求2-5任一项的方法，其中vWF或FVIII/vWF分离自人血浆。
7.权利要求1或3-5任一项的vWF或权利要求2-5任一项的方法，其中将vWF或FVIII/vWF作为重组蛋白给予。
8.权利要求1或3-7任一项的vWF或权利要求2-7任一项的方法，其中以10-1000单位vWF/kg体重或5-400单位FVIII和10-1000单位vWF/kg体重的剂量对患者给予vWF或FVIII/vWF。
9.权利要求8的vWF或方法，其中以30-500单位vWF/kg体重或20-200单位FVIII和30-500单位vWF/kg体重的剂量对患者给予vWF或FVIII/vWF。
10.权利要求1或3-9任一项的vWF或权利要求2-9任一项的方法，其中抑制凝血细胞的物质是环加氧酶抑制剂、ADP受体抑制剂或其组合。
11.权利要求10的vWF或方法，其中环加氧酶抑制剂是乙酰水杨酸，且其中ADP受体抑制剂是噻吩并吡啶并衍生物，优选氯吡格雷或噻氯匹定。
12.包含vWF的组合物和包含FVIII的组合物，其同时、单独或依次用于治疗和/或预防与抑制凝血细胞的物质诱导的血小板紊乱相关的出血情况。
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| CN109111526A (zh) * | 2012-01-12 | 2019-01-01 | 比奥贝拉蒂治疗公司 | 嵌合因子viii多肽及其用途 |
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| US11197916B2 (en) | 2007-12-28 | 2021-12-14 | Takeda Pharmaceutical Company Limited | Lyophilized recombinant VWF formulations |
| AR069989A1 (es) | 2007-12-28 | 2010-03-03 | Baxter Int | Formulaciones de vwf recombinantes |
| KR101804136B1 (ko) * | 2008-06-24 | 2017-12-04 | 옥타파마 아게 | 응고 인자 ｖｉｉｉ을 정제하는 방법 |
| DE102008032361A1 (de) * | 2008-07-10 | 2010-01-21 | Csl Behring Gmbh | Der Einsatz von Faktor VIII und vWF bzw. vWF-enthaltenden Konzentraten zur Therapie der durch Thrombocyten-Inhibitoren induzierte Koagulopathie |
| TWI508735B (zh) | 2008-10-21 | 2015-11-21 | 巴克斯特國際公司 | 凍乾的重組ｖｗｆ調配物 |
| JP2015515482A (ja) | 2012-04-24 | 2015-05-28 | ノヴォ ノルディスク アー／エス | 血友病の治療に適する化合物 |
| EP2662083A1 (en) | 2012-05-08 | 2013-11-13 | CSL Behring GmbH | Sugar compositions for treating hemophilia a and/or von willebrand disease |
| CN102776260B (zh) * | 2012-07-26 | 2015-04-29 | 上海泰龙生物医药科技有限公司 | 一种高效表达重组人凝血八因子的方法 |
| DK2796145T3 (da) | 2013-04-22 | 2018-01-29 | Csl Ltd | Et kovalent kompleks af von Willebrand-faktor og faktor VIII linket af en disulfidbro |
| WO2014210546A1 (en) | 2013-06-27 | 2014-12-31 | University Of Washington Through Its Center For Commercialization | Biocompatible polymeric system for targeted treatment of thrombotic and hemostatic disorders |
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| DE102008032361A1 (de) * | 2008-07-10 | 2010-01-21 | Csl Behring Gmbh | Der Einsatz von Faktor VIII und vWF bzw. vWF-enthaltenden Konzentraten zur Therapie der durch Thrombocyten-Inhibitoren induzierte Koagulopathie |
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Application publication date: 20110608 |