CN106659723A - 用于治疗神经病症的方法 - Google Patents
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Abstract
本发明提供用于治疗神经病症的方法,其包括向有此需要的患者施用一定剂量的VX‑745或其药学上可接受的组合物,从而提供在约15与45ng/mL之间,或在约20与约40ng/mL之间,或在约25与约35ng/mL之间,或在约30与约40ng/mL之间的血液浓度,其中所述血液浓度实现对细胞因子信号传导的抑制而非对细胞因子产生的抑制。
Description
背景技术
细胞内酶p38MAPKα已被充分表征为由巨噬细胞和小神经胶质细胞产生促炎性细胞因子(IL-1β和TNFα)的调控剂,并且被视为阿尔茨海默氏病(Alzheimer’s disease)中的治疗靶标(Munoz,2010);主要基本原理是降低来自小神经胶质细胞的炎症性介体以及它们在Aβ下游的影响:兴奋毒性、突触功能障碍和τ蛋白磷酸化。IL-1β-p38MAPKα也可通过影响长期增强/抑制来直接调节记忆形成和认知功能(MacAfoose,2009;Barrientos,2012)。然而,由于血脑屏障(BBB)穿透性化合物先前不可用,所以尚未开发针对AD的p38MAPKα拮抗剂。鉴于P38MAPK抑制剂对促炎性细胞因子产生所具有的已知作用,它们另外已作为消炎剂在广泛范围的非CNS疾病(类风湿性关节炎、炎症性肠病、COPD)中加以评估。因此,对开发穿透BBB,作为AD和其他神经病状的治疗剂的p38MAPKα拮抗剂仍然存在重要未满足需要。
附图说明
图1描绘莫里斯水迷宫测试的潜伏时间结果的变化,在高龄大鼠中比较0.5mg/kg、1.5mg/kg和4.5mg/kg剂量的VX-745。
图2描绘莫里斯水迷宫测试的距离结果的变化,在高龄大鼠中比较0.5mg/kg、1.5mg/kg和4.5mg/kg剂量的VX-745。
图3描绘VX-745的蛋白质水平。
图4描绘在0.5mg/kg、1.5mg/kg和4.5mg/kg剂量的VX-745下,VX-745的中值血浆浓度。
图5描绘在缺血性中风之后肢体放置以及7分和20分神经评分的功能恢复结果,在高龄大鼠中比较0.5mg/kg、1.5mg/kg和4.5mg/kg剂量的VX-745。
图6描绘在缺血性中风之后圆筒测试的功能恢复结果,在高龄大鼠中比较0.5mg/kg、1.5mg/kg和4.5mg/kg剂量的VX-745。
具体实施方式
定义
载体:术语“载体”是指可并入含有活性剂(例如p38抑制剂)的组合物中而不显著干扰所述药剂的稳定性和/或活性(例如所述药剂的生物活性)的任何化学实体。在某些实施方案中,术语“载体”是指药学上可接受的载体。本文中的一示例性载体是水。
组合。如本文所用,术语“组合(combination/combined)”和相关术语是指受试者同时暴露于两种或更多种本发明的治疗剂。举例来说,本发明的药剂(例如p38抑制剂)可与另一治疗剂同时或依序以单独单位剂型或一起以单一单位剂型加以施用。因此,本发明尤其提供涉及施用至少本发明的药剂(例如p38抑制剂)、另一治疗剂和药学上可接受的载体、佐剂或媒介物(所述药学上可接受的载体、佐剂或媒介物通常与所述p38抑制剂和所述另一治疗剂中的一者或两者缔合)的给药方案。
制剂。术语“制剂”是指用于向患者施用的包括至少一种活性剂(例如VX-745)以及一种或多种载体、赋形剂或其他药物添加剂的组合物。一般来说,特定载体、赋形剂和/或其他药物添加剂是根据本领域中的知识加以选择以实现活性剂的所需稳定性、释放、分布和/或活性,并且其应适于特定施用途径。
中等剂量。如本文所用的术语“中等剂量”是指VX-745的向血流中递送,足以抑制在细胞因子和其他受体活化之后p38MAPK介导的细胞内信号传导事件,但低于VX-745的治疗有效量以对通过降低细胞因子产生达成的消炎作用产生抑制的剂量。在一些实施方案中,术语“中等剂量”是指实现血液浓度是为减轻炎症和治疗除本发明的神经病症以外的病症所需的血液浓度的一半、三分之一、四分之一、五分之一、六分之一、七分之一、八分之一的剂量。举例来说,VX-745在治疗类风湿性关节炎时的平均血液浓度是约75ng/mL,这与VX-745抑制细胞因子产生(消炎活性)的全血IC50是65-80ng/mL一致。在一些实施方案中,VX-745的“中等剂量”提供血液浓度在约15与45ng/mL之间,或在20与约40ng/mL之间,或在约25与约35ng/mL之间,或在约30与约40ng/mL之间,其中所述血液浓度实现对细胞因子信号传导的抑制而非对细胞因子产生的抑制。
胃肠外。如本文所用的术语“胃肠外”包括皮下、静脉内、肌肉内、关节内、滑膜内、胸骨内、鞘内、肝内、病变内和颅内注射或输注技术。优选地,口服、腹膜内或静脉内施用组合物。本发明组合物的无菌可注射形式可为水性或油性混悬液。这些混悬液可根据本领域中已知的技术,使用适合分散剂或湿润剂和混悬剂配制。无菌可注射制剂也可为于无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如呈于1,3-丁二醇中的溶液形式。在可采用的可接受的媒介物和溶剂之中的是水、林格氏溶液(Ringer's solution)和等张氯化钠溶液。此外,无菌不挥发性油常规用作溶剂或混悬介质。
患者。如本文所用的术语“患者”意指向其施用制剂或包含制剂的组合物的哺乳动物,并且在一些实施方案中包括人。
药学上可接受的载体、佐剂或媒介物。术语“药学上可接受的载体、佐剂或媒介物”是指不破坏它与其一起配制的化合物的药理学活性的无毒载体、佐剂或媒介物。可用于本发明组合物中的药学上可接受的载体、佐剂或媒介物包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白质(诸如人血清白蛋白)、缓冲物质(诸如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(诸如硫酸鱼精蛋白(protamine sulfate))、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。
治疗剂。如本文所用,短语“治疗剂”是指在向生物体施用时引发所需生物或药理学作用的任何药剂。
治疗有效量和有效量。如本文所用,并且除非另外规定,否则术语药剂的“治疗有效量”和“有效量”是指足以在治疗、预防和/或管理疾病、病症或病状方面提供治疗益处,例如用以使一种或多种与待治疗的所述疾病、病症或病状相关的症状的发作延迟或使所述症状最小化(例如降低所述症状的发生和/或等级)的量。在一些实施方案中,如果组合物含有在治疗方案的情形下在以单次剂量形式施用时有效的量,那么它可被称为含有“治疗有效量”的药剂。在一些实施方案中,治疗有效量是在作为给药方案的一部分施用时,在统计上有可能使疾病、病症或病状的一种或多种症状或副作用的发作延迟或使所述症状或副作用最小化(降低所述症状或副作用的发生和/或等级)的量。
治疗(Treat/Treating)。如本文所用的术语“治疗”是指部分或完全缓和、抑制病症、疾病或病状或所述病症、疾病或病状的一种或多种症状或表现形式,延迟其发作,降低其发生,对其产生防治,对其进行改善和/或减轻。
单位剂量。如本文所用的表述“单位剂量”是指制剂的适于待治疗的受试者的物理离散单元(例如用于单次剂量);各单元含有被选择用以在根据治疗方案,任选连同可以预定量提供的药学上可接受的载体一起施用时产生所需治疗作用的预定量的活性剂(应了解多次剂量可能为实现所需或最优作用所需)。单位剂量可为例如一定体积的含有预定量的一种或多种治疗剂的液体(例如可接受的载体)、预定量的一种或多种呈固体形式的治疗剂(例如片剂或胶囊)、含有预定量的一种或多种治疗剂的持续释放制剂或药物递送装置等。应了解除治疗剂之外,单位剂量也可含有多种组分。举例来说,可接受的载体(例如药学上可接受的载体)、稀释剂、稳定剂、缓冲剂、防腐剂等可如下文所述加以包括。然而,应了解,本发明制剂的总每日用量将由主治医师在合理医学判断的范围内决定。用于任何特定受试者或生物体的特定有效剂量水平可取决于多种因素,包括所治疗的病症和病症的严重性;所用特定活性化合物的活性;所用特定组合物;受试者的年龄、体重、总体健康、性别和膳食;所用特定活性化合物的施用时间和排泄速率;治疗的持续时间;与所用特定化合物组合或同时使用的药物和/或额外疗法;以及医学领域中熟知的类似因素。在一些实施方案中,VX-745的单位剂量是约1mg、3mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg或50mg。
VX-745-一种p38MAPK抑制剂
许多细胞外刺激物,包括促炎性细胞因子和其他炎症性介体,通过活化有丝分裂原活化的蛋白质激酶(MAPK)信号传导路径来引发特定细胞应答。MAPK是靶向脯氨酸的丝氨酸-苏氨酸激酶,其将环境刺激物转导至核。一旦被活化,MAPK即通过磷酸化来活化其他激酶或核蛋白质,包括潜在转录因子和底物。新型哺乳动物再活化蛋白质激酶(p38/RK)MAPK是应激活化的蛋白质激酶,其介导对细胞应激和炎症性信号的应答。
新近人遗传学数据指示阿尔茨海默氏病的主要驱动因素是调控异常的小神经胶质细胞和神经炎症。因为体外数据指示IL-1β-p38MAPK系统是小神经胶质细胞/炎症的关键调控因素,所以p38MAPK被认定为重要治疗靶标(Munoz,2010)。P38MAPK也在神经元内产生,并且似乎在调节与神经功能相关的神经元内信号传导事件方面具有直接作用(McAfoose,2009;Correa,2012)。然而,由于血脑屏障(BBB)穿透性p38MAPK拮抗剂先前不可用,所以在慢性阿尔茨海默氏病模型中抑制p38MAPK的作用未知(Munoz,2010)。因此,先前也未知的是相对于抑制p38MAPK的其他作用,诸如对IL-1β或TNFα的神经元内信号传导的作用,抑制炎症的相对重要性和作用。
p38MAPK在炎症的各个阶段中的作用已促使发现能够抑制p38的若干化合物(SB203580、RWJ 67657、L-167307、VX-745、RPR200765A和其他化合物)。参见例如Kumar等,“p38MAP Kinases:Key Signaling Molecules as Therapeutic Targets forInflammatory Diseases,”Nature Reviews,2:717-726(2003);Brown等,“p38MAP kinaseinhibitors as potential therapeutics for the treatment of joint degenerationand pain associated with osteoarthritis,”J.Inflammation 5:22(2008),其各自的整体以引用的方式并入本文。这些药理学抑制剂是导致体外和体内抑制脂多糖诱导的肿瘤坏死因子-α(TNF-α)产生的细胞因子抑制性消炎药物,并且已根据假定是减轻炎症的主要药理学作用来开发;例如在临床研究中,施用各剂量以实现血液浓度满足或超过抑制细胞因子(IL-1β或TNFα)的全血IC50(用于达成50%最大作用的抑制浓度)。
VX-745是p38MAPK的选择性小分子抑制剂,先前由Vertex Pharmaceuticals开发用于治疗类风湿性关节炎(RA)。
VX-745对MAPK的抑制会阻断炎症性细胞因子TNF-α和IL-1β的下游合成。VX-745的全血IC50是150至180nM,或在65与80ng/mL之间(Duffy,2011)。因为VX-745在啮齿动物关节炎模型中展现显著消炎活性,所以Vertex启动在人类风湿性关节炎(RA)的情况下的临床研究。在用实现约75ng/m的平均血浆药物浓度的250mg VX-745(b.i.d)治疗的2期临床中,显著炎症性标志物降低和临床改进得以证明。然而,患者经历不利事件,包括胃肠影响(诸如腹泻和腹部疼痛)和肝转氨酶升高。此外,已知VX-745会穿透动物中的血脑屏障(BBB)。实际上,VX-745实现的脑浓度是血浆中的1.7倍。经受极高剂量的VX-745的动物经历不利神经影响,但这些不利事件未在人中观察到。尽管确认作为针对RA的治疗剂用于抑制p38MAPK的概念验证,但VX-745被中断以让位于非血脑屏障穿透性化合物VX-702,其将允许针对诸如类风湿性关节炎的疾病在脑外部更大抑制p38MAPK介导的细胞因子产生,而不招致神经副作用的风险。
在关节炎模型中利用VX-745作为参照化合物进行的另一研究证明10mg/kg剂量的VX-745在抑制爪肿胀方面不如同其他测定化合物一样有效。参见Chopra等,“Pharmacological profile of AW-814141,a novel,potent,selective and orallyactive inhibitor of p38MAP kinase,”International Immunopharmacology,10:467-473(2010),其整体以引用的方式并入本文。
在一骨关节炎模型中,当在50mg/kg下向大鼠施用时,相较于对照动物,VX-745显示统计显著抑制膝部退化。也在痛觉过敏模型中测定VX-745,并且显示当在30mg/kg、10mg/kg和3mg/kg的剂量下向大鼠施用时,显著抑制痛觉过敏应答。研究者发现在3mg/kg、10mg/kg和30mg/kg剂量下,小鼠展现痛觉过敏。然而,研究者在3mg/kg剂量下观察到最小作用。参见Brown等,“p38MAP kinase inhibitors as potential therapeutics for thetreatment of joint degeneration and pain associated with osteoarthritis,”J.Inflamm.,5:22(2008),其整体以引用的方式并入本文。
在不希望受理论束缚下,据信p38抑制剂用以治疗诸如类风湿性关节炎的慢性炎症性病状的临床失败是由于炎症性(细胞因子产生)路径的冗余。所述冗余导致当p38MAPK介导的细胞因子产生被长期抑制时,反馈环路被上调,从而导致总体缺乏功效。
本发明方法
在高龄26个月大的Tg2576小鼠中进行的2周探索性研究中,以VX-745治疗的小鼠比对照动物具有更低淀粉状蛋白斑块载荷,但另外不能评估药物作用,因为少许炎症是明显的。这个信息与转基因Aβ小鼠显示代偿性吞噬(消炎)小神经胶质细胞表型的报道相结合,决定不在小鼠中进行进一步研究。作为替代,对于用以预测人剂量的深入剂量-响应研究,选择高龄大鼠模型;其中促炎性细胞因子表达增加得以明确确定,并且因此更好反映人衰老和AD中的炎症性环境(Barrientos,2012)。大鼠模型的另一优势是先前已确定在大鼠与人之间具有VX-745极其良好药物动力学-药力学关联(在大鼠佐剂关节炎模型中的研究与人RA临床试验之间)。在缺血性中风后的功能恢复模型中进行大鼠第二剂量-响应研究。
惊人地,在两个研究中,对神经功能的最佳作用均处于中等剂量水平下,所述中等剂量水平实现血液浓度低于为抑制细胞因子产生所需的血液浓度,并且因此不能产生消炎作用,但足以抑制p38MAP介导的细胞内信号传导事件。更惊人地,发现在脑中确实产生明显消炎作用的较高剂量下对神经功能的作用小于中等剂量水平的神经功能作用。因此,在一些实施方案中,本发明涵盖了解到VX-745用于抑制在细胞因子受体活化之后细胞内信号传导的效能是用于抑制细胞因子产生的效能的约两倍;从而提供一种用以施用VX-745以实现对细胞因子信号传导的抑制,以及与此相伴改进神经功能,而不抑制导致全身性消炎状态的细胞因子产生的手段。
如上所述,在一些实施方案中,本发明提供一种治疗有需要的患者的神经病症的方法,其包括向所述患者施用足以抑制细胞因子信号传导,同时不实质上影响细胞因子产生的量的VX-745。在一些实施方案中,本发明提供一种通过施用足以抑制IL-1β信号传导,同时不实质上影响IL-1β产生的量的VX-745来治疗神经病症的方法。
如本文所用,术语“神经病症”是指以下中的任何一个或多个:阿尔茨海默氏病、轻度认知障碍、血管性痴呆、路易体痴呆(Lewy Body Dementia)和痴呆;帕金森氏病(Parkinson’s Disease);中风后的功能恢复;额颞叶痴呆(FTD)和阵发性痉挛性截瘫(PSP)和其他τ蛋白病变;认知衰弱;慢性耳鸣;和亨廷顿氏病(Huntington's Disease)。在某些实施方案中,通过提供的方法来治疗的神经病症选自阿尔茨海默氏病、轻度认知障碍、血管性痴呆、路易体痴呆和痴呆症;帕金森氏病;中风后的功能恢复;额颞叶痴呆(FTD)和阵发性痉挛性截瘫(PSP)和其他τ蛋白病变;认知衰弱;慢性耳鸣;和亨廷顿氏病。
如本文所用,短语“足以抑制细胞因子(即IL-1β)信号传导,同时不实质上影响细胞因子(即IL-1β)产生的量”是指VX-745的导致患者血液浓度小于为抑制细胞因子产生所需的血液浓度的一半的剂量。在一些实施方案中,“足以抑制细胞因子(即IL-1β)信号传导,不实质上影响细胞因子(即IL-1β)产生的量”是VX-745的导致患者血液浓度比为抑制细胞因子(即IL-1β)产生所需的血液浓度低50%,低60%,低70%,低80%或低90%的剂量。
如本文所用,短语“同时不实质上影响细胞因子(即IL-1β)产生”意指提供的方法导致VX-745的血液浓度不以可测量程度抑制细胞因子产生。
在不希望受任何特定理论束缚下,本发明的一个方面是了解到VX-745在比为抑制细胞因子产生所需的血液浓度低得多的血液浓度下实现对细胞因子信号传导的抑制。本发明的另一方面是了解到VX-745在其中细胞因子信号传导受抑制,但细胞因子产生不受影响的较低浓度下实现正性神经影响。
在一些实施方案中,本发明提供一种改进认知的方法,其包括施用足以抑制细胞因子信号传导,同时不实质上影响细胞因子产生的量的VX-745。在一些实施方案中,本发明提供一种通过施用足以抑制IL-1β信号传导,同时不实质上影响IL-1β产生的量的VX-745来改进认知的方法。
如本文所用,术语“改进认知”是指在任何神经病症的认知衰退或其他认知症状方面的任何可测量改进,所述神经病症诸如阿尔茨海默氏病、轻度认知障碍、血管性痴呆、路易体痴呆和痴呆症;帕金森氏病;中风后的功能恢复;额颞叶痴呆(FTD)和阵发性痉挛性截瘫(PSP)和其他τ蛋白病变;认知衰弱;慢性耳鸣;和亨廷顿氏病。
在一些实施方案中,本发明提供一种通过施用足以抑制细胞因子信号传导,同时不实质上影响细胞因子产生的量的VX-745来改进神经功能的方法。在一些实施方案中,本发明提供一种通过施用足以抑制IL-1β信号传导,同时不实质上影响IL-1β产生的量的VX-745来改进神经功能的方法。
在一些实施方案中,提供的方法包括在足以实现血液浓度导致抑制细胞因子信号传导的剂量下向有此需要的患者施用VX-745,但其中所述血液浓度不足以导致抑制细胞因子产生。在某些实施方案中,提供的方法包括在足以实现血液浓度导致抑制IL-1β信号传导的剂量下向有此需要的患者施用VX-745,但其中所述血液浓度不足以导致抑制IL-1β产生。
在某些实施方案中,提供的方法包括在提供在约15与约45ng/mL之间的血液浓度的剂量下向有此需要的患者施用VX-745或其药学上可接受的组合物。在一些实施方案中,提供的方法包括向有此需要的患者施用一定剂量的VX-745或其药学上可接受的组合物,从而提供在约20与约40ng/mL之间,或在约25与约35ng/mL之间,或在约30与约40ng/mL之间的血液浓度。
在某些实施方案中,本发明提供一种治疗神经病状的方法,其包括向有此需要的患者施用一定剂量的VX-745或其药学上可接受的组合物,从而提供在约15与45ng/mL之间,或在约20与约40ng/mL之间,或在约25与约35ng/mL之间,或在约30与约40ng/mL之间的血液浓度。
在一些实施方案中,本发明提供一种治疗神经病状的方法,其包括向有此需要的患者施用一定剂量的VX-745或其药学上可接受的组合物,从而提供在约15与45ng/mL之间,或在约20与约40ng/mL之间,或在约25与约35ng/mL之间,或在约30与约35ng/mL之间的血液浓度,其中所述血液浓度实现对细胞因子信号传导的抑制而非对细胞因子产生的抑制。
组合疗法
在某些实施方案中,本发明提供一种治疗神经病症的方法,其包括向受试者施用低剂量的VX-745以及一种或多种另一治疗剂。在一些实施方案中,本发明提供一种治疗神经病症的方法,其包括与一种或多种另一治疗剂组合向受试者施用足以抑制细胞因子信号传导,同时不实质上影响细胞因子产生的治疗有效量的VX-745,所述治疗剂选自胆碱酯酶抑制剂、N-甲基-D-天冬氨酸拮抗剂、维生素E、抗抑郁剂、抗焦虑剂、抗精神病药、情绪稳定剂和睡眠助剂。
代表性胆碱酯酶抑制剂包括不限于多奈哌齐(donepezil)利伐斯的明(rivastigmine)加兰他敏(galantamine)和塔克林(tacrine)
代表性抗抑郁剂包括不限于丁氨苯丙酮(bupropion)西酞普兰(citalopram)费洛克汀(fluoxetine)米氮平(mirtazapine)帕罗西汀(paroxetine)舍曲林(sertraline)曲唑酮(trazodone)文拉法辛(venlafaxine)去甲替林(nortriptyline)和去甲丙咪嗪(desipramine)
代表性抗焦虑剂包括不限于劳拉西泮(lorazepam)和奥沙西泮(oxazepam)
代表性抗精神病药包括不限于阿立哌唑(aripiprazole)氯氮平(clozapine)氟哌啶醇(haloperidol)奥氮平(olanzapine)喹硫平(quetiapine)利培酮(risperidone)和齐拉西酮(ziprasidone)
代表性情绪稳定剂包括不限于卡马西平(carbamazepine)和双丙戊酸盐(divalproex)
代表性睡眠助剂包括不限于唑吡旦(zolpidem)、扎来普隆(zaleplon)和水合氯醛(chloral hydrate)。
代表性N-甲基-D-天冬氨酸拮抗剂包括不限于美金刚胺(memantine)
在一些实施方案中,本发明提供一种治疗神经病症的方法,其包括与一种或多种另一治疗剂组合向受试者施用足以抑制细胞因子信号传导,同时不实质上影响细胞因子产生的治疗有效量的VX-745,所述治疗剂选自由以下组成的组:艾塞那肽(exenatide)伐仑克林(varenicline)、PF-04360365、利伐斯的明、LY450139、ST101、苔藓抑素(bryostatin)、EVP-6124、阿托西汀(atomoxetine)、HF0220、白藜芦醇(resveratrol)、加兰他敏、PF-01913539、塞美司他(semagacestat)、3APS、免疫球蛋白、代姆博(dimebon)、α-生育酚、BAY85-8101、雌激素、孕酮、ACC-001、银杏(ginko biloba)、尼麦角林(nicergoline)、吡乙酰胺(piracetam)、NIC5-15、扎利罗登(xaliproden)(SR57746A)、吲哚美辛(indomethacin)、DMXB-A、LY2062430、11-C PIB、巴匹珠单抗(bapineuzumab)、依那西普(etanercept)、雷米普利(ramipril)、干扰素β-1a、辛伐他汀(simvastatin)、硫辛酸(lipoic acid)、鱼油、姜黄素(curcumin)、PF-04447943、叶酸盐、维生素B6、维生素B12、亮脯利特(leuprolide)、INM-176、AH110690、色氨酸、SK-PC-B70M、BMS-708163、依地普仑(escitalopram)、TRx0014、BAY94-9172、脑活素(cerebrolysin)、没食子酸表没食子儿茶素(epigallocatechin-galate)、SB-742457、锂、罗格列酮(rosiglitazone)、双丙戊酸盐、SAR110894D、PRX-03140、CX516(安帕来斯(Ampalex))、烟酰胺、雷沙吉兰(rasagiline)、AC-1202吲度酰胺(enduramide)、奈拉美仙(neramexane)、拉扎达恩(razadyne)、NS 2330他米巴罗汀(tamibarotene)、阿维A(acitretin)、哌甲酯(methylphenidate)、米非司酮(mifepristone)、ZT-1、AFFITOPE AD01、AFFITOPE AD02、GSK239512、GSK933776、SR57667B、PPI-1019、MPC-7869、AZD3480、PAZ-417、苏兰珠单抗(solanezumab)、马赛替尼(masitinib)(AB1010)、BAY1006578、二十二碳六烯酸、QS-21、MNI-558、利忆灵缓释剂(reminyl retard)、氟美他芬(flutemetamol)、雌二醇、甲孕酮、丙戊酸盐、T-817MA、AZD1446、AAB-003(PF-05236812)、莫达非尼(modafinil)、雷洛昔芬(raloxifene)、阿托伐他汀(atorvastatin)、多西环素(doxycycline)、曲唑酮(trazadone)、羟丁酸钠、石杉碱A(huperzine A)、叶黄素(lutein)、玉米黄质(zeaxanthin)、AC-3933、右旋安非他明(dextroamphetamine)、EPAX 1050TG、SRA-333、MNI-168、CAD106、SGS742、NP031112、SSR180711C、GSI-953、哌唑嗪(prazosin)、MEM 1003、AndroGel、AVE1625、环磷酰胺酯(cyclophosphamate)、TC-5619-238、MK0249、来考佐坦(lecozotan)、舍卡丁(circadin)、MEM 3454、PPI-1019、UB 311、PF-04494700、ABT-089、LY451395、E2020、罗非昔布(Rofecoxib)、PF-03654746、EHT 0202依地唑酯(etazolate)、DCB-AD 1、ONO-2506PO、甘特如单抗(gantenerumab)、氟贝塔帕(florbetapir)、ELND005、泼尼松(prednisone)、诺瓦索(novasoy)、人参、匹格列酮(pioglitazone)、辛炔、ABT-288、ABT-384、奈非西坦(nefiracetam)、AQW051、匹伐他汀(Pitavastatin)、萘普生钠(naproxen sodium)氯诺昔康(lornoxicam)、AN-1792、SR57667B、褪黑素(melatonin)、SAM-531、MK0952、MK0677、IFN-α2A、BAY 94-9172、PYM50028、来考佐坦SR、沙利度胺(thalidomide)、曲米沙特(tramiprosate)、FK962、IVIG、RO5313534、联苯芦诺(bifeprunox)、LNK-754、ELND005、NSA-789、雷美尔通(ramelteon)、氟比他班(Florbetaben)、SRA-444、VP4896、塞来昔布(celecoxib)、氢可酮(hydrocodone)、GSI-136、唑吡旦(Zolpidem)、MK3328、二甲双胍(metformin)、CTS21166、依隆曲(elontril)、布洛芬(ibuprofen)、酒石酸泊斯芬(posiphen tartrate)、JNJ-39393406、睪固酮(testosterone)、BRL-049653、BMS-708163、SAM-315、酮康唑(ketoconazole)、氟康唑(fluconazole)、华法林(warfarin)、E2609、AZD0328、LY2886721、CHF 5074、E2212、乙酰胺酚(acetaminophen)、LY2811376、ABT-126、褪黑素、GSK1034702、阿莫达非尼(armodafinil)、德巴科特(depakote)、吉非罗齐(gemfibrozil)、AL-108、左乙拉西坦(levetiracetam)和奎纳克林(quinacrine)。
药物组合物
在一些实施方案中,提供的方法包括向患者施用包含VX-745以及一种或多种治疗剂和药学上可接受的载体、佐剂或媒介物的药物组合物。在一些实施方案中,本发明提供一种包含一定剂量的VX-745以及一种或多种治疗剂和药学上可接受的载体、佐剂或媒介物的药物组合物,其中所述剂量的VX-745导致血液浓度在约5与45ng/mL之间,在约10与45ng/mL之间,在约15与45ng/mL之间,或在约20与约40ng/mL之间,或在约25与约35ng/mL之间,或在约30与约40ng/mL之间。在一些实施方案中,VX-745的剂量导致血液浓度在约5与35ng/mL之间,在约10与30ng/mL之间,在约10与25ng/mL之间,在约5与20ng/mL之间,或在约10与20ng/mL之间。
在某些实施方案中,本发明的药学上可接受的组合物被配制供口服施用。本发明的药学上可接受的组合物可以任何口服可接受的剂型口服施用,所述剂型包括但不限于胶囊、囊片、片剂、水性混悬液或溶液。在供口服使用的片剂的情况下,通常使用的载体包括乳糖和玉米淀粉。通常也添加诸如硬脂酸镁的润滑剂。对于以胶囊形式口服施用,适用稀释剂包括乳糖和干燥玉米淀粉。当水性混悬液为口服使用所需时,使活性成分与乳化剂和混悬剂组合。必要时,也可添加某些甜味剂、调味剂或着色剂。
与载体物质组合以产生呈单一剂型的组合物的本发明化合物的量将视患者和特定施用模式而变化。优选地,应配制提供的组合物以使可向接受这些组合物的患者施用1-50mg/天之间的剂量的VX-745。组合物的实例包括被配制以向接受这些组合物的患者施用每天1-10mg、10-25mg或25-50mg之间的剂量的VX-745的组合物。在本发明的其他实施方案中,组合物包括被配制以向接受这些组合物的患者施用每天3-5mg、5-10mg、10-20mg、20-30mg、30-40mg或40-50mg之间的剂量的抑制剂的组合物。在一些实施方案中,将组合物配制成含有1mg、3mg、5mg、10mg、20mg、25mg、30mg或50mg活性组分的剂量。用于这些制剂的给药方案可包括但不限于单次施用给药、每日一次、两次或三次给药、每周给药和每月给药。在一些实施方案中,配制提供的组合物以提供40mg/天的VX-745。
也应了解用于任何特定患者的特定剂量和治疗方案将取决于多种因素,包括所用特定化合物的活性、年龄、体重、总体健康、性别、膳食、施用时间、排泄速率、药物组合、以及治疗医师的判断和所治疗特定疾病的严重性。本发明化合物在组合物中的量也将取决于组合物中的特定化合物。
例示
实施例1-莫里斯水迷宫(Morris Water Maze)
背景
新近人遗传学数据指示阿尔茨海默氏病的主要驱动因素是调控异常的小神经胶质细胞和神经炎症。此外,体外数据指示IL-1β-p38MAPK系统可通过影响神经元中的长期增强(LTP)和长期抑制(LTD)来影响记忆(McAfoose,2009);并且p38MAPK已被鉴定为寡聚Aβ抑制LTP的介体(Li,2011)。然而,由于血脑屏障(BBB)穿透性p38MAPK拮抗剂先前不可用,所以在慢性阿尔茨海默氏病模型中抑制p38MAPK的作用未知(Munoz,2010)。此外,未知的是相对于神经元内p38MAPK介导的细胞因子信号传导,p38MAPK在以下方面的相对重要性以及抑制p38MAPK对以下方面的作用:p38MAPK介导由小神经胶质细胞产生细胞因子(IL-1β和TNFα)。
VX745(BBB穿透选择性p38MAPKα拮抗剂)抑制IL-1β产生与信号传导两者,其中对于信号传导的效能要高两倍。为在先前非CNS临床经验之后关于阿尔茨海默氏病进行重新定位,在高龄大鼠模型中;以及在大鼠缺血性中风后的功能恢复模型中进行的第二支持性研究中测试VX-745。
目的
这个研究的主要目标在于探究用化合物VX-745预治疗是否缓和高龄大鼠的认知缺陷。在研究结束时,用LC-MS/MS测定在给药后1小时收集的样品的VX-745血浆浓度。此外,通过特异性ELISA测定来分析腹侧皮质和海马中的PSD95蛋白质水平以及海马中的IL-1β水平以评估VX-745在脑中的潜在消炎作用。
方法
总共60只雌性高龄(20-24个月)和15只幼小成体雌性Fischer大鼠(2-3个月)用于实验。1天两次以口服管饲用媒介物或0.5、1.5或4.5mg/kg VX-745治疗大鼠直至取样(23天)。在开始治疗之后1周,用莫里斯水迷宫(MWM)分析学习和记忆缺陷。
测试动物
所有动物实验都根据国立卫生研究院(National Institute of Health,NIH)关于护理和使用实验室动物的指导方针进行,并且由芬兰国立动物实验委员会(AnimalExperiment Board,Finland)核准。总共60只雌性高龄(20-24个月)和15只幼小(2-3个月)成体雌性Fischer大鼠(Charles River,France)用于实验。在标准温度(22±1℃)下以及在控制光照环境(从7am至8pm开启光照)中舍饲动物,其中随意获取食物和水。如下将动物分组:
●组1:15只高龄大鼠,用媒介物口服治疗(BID)
●组2:15只高龄大鼠,用VX-745(0.5mg/kg)口服治疗(BID)
●组3:15只高龄大鼠,用VX-745(1.5mg/kg)口服治疗(BID)
●组4:15只高龄大鼠,用VX-745(4.5mg/kg)口服治疗(BID)
●组5:15只幼小成体对照大鼠,用媒介物口服治疗(BID)
药物递送和大鼠标识
将大鼠基于它们的体重和可见平台预训练表现同等分配至治疗组中以确保良好学习者与不良学习者两者均同等存在于所有治疗组中。1天两次通过口服管饲来给与治疗直至取样。媒介物是1%普洛尼克(Pluronic)F108,并且给药体积是5ml/kg。在测试前时期,在7-9am和3-5pm进行媒介物和测试化合物的施用。在行为测试当天,至少在第一测试试验之前1小时给与治疗。根据由发起人提供的指示配制和储存测试化合物。将大鼠用永久性标记对尾部进行相应标记。关于治疗组和每日治疗时间做记录。
莫里斯水迷宫
水迷宫任务最初由Morris等人(J Neurosci Methods.1984;11:194 47–60)设计。测试在填充有清水的大型深色槽(直径是200cm)中在25.0±1.0℃的温度下进行。将浸没平台(正方形平台:10x 10cm;水面下1.5cm)放置在NW象限的中部。在池边缘上任意定位标以N、NE、E、SE、S、SW、W、NW的起始位置。将大鼠以它们的鼻部指向一个起始点处的池壁的方式下降至池中。不使用邻近于平台位置的释放点(NW)。
在开始化合物治疗之前,进行可见平台预训练以确定是否存在可能影响在定位或探索试验时的表现的任何非认知表现损害(例如视觉损害和/或游泳困难)。在完成可见平台预训练之后,分析数据,并且将大鼠基于它们的预训练表现分配至不同治疗组中。进行这个程序以确保在暗示形式的水迷宫任务中,各治疗组同等地由良好表现者与不良表现者两者组成。
采集训练–第1周(第8-11天)和第2周(第15-18天):在完成暗示试验之后,执行采集(定位)试验以确定大鼠学习远端暗示与对于所有定位试验都保持在相同位置中的浸没逃离平台之间的空间关系的能力。起始点是随机的(不使用NW)。大鼠持续4天/周每天接受4次试验(相隔15分钟,各次试验最多60秒)。评估潜伏时间和路径长度(距离)。
探索实验(第19天):在最后的定位试验之后24小时进行单次探索实验以评估记忆保留。将平台从池移除,并且将大鼠放置至池中与之前放置平台的象限相对的象限中。使大鼠在无平台的情况下游泳60秒。在探索实验期间,测量在目标象限和目标平台环形区(在平台周围的直径36cm的环状区域)中花费的时间以及跨越目标平台位置的次数。VX-745治疗在任何探索参数方面都不存在正性或负性作用,并且因此另外不在本申请中讨论。
关于PK 257的终点、血液样品和组织处理
在末次媒介物或VX-745早晨给药之后1小时,用戊巴比妥(pentobarbital)使动物(每个给药组10个动物)深度麻醉,并且通过心脏穿刺来收集血液样品。将500μl血液收集至EDTA微管中,离心并收集血浆。用肝素化盐水灌注脑,并且收集脑。通过在含4%PFA的0.1MPB中浸渍24小时来后固定右侧半球。在用磷酸盐缓冲液短暂洗涤之后,将半球低温保护在含30%蔗糖的PB中2-3天,此后在液氮的情况下将它冷冻并储存在-80℃下以供任选未来免疫组织化学分析。解剖左侧半球以获得腹侧和背侧皮质、海马和剩余脑部分,并且在干冰的情况下新鲜冷冻。
使用ELISA试剂盒(Cusabio Biotech Ltd.,#CSB-EL006938RA,批号O31154387)分析皮质和海马可溶性提取物中的PSD95含量,同时仅分析来自海马的Il-1β的水平(R&DSystems,#RLB00,批号308544)。
使用乙腈沉淀来处理血浆样品,接着通过LC-MS/MS来分析VX745药物浓度。
结果
以媒介物治疗的幼小大鼠显示有效学习,其中在依序测试的情况下,MWM潜伏时间/距离快速降低。以媒介物治疗的高龄大鼠似乎在认知方面受损害,在研究期间展现比幼小大鼠更久的时间和更长的距离以及少许改进。以VX-745治疗的高龄大鼠展现较大渐进性游泳时间和距离缩短,这是认知表现改进的迹象。对于潜伏时间与距离两者,1.5mg/kg剂量的VX-745具有最大作用,其中在最后的第17测试日,这组大鼠的表现近似等于以媒介物治疗的幼小大鼠的表现。相较于以媒介物治疗的高龄大鼠,1.5mg/kg剂量组在第17天关于潜伏时间与距离两者均显示统计显著更好表现(p分别=0.013和0.0.019)。参见图1。此外,就距离而言,在第一测试日存在显著较糟表现(p=0.018),此外也在通过比较从第一测试日至最后一个测试日在潜伏时间和距离方面的变化进行标准化之后分析数据;同样通过这个分析,以1.5mg/kg治疗的高龄大鼠表现显著好于以媒介物治疗的高龄大鼠,其中对于潜伏时间变化,p=0.007,并且对于距离变化,p=0.012。参见图2。
PSD95是一种存在于突触后结构中,被认为促进保证突触后应答的受体和离子通道的群集的蛋白质。已显示PSD95水平在阿尔茨海默氏病中降低,并且当用消炎剂治疗时,在动物模型中增加(Frautchy,2001)。对PSD95蛋白的分析显示相较于以媒介物治疗的高龄组,存在VX-745高剂量(4.5mg/kg)组中PSD95水平较高的统计趋势(根据曼-惠特尼秩和检验(Mann-Whitney rank sum test),p=0.063)。
对海马中IL-1β水平的分析指示存在在高龄大鼠中水平较高的趋势。在VX-745高剂量(4.5mg/kg)组中,IL-1β水平类似于幼小大鼠的水平,并且相对于以媒介物治疗的高龄组较低(根据曼-惠特尼秩和检验,p=0.038)。
1.5mg/kg剂量水平对PSD95或IL-1β不存在明显影响,所述水平另外显示在莫里斯水迷宫测试中的表现显著改进;从而指示在这个剂量水平下在莫里斯水迷宫测试层面上的作用不由抑制细胞因子产生介导(即不通过消炎作用介导)。参见图3。
在末次剂量之后1小时的VX-745血浆药物水平以剂量比例方式增加。参见图4。基于由先前临床前研究获得的已知大鼠中血浆药物概况,在稳态下,给药后1小时水平应接近稳态C平均值(CAVG)。作为先前事项,先前未公开的研究指示VX-745在人系统中用于抑制IL-1β产生的IC50约为用于抑制IL-1β信号传导的IC50的一半,1.5mg/kg达到为阻断IL-1β信号传导所需的药物浓度;仅4.5mg/kg达到超过针对IL-1β产生的全血IC50的浓度。
结论
本发明部分涉及发现在不足以产生消炎作用的剂量水平下,在慢性阿尔茨海默氏病动物模型中抑制p38MAPK具有正性认知作用。与那个研究结果一致,PK/PD关联指示所述作用由抑制IL-1β信号传导,而非由遏制IL-1β产生介导。
实施例2
大鼠短暂MCAO–功能恢复
这个研究的目标在于探究在阻塞后48小时开始用VX-745长期1天两次治疗是否在于第0天经受120分钟大脑中动脉阻塞(tMCAO)的大鼠中提供感觉-运动恢复和神经保护。在缺血后第1、3、7、14、21、28、35和42天进行7分和20分神经评分测试以研究感觉-运动缺陷和一般状况。在缺血后第7、14、21和35天进行圆筒测试,并且在第1、3、7、14、21、28、35和42天进行肢体放置测试。
在缺血后24小时通过T2-MRI评估梗塞体积,并且在第2天基于病变数据将大鼠分配至治疗组中并在MRI之后在第2天开始治疗。
方法–在120分钟tMCAO之后48小时开始,使雄性Sprague-Dawley大鼠经受用VX-745 1天两次长期治疗。在24小时用MRI测量病变尺寸,并且在第2天(在第0天进行tMCAO)基于病变尺寸和肢体放置结果将大鼠分配至给药组中。将大鼠用2种不同剂量治疗,并且在整个实验中经受感觉运动行为测试。在阻塞之前以及在缺血后第1、3、7、14、21、28、35和42天进行7分和20分神经评分和肢体放置测试以研究感觉-运动缺陷和一般状况。在阻塞之前以及在缺血后第7、14、21和35天进行圆筒测试。
动物。购自Charles River Laboratories(Sulzfeld,Germany),并且称重250-300g的总共45只成体雄性Sprague Dawley大鼠用于实验。在标准温度(22±1℃)下以及在控制光照环境(从7am至8pm开启光照)中舍饲动物,其中随意获取食物和水。
如下将动物分组:
■组A:15个tMCAO动物从第2天至第42天用媒介物1天两次治疗(5ml/kg,口服)
■组B:15个tMCAO动物从第2天至第42天用VX-745 1天两次治疗(1.5mg/kg,口服)。
■组C:15个tMCAO动物从第2天至第42天用VX-745 1天两次治疗(4.5mg/kg,口服)。
短暂MCAO
在第0天根据Koizumi,在修改的情况下通过MCA阻塞来在雄性Sprague-Dawley大鼠中产生短暂灶性脑缺血(Koizumi等Jpn.J.Stroke 8:1-8,1986)。用5%异氟烷(于70%N2O和30%O2中;流速300ml/min)使大鼠麻醉。在手术期间,使麻醉剂的浓度降低至1.0-2.0%。用恒温毯系统使直肠温度维持在37.0±1.0℃下。在中线皮肤切开之后,使右侧颈总动脉(CCA)暴露,并且远离颈动脉分叉结扎颈外动脉(ECA)。将具有钝化尖端的0.22mm直径单丝尼龙线插入颈内动脉(ICA)中22-23mm直至MCA的起点。在单丝插入之后,用缝合线阻塞CCA 2小时。在缺血120分钟之后,通过移除丝线和缝合线来恢复MCA血流。将创伤闭合,消毒,并且使动物从麻醉恢复。在tMCAO之后,仔细监测大鼠的可能手术后并发症。在tMCAO之后,将大鼠用混悬在自来水中的标准实验室膳食喂养。为防止脱水,所有大鼠都根据需要给与1天一次或两次腹膜内注射盐水(每只大鼠4mL)。
药物递送。在MRI之后在缺血后48小时(即第2天)开始口服施用(5ml/kg)VX-745或媒介物,并且继续1天两次(早晨和下午)直至第42天终点。
总体健康状态和人道终点。由实验室人员1天两次监测动物。在动物的总体健康状态显著恶化的情况下,用过度剂量的CO2终结大鼠,并且斩首。可接受的终点的定义包括:在24小时观察时期中不自发运动以及不能饮用或进食、大量流血、自发炎症、解剖结构缺失、肿胀或肿瘤大于20mm、以及不能在30秒时期中恢复常态。
治疗分配
在tMCAO之后24小时(即第1天)对所有大鼠进行体内MRI采集。使用绝对T2-MRI确定病变尺寸、组织活力(T2在数毫秒内)和脑水肿。在第2天基于病变数据将大鼠分配至治疗组中,并且在第2天开始治疗。
20分神经评分
20分神经评分测试用于评估缺血后运动和行为缺陷。在中风前(基线)以及在缺血后第1、3、7、14、21、28、35和42天由不知情的研究者进行神经测试。
分析以下参数:
●爪放置(最高4分)
●翻正反射(最高1分)视觉前爪伸展(最高2分)
●转圈(最高4分)
●对侧(最高1分)
●抓握强度(最高2分)
●运动性(最高3分)
●一般状况(最高3分)
●正常大鼠的最高评分是20分。
7分神经评分
同时,7分神经评分测试用于评估缺血后运动和行为缺陷(根据Zausinger等,2000修改)。在中风前(基线)以及在缺血后第1、3、7、14、21、28、35和42天由不知情的研究者进行神经测试。
●6级:当通过尾部温和提升时,两个前肢均朝向地面正常延伸。
●5级:受损半球对侧的前肢始终弯曲,从轻度腕弯曲和肩部内收至呈现以完全腕、肘弯曲和肩部的内收伴内旋的重度姿态进行变化。
●4级:对朝向局部麻痹侧的侧向推动具有始终降低的抗性的功能异常大鼠。
●3级:如果通过尾部牵拉和提升,那么朝向局部麻痹侧转圈的大鼠。
●2级:如果通过尾部牵拉,那么朝向局部麻痹侧转圈的大鼠。
●1级:朝向局部麻痹侧自发转圈的大鼠。
●0级:不自发运动的大鼠。
肢体放置测试
肢体放置测试用于评估前肢和后肢对触觉和本体感受性刺激的应答的感觉-运动统合(de Ryck等,1989;Jolkkonen等,2000)。在tMCAo之前(基线)以及在缺血后第1、5、7、14、21、28和35天由不知情的研究者进行肢体放置测试。
测试具有7个肢体放置任务,其被如下评分:
●2分,大鼠正常表现;
●1分,大鼠延迟(>2秒)和/或不完全表现
●0分,大鼠不正常表现
●身体的两侧均加以测试。
在第一任务中,将大鼠悬吊在工作台表面上方10cm处。非病变大鼠朝向工作台伸出两个前肢。在第二任务的情况下,将大鼠面向工作台固持,使它的前肢搁置在工作台边缘上。向下温和牵拉前肢,离开工作台,并且检查随后复原和肢体放置。非病变大鼠将两个肢体重新放置在工作台上。第三任务与第二任务相同,例外之处是大鼠不能看见工作台或进行触须接触,因为向上以45°角固持头部。接着沿工作台边缘放置大鼠以检查前肢(第四任务)和后肢(第五任务)的侧向放置。如任务2中所述向下牵拉肢体,并且对肢体复原相应评分。在第六任务中,将大鼠以它们的后端处于工作台的边缘加以放置,其中后肢搁置在工作台边缘上。向下温和牵拉后肢(1次1个)并离开工作台。必要时,可通过朝向工作台边缘推动动物来刺激肢体复原至工作台边缘上的原始搁置位置。在第七任务中,将大鼠放置在工作台边缘,背向工作台表面。将大鼠的前肢放置在工作台的边缘上,并且从后面朝向边缘温和推动大鼠。受损大鼠不能保持它们的抓握,并且受损肢体从边缘滑脱。正常大鼠的最高评分是14分。
圆筒测试。
圆筒测试(根据Schallert和Tillerson,Innovative models of CNS disease:from molecule to therapy.Clifton,NJ,Humana,1999修改)用于定量当动物对着舍笼壁站立时前肢使用不对称性。在tMCAO之前以及在tMCAO之后第7、14和21天进行测试。当大鼠在它们的舍笼中自由移动时对它们监测。由不知情的观察者对当站立时由各前爪与笼壁进行的接触评分。记录各动物总计15-20次接触,并且以总接触的百分比形式计算损害(左侧)和非损害前肢接触的数目。
结果
分析功能恢复,分析从基线(第3天)至终点(第42天)的肢体放置和7分和20分变化。参见图5。在圆筒测试中,分析从第7天至第35天的变化。1.5mg/kg VX-745剂量组似乎始终好于4.5mg/kg VX-745组。此外,相对于媒介物治疗动物,1.5mg/kg VX-745剂量组显示朝向从第7天至第35天圆筒测试表现变化的改进增加的趋势(p=0.088,双侧t检验);这是在4.5mg/kg剂量组中不明显的趋势。参见图6。
结论
关于在这个研究中用肢体放置、7分或20分神经评分衡量的功能恢复的结果显示在媒介物治疗动物中在tMCAO之后存在实质性功能改进,并且施用1.5mg/kg VX-745或4.5mg/kg不进一步改进根据这些量度的功能恢复。在圆筒测试中在以媒介物治疗的情况下,最小功能恢复是明显的,并且在1.5mg/kg VX-745的情况下,相较于媒介物治疗,朝向在关于圆筒测试的从第7天至第35天的表现变化方面的改进的趋势(p=0.088)是明显的。对于所有量度,在变化分析中,1.5mg/kg VX-745剂量组似乎始终好于4.5mg/kg VX-745组,从而进一步支持以下观念:VX-745对神经功能的任何正性作用都发生在不具有可测量消炎作用的剂量水平下,与此一致的是那个剂量水平不实现影响细胞因子产生的血液浓度;而实现抑制细胞因子产生的血液浓度,并且因此具有消炎性的剂量水平对神经功能的作用较小。
Claims (9)
1.一种治疗有需要的患者的神经病症的方法,其包括向所述患者施用足以抑制细胞因子信号传导,同时不实质上影响细胞因子产生的剂量的VX-745。
2.根据权利要求1所述的方法,其中所述细胞因子是IL-1β。
3.根据权利要求1所述的方法,其中所述剂量导致患者血液浓度小于为抑制细胞因子产生所需的血液浓度的一半。
4.根据权利要求3所述的方法,其中所述剂量导致患者血液浓度比为抑制细胞因子产生所需的血液浓度低50%、60%、70%、80%或90%。
5.根据权利要求1所述的方法,其中所述神经病症选自阿尔茨海默氏病、轻度认知障碍、血管性痴呆、路易体痴呆和痴呆症;帕金森氏病;中风后的功能恢复;额颞叶痴呆(FTD)和阵发性痉挛性截瘫(PSP)和其他τ蛋白病变;认知衰弱;慢性耳鸣;和亨廷顿氏病。
6.一种改进有需要的患者的神经功能的方法,其包括向所述患者施用足以抑制细胞因子信号传导,同时不实质上影响细胞因子产生的剂量的VX-745。
7.根据权利要求6所述的方法,其中认知得以改进。
8.一种治疗有需要的患者的神经病症的方法,其包括向有此需要的患者施用一定剂量的VX-745或其药学上可接受的组合物,从而提供在约15与45ng/mL之间,或在20与约40ng/mL之间,或在约25与约35ng/mL之间,或在约30与约40ng/mL之间的血液浓度。
9.根据权利要求1、6或8中任一项所述的方法,其进一步包括施用另一治疗剂。
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