CN114007609A - 用于蛋白质感染的三重药物组合物 - Google Patents
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- CN114007609A CN114007609A CN202080042131.XA CN202080042131A CN114007609A CN 114007609 A CN114007609 A CN 114007609A CN 202080042131 A CN202080042131 A CN 202080042131A CN 114007609 A CN114007609 A CN 114007609A
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Abstract
公开了朊病毒蛋白复合物感染的治疗和预防方法。淀粉样蛋白前体蛋白基因和PrP基因的转录以及RNA转录是限速步骤,最容易阻断和控制淀粉样蛋白形成和PrPsc形成的过程。因此,朊病毒蛋白复合物感染的治疗和预防方案在DNA转录到RNA、RNA转运到线粒体以进行蛋白质合成和沉积在大脑皮层神经元的水平上中断了这一过程。
Description
技术领域
本公开涉及阿尔兹海默病(AD)疗法。
背景技术
AD通常被认为是一种局部脑部疾病。在美国,伴随神经***疾病的AD是仅次于心血管疾病和癌症的第三大死因。AD通常遵循以下这种一种顺序,即神经炎症、淀粉样蛋白和tau原发病、累积性贮积病、神经毒性和神经损伤、功能丧失(即日常生活活动(ADL)和认知技能),最后是死亡。AD死亡的原因如下:出现人格解体,食欲不振的这些患者觉得一切都是徒劳,没有了生的意愿,同时在诊断有AD的五至十年里由于身体日渐消瘦,没有好转而导致出现过早死亡。
关于AD的病因有四种主要的流行理论:(a)胆碱能假说,(b)淀粉样蛋白沉积假说,(c)tau蛋白沉积假说,和(d)神经血管假说。目前还没有能够改变阿尔茨海默病进程或预防其发作的有效治疗方法。目前现有的疗法仅能改善症状,而开发能够阻断或延缓疾病进展的疗法仍然是一个具有挑战性的未满足需求。
根据胆碱能假说,基底前脑中胆碱能神经元的退化以及大脑皮层和其他区域中胆碱能神经传递的相关丧失是导致患有阿尔茨海默病患者出现认知功能退化的重要原因。
根据淀粉样蛋白沉积假说,人们认为淀粉样蛋白斑块和神经原纤维缠结的形成导致大脑中神经元(神经细胞)降解和出现阿尔茨海默病的后续症状。淀粉样蛋白是一大类蛋白质,已描述了其中的60种不同类型的蛋白质。36种淀粉样蛋白与人类疾病有关。淀粉样蛋白是由Rudolf Virchow首次发现且其进行了描述,他认为它是一种淀粉质物质,因此淀粉样蛋白的名称与淀粉或拉丁文中的“淀粉不溶素”有关。后来人们认为它是一种脂肪物质,但后来发现它是一种蛋白质物质。自从引入了精细的蛋白质化学、质谱和X射线晶体学,淀粉样蛋白在各种人类疾病和病症中得到了更好的表征和鉴定。
淀粉样蛋白疾病曾经被分类为原发性或继发性淀粉样变性。原发性疾病被认为是家族性疾病,蛋白质在心脏、肾脏、皮肤、舌头、脂肪组织和直肠等器官中合成和沉积。在继发性疾病中,淀粉样蛋白沉积被认为是继发于慢性化脓性疾病,如结核病或其他不受控制的细菌性脓肿,这在世界发展中国家和不发达国家很常见。同样,慢性炎症,如类风湿性关节炎和肾透析,会导致继发性和反应性淀粉样蛋白沉积。
在21号染色体中编码的淀粉样前体蛋白(APP)在AD中起作用。APP是一种跨膜蛋白,可穿透神经元膜,对神经元生长、存活和损伤后修复至关重要。因此,神经元APP的缺失可能会影响导致痴呆的生理和病理生理缺陷。唐氏综合症(即21三体综合征)患者的临床数据表明,他们在30到40多岁患上AD,因为APP的基因位于21号染色体中,并且携带着三个拷贝。这类似于炎症性肠病(IBD)患者,这类患者在30-40多岁患结肠癌,而正常人群在50-80多岁时患结肠癌。APP被复制并用于合成淀粉样蛋白。
淀粉样蛋白β(Aβ)是与AD相关的特定淀粉样蛋白。淀粉样斑块由小多肽组成,长度为39-43个氨基酸。β-淀粉样蛋白前体蛋白裂解酶1(BACE-1)和γ-分泌酶依次裂解APP,从而产生β淀粉样蛋白。在AD中,γ分泌酶和β分泌酶在蛋白水解分解代谢反应中共同作用,裂解更小的APP片段。这些蛋白质分解代谢片段然后形成淀粉样蛋白β的原纤维,淀粉样蛋白β的原纤维进一步形成沉积在神经元外的团块,称为老年斑。
因为Aβ在AD中过度积累,所以有一个逻辑推论,即其前体APP也会升高。然而,一项研究表明,根据它们与淀粉样斑块的接近程度得到神经元细胞体含有较少的APP。有理论认为,Aβ斑块附近的这种APP缺陷源于APP的产生下降,而APP的产生通常会因压力而增加。
几种BACE-1抑制剂、BACE-2抑制剂和针对可溶性淀粉样蛋白的人源化单克隆抗体已在AD中进行临床试验。这些试验未能兑现成为治疗AD的疾病改善药物(DMD)药剂(即,它们改变疾病的潜在病理学)的承诺。同样,已尝试使用疫苗清除AD中的淀粉样蛋白斑块,但均无济于事。鉴于使用BACE抑制剂的临床试验失败,以及静脉注射索拉珠单抗的淀粉样蛋白免疫治疗失败,淀粉样蛋白沉积理论受到质疑。
tau蛋白沉积假说提出tau蛋白异常引发疾病级联。在这个模型中,过度磷酸化的tau开始与其他tau线配对。最终,它们在神经细胞体内形成神经原纤维缠结。发生这种情况时,微管解体,破坏细胞骨架的结构,使神经元的运输***崩溃。这可能首先导致神经元之间的生化通讯出现故障,然后导致细胞死亡。
神经血管假说声称阿尔茨海默病患者大脑中的大量Aβ肽起源于体循环。根据这一理论,涉及血脑屏障(BBB)功能不良。这种不良功能的一个副作用是产生淀粉样蛋白和tau蛋白过度磷酸化。
朊病毒蛋白(PrP)是由正常蛋白质的错误折叠产生的蛋白质。朊病毒蛋白的两种形式被指定为PrPc,它是一种正常折叠的蛋白质,以及PrPsc,一种导致疾病的错误折叠形式。这两种形式的氨基酸序列没有区别,但是致病性PrPsc异构体在二级和三级结构上与正常PrPc形式不同。PrPsc异构体更多地富含β折叠,而正常的PrPc形式富含α螺旋。构象的差异使PrPsc与淀粉样蛋白β原纤维聚集,并且对酶或其他化学、辐射和物理方法引起的蛋白质降解具有极强的抵抗力。另一方面,正常形式易于完全蛋白水解并溶于非变性洗涤剂。有人提出,预先存在或获得的PrPsc可以促进PrPc转化为PrPsc,PrPsc进而转化其他PrPc。这引发了一个连锁反应,允许其快速传播,导致朊病毒疾病的发病机制。PrPc蛋白是可溶性淀粉样蛋白β(Aβ)寡聚体的几种细胞受体之一。
仍缺乏表征的功能PrP的高度保守的基因序列多年来一直困扰着研究人员。研究人员试图将PrP和Aβ与其他疾病联系起来,但一直没有成功。一些研究试图假设,因为Aβ是一种蛋白质斑块,所以它也必须与心脏病有关。然而,一些心脏病不含Aβ斑块,并且大量AD患者没有心脏病。已证明用抗生素治疗心脏病的研究是不成功的。这些研究不仅专注于治疗细菌而不是炎症或斑块积聚,而且这些研究得出的结论是,用抗生素治疗可能没有任何有益效果。一项研究将该领域的现状总结为:“[迄今为止,临床试验数据并没有为在一级或二级预防冠心病中临床使用抗生素提供足够的支持。”[Anderson等人,2004年]。
载脂蛋白E(ApoE)将脂质、脂溶性维生素和胆固醇输送到淋巴***,然后输送至血液,血液是大脑中的主要胆固醇载体。ApoE的基因位于19号染色体。ApoE是多态的,具有三个主要等位基因:ApoE-ε2、ApoE-ε3和ApoE-ε4。尽管这些等位基因形式彼此仅差了一个或两个氨基酸,但这些差异会改变ApoE的结构和功能。这些差异会产生生理后果。ApoE-ε4的等位基因频率约为14%,与晚发性阿尔茨海默病(LOAD)密切相关。
针对有关治疗AD的方法的研究也没有产生有希望的结果。研究人员尝试了治疗策略,从设计药物到定制蛋白质再到抗生素,但都没有成功。许多研究表明,抗生素治疗不能治愈AD。2013年,研究人员对强力霉素和利福平进行了一项研究,“结论:强力霉素或利福平单独或联合治疗12个月对AD的认知或功能没有有益影响”[Molloy等人,2012]。
另一项寻找AD可能的治疗方法的研究描述了Molloy研究,“但在3个月和12个月时,治疗组和安慰剂组之间没有差异。然而,当单独使用或与利福平联合使用时,没有检测到对认知或功能产生有益影响”[Appleby等人,2013]。强力霉素
其他用抗生素治疗AD患者的研究表明,治疗组和未治疗组的认知功能均下降。[Boyles 2003]。AD的研究人员一直对抗生素疗法作为AD的治疗方法持怀疑态度,一位研究人员评论道,“[我们]不建议长期服用抗生素将成为一种治疗方法——不论哪一点原因,这都是很荒谬的……”[Minter 2016]。
研究人员还怀疑其他药物可以治疗AD。国家老龄化研究所表示,尽管NSAID主要通过针对炎症起作用,但迄今为止,还没有临床试验表明AD患者从NSAID的实际使用中受益。出于多种原因,人们认为NSAID并不是治疗AD的优选。一方面,AD常发生于老年患者,老年患者一般心脏较弱。事实上,一项检查NSAID是否可用于对抗AD的研究不得不停止,因为人们担心参与者的心血管健康。[Terrie,2009年]。在一项研究中未发现对乙酰氨基酚和阿司匹林对AD有有益作用。[Szekely等人,2008年]。在另一项研究中,萘普生和塞来昔布没有改善AD患者的认知功能[Martin等人,2007]。
在朊病毒蛋白复合物感染的这种背景下,我们转向几种尚未被提议用于治疗朊病毒蛋白复合物感染的药物。例如,虽然已经尝试过基因工程抗体,但尚未考虑将抗生素作为朊病毒蛋白复合物感染的可能疗法。以前未考虑的另一类是免疫抑制剂。
四环素是一组非常古老的抑菌抗生素,由四环素、强力霉素和米诺环素组成。它们通过抑制细菌和原生动物细胞以及真核生物线粒体中的蛋白质合成起作用,从而抑制氨酰-tRNA与mRNA核糖体复合物结合。它们主要通过与mRNA翻译复合物中的30S核糖体亚基结合来实现。除了抑制蛋白质合成外,这些药物还具有抗炎作用,为脂溶性的,且中枢神经***浓度高。
附图说明
图1是四环素的骨架配方,其中包含编号和标记的原子和四个环。
图2是强力霉素的配方。
图3是米诺环素的配方。
图4是西罗莫司的配方。
图5是示出Aβ和PrPsc存在的指数增长基础的概念图。
具体实施方式
AD不是局部脑部疾病。AD是一种朊病毒蛋白复合物感染,是一种涉及身体和末梢循环以及B细胞的全身性疾病。AD包括新皮质中的局部反应。事实上,证明这一点的事实是,通过检测Aβ42水平(使用ELISA检测)、血液Aβ42/40比率和脑脊髓Aβ42水平,可以在唾液中诊断AD。此外,AD可由其他疾病引起的大脑炎症引发,如帕金森病和慢性创伤性脑病(CTE),这些疾病源自拳击手和足球运动员等出现的反复脑外伤。
在AD中看到的淀粉样蛋白β蛋白沉积继发于大脑皮层乙酰胆碱放电神经元中慢性神经炎性疾病。这种淀粉样蛋白沉积在患者临床诊断为AD前的10到15年就开始了,并一直持续到患者死亡。APP基因的转录和RNA转录是限速步骤,最容易受到淀粉样蛋白形成过程的阻断和控制。因此,本文基于在DNA转录到转录物RNA(tRNA)、信使RNA(cmRNA)、RNA转运至线粒体以使蛋白质合成和沉积在大脑皮层神经元的水平上中断该过程的治疗AD的方法。这是我们在AD中引入第一个DMD的主要努力。
新皮质中的这种神经炎症伴随着β淀粉样蛋白局部分泌到乙酰胆碱分泌记忆神经纤维,以及细胞朊病毒蛋白(PrPc)肽和tau蛋白肽的分泌。由于淀粉样蛋白寡聚体的神经毒性,存在PrPc肽的错误折叠,将它们从α螺旋结构转化为β螺旋结构(即,PrPsc)。PrPscβ螺旋结构与Aβ原纤维相互作用并开始铺设具有神经毒性并导致神经毒性和使神经纤维和神经细胞死亡的Aβ原纤维片,从而产生具有特征性的淀粉样斑块和tau蛋白缠结。
图5示出了了AD中Aβ和PrPsc的存在呈指数增长的基础。如图5所示,当PrPsc应用于PrPc时,PrPc错误折叠成PrPsc。APP和Aβ也会出现相同的行为:Aβ是从APP产生更多Aβ的种子。然而,这两个循环并不是独立的。它们是相互依存的。也就是说,Aβ种子将PrPc转化为PrPsc,而PrPsc种子从APP产生Aβ。因此,这种在AD淀粉样斑块中朊病毒蛋白复合物核心处的Aβ和PrPsc的女巫酿造导致死亡循环,这种循环无法通过仅干扰PrPc错误折叠为PrPsc的疗法或仅干扰由APP生成Aβ的疗法停止。本文描述的疗法解决了一种前体蛋白(或寡肽)的错误折叠和生成。
AD可以通过两种治疗形式来治疗和预防。存在于血液中的淀粉样β蛋白会扩散到脑脊液中,脑脊液会冲刷大脑和新皮质。这会通过铺设淀粉样β原纤维片产生继发性新皮质反应,导致记忆细胞的死亡和破坏,并产生淀粉样斑块和神经原纤维tau蛋白缠结。一种治疗形式使用免疫抑制剂来解决全身体液B细胞反应和朊病毒蛋白的转录、翻译和合成。另一种治疗形式使用抗生素来解决淀粉样β蛋白的合成。通过组合治疗形式获得益处。
AD源于一种流氓朊病毒蛋白的复合物——一种女巫的酿造。这种流氓朊病毒蛋白复合物由Aβ原纤维和朊病毒受体蛋白(PRP)β(PrPsc)原纤维组成。身体对朊病毒蛋白复合物的自然反应是一种自我防御机制,它本身会伤害组织。这些防御机制采用自组装Pacman的形式,它攻击并吃掉流氓朊病毒蛋白复合物。相应组织的损伤是AD和其他朊病毒蛋白复合物感染发病机制的罪魁祸首。
AD的全身性疾病成分可用免疫抑制剂如西罗莫司治疗。西罗莫司通过对B细胞的影响,通过合成体液抗体和APP来损害体液免疫***。这消除了AD发病机制的全身性成分。目前,西罗莫司仅用于接受移植和某些癌症的患者。没有将西罗莫司与四环素联合使用的迹象。西罗莫司还抑制抗体形成,并通常通过浆细胞和B细胞消除β淀粉样蛋白的合成。它还抑制先天免疫***以及小胶质细胞和巨噬细胞产生的细胞因子,如TNFα、IL-1β、IL-6和γ干扰素。
AD的中枢神经***(CNS)局部效应可用抗生素例如四环素治疗。四环素通过影响与核糖体蛋白复合物转录、翻译和结合来阻断蛋白质合成。四环素类化合物可以通过抑制21号染色体上APP基因的转录和20号染色体上PrP基因的转录来处理AD发病机制的CNS/新皮质成分。此外,四环素通过结合核糖体蛋白复合物的30S和50S亚基来阻断基因的翻译和蛋白质合成。
通过治疗全身性疾病成分和CNS局部作用的双重作用,导致在AD中阻碍或消除流氓朊病毒蛋白复合物的作用。通过抑制AD患者中淀粉样蛋白的转录以及通过阻断淀粉样蛋白的合成,我们阻止了大脑皮层中进一步的淀粉样蛋白沉积以及随后的神经毒性和神经元损伤以及记忆和功能的丧失。患者相应地恢复功能并能够参与他们的日常生活活动和与家庭成员的互动。同样,通过阻断PrPsc的转录和合成,流氓朊病毒蛋白复合物的第二部分被扰乱。
AD患者可以表征为三种类型。在I型中,患者患有唐氏综合症,约占所有AD病例的0.001%。在I型患者中,AD出现在大约30-40岁。它的遗传标记是21三体。在II型中,患者患有早发性阿尔茨海默病(EOAD),这大约占所有AD病例的1-5%。在II型患者中,AD出现在大约50-60岁。其遗传标记分别是14号和1号染色体上的PSEN1和PSEN2。在III型中,患者患有迟发性阿尔茨海默病(LOAD),约占所有AD病例的95%。在III型患者中,AD出现在大约65-90岁。三分之二的III型患者是APOEε4阳性,APOEε4位于19号染色体上。III型患者可以进一步区分为APOEε4阳性或APOEε4阴性。
III型APOEε4阳性会产生有缺陷的载脂蛋白E(ApoE)蛋白。这种有缺陷的蛋白使身体更难代谢蛋白质、脂肪和脂质,也使身体更难将营养和胆固醇输送到大脑。因此,与仍然产生功能性APOE(APOEε4阴性)的III型AD患者相比,APOEε4阳性患者在发展为AD时受到的打击更大。
合适的疗法可能取决于患者所具有的AD的特征。所有类型都将受益于抗生素(如四环素)与免疫抑制剂(如西罗莫司)的组合。APOEε4阳性的III型患者还应接受亲脂性他汀类药物,例如阿托伐(阿托伐他汀),它可以穿过血脑屏障。
剂量可以采用单位剂量的形式。也就是说,单位剂量是一粒药丸、一粒药片或一粒胶囊——一个且只有一个。
对于成人而言,合适的疗法可以是以下之一:(a)50mg四环素、1mg西罗莫司、10mg阿托伐他汀;(b)50mg四环素、1mg西罗莫司、20mg阿托伐他汀;(c)100mg四环素、1mg西罗莫司、40mg阿托伐他汀;(d)100mg米诺环素、1mg西罗莫司、80mg阿托伐他汀;(e)50mg四环素、2mg西罗莫司、10mg阿托伐他汀;(f)50mg四环素、2mg西罗莫司、20mg阿托伐他汀;(g)100mg四环素、2mg西罗莫司、40mg阿托伐他汀;(h)100mg米诺环素、2mg西罗莫司、80mg阿托伐他汀;(i)2mg西罗莫司、100mg米诺环素和20mg阿托伐他汀。请注意,阿托伐他汀的剂量可以是白天两次,例如要达到20mg的剂量,患者可能在早上服用10mg阿托伐他汀,并在其他时间服用10mg阿托伐他汀。上面列出的四环素可以是米诺环素或强力霉素。也可以使用其他口服或静脉内四环素。也可以使用亲脂性的辛伐他汀和洛伐他汀。
开出这种三药方法的医生应该了解他汀类药物对患者胆固醇和甘油三酯水平的影响。在不应使用阿托伐他汀的情况下,可以将阿托伐他汀换成上面列出的另一种他汀类药物。新他汀类药物的剂量可以与阿托伐他汀相同,也可以根据他汀类药物的作用进行调整。对于高胆固醇或心脏病患者,他汀类药物或阿托伐他汀的剂量可能会进一步微调,以考虑患者的血液化学和神经***影响。
如果制成一种包括米诺环素或强力霉素、西罗莫司和阿托伐他汀的三药药物,可能需要生产具有不同阿托伐他汀剂量的不同药物并将其分发给患有某些疾病的患者。例如,如果制成一种含有这三种药物的药丸,对于大多数患有AD的人群来说,一粒药丸可能含有50mg米诺环素、1mg西罗莫司和40mg阿托伐他汀,但对于已经患有高胆固醇和AD的患者来说,另一种药丸可能含有可能需要含有50mg米诺环素、1mg西罗莫司和80mg阿托伐他汀的药丸。在其他情况下,对于已经服用单独剂量的阿托伐他汀或另一种他汀类药物的患者来说,可以生产较低剂量的阿托伐他汀药丸,例如50mg米诺环素、1mg西罗莫司和20mg阿托伐他汀。
本文描述的疗法的效果可在短至72小时内显现。其他时候可能会在三到十二个月内看到效果。一旦治疗有效,患者可以在受控观察下停止治疗以防止复发和可能的再治疗或继续维持剂量。对于AD患者来说,有效性可以通过阿尔茨海默病评估量表-认知(ADAS-Cog)分量表和阿尔茨海默病合作研究-日常生活活动(ADCS-ADL)量表或简易精神状态检查(MMSE)来衡量。这两类测试已经开发了很多年,预计它们将继续完善。
服用药物的频率可以变化,一天中服药的时间也可以变化。对于某些患者来说,每天或每隔一天可能就足够了,或者连吃三天,然后两天不吃。这些是药物假期的例子。每天的剂量可能不同。可以基于患者空腹来选择服药的时间以更好地吸收。
治疗中的药物可以一起给药、分开给药,或至少一种分开给药和至少一些一起给药。治疗中的药物可以口服(例如片剂)、局部(例如贴剂)、鼻内(例如吸入)或肠胃外给药,例如通过速效制剂或缓释制剂、半衰期延长的可注射制剂或至少一种缓释制剂,和至少一种半衰期延长的可注射制剂。
剂量水平可以变化,强力霉素的日剂量低至40mg,米诺环素低至25mg,西罗莫司低至0.5mg。上限剂量可以是强力霉素400mg(例如,每天两次200mg)、米诺环素300mg(例如,每天两次150mg)和西罗莫司4mg(例如,每天两次2mg)。以上指定的剂量适用于一般成年人,剂量可能与体重相关,较重的患者接受较大的剂量,较轻的患者接受较小的剂量。剂量不需要与年龄相关。剂量可能会缓慢释放。
可使用四环素、免疫抑制剂和他汀类药物实现渐进式剂量递增。渐进式剂量递增可用于使治疗更有效或减轻药物引起的不良副作用,或使副作用在治疗后期出现从而减少患者不适。列出的治疗可以通过渐进式剂量递增进行修改。渐进式剂量递增可以跨越数天或数周,例如第一天或第一周全剂量的25%,第二天50%,第三天75%,以及随后的100%。其他渐进式剂量递增可能采用初始剂量为50%,然后为100%的形式。
可以使用抑制蛋白质基因转录、翻译和合成的其他抗生素。使用的四环素可以是合成的、半合成的或天然存在的。此外,如果将来发明更多的合成四环素,由于所有四环素的基本结构相同,因此这些四环素也可能有用。可以使用以下四环素列表:金霉素、土霉素、地美环素、赖甲环素、甲氯环素、美他环素、米诺环素、罗列四环素、甘油环素、替加环素、奥马环素、萨瑞环素和伊拉瓦环素。
可以使用阻断B细胞功能和β淀粉样蛋白和PrPsc合成的其他免疫抑制剂,例如环孢菌素、他克莫司和依维莫司。也可以使用大环内酯类。合适的大环内酯类包括阿奇霉素、克拉霉素、红霉素、非达霉素、泰利霉素。也可以使用其他免疫抑制剂,包括皮质类固醇、Janus激酶抑制剂、钙调神经磷酸酶抑制剂、mTOR抑制剂、IMDH抑制剂、生物制剂和单克隆抗体。
他汀类药物可用于具有III型且APOEε4阳性的患者。合适的他汀类药物包括阿托伐、阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、美伐他汀、匹伐他汀、普伐他汀、非诺贝酸、阿利库单抗、依曲韦林、环丙孕酮、泊沙康唑、替格瑞洛、苯扎贝特、辅酶Q-10考来维仑、瑞舒伐他汀、辛伐他汀、辛伐他汀+依替米贝、洛伐他汀+烟酸缓释剂、阿托伐他汀+氨氯地平和辛伐他汀+烟酸缓释剂。
于某些接受AD治疗的患者而言,可能需要三种药物方法。患者可能需要由米诺环素、西罗莫司和阿托伐他汀组成的治疗。阿托伐他汀也称为阿托伐他汀的剂量范围为1mg–100mg。合适的剂量可包括50mg米诺环素、1mg西罗莫司和10mg阿托伐他汀。如果不使用阿托伐他汀而必须使用另一种他汀类药物,则其他他汀类药物的范围可能为0.01mg-200mg。例如,如果使用西立伐他汀,适当的剂量会大大减少,例如0.8mg西立伐他汀、50mg米诺环素和1mg西罗莫司。
尽管BACE抑制剂在治疗AD方面并不起效,但淀粉样蛋白沉积假说是有效的。这些研究失败了,因为抑制剂在淀粉样蛋白代谢的下游起作用。本文所述的疗法通过与RNA的30S和50S亚基结合以阻断淀粉样蛋白合成,在DNA转录为RNA和RNA转运至线粒体以进行蛋白质合成的水平上起作用。此外,正常的细胞分解代谢会消除已经沉积的β淀粉样蛋白。
针对AD的联合疗法起作用。在医生进行的试验中,接受三种药物联合治疗的患者取得了意想不到的效果。用适当剂量和选择的抗生素、免疫抑制剂和他汀类药物的组合对若干患者(包括本文中确定为患者A和患者B的两人)进行治疗,显示出令人惊讶的良好结果。尽管先前出现其他失败现象且该领域有诸多怀疑,但是该治疗完全奏效了,这是我们之前完全没有想到的,同时它的起效速度之快让我们很是惊喜,且这种治疗取得了意想不到的益处。
患者A是54岁的APOE4阳性E3/E4男性,在治疗前患有AD五年。患者A连说一句完整的话都很困难,需要借助带有图片的图表进行交流。对于基本功能,例如吃饭或上厕所,患者必须做出手势或指向图表上展示活动的图片。患者A表现出极度沮丧的迹象,有时在护理人员无法理解他的情况下患者会发飙。患者A也难以完成简单的任务。患者A不会自己系鞋带,并且在试图打开门时经常摸门把手好几次。在治疗前进行改编自阿尔茨海默病评估量表的单词回忆测试。患者无法记住或交流测试中的任何单词。
患者A用以下方式进行治疗,每天服用一次2mg西罗莫司和100mg米诺环素和20mg阿托伐他汀,持续四个月。患者A的言语功能恢复,可以形成短语,有时可以完成整个句子。患者A使用图片图表的次数增多,变得不那么沮丧,也减少了向护理人员发泄情绪的次数。患者A经历了失语症解决、短期记忆改善和长期记忆改善。进行了改编自阿尔茨海默病评估量表的单词回忆测试,患者最多可以记住五个单词。
患者B是患有AD的65岁APOE4阳性男性。患者B在日常生活中遇到困难,例如穿衣、记得吃饭、与护理人员交流以及记得他的家人。他经常会在扣衬衫时忘记扣扣子或扣子错位。他会忘记袜子或内衣等衣服,也很难穿鞋。护理人员必须准备膳食并提醒患者B进食。患者B也很难记住护理人员为什么在他家,并会不断询问他们的身份。患者B可以记住他的孩子并与之交谈,但在谈话中途经常会问他的孩子他们是谁,就好像他们是陌生人一样。在治疗前进行改编自阿尔茨海默病评估量表的单词回忆测试。患者B在进行3次测试时,每次都能记住一个单词。
患者B每天服用2mg西罗莫司、100mg米诺环素和20mg阿托伐他汀,持续两个月。患者B经的短期记忆得到改善,且长期记忆得到改善。患者B不再错过扣子,并且可以很好地进行穿戴。患者B没有忘记他的护理人员为他准备的饭菜。询问他的孩子和护理人员是谁的频率也有所减少。在治疗后进行改编自阿尔茨海默病评估量表的单词回忆测试时,患者B最多可以回忆起4个单词。
研究人员未能成功治疗AD,因为他们未能了解该疾病的病理生理学及其工作原理,以及单一药物不足以治疗该疾病。这就是为什么研究人员单独使用四环素或单独使用他汀类药物来治疗AD是不成功的。
结束评论
阿尔茨海默病是一种复杂的疾病,它具有多种可药物靶点,包括a.脑内淀粉样变性,b.***性淀粉样变性,c.中枢神经***星形胶质细胞和小胶质细胞中的APOE4和脂质代谢障碍,d.脑神经炎症,f.肿瘤坏死因子α和白细胞介素1b和IL 6引起的全身炎症。这些靶点要求联合药物疗法。最简单的AD疗法可以简化为APOE4阴性(E2/E3)AD的两种药物疗法和APOE4阳性AD的三种药物疗法。
在整个说明书中,所示的实施方式和实施例应被认为是示例,而不是对所公开或要求的设备和过程的限制。尽管本文提供的许多示例涉及方法动作或***元素的特定组合,但应当理解,可以以其他方式组合那些动作和那些元素以实现相同的目标。关于流程图,可以采取额外的步骤和更少的步骤,并且可以组合或进一步细化所示的步骤以实现本文所述的方法。仅结合一个实施例讨论的动作、要素和特征不旨在排除其在其他实施例中的相似作用。
如本文所用,“多个”是指两个或更多个。如本文所用,“一组”项目可以包括一个或多个这样的项目。如本文所用,无论在书面具体实施方式中还是在权利要求中,术语“包括”,“包含”,“携带”,“具有”,“含有”,“涉及”等应被理解为开放式的,即,指的是包括但不限于。相对于权利要求,仅过渡短语“由…组成”和“基本上由…组成”是封闭式或半封闭式的过渡短语。权利要求中用到的序数词,例如“第一”、“第二”、“第三”等是用来修饰权利要求元素,这本身不表示一个权利要求元素相较于另一个权利要求元素的优先权,或顺序,或执行方法动作的先后顺序,而只是用于区分具有相同名称的一个权利要求元素与另一个具有相同名称的元素(但是有用到序数词),从而区分权利要求元素。如本文所用,“和/或”是指所列项目是替代方案,但是替代方案也包括所列项目的任何组合。
Claims (2)
1.一种药物组合物,包括:抗生素或其药学上可接受的盐,其特征在于,所述抗生素包含100mg米诺环素;一种免疫抑制剂或其药学上可接受的盐,其中所述免疫抑制剂包含2mg西罗莫司;他汀类药物或其药学上可接受的盐,其中所述他汀类药物由20mg阿托伐他汀;和一种或多种药学上可接受的载体、稀释剂或赋形剂组成。
2.一种治疗患有阿尔茨海默病的个体的方法,包括向个体施用有效量的药物,所述药物包含:抗生素或其药学上可接受的盐,其特征在于,所述抗生素包含100mg米诺环素;一种免疫抑制剂或其药学上可接受的盐,其中所述免疫抑制剂包含2mg西罗莫司;他汀类药物或其药学上可接受的盐,其中所述他汀类药物由20mg阿托伐他汀;和一种或多种药学上可接受的载体、稀释剂或赋形剂组成。
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