CN1482919A - 用活化的凝血因子vii治疗血栓溶解疗法引起的大出血 - Google Patents
用活化的凝血因子vii治疗血栓溶解疗法引起的大出血 Download PDFInfo
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Abstract
本发明涉及通过向受试者给药有效量的活化的凝血因子VII(VIIa)或其功能衍生物，治疗由血栓溶解疗法/纤维蛋白溶解疗法所导致的大出血，包括颅内出血。
Description
背景技术
止血系统，包括血小板，血凝固和纤维蛋白溶解作用，在维持血流和限制血管损伤时血液的丢失方面起着至关重要的作用。血管损伤时，血小板粘附到血管壁上，聚集并形成栓(plug)，这种栓得到纤维蛋白网状物的固化，所述纤维蛋白网状物是血凝固活化时，通过凝血因子VII，凝血因子X和凝血酶原的活化而形成的。失血停止后，伤口的愈合开始，之后纤维蛋白溶解系统通过组织纤维蛋白溶酶原激活物(t-PA)诱导的纤维蛋白溶酶的产生将血凝块消散。
在病理情况下，如在心血管疾病时，该系统逃脱正常的生理调节，引起血管的完全堵塞，如同动脉粥样硬化斑块脱落后所观察到的一样。为治疗血栓形成的堵塞，恢复血流，常常应用血栓溶解疗法(参考文献1)。
血栓溶解疗法包括抗血小板剂(例如乙酰水杨酸)，抗凝血剂(例如肝素)和纤维蛋白溶解剂(例如，组织纤维蛋白溶酶原激活物，链激酶，葡萄球菌激酶，尿激酶或它们的衍生物)的联合治疗。这些制剂的联合应用虽然在治疗上非常有效，但仍然存在引起出血并发症包括出血性休克的极大危险(参考文献2，3)。在接受血栓溶解疗法的患者中有许多人出现严重的出血。根据最近大量的血栓溶解疗法的临床实验(即涉及16949名患者的Assent-2实验)发现，tenecteplase(组织纤维蛋白溶酶原激活物(t-PA)的衍生物)治疗的患者颅内出血的发生率是0.93％，alteplase(也是t-PA的衍生物)治疗的患者颅内出血的发生率是0.94％，对tenecteplase和alteplase而言，非脑出血并发症的发生率分别是26.43％和28.95％。有4.25％和5.49％的人需要输血。用Tenecteplase或alteplase治疗，在30天时死亡率或非致死性休克率分别是7.11％和7.04％(参考文献3)。
因此，有必要在所使用的血栓溶解药物以外给医生提供一种解毒剂，以扭转这种血栓溶解疗法所导致的大出血。
发明简述
本发明的一个目的是提供治疗受试者体内血栓溶解疗法/纤维蛋白溶解疗法引起的大出血(major bleeding)的组合物和方法，所述受试者例如是人或动物。
本发明是基于这一发现而进行的，即上述目的可以通过使用活化的凝血因子VII(VIIa)来实现。
凝血因子VII是维生素K依赖性糖蛋白，其通过肝细胞生理性合成，并以由406个氨基酸残基组成的单链分子形式分泌到血液中。凝血因子VII活化变成凝血因子VIIa的过程涉及在第152位精氨酸和第153位异亮氨酸之间单个肽键的水解，形成一个双链分子，所述分子由152个氨基酸残基的轻链和254个氨基酸残基的重链通过一个二硫键结合在一起形成。该蛋白处于活化形式时，作为丝氨酸蛋白酶起作用，参与凝血级联反应的备选途径(extrinsic pathway)。受损血管壁部位一旦接触到组织因子(TF)，该组织因子便与凝血因子VII形成复合物，产生活化的凝血因子VII(凝血因子VIIa)，TF和凝血因子VIIa的复合物将凝血因子X活化成Xa，继而将凝血酶原转变为凝血酶。凝血酶在血液凝固和伤口愈合方面起关键作用。在血管损伤的最初阶段，其诱导血小板聚集并诱导纤维蛋白形成，之后刺激细胞生长从而促进受损血管的修复(参考文献1)。
用编码凝血因子VII的人DNA转染幼龄仓鼠肾细胞可表达重组凝血因子VII(rFVII)，在纯化过程中可将其转变成活化的凝血因子VII(rFVIIa)(参考文献4)。市售的重组凝血因子VIIa有NovoSeven(Novo Nordisk，Bagsvaerd，丹麦)，它已越来越多地用于治疗广泛多种流血性疾病的流血事件，尤其是带有凝血因子VII或IX的抑制物而其它疗法无效的血友病患者(参考文献5-10)。
尽管对该药的使用已积累了13年的经验，但却从未有人提出或研究过用凝血因子VIIa扭转血栓溶解疗法导致的大出血事件。
发明详述
第一方面，本发明涉及活化的凝血因子VII(VIIa)或其功能衍生物在制备治疗血栓溶解疗法/纤维蛋白溶解疗法导致的大出血，包括颅内出血的药物方面的应用。
第二方面，本发明涉及治疗血栓溶解疗法/纤维蛋白溶解疗法导致的大出血，包括颅内出血的方法，该方法包括给药患所述出血的受试者有效量的活化的凝血因子VII(VIIa)或其功能衍生物。该方法尤其可用于治疗哺乳动物，包括人。
适合用于本发明的人的纯化的凝血因子VIIa可从天然来源分离，或优选通过重组DNA技术制备，例如如参考文献20所描述的。通过重组技术制备的凝血因子VIIa可与天然的凝血因子VIIa基本相同，如来自NovoNordisk的产品NovoSeven便是这样。术语“功能衍生物”是指凝血因子VIIa经过修饰的衍生物，具有基本相同的所需要的生物活性。这种凝血因子VIIa的功能性衍生物可如下制备：例如通过对编码凝血因子VII的核酸序列进行定点诱变产生修饰型重组蛋白，该蛋白具有与天然氨基酸序列相差一个或多个氨基酸残基的氨基酸序列。所述修饰可包含，例如氨基酸取代，插入，添加，置换，倒位或缺失。另外，还可进行有用的翻译后修饰，例如去除或改变糖基化模式。
用于血栓溶解疗法/纤维蛋白溶解疗法的血栓溶解/纤维蛋白溶解性药物可包含任何形式的天然或重组的组织纤维蛋白溶酶原激活物，如alteplase，reteplase，duteplase，saruplase，重组的DSPAα1(BAT PA)，链激酶，anistreplase，葡萄球菌激酶包括pegilated葡萄球菌激酶和无免疫原性或免疫原性降低的葡萄球菌激酶的突变体，尿激酶，单链尿激酶，本领域已知的任何第三代血栓溶解剂例如amediplase，tenecteplase，monteplase，lanoteplase，pamiteplase(参考文献2，3，11-15，19)，或上述药物的治疗上可接受的衍生物。
优选包含凝血因子VIIa的药物或药物组合物通过静脉大丸剂注射或通过间歇的或连续的静脉输注来给药。另外，在单次静脉大丸剂注射之后再静脉输注凝血因子VIIa可能是有益的。
用于注射或输注目的的适当的药物制剂包括无菌水溶液和无菌粉末，这种无菌粉末在使用时制备成无菌的可注射或输注的溶液。通常，终溶液还包含适当的盐和本领域已知的其它辅助剂。例如，Novo Nordisk制备并出售的NovoSeven的重新配制的水溶液包含3mg/ml氯化钠，1.5mg/ml氯化钙二水合物，1.3mg/ml N-甘氨酰甘氨酸，0.1mg/ml polysorbate 80和30mg/ml甘露醇。
凝血因子VIIa的给药剂量可以根据，例如具体受试者的年龄和身体状况，所治疗的出血并发症的严重性以及所选择的给药途径而有所不同。适当的剂量可由本领域技术人员很容易地确定的。
通常，静脉大丸剂注射凝血因子VIIa的适当剂量范围是约3000-6000IU(国际单位；与涉及凝血因子VIIa 89/688的第一国际标准相一致)，这相当于每公斤体重给药重组凝血因子VIIa约60-120μg。优选，静脉大丸剂注射的剂量范围是约每公斤体重4500-6000IU。因为重组凝血因子VIIa的系统半寿期通常是仅约2-3个小时，所以，以相对短的时间间隔，优选以2-3小时的时间间隔，更优选以2小时的时间间隔，重复静脉大丸剂注射可能是必要的。适当时，治疗过程中最初的时间间隔可以延长至例如4，6，8，12小时。
治疗上需要时，可以在约2-5分钟之内静脉大丸剂注射给药。
凝血因子VIIa的间歇输注的适当剂量方案可以是每2-6小时每公斤体重约4500-6000IU。
凝血因子VIIa的连续输注的适当剂量可以是约500-1500IU/kg/h，这相当于约10-30μg rFVIIa/kg/h。适当时，在连续输注凝血因子VIIa之前可给予一次剂量为每公斤体重约4500-6000IU的大丸剂注射。连续输注重组凝血因子VIIa的在先研究的结果(参考文献17，18)提示，与大丸剂注射相比，连续输注凝血因子VIIa的治疗达到有效时所需的药物总量较低。
时至今日，凝血因子VIIa的已知应用中副作用的发生率低，并且生物化学征象提示不发生血栓或消耗性凝血病，所以人们期待着通过活化的凝血因子VIIa可有效扭转与血栓溶解疗法有关的大出血，而又不对受试者产生明显的损害。
参考文献
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11.Gissi International Study Group.In-hospital mortality and clinical courseof 20,891 patients with suspected acute myocardial infarction randomisedbetween alteplase and streptokinase with or without heparin.The Lancet.1990；336：71-5。
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13.Van de Werf F，Cannon CP，Luyten A，Houbracken K，McCabe CH，Berioli S，Bluhmki E，Sarelin H，Wang-Clow F，Fox NL，Braunwald E.Safetyassessment of single-bolus administration of TNK tissue-plasminogen activatorin acute myocardial infarction：the ASSENT-1 trial.The ASSENT-1Investigators.Am Heart J.1999；137：786-91。
14.Collen D，Sinnaeve P，Demarsin E，Moreau H，De Maeyer M，Jespers L，Laroche Y，Van De Werf F.polyethylene glycol-derivatized cystein-substitutionvariants of recombinant staphylokinase for single-bolus treatment of acutemyocardial infarction.Circulation.2000；102：1766-72。
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17.Schulman S，Bech Jensen M，Varon D，Keller N，Gitel S，Horoszowski H，Heim M，Martinowitz U.Feasibility of using recombinant factor VIIa incontinuous infusion.Thromb Haemost.1996 Mar；75(3)：432-6。
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Claims (10)
1.活化的凝血因子VII(VIIa)或其功能衍生物在制备治疗血栓溶解疗法/纤维蛋白溶解疗法引起的大出血的药物方面的用途。
2.权利要求1的用途，其中所述出血是使用如下物质进行血栓溶解疗法/纤维蛋白溶解疗法引起的，所述物质是任何形式的天然或重组的组织纤维蛋白溶酶原激活物，如alteplase，reteplase，duteplase，saruplase，重组的DSPAα1(BAT PA)，链激酶，葡萄球菌激酶包括pegilated葡萄球菌激酶和无免疫原性或免疫原性降低的葡萄球菌激酶的突变体，尿激酶，单链尿激酶，第三代血栓溶解剂，或上述药物的治疗上可接受的衍生物。
3.权利要求1或2的用途，其中所述出血是颅内出血。
4.权利要求1-3任一项的用途，其中所述药物适宜于通过静脉大丸剂注射或静脉输注方式给药有效量的凝血因子VIIa或其功能衍生物。
5.权利要求4的用途，其中所述凝血因子VIIa或其功能衍生物的有效量包括一次或多次单剂静脉大丸剂注射和/或静脉输注，其中所述单剂静脉大丸剂注射剂量为每公斤体重约3000-6000IU，相当于约60-120μg的重组凝血因子VIIa，所述静脉输注的剂量为每公斤体重每小时约500-1500IU，相当于约10-30μg的重组凝血因子VIIa。
6.权利要求4或5的用途，其中所述有效量的凝血因子VIIa或其功能衍生物是以约2小时的间隔进行多次静脉大丸剂注射给药。
7.一种治疗血栓溶解疗法/纤维蛋白溶解疗法引起的大出血，包括颅内出血的方法，该方法包括给药患所述出血的受试者有效量的活化的凝血因子VII(VIIa)或其功能衍生物。
8.权利要求7的方法，其中所述出血是使用如下物质进行血栓溶解疗法/纤维蛋白溶解疗法引起的，所述物质是任何形式的天然或重组的组织纤维蛋白溶酶原激活物，如alteplase，reteplase，duteplase，saruplase，重组的DSPAα1(BAT PA)，链激酶，葡萄球菌激酶包括pegilated葡萄球菌激酶和无免疫原性或免疫原性降低的葡萄球菌激酶的突变体，尿激酶，单链尿激酶，第三代血栓溶解剂，或上述药物的治疗上可接受的衍生物。
9.权利要求7或8的方法，其中所述有效量的凝血因子VIIa或其功能衍生物是通过静脉大丸剂注射或静脉输注给药的，优选通过间隔约2小时的多次静脉大丸剂注射给药。
10.权利要求9的方法，其中所述凝血因子VIIa或其功能衍生物的有效量包括一次或多次单剂静脉大丸剂注射和/或静脉输注，其中所述单剂静脉大丸剂注射剂量为每公斤体重约3000-6000IU，相当于约60-120μg的重组凝血因子VIIa，所述静脉输注的剂量为每公斤体重每小时约500-1500IU，相当于约10-30μg的重组凝血因子VIIa。
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| WO2007009895A2 (en) * | 2005-07-15 | 2007-01-25 | Novo Nordisk Health Care Ag | USE OF FACTOR VIIa OR FACTOR VIIa EQUIVALENTS FOR PREVENTING OR ATTENUATING HAEMORRHAGE GROWTH, AND/OR OEDEMA GENERATION FOLLOWING INTRACEREBRAL HAEMORRHAGE (ICH) IN PATIENTS TREATED WITH ANTIPLATELET THERAPY |
| JP2011509978A (ja) | 2008-01-18 | 2011-03-31 | ノボ ノルディスク ヘルス ケア アーゲー | 選択されたＩＣＨ患者亜集団における脳内出血（ＩＣＨ）後の出血拡大、及び／又は浮腫生成の予防又は減弱のための、第ＶＩＩａ因子又は第ＶＩＩａ因子等価物の使用 |
| RU2552339C1 (ru) * | 2014-02-19 | 2015-06-10 | Общество с ограниченной ответственностью фирма "Технология-Стандарт" | Способ профилактики кровотечений, вызванных применением стрептокиназы, в эксперименте |
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| US5846517A (en) * | 1996-09-11 | 1998-12-08 | Imarx Pharmaceutical Corp. | Methods for diagnostic imaging using a renal contrast agent and a vasodilator |
| WO1998058661A1 (en) * | 1997-06-23 | 1998-12-30 | Novo Nordisk A/S | Use of fviia for the treatment of bleedings in patients with a normal blood clotting cascade and normal platelet function |
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