CN105106186A - 治疗冠状动脉和动脉的动脉瘤性蛛网膜下腔出血的方法和组合物 - Google Patents
治疗冠状动脉和动脉的动脉瘤性蛛网膜下腔出血的方法和组合物 Download PDFInfo
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- CN105106186A CN105106186A CN201510522527.5A CN201510522527A CN105106186A CN 105106186 A CN105106186 A CN 105106186A CN 201510522527 A CN201510522527 A CN 201510522527A CN 105106186 A CN105106186 A CN 105106186A
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及治疗冠状动脉和动脉的动脉瘤性蛛网膜下腔出血的方法和组合物。具体而言，本发明涉及治疗与动脉瘤性蛛网膜下腔出血(SAH)有关的并发症的方法和组合物，所述方法包括向有此需要的个体给药有效量的一氧化氮前体。本发明还涉及治疗血管痉挛的方法和组合物，所述方法包括向有此需要的个体给药有效量的一氧化氮前体。
Description
本申请是2009年2月2日提交的发明名称为“治疗冠状动脉和动脉的动脉瘤性蛛网膜下腔出血的方法和组合物”的中国专利申请200980109147.1的分案申请。
相关申请信息
本申请基于2008年1月31日提交的美国临时专利申请第61/025,170号，并要求其优先权，该临时专利申请的全部内容援引加入本文。
技术领域
本发明涉及动脉瘤性蛛网膜下腔出血(SAH)、与SAH有关的并发症(包括血管痉挛)以及与包括但不限于与冠状动脉疾病有关的动脉粥样硬化有关的血管痉挛的治疗。
发明背景
动脉瘤性蛛网膜下腔出血(SAH)在全世界是与中风有关的发病率和死亡率的首要原因之一。SAH是神经系统急症，其特征在于血液外渗入覆盖充满脑脊液的覆盖中枢神经系统的空间。诸如脑积水、再出血、脑血管痉挛、癫痫发作、心肌损伤和肺水肿的几种并发症可以源自SAH。
SAH是全世界主要关注的问题，其变化的发病率为每100,000人/年约1至96起(BatistadaCostaJr.等人(2004)ArqNeuro-Psiquiatr(SaoPaulo)62:245-249)，并且其世界范围内的发病率为每100,000人/年约10起(Batista daCostaJr.等人(2004)ArqNeuro-Psiquiatr(SaoPaulo)62:245-249)。根据Suarez等人的调查，SAH在美国每年侵袭21,000-33,000人，并且代表了全部新中风的约2-5％(Suarez等人(2006)NEnglJMed354:387-396)。约80％的SAH病例是由颅内动脉瘤的破裂导致的，其本身与包括死亡在内的并发症的重大风险有关。发病的高峰年龄为55-60岁，并且约20％发生在15岁至45岁之间。SAH有性别差异，其女性优势的特征在于女性患者与男性患者的比率为1.6-4.16:1。非洲裔美国人的SAH发病率比白种人更高。
最新统计表明约30％的SAH患者在最初的24小时内死亡，并且另外的25-30％在接下来的4周内死亡(Flett等人(2005)AJNRAmJNeuroradiol26:367-372)。除了与SAH有关的首要风险以外，相当比例的患有SAH的患者还患有长期认知缺损(Suarez等人(2006)NEnglJMed354:387-396)，因此，SAH与对保健资源的实质影响有关。
尽管症状控制在SAH的治疗中起到主要作用，但是始终长期亟需解决产生SAH的并发症(secondarycomplication)的根本生理学基础的治疗策略。
发明概述
本发明提供了治疗个体的SAH和/或相关并发症的方法和组合物。在某些实施方案中，向患有SAH和/或相关并发症和/或面临罹患与SAH有关的并发症(例如血管痉挛)风险的个体给药有效量的一氧化氮前体。在某些实施方案中，所述一氧化氮前体包括瓜氨酸、在体内产生瓜氨酸的前体、其药学可接受的盐及其组合中的至少一种。在某些实施方案中，将诸如瓜氨酸的一氧化氮前体口服给药。在某些实施方案中，将诸如瓜氨酸的一氧化氮前体静脉内给药。在某些实施方案中，待治疗个体是患有血管痉挛的个体。在某些实施方案中，待治疗个体是患有与血管痉挛有关的急性病症的个体。
本发明还提供了治疗血管痉挛的方法和组合物。在某些实施方案中，待治疗个体患有与SAH有关的血管痉挛。在某些实施方案中，待治疗个体患有导致血管痉挛的创伤(例如导致SAH的创伤)。所述方法可包括向有此需要的个体给药有效量的一氧化氮前体。在某些实施方案中，所述一氧化氮前体包括瓜氨酸、在体内产生瓜氨酸的前体、其药学可接受的盐及其组合的至少一种。在某些实施方案中，待治疗个体是患有与SAH有关的血管痉挛的个体。在某些实施方案中，将诸如瓜氨酸的一氧化氮前体口服给药。在某些实施方案中，将诸如瓜氨酸的一氧化氮前体静脉内给药。
因此，本发明旨在提供对个体的SAH、血管痉挛和/或相关并发症的治疗。
当与附图和下文详细描述的实施例相联系时，会随着说明书的进行而清楚本发明的上述目的、其它目的。
附图简述
图1为尿素循环的示意图。
发明详述
全世界有相当多的人患有动脉瘤性蛛网膜下腔出血(SAH)。这种病症的死亡率相当高，而且甚至幸存的SAH患者的生命质量也常常发生明显下降。如果在合适的时间范围内开始治疗，那么目前使用的疗法通常可以防止患有SAH的人的死亡，但是即使成功地防止患者的死亡，也不能解决严重的并发症的产生。根据本发明的一些方面，提供了旨在预防并发症，如血管痉挛及其后遗症的疗法。
I.一般考虑
精氨酸的体内合成途径以鸟氨酸开始。鸟氨酸与氨甲酰磷酸结合产生瓜氨酸，其又在三磷酸腺苷(ATP)的存在下与天冬氨酸结合产生精氨琥珀酸。在最终步骤中，延胡索酸从精氨琥珀酸断开产生精氨酸。精氨酸的降解途径是通过精氨酸酶的水解作用产生鸟氨酸和尿素。这些反应形成了尿素循环。所述尿素循环充当除去由内源和外源蛋白质代谢产生的废氮的主要途径，并图示于图1中。除了在氮清除中的作用以外，尿素循环还是身体中充当一氧化氮(NO，有效血管扩张剂)前体的精氨酸的内在来源。
SAH通常是由颅动脉瘤的破裂引起的，这导致血液渗入含有脑脊液的神经系统的区室中。主要症状一般包括通常非常严重的头痛、恶心、呕吐、颈痛、畏光和意识丧失的突然发作(Suarez等人(2006)NEnglJMed354:387-396)，其常常与在体检时变得明显的神经功能缺损有关(Suarez等人(2006)NEnglJMed354:387-396)。甚至在修复了对基本血管(underlyingvessel)的损伤的情况下，还是有相当比例的患者发生脑积水(20％)、再出血(7％)、脑血管痉挛(46％)、癫痫发作(30％)、低钠血症(28％)、心肌损伤(35％)和肺水肿(23％)。这些事件还通常导致其它并发症，其包括癫痫发作、肺水肿、心律不齐、电解质紊乱和神经心理并发症，如与记忆、情绪和神经心理功能有关的问题。
尽管造成SAH的各种后遗症的原因是多因素的，但是也已进行了某些观察。例如，已经观察到脑血管中一氧化氮利用率的降低，这增加了内皮缩血管肽的合成或者增加了动脉对该因素的敏感性。还报道了促进收缩状态的平滑肌细胞的改变以及能够改变钙敏感性的信号转导机制的激活。另外，可以发生导致动脉功能障碍的内皮血栓性和/或血小板粘附的增加，这可以造成血脑屏障的破坏、炎症、血管收缩以及所有大小的脑血管的损伤。
考虑到SAH对患者的破坏性作用，对其进行快速诊断和治疗是非常重要的。通常，使表现出SAH症状的患者进行头部CT，这可以检测SAH的存在。如果检测到蛛网膜下腔出血，则FT血管造影术和/或脑血管造影术可以定位动脉瘤，然后将其修复。然而，如果血管造影是正常的，则通常在初始表现之后重复1-3周的CT血管造影术，随后任选地进行脑、脑干和/或脊髓成像。在热CT未检测到蛛网膜下腔出血的情况下，测试由腰椎穿刺获得的脑脊液也能够提供SAH的指示剂，其随后可以通过血管造影术得以证实。
一旦诊断了SAH，治疗通常包括通过神经外科钳(neurosurgicalclipping)或血管内弹簧圈(endovascularcoiling)来固定动脉瘤。视需要进行相关症状的治疗，所述相关症状包括但不限于高血压、过热、高血糖和缺血。考虑到与SAH有关的并发症通常在几周的过程中产生，个体通常保持住院延长的时间以提供个体病症的持续监测。
II.治疗方法
本发明提供了治疗个体的SAH和/或相关并发症的方法。在某些实施方案中，向患有SAH和/或相关并发症和/或面临罹患与SAH有关的并发症(例如血管痉挛)风险的个体给药有效量的一氧化氮前体。上文中公开了这些并发症的代表性实例。
在某些实施方案中，所述一氧化氮前体包括瓜氨酸、在体内产生瓜氨酸的前体、其药学可接受的盐及其组合中的至少一种。参见图1。在某些实施方案中，所述一氧化氮前体选自包括但不限于瓜氨酸、精氨酸或其组合。在某些实施方案中，将诸如瓜氨酸的一氧化氮前体口服给药。在某些实施方案中，将诸如瓜氨酸的一氧化氮前体静脉内给药。在某些实施方案中，待治疗个体是患有血管痉挛的个体。在某些实施方案中，待治疗个体是患有与血管痉挛有关的急性病症的个体。上文中公开了这些病症的代表性实例。
在某些实施方案中，患有诸如血管痉挛的并发症的个体还患有相对低瓜氨酸血症(relativehypocitrullinemia)。术语“相对低瓜氨酸血症”是指这样的状态，其中与未患有并发症的个体相比，患有并发症的个体具有降低的血浆瓜氨酸。
在某些实施方案中，所述个体患有低瓜氨酸血症。在某些实施方案中，所述低瓜氨酸血症的特征在于血浆瓜氨酸水平为≤37μmol/升，在某些实施方案中为≤25μmol/升，在某些实施方案中为≤20μmol/升，在某些实施方案中为≤10μmol/升，在某些实施方案中为≤5μmol/升。
本发明还提供了治疗血管痉挛的方法和组合物。在某些实施方案中，待治疗个体患有与SAH有关的血管痉挛。在某些实施方案中，待治疗个体患有导致血管痉挛的创伤(例如导致SAH的创伤)。在某些实施方案中，血管痉挛与个体的动脉粥样硬化有关。在某些实施方案中，动脉粥样硬化与个体的冠状动脉疾病、颈动脉疾病、外周动脉疾病及其组合有关。
在某些实施方案中，所述一氧化氮前体包括瓜氨酸、在体内产生瓜氨酸的前体、其药学可接受的盐及其组合的至少一种。参见图1。在某些实施方案中，所述一氧化氮前体选自包括但不限于瓜氨酸、精氨酸或其组合。在某些实施方案中，将诸如瓜氨酸的一氧化氮前体口服给药。在某些实施方案中，将诸如瓜氨酸的一氧化氮前体静脉内给药。在某些实施方案中，待治疗个体是患有血管痉挛的个体。在某些实施方案中，待治疗个体是患有与血管痉挛有关的急性病症的个体(例如冠心病中的缺血和/或绞痛)。
在某些实施方案中，患有诸如血管痉挛的并发症的个体还患有相对低瓜氨酸血症。术语“相对低瓜氨酸血症”是指这样的状态，其中与未患有并发症的个体相比，患有并发症的个体具有降低的血浆瓜氨酸。
本文所用的短语“治疗”是指为改善个体的病症而设计的干预措施(例如，在疾病过程开始后或者在损伤后)以及为预防个体的病症发生而设计的干预措施。换言之，术语“治疗”及其语法变体旨在被广义地解释为涵盖意指减少病症的严重性和/或治愈病症的含义，以及意指预防的含义。在后一方面，“治疗”可以指“预防”至任何程度，或者以其它方式增强诸如面临罹患所述病症的个体的个体抵抗病症过程的能力。
在本发明的许多实施方案中治疗的个体期望地为人，但是应当理解本发明的原理表明本发明对于包括诸如哺乳动物和鸟类的温血脊椎动物在内所有脊椎动物物种是有效的，其意图被包括在术语“个体”中。在本文的语境中，哺乳动物被理解为包括期望治疗的任何哺乳动物物种，例如但不限于农业哺乳动物物种和饲养哺乳动物物种。
因此，本发明提供了对诸如人的哺乳动物的治疗，以及对以下哺乳动物的治疗，其由于濒临绝种而对人类具有重要性(例如西伯利亚虎)、对人类具有经济重要性(为人类食用而在农场饲养的动物)和/或对人类具有社会重要性(作为宠物或在动物园中饲养)，例如除人以外的食肉动物(如猫和狗)、猪(swine)(小猪(pig)、肉猪(hog)和野猪)、反刍动物(例如牛(cattle)、阉牛(oxen)、绵羊、长颈鹿、鹿、山羊、野牛和骆驼)和马。本发明还提供了对鸟类的治疗，包括对濒临灭绝的鸟、饲养在动物园中的鸟，以及家禽(fowl)，更特别的是驯养家禽，即诸如火鸡、鸡、鸭、鹅、珍珠鸡等家禽(poultry)的治疗，因为它们也对人类具有经济重要性。因此，本发明提供了对家畜的治疗，所述家畜包括但不限于家猪(小猪和肉猪)、反刍动物、马、家禽等。
III.药物组合物
将有效剂量的本发明的组合物向有此需要的个体给药。“有效量”是足以产生可测量的反应(例如正在接受治疗的个体中的生物或临床相关的反应)的组合物的量。可以改变本发明的组合物中的活性成分的实际剂量水平，从而以有效实现特定个体的期望治疗反应的量将活性化合物给药。所选的剂量水平取决于治疗组合物的活性、给药途径、与其它药物或疗法的组合、被治疗的病症的严重性以及被治疗的个体的病症和既往医疗史。以示例而非限制的方式，组合物的剂量可以以低于实现期望疗效所需的水平开始，并且逐渐地增加剂量直至实现期望的效果。组合物的效力可以变化，因此“有效量”可以变化。
阅读了本文所提供的本发明的公开内容之后，考虑到具体制剂、用所述组合物实施的给药方法以及治疗的具体疾病，本领域技术人员可以为单独的个体制定剂量。剂量的进一步计算可以考虑个体的身高和体重、性别、症状的严重性和阶段，以及其它有害身体病症的存在。
以其它实例的方式，可以与载体材料组合以产生单一剂型的活性成分的量取决于待治疗个体和具体给药方式而变化。例如，意图向人类给药的制剂可以含有与合适且方便的量的载体材料混合的0.5mg至5g的活性剂，所述载体材料可以为全部组合物的约5％至约95％不等。例如，在成人中，每人每次给药的剂量通常为1mg至500mg，并且每天多达数次。因此，单位剂型通常含有约1mg至约500mg的活性成分，通常为25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg的活性成分。
在某些实施方案中，以约0.01mg至约1,000mg的剂量将一氧化氮前体给药，在某些实施方案中，剂量为约0.5mg至约500mg，并且在某些实施方案中，剂量为约1.0mg至约250mg。在某些实施方案中，还可以以约100mg至约30,000mg的剂量将一氧化氮前体给药，并且在某些实施方案中，剂量为约250mg至约1,000mg。代表性剂量为3.8g/m2/天的精氨酸或瓜氨酸(摩尔当量，MWL-瓜氨酸175.2，MWL-精氨酸174.2)。
代表性的静脉内瓜氨酸溶液可以包括100mg/ml(10％)的溶液。代表性的静脉内瓜氨酸剂量可以包括200mg/kg、400mg/kg、600mg/kg和800mg/kg。在某些实施方案中，所述剂量例如但不限于600mg/kg或800mg/kg，可以将所述剂量减少50mg/kg至100mg/kg的量以缓和所观察到的对全身血压的不期望作用。在某些实施方案中，在诸如1天的给定时间内，可以给药一次或多次的剂量。
在某些实施方案中，药物组合物包含有效地升高血浆瓜氨酸水平以治疗个体的本文公开的并发症的量的瓜氨酸。在某些实施方案中，所述水平是通过将待治疗个体的血浆瓜氨酸水平与在未患有并发症的个体中所观察到的水平进行比较而测定的。在某些实施方案中，瓜氨酸的量将个体的血浆瓜氨酸水平有效升高到至少5μmol/升，任选至少10μmol/升，任选至少20μmol/升，任选至少25μmol/升以及任选约37μmol/升。
在某些实施方案中，本发明提供了药物组合物，其包含一氧化氮前体和药学可接受的载体，如在人类中药学可接受的载体。在某些实施方案中，本发明提供了药物组合物，其包含上述剂量的瓜氨酸或精氨酸。
通常以单位剂量制剂(dosageunitformulation)将本发明的组合物口服或胃肠外给药，所述制剂视需要含有标准无毒的药学可接受的载体、佐剂和媒介物(vehicle)。本文所用的术语“胃肠外”包括静脉内、肌肉内、动脉内注射或输注技术。
根据已知技术，利用合适的分散剂或润湿剂及助悬剂配制诸如无菌注射水性或油性悬浮液的注射制剂。所述无菌注射制剂还可以为在无毒可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液，例如，1,3-丁二醇中的溶液。
可用的可接受的媒介物和溶剂中包括水、林格溶液(Ringer’ssolution)和等渗氯化钠溶液。另外，通常将无菌非挥发油用作溶剂或悬浮介质。为了该目的，可以使用包括合成甘油单酯或甘油二酯在内的任何温和的非挥发油。此外，诸如油酸的脂肪酸可用于注射剂的制备。示例性载体包括用磷酸盐、乳酸盐、Tris等缓冲的中性盐溶液。
在代表性实施方案中，可以在相关治疗期间向个体给药若干次的剂量，其包括但不限于1、2、3、4、5、6或更多次的剂量。
然而，应当理解，对于任何特定个体的具体剂量水平取决于多种因素，其包括年龄、体重、一般健康、性别、饮食、给药时间、给药途径、排泄速率、药物组合以及在治疗的特定疾病的严重性。
实施例
本发明包括以下实施例以示例本发明的代表性方式。根据本公开内容和本领域的一般技术水平，本领域技术人员应当理解，由于可以在不偏离本发明的精神和范围的情况下采用多种变化、修改和改变，以下实施例仅仅旨在示例。
实施例概述
尽管症状控制在SAH的治疗中起到主要作用，但是始终长期亟需解决产生SAH的并发症的根本生理学基础的治疗策略。例如，动脉瘤SAH的关键病理机制之一是脑血管中一氧化氮利用率的降低，这导致平滑肌收缩或血管痉挛。通过将患有和未患有血管痉挛的患者进行比较，本共同发明人已确定瓜氨酸水平具有显著差异，与未患有血管痉挛的患者相比，患有血管痉挛的患者的瓜氨酸水平较低。尽管不期望被任何具体操作理论所束缚，但是这些结果表明，充当NO前体的瓜氨酸可以通过支持血管舒张的类似机制来治疗SAH和冠状动脉疾病，所述支持血管舒张是通过恢复充当一氧化氮前体等作用的瓜氨酸的充分供给实现的。
实施例1和2提供了患有和未患有血管痉挛的个体中的瓜氨酸、鸟氨酸、精氨酸和一氧化氮的血浆水平的测定结果。收集后24小时内将样品分离。在实施例1中，早期收集后测定水平，而在实施例2中，晚期收集后测定水平。
实施例1
未患有和患有血管痉挛的患者中的血浆(早期收集)比较
1n＝5；数据表示为平均值±标准误差
实施例2
未患有和患有血管痉挛的患者中的血浆(晚期收集)比较
1n＝5；数据表示为平均值±标准误差
参考文献
以下所列参考文献以及本说明书中引用的全部参考文献均援引加入本文，达到它们对本文所用的方法、技术和/或组合物做出补充、解释、提供背景或教导的程度：
BatistadaCostaJr.等人(2004)ArqNeuro-Psiquiatr(SaoPaulo)62:245-249。
Suarez等人(2006)NEnglJMed354:387-396。
Flett等人(2005)AJNRAmJNeuroradiol26:367-372。
2004年11月25日公开的美国专利申请第US-2004-0235953-A1号。
2005年9月9日公开的PCT国际专利申请公开第WO2005/082042号。
美国专利第6,343,382号。
美国专利第6,743,823号。
应当理解，可以在不偏离本发明的范围的情况下对本发明的各种细节做出改变。而且，前述说明仅用于示例的目的，而并非用于限制的目的。
Claims (18)
1.治疗与动脉瘤性蛛网膜下腔出血(SAH)有关的并发症的方法，所述方法包括向有此需要的个体给药有效量的一氧化氮前体。
2.如权利要求1所述的方法，其中所述个体患有导致SAH的创伤。
3.如权利要求1所述的方法，其中所述一氧化氮前体包括瓜氨酸、在体内产生瓜氨酸的前体、其药学可接受的盐及其组合中的至少一种。
4.如权利要求1所述的方法，其中所述给药是静脉内或口服给药。
5.如权利要求1所述的方法，其中将所述一氧化氮前体以约100mg至约30,000mg的剂量给药。
6.如权利要求5所述的方法，其中将所述一氧化氮前体以约250mg至约1,000mg的剂量给药。
7.治疗血管痉挛的方法，所述方法包括向有此需要的个体给药有效量的一氧化氮前体。
8.如权利要求7所述的方法，其中所述血管痉挛与所述个体的动脉瘤性蛛网膜下腔出血有关。
9.如权利要求7所述的方法，其中所述个体患有导致血管痉挛的创伤。
10.如权利要求7所述的方法，其中所述血管痉挛与所述个体的动脉粥样硬化有关。
11.如权利要求10所述的方法，其中所述动脉粥样硬化与冠状动脉疾病、颈动脉疾病、外周动脉疾病或其组合有关。
12.如权利要求7所述的方法，其中所述一氧化氮前体包括瓜氨酸、在体内产生瓜氨酸的前体、其药学可接受的盐及其组合中的至少一种。
13.如权利要求7所述的方法，其中所述给药是静脉内或口服给药。
14.如权利要求7所述的方法，其中将所述一氧化氮前体以约100mg至约30,000mg的剂量给药。
15.如权利要求14所述的方法，其中将所述一氧化氮前体以约250mg至约1,000mg的剂量给药。
16.药物组合物，其包含药学可接受的载体以及有效升高血浆瓜氨酸水平以治疗个体的与动脉瘤性蛛网膜下腔出血(SAH)有关的并发症或血管痉挛的量的瓜氨酸，其中所述水平是通过将待治疗个体的血浆瓜氨酸水平与在未患有与动脉瘤性蛛网膜下腔出血(SAH)有关的并发症或血管痉挛的个体中所观察到的血浆瓜氨酸水平进行比较而测定的。
17.如权利要求16所述的药物组合物，其中瓜氨酸的量将个体的血浆瓜氨酸水平有效升高到至少5μmol/升，任选至少10μmol/升，任选至少20μmol/升，任选至少25μmol/升，以及任选约37μmol/升。
18.如权利要求16所述的药物组合物，其中所述药物组合物适合于静脉内或口服给药。
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| US5767160A (en) * | 1994-10-05 | 1998-06-16 | Notol, Inc. | Method and formulation of stimulating nitric oxide synthesis |
| US6358536B1 (en) * | 1997-10-15 | 2002-03-19 | Thomas Jefferson University | Nitric oxide donor compositions, methods, apparatus, and kits for preventing or alleviating vasoconstriction or vasospasm in a mammal |
| US20010056068A1 (en) * | 1998-03-04 | 2001-12-27 | Kristof Chwalisz | Method of treatment and prevention of nitric oxide deficiency-related disorders with citrulline and citrulline derivatives |
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