CN111050780B - 脑活素的用途 - Google Patents
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- CN111050780B CN111050780B CN201880055542.5A CN201880055542A CN111050780B CN 111050780 B CN111050780 B CN 111050780B CN 201880055542 A CN201880055542 A CN 201880055542A CN 111050780 B CN111050780 B CN 111050780B
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Abstract
公开了用于降低CADASIL(脑常染色体显性遗传性动脉病合并皮质下梗死和白脑病)患者死亡率的脑活素。
Description
本发明涉及治疗CADASIL。
CADASIL(脑常染色体显性遗传性动脉病合并皮质下梗死和白脑病；或：CADASIL综合征)引起一种伴有遗忘的腔隙综合征，其主要特征包括复发性皮质下缺血事件和血管性痴呆，并且与神经影像学上的弥漫性白质异常有关。CADASIL以常染色体显性方式遗传。大多数受累个体都有一个受累父母。致病性从头变异似乎很少见。受累者的每个孩子都有50％的风险会继承致病性变异和发展出疾病迹象。如果已知家族有致病性变异，则可以对风险较高的妊娠进行产前检查，并进行植入前遗传学诊断；然而，针对典型的成人发病进行产前检查的申请并不常见。病理检查发现多发性小而深的脑梗死(cerebral infarcts)，白质脑病(leukoencephalopathy)和主要累及小脑动脉的非动脉粥样硬化、非淀粉样的血管病。血管平滑肌细胞的严重改变明显可见于超微结构分析中。该突变基因被定位到19号染色体，并在导致严重破坏该基因的CADASIL患者中鉴定出了人Notch3基因的多个突变。实际上，超过95％的CADASIL个体在Notch3中有致病性错义变异(Rutten et al.,in:Pagon etal.(Eds.)(2000；updated 2016)；Seattle(WA):University ofWashington,Seattle；1993-2017；Joutel et al.,Nature 383(1996),707-710)。CADASIL患者中超过95％的Notch3突变是错义突变，而其他突变则是较小的框内缺失或剪接位点突变。令人惊讶的是，所有致病性突变都会导致给定的EGFR中存在奇数个半胱氨酸残基。据信半胱氨酸残基负责蛋白质的结构完整性，因此增加或丢失半胱氨酸残基可能损害正确的蛋白质折叠。从头突变很少见，但个别病例已有报道。
CADASIL的病理特征是，小动脉介质中有电子致密颗粒，且动脉壁的Notch3染色增强，这可在皮肤活检中评估。目前针对CADASIL尚无证实疗效的治疗方法。抗血小板治疗经常使用，但在CADASIL中尚未证明有效。偏头痛应根据发病频率进行对症地预防性治疗。高血压、糖尿病或高胆固醇血症的并发应予以治疗。支持性的护理(实践帮助，情感支持，和心理咨询)适用于受累个体及其家人。但是，建议避免使用可能引起脑血管意外的血管造影和抗凝剂等药物。还已知吸烟会增加缺血事件的风险。严禁溶栓治疗(静脉溶栓)，因为脑出血的风险可能会增加(Pagon et al.,2000；updated 2016)。
由于针对CADASIL尚无有效的治疗方法，因此，治疗旨在寻找可能的疾病缓解策略以减轻临床表现。但是，到目前为止，仅报道了一些非常初步的研究。
传闻有病例也使用丙戊酸钠进行偏头痛治疗。据报道，乙酰胆碱酯酶抑制剂在治疗认知功能减退的一级终点(18周后血管性痴呆评估量表)无效，但观察到额叶皮层下功能障碍的改善。已测试抗血小板药物对原发和继发中风的阻止效果；结果不确定，疗效有争议。还测试了乙酰唑胺使脑灌注增加的效果，是通过灌注MRI、经颅多普勒超声检查和Tc-99m胞外域脑灌注SPECT来评估。此外，它已被用作偏头痛的预防剂，目的是减少偏头痛发作的频率。对于阿托伐他汀(Atorvastatin)，经颅多普勒检查未见对脑血流有何影响。经颅多普勒检查发现，L-精氨酸表现出诱导型血管反应性。沙丙蝶呤(200-400mg，每日两次，24个月)的最终结果是，在一级终点(反应性充血指数的均差)，对外周血管反应性的任何改善均无显著意义。据报道，在小鼠模型中，干细胞因子和粒细胞集落刺激因子的组合限制了CADASIL的病理进展(综述见:Di Donato et al.,BMC Medicine(2017)15:41；DOI10.1186/s12916-017-0778-8)。
鉴于有证据表明，具有血管风险因子(尤其是吸烟和高血压)的患者病程更严重，故而控制血管风险因子被视为CADASIL管理的重要组成部分。关于抗血小板药物(如阿司匹林或氯吡格雷)的使用，大多数神经科医师在治疗CADASIL患者时均适用针对偶发性卒中的指南。但此法的适当性尚未确定。实际上，此病中的缺血性事件的血栓形成尚未得到证实。另一方面，许多报告都强调在相当大比例的CADASIL患者中存在微出血。由于这些原因，抗血小板药物在此病中的安全性尚待阐明。同样，溶血栓的益处尚不确定，尽管有人认为它对散发性腔隙性脑卒中有益。
在一项有168个病例的多奈哌齐(donepezil)多中心临床试验中，血管性痴呆评估量表的初步结局-认知子量表未有改善。但是，在几项执行功能(executive function)指标上已有改进，只是它们的临床相关性尚不清楚。CADASIL的并发症(例如抑郁症和偏头痛)似乎对与散发疾病中使用的类似疗法产生了反应(Di Donato et al.,2017)。Chen等人综述了用于血管性痴呆的脑活素(Cochrane Database of System.Rev.1(2013):DOI:10.1002/146 1858.CD008900.pub)。
在缺乏CADASIL的具体数据的情况下，大多数神经科医师对年龄较大的患者(例如40岁以上的患者)缺血性卒中后使用阿司匹林进行二级预防，但没有证据支持或反对使用阿司匹林。鉴于可能增加的出血风险，尚不确定该策略是否适用于CADASIL，尚需进一步研究。考虑到已报告的脑出血风险，应仔细随访有明确指症(例如高危房颤)而需要抗凝治疗的患者。
因此，很明显，需要针对CADASIL患者的新的合理治疗干预措施，以解决疾病症状和疾病进展，尤其是分别降低死亡率或提高生存率的治疗干预措施。
因此，本发明提供了脑活素(Cerebrolysin)，用于降低CADASIL(脑常染色体显性遗传性动脉病合并皮质下梗死和白脑病)患者的死亡率。
脑活素，一种通过脑蛋白的标准化酶促分解而制得的肽制剂，包括低分子量肽(<10kDa)和游离氨基酸。
脑活素是一种具有神经营养样特性的肽混合物，可消除临床前模型和痴呆症患者的行为和认知缺陷，并在卒中和TBI中改善运动功能、认知能力和日常生活活动。脑活素的作用方式是多营养的(pleiotrophic)，范围从神经保护特性(例如减少兴奋性毒性和自由基形成)到通过增加神经可塑性和神经发生而促进恢复。
脑活素已用于卒中和血管性痴呆。有报道称，对血管性痴呆患者的认知功能产生有益作用，可能是通过减少β-淀粉样蛋白沉积来实现。脑活素在欧洲和亚洲多个国家已获批用于治疗卒中。
通过本发明，令人惊讶地观察到脑活素对降低死亡率具有显著影响，因此对于提高CADASIL患者的存活率具有显著影响。尽管没有观察到对作为CADASIL标志的白质空泡化的影响(这使本发明更加令人惊讶)，但在现有的CADASIL小鼠模型中，脑活素治疗的死亡率具有统计学上非常显著的降低。
此效果是完全出乎意料的，特别是考虑到以下事实：在先前的出版物中，有报道称，脑活素在体外对来自CADASIL患者的细胞的氧化应激诱导型凋亡不具有保护作用(Formichi et al.,Neurol.Sci.34(2013),553-556；doi:10.1007/s10072-012-1174-y)。
在这项研究中，Formichi等人使用了来自15位CADASIL患者(年龄在34-70岁之间)的外周血淋巴细胞(PBL)和2-脱氧-D-核糖(dRib)，后者是高还原糖，用作促凋亡刺激物的范例。凋亡通过流式细胞术和荧光显微镜检来分析。对标准条件下培养的CADASIL患者PBL给予脑活素不影响凋亡细胞的百分比。对dRib培养的PBL给予Cere，导致培养48h后，仅5位患者的凋亡显著减少，而在其他10位患者中，脑活素治疗与凋亡百分比的任何显著差异无关。该结果表明，仅在30％的CADASIL患者中，脑活素对氧化应激诱导型凋亡具有保护作用。因此得出结论，Notch3基因在体外可能不影响脑活素的抗凋亡特性。这也可以解释在本发明的过程中获得的结果，即脑活素对空泡化没有作用。无论如何，脑活素可能对主要参数死亡率产生影响因此是完全出乎意料的。
不管Formichi等人所获得的结果，也不管CADASIL患者的Notch3基因有突变的事实，脑活素可以有效地用于治疗所有CADASIL患者，而获得本发明的效果。
CADASIL常常通过遗传学来诊断，优选对整个Notch3基因进行测序。多个位于NOTCH3外显子33(编码该蛋白的胞内部分的PEST结构域)中的杂合截短致病变体已在单侧脑膜综合征(雷曼综合征)中描述。推测这些致病变体通过获得Notch3信号传导功能而起作用，它们与CADASIL中的NOTCH3致病变体不同。一个Notch3外显子25致病变体(c.4556T>C,p.Leu1519Pro)已在常染色体显性婴儿性肌纤维瘤病中描述。
CADASIL患者的脑部磁共振成像(MRI)表现出T1加权图像上的低强度和T2加权图像上的高强度，通常是多种尺寸的融合性白质病变。这些病变集中在基底神经节、脑室周围白质和脑桥周围，且与Binswanger病中所见相似。这些白质病变在具有突变基因的无症状个体中也可见到。尽管MRI未用于诊断CADASIL，但它可以在症状发作的甚至数十年前就显示白质变化的进展。
CADASIL患者的白质变化常累及颞叶前部(anterior temporal lobe)、外囊(external capsule)和额上回(superior frontal gyrus)。颞叶前部的改变已显示出对该疾病具有高敏感性和特异性(每种情况约90％)，可用于诊断。在亚洲人群中，颞叶前部受累较少见。外囊改变也具有较高敏感度(大约90％)，但特异性较低(大约50％)。实际上，最近一项系统分析表明，外囊也类似地参与了CADASIL和散发的SVD。在散发的SVD中很少见到胼胝体信号异常在CADASIL有描述；这种异常也是多发性硬化的特征，这是将CADASIL误诊为多发性硬化的原因之一。经Gradient-回波成像显示有斑点样低信号病变的脑部微出血可见于各种比例的病例中(30～70％)，并且常随着年龄增长和诸如高血压之类的风险因子的增加而增加，脑出血也可见于不少患者，尤其是亚洲血统的患者(di Donato et al.,2017)。
CADASIL的ICD-10-CM诊断代码被归类为I67.8(“其他指定的脑血管疾病”)，且已被定义为皮质下疾病，但是最近对允许更高分辨率成像的高场7-Tesla MRI的研究检测到皮质的主要累及，包括确认皮质微梗死以及额叶和顶叶区的早期弥漫性皮质改变，其大都通常是在两个半球遵循对称模式。这些改变与皮质变薄或皮质下病变无关，有人假设其继发于静脉血管密度或髓内水肿。类似的数据也在实验模型中有报道。此外，皮质下改变可能诱发继发性皮质改变。在一项纵向研究中，偶发腔隙(incident lacunes)之后，皮层变薄，特别是在相连的大脑区域。最近的另一项研发是用扩散张量成像(diffusion tensorimaging)来表征组织损伤。在CADASIL患者中观察到的扩散指标的典型变化是分数各向异性(衡量扩散方向的指标)降低和表观扩散系数或平均扩散率(衡量扩散程度的指标)增加。直方图分析已被提议为一种可用于横向和纵向测量CADASIL相关变化的敏感工具(诊断和鉴别诊断参见di Donato等人，2017年和Rutten等人，2000年，更新于2016年)。
尽管仍被认为是诊断不足，但CADASIL诊断在过去20年中已显著改善，现在更加准确。
脑活素是经蛋白水解产生的来自于纯化的脑蛋白的神经肽的药物制剂。脑活素通常以标准化产品的形式在市场上出售。脑活素包含15％～30％的低分子量肽(<10kDa)和70～85％的游离氨基酸，例如丙氨酸，天冬氨酸，精氨酸，谷氨酸，甘氨酸，组氨酸，异亮氨酸，亮氨酸，赖氨酸，蛋氨酸，苯丙氨酸，脯氨酸，丝氨酸，苏氨酸，色氨酸，半胱氨酸和缬氨酸。溶液优选是无菌的，并且已准备好用于注射或输注(即，其满足将药物制剂施用于人类患者的所有标准和要求)。EP 0 452 299 A1 CN和Gromova等人(Difficult Patient 8(2010),25-31)公开了脑活素制剂。
根据本发明使用的优选的脑活素浓度在水溶液中每毫升包含50～1000mg，优选100～500mg，尤其是150～250mg脑活素浓缩物。如上所述，按总氮量计，脑活素包含约85％的游离氨基酸和15％的低分子量肽(<10kDa)。
脑活素浓缩物针对具体氨基酸有标准化含量。在浓缩物中(给药时，按所需，浓度可能会有所不同)，脑活素具有以下氨基酸含量(以mg/ml脑活素浓缩物计)：丙氨酸：2.40～3.60，尤其是3.10～3.50；天冬氨酸：2.40～3.60，尤其是2.20～3.50；缬氨酸：1.60～2.40，尤其是2.10～2.40；组氨酸：1.04～1.56，尤其是1.10～1.50；甘氨酸：1.20～1.80，尤其是1.60～1.90；谷氨酸：3.20-4.80，尤其是3.30-4.60；异亮氨酸：1.60～2.40，尤其是2.20～2.40；亮氨酸：4.80～7.20，尤其是5.70～6.30；赖氨酸：4.80～7.20，尤其是5.80～7.20；蛋氨酸：0.35～0.65，尤其是0.40～0.70；脯氨酸：1.60～2.40，尤其是2.00～2.40；丝氨酸：0.21～0.39，尤其是0.23～0.36；苏氨酸：0.21～0.39，尤其是0.26～0.35；色氨酸：0.35～0.65，尤其是0.40～0.70；苯丙氨酸：1.60～2.40，尤其是1.60～2.40。很明显，该浓缩物稀释后，每毫升中具体氨基酸的绝对量降低；然而，氨基酸彼此之间的比例以及相对于低分子量肽(10,000或更小)的比例经过稀释仍保持不变，这种相对比例是获得本发明疗效的基本要素。
在EP 0 452 299 A1中公开了一种生产脑活素的方法，是通过猪脑蛋白质组分的酶促水解获得的。每毫升该产品包含3.00mg丙氨酸，3.00mg天冬氨酸，0.06g胱氨酸，4.30mg谷氨酸，1.50mg甘氨酸，1.30mg组氨酸，2.00mg异亮氨酸，6.00mg亮氨酸，0.50mg蛋氨酸，2.00mg苯丙氨酸，2.00mg脯氨酸，0.30g丝氨酸，0.30g苏氨酸，0.50g色氨酸和2.00mg酪氨酸作为氨基酸以及分子量10.000以下的肽。在EP 0 452 299 A1中公开的制剂中，肽和氨基酸的混合物包含(对于典型的脑活素产品而言)约15％的分子量为10,000以下的肽和约85％的游离氨基酸。
所施加的剂量可优选在100～10000mg(0.5～50ml脑活素浓缩物)的范围内。优选地，CADASIL患者用0.1～100ml，优选1～50ml范围内的脑活素剂量治疗，相当于21.5～21,520mg脑活素浓缩物(优选的脑活素浓缩物包含215.2mg/ml)。如果是肌内施用，则剂量通常低于静脉内(例如，静脉内优选0.5～5ml，优选0.5～10ml)。因此，优选地，CADASIL患者用0.1～10ml，优选0.5～5ml的肌内给药剂量进行治疗，相当于21.5mg～2152mg脑活素浓缩物。脑活素也可以连续输注(通常以10ml以上的体积)，因此脑活素浓缩液可以例如用0.9％氯化钠溶液(9mg NaCl/ml)，林格氏液(Na+153.98mmol/l,Ca2+2,74mmol/l,K+4,02mmol/l,Cl-163,48mmol/l)，5％葡萄糖稀释。输注通常持续5分钟～4小时，优选10分钟～2小时，尤其是15～60分钟，(优选每天进行输注)，例如输注1～100天，优选5～50天，优选10～30天(通常地，仅在工作日给药，周末不给，因此一个治疗周期通常有3～5x 5个连续给药天数)。根据一优选实施方案，CADASIL患者用0.1～100ml、优选1～50ml的静脉内给药剂量来治疗，相当于215.2～21,520mg脑活素浓缩物。
可以在1～6个月、1～3个月、优选2～3个月的无治疗期之后重复治疗周期。
本发明用以下实施例和附图进一步说明，但不限于此。
图1显示了经计算的盐水处理组与脑活素组的小鼠死亡率(35％比0％)。
图2显示了CADASIL小鼠中线偏外0.5mm处矢状脑切面的luxol固蓝和Nissl染色。细胞体为深蓝；白质染成蓝绿。虚线包括观察到的区域，胼胝体前部(anterior corpuscallosum)。
图3显示了一只年轻健康小鼠(A)和一只18月龄CADASIL小鼠(B)中的胼胝体前部。六周龄雄性C57BL/6(A)的胼胝体(corpus callosum)前中部未见空泡化，而CADASIL小鼠(B)中明显空泡化。与圆形空泡相对照，可看到血管为细长结构(见内框)。
图4显示了18月龄CADASIL转基因小鼠在12～18个月期间用三轮载体(左)或脑活素(右)治疗后，胼胝体前部中的空泡数目。在这两组中，均观察到预期的病理，即白质的空泡化(两组之间无统计学显著性差异(p＝0.12；Student t-检验))。
实施例
脑活素在CADASIL小鼠模型中的疗效
材料和方法
CADASIL小鼠模型：NOTCH3R169C突变(品系88)
在表达NOTCH3R169C突变的现有转基因CADASIL小鼠模型(品系88)中进行概念验证研究，以检查脑活素在CADASIL中的疗效。外显子4中第169位残基从精氨酸变为半胱氨酸的这种特定取代已在CADASIL患者中报道，这似乎是一个频繁的突变(Joutel等，1997)。该转基因小鼠品系已在此前有详细表征来显示CADASIL的一些生化特征，因此被认为是适合该疾病的遗传动物模型(Ghosh等人，2015；Joutel等人，2010)。Joutel及其同事(Joutel等人，2010年)证明，这种小鼠体内突变的转基因的体内表达复制了内源性NOTCH3表达模式和CADASIL的主要病理特征，包括典型的NOTCH3ECD聚集物、脑血管中的GOM沉积、进行性白质损害和脑血流量减少。突变小鼠表现出肌原反应减弱，脑动脉内径缩小，以及脑血管自调节能力受损，功能性充血和白质毛细血管密度显著降低。最近一项对NOTCH3R169C模型的鉴定揭示了周细胞在脑血管功能失调和BBB渗漏中的重要作用，此作用引起CADASIL病理(Ghosh等人，2015)。这些作者表明，随着年龄增长，周细胞和平滑肌细胞周围聚集了突变的NOTCH3。NOTCH3积累引起细胞凋亡，导致周细胞数量显著减少，并且周细胞进展覆盖了毛细血管。这些变化与星形尾足脱离脑部微血管、BBB开放和微血管功能失调有关，指症表现为，血浆蛋白渗漏，内皮粘附连接蛋白的表达减少以及微血管对二氧化碳的反应性降低。
实验流程：
为了评估脑活素在该CADASIL小鼠模型中的作用，在启动三轮治疗周期之前，先对28只动物进行饲养并使其年龄超过12个月。给予突变小鼠2.5ml/kg用0.9％生理盐水稀释的脑活素或单独的生理盐水。随机全盲治疗以3周为一轮周期，每周5次IP注射(每只小鼠每次疗程共3x 15次注射)。动物分别在12、14和16月龄时治疗，在18月龄时处死以进行分析。这种治疗方案是基于在不同神经退行性疾病中测试脑活素疗效的实验研究中获得的数据而选出的。启动治疗前允许12个月的生长过程是源于以下发现：该模型的小鼠在此月龄左右开始显出CADASIL的典型疾病特征(Joutel等，2010)。
此外，考虑到药物实际应用转化，选择了治疗性而非预防性干预方法来代表现实的临床情况，一旦病理学发展到可以诊断的阶段，治疗便会开始。死亡率被选为主要参数，它代表了可靠且临床有效的结果指标。另外，CADASIL特异性白质病变的范围通过用luxol固蓝染色进行的组织学分析来定量。为此，对动物进行灌注，将脑部包埋在石蜡中。每只动物检查胼胝体前中部三个矢状切面的两个计数区域。
结果
脑活素治疗完全预防了CADASIL转基因小鼠的死亡。在12到18个月的观察期内(对应动物年龄)，对照组的14只小鼠中有5只死亡(36％)，但是脑活素治疗组中没有一只动物死亡。盐水治疗组的计算死亡率为35％，而脑活素组为0％，表明脑活素疗法在该疾病中具有促进存活的作用(图1)。
然后通过灌注固定杀死动物，取出大脑，包埋在石蜡中，矢状切开，并用luxol固蓝染色以测试白质中的空泡化。图2显示了CADASIL小鼠中线外侧0.5mm处矢状脑切面的luxol固蓝和Nissl染色。细胞体为深蓝色；白质染成蓝绿色。虚线包括观察到的区域，胼胝体前部。
六周龄雄性C57BL/6在胼胝体前中部未见空泡化(图3A)，已知胼胝体前中部在CADASIL小鼠中发生了病理改变(Joutel et al,J.Clin.Invest.120(2010),433-445)。相反，在CADASIL小鼠中观察到明显的空泡化(图3B)。因此，有可能再现文献中已知的CADASIL小鼠的白质的病理变化。在用载体物质治疗的动物中，测出了22±7个空泡(平均值±标准偏差，n＝8)，在用脑活素治疗的动物中测出了26±5个空泡(n＝14)。组间差异不显著(图4；p＝0.12；Student t检验)。在这方面，脑活素看来对CADASIL小鼠的白质空泡化无效。
综上，对死亡率的突出积极作用表明，脑活素是对抗CADASIL疾病的有效治疗剂候选物。
Claims (24)
1.脑活素在制备用于降低CADASIL患者死亡率的脑活素制剂中的用途。
2.根据权利要求1所述的用途，其中所述CADASIL患者在Notch3基因中具有突变。
3.根据权利要求1所述的用途，其中所述脑活素制剂在每ml水溶液中含有50～1000mg脑活素浓缩物。
4.根据权利要求1所述的用途，其中所述脑活素制剂在每ml水溶液中含有100～500mg脑活素浓缩物。
5.根据权利要求1所述的用途，其中所述脑活素制剂在每ml水溶液中含有150～250mg脑活素浓缩物。
6.根据权利要求1所述的用途，其中所述脑活素制剂的治疗剂量为0.1～100ml的脑活素剂量，这相当于21.5～21,520mg脑活素浓缩物。
7.根据权利要求6所述的用途，其中所述脑活素制剂的治疗剂量为1～50ml的脑活素剂量。
8.根据权利要求1所述的用途，其中所述脑活素制剂的治疗剂量为0.1～10ml的肌内给药剂量，这相当于21.5mg～2152mg脑活素浓缩物。
9.根据权利要求8所述的用途，其中所述脑活素制剂的治疗剂量为0.5～5ml的肌内给药剂量。
10.根据权利要求1所述的用途，其中所述脑活素制剂的治疗剂量为0.1～100ml的静脉内给药剂量，这相当于215.2～21,520mg脑活素浓缩物。
11.根据权利要求10所述的用途，其中所述脑活素制剂的治疗剂量为1～50ml的静脉内给药剂量。
12.根据权利要求1所述的用途，其中所述脑活素制剂是用于连续输注的制剂。
13.根据权利要求12所述的用途，其中以5分钟至4小时的输注持续时间来进行输注。
14.根据权利要求12所述的用途，其中以10分钟至2小时的输注持续时间来进行输注。
15.根据权利要求12所述的用途，其中以15至60分钟的输注持续时间来进行输注。
16.根据权利要求12所述的用途，其中输注进行1至100天。
17.根据权利要求12所述的用途，其中输注进行5至50天。
18.根据权利要求12所述的用途，其中输注进行10至30天。
19.根据权利要求13所述的用途，其中输注每天进行一次。
20.根据权利要求1所述的用途，其中脑活素通过用0.9％氯化钠溶液、林格氏溶液或5％葡萄糖稀释来进行输注。
21.根据权利要求1所述的用途，其中所述脑活素制剂含有氢氧化钠。
22.根据权利要求1所述的用途，其中所述CADASIL患者以治疗周期进行治疗，所述治疗周期在1至6个月的无治疗期之后重复。
23.根据权利要求1所述的用途，其中所述CADASIL患者以治疗周期进行治疗，所述治疗周期在1至3个月的无治疗期之后重复。
24.根据权利要求1所述的用途，其中所述CADASIL患者以治疗周期进行治疗，所述治疗周期在2至3个月的无治疗期之后重复。
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| US20220168325A1 (en) * | 2019-03-25 | 2022-06-02 | The University Of Vermont | Methods to promote cerebral blood flow in the brain |
| EP4114843B1 (en) | 2020-07-13 | 2023-08-16 | EVER Neuro Pharma GmbH | Method for producing a mammalian brain protein hydrolysate |
| EP4347634A1 (en) * | 2021-06-02 | 2024-04-10 | Regeneron Pharmaceuticals, Inc. | Treatment of cerebrovascular disease with neurogenic locus notch homolog protein 3 (notch3) agents |
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| MX2011001864A (es) * | 2008-08-20 | 2011-06-20 | Univ Texas | Extrusion de fusion en caliente de multiples particulas de liberacion modificada. |
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| Title |
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| ILARIA DI DONATO ET AL.Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. BMC MEDICINE.2017,第15卷(第15期),全文. * |
| NING CHEN ET AL.Cerebrolysin for vascular dementia.COCHRANE DATABASE OF SYSTEMATIC REVIEWS.2013,全文. * |
| PATRIZIA FORMICHI ET AL.Effects of cerebrolysin administration on oxidative stress-induced apoptosis in lymphocytes from CADASIL patients.NEUROLOGICAL SCIENCES.2012,第34卷(第34期),全文. * |
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| EA202090108A1 (ru) | 2020-03-31 |
| MX2020002267A (es) | 2020-10-22 |
| AU2018326339A1 (en) | 2020-03-05 |
| EP3449931A1 (en) | 2019-03-06 |
| HRP20200031T1 (hr) | 2020-03-20 |
| ES2901508T3 (es) | 2022-03-22 |
| CN111050780A (zh) | 2020-04-21 |
| JP2020531568A (ja) | 2020-11-05 |
| EP3675879A1 (en) | 2020-07-08 |
| WO2019042983A1 (en) | 2019-03-07 |
| KR20200045503A (ko) | 2020-05-04 |
| US20200376040A1 (en) | 2020-12-03 |
| KR102676274B1 (ko) | 2024-06-18 |
| JP7281450B2 (ja) | 2023-05-25 |
| PL3675879T3 (pl) | 2022-02-14 |
| EP3449931B1 (en) | 2019-10-16 |
| CA3073991A1 (en) | 2019-03-07 |
| PL3449931T3 (pl) | 2020-06-01 |
| PH12020500376A1 (en) | 2020-12-07 |
| ES2767070T3 (es) | 2020-06-16 |
| EP3675879B1 (en) | 2021-09-15 |
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