CN105640931A - 用于治疗神经性障碍的乙酰乙酸的单甘油酯及其衍生物 - Google Patents
用于治疗神经性障碍的乙酰乙酸的单甘油酯及其衍生物 Download PDFInfo
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Abstract
本发明涉及用于治疗神经性障碍的乙酰乙酸的单甘油酯及其衍生物。本发明涉及使用乙酰乙酸的单甘油酯和代谢前体治疗、预防、抑制或减轻与神经元代谢减退有关的神经学疾病的方法，所述疾病例如为阿尔茨海默病、帕金森病、弗里德赖希共济失调症(FRDA)、GLUT1-缺陷型癫痫、矮妖精貌综合征和Rabson-Mendenhall综合征、冠状动脉绕道移植术(CABG)、痴呆、麻醉诱发的记忆丧失、与年龄有关的记忆缺陷(AAMI)、外伤性脑损伤(TBI)、亨廷顿病和许多其它疾病。
Description
本申请是申请日为2009年7月2日、申请号为200980128636.1、发明名称为“用于治疗神经性障碍的乙酰乙酸的单甘油酯及其衍生物”的发明专利申请的分案申请。
技术领域
本发明涉及用于治疗、预防、抑制或减轻与神经元代谢减退有关的神经学疾病的方法，诸如阿尔茨海默病、帕金森病、弗里德赖希共济失调症(FRDA)、GLUT1-缺陷型癫痫、矮妖精貌综合征和Rabson-Mendenhall综合征、冠状动脉绕道移植术(CABG)、痴呆、麻醉诱发的记忆丧失、与年龄有关的记忆缺陷(AAMI)、外伤性脑损伤(TBI)、亨廷顿病和许多其它疾病。
背景技术
阿尔茨海默病
阿尔茨海默病(AD)是主要影响老年人的渐进性神经变性疾病。在1984年，Blass和Zemcov(Blass和Zemcov，1984)提出，AD源自胆碱能神经元的亚群中的代谢速率降低。但是，已经变得清楚的是，AD不限于胆碱能系统，而且涉及许多类型的递质系统和几个离散的脑区域。降低的代谢速率似乎与葡萄糖利用的减少有关。脑成像技术已经揭示了AD患者的脑中放射性标记的葡萄糖的摄取的减少，且这些缺陷可以在发生痴呆的临床迹象之前较好地被检测出来(Reiman,Caselli等人1996)。脑葡萄糖代谢的测量表明，AD中的葡萄糖代谢减少了20-40％，导致ATP的危险的较低的水平。
葡萄糖代谢减少的原因仍然尚未明确，但是可能与淀粉样蛋白前体蛋白(APP)的加工有关。改变APP的加工的突变已经涉及早发AD。早发病例发生在60岁之前，并且在许多情况下，已经与3个基因：APP、早老素1(PS1)和早老素2(PS2)中的突变有关。这些基因中的突变导致APP蛋白的异常加工(综述参见(Selkoe1999))。在检查时，这些病理学突变导致脑葡萄糖代谢的早期缺陷。携带在APP670/671处的双突变(称为“瑞典突变”)的个体表现出颞叶中的葡萄糖代谢的病理学降低，这经常在痴呆的临床表现之前显现。携带APPV717F转基因的小鼠表现出脑葡萄糖代谢的区域性缺陷。另外，早老素基因中的突变可能直接增加对葡萄糖缺乏的敏感性。
补偿AD中减少的脑代谢速率的尝试已经取得一些成功。AD患者中血清酮体水平的升高会增加认知评分(Reger,Henderson等人2004)和USP。但是，报道的这种方法需要施用大量脂肪以产生足够水平的酮体。因此，需要可以不消耗大量脂肪而升高酮水平的化合物。
帕金森病(PD)
帕金森病(PD)是一种渐进性神经变性疾病，是在阿尔茨海默病之后的第二最常见的神经变性疾病。据估计，在一般美国人群中PD的患病率是0.3％，且在超过85岁的人群中的患病率是4-5％。PD的特征在于运动异常，包括震颤、肌强直、随意运动缺乏和姿势不稳。PD的主要神经病理学特征是在黑质致密部(SNpc)中缺少多巴胺能神经元和在残余多巴胺能神经元中存在嗜曙红性胞浆内包含体(Lewy体)。
PD的现有治疗包括单胺氧化酶-B(MAO-B)抑制剂、金刚烷胺(盐酸金刚烷胺制剂)或抗胆碱药。这些药剂可以适度改善轻度的征状。但是，由于大规模细胞损失，当需要多巴胺能治疗时，美国神经病学学会(AAN)推荐左旋多巴或多巴胺激动剂。典型地，将左旋多巴施用给需要那些改善运动性残疾的人，而将多巴胺激动剂施用给那些需要减少运动并发症的人。一般而言，在具有轻度疾病的年轻患者中施用多巴胺激动剂，而在具有严重运动征状的老年患者中施用左旋多巴。
尽管对早期PD的治疗被认为是相对成功的，在用左旋多巴治疗约5年后，约40％的患者发展成运动障碍(即，无意识的舞蹈病样运动或刻板运动，所述运动涉及头、躯干、四肢，偶尔涉及呼吸肌)。患者经历“磨耗”效应，其特征在于来自单一左旋多巴给药的益处减弱，造成帕金森病征状再次出现。患者还可能经历“开-关”效应，其特征在于不可预知的、突然的运动状态的波动。因此，存在对更有效的PD治疗、尤其是神经保护性治疗的需求。
尽管散发性的PD的原因尚未明确，一系列证据表明，氧化磷酸化的缺陷可能促成其发病机理。例如，1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)会阻断线粒体电子传递链的复合物I(NADH-泛醌氧化还原酶)，并造成多巴胺能神经元的缺失和PD的典型征状。还已经报道了PD组织中复合物I活性的减少。该缺陷不仅限于脑，还已经在来自PD患者的血小板中被发现。
D-β-羟基丁酸酯(BHB)是由肝细胞、且在更低的程度上由星形细胞生成的酮体。当葡萄糖供应有限时，诸如在饥饿期间，BHB的作用是脑中能量的替代源。已经发现，通过增强氧化磷酸化，BHB会保护免于受到MPTP-有关的复合物I抑制{Tieu,2003#295}。
弗里德赖希共济失调症(FRDA)
FRDA是特征在于渐进性共济失调、肥厚性心肌病、胰岛素抵抗性糖尿病的早期发作、慢性衰弱病和早产儿死亡的隐性疾病。FRDA是Frataxin缺乏造成的遗传性障碍，所述Frataxin是细胞核编码的210氨基酸线粒体蛋白。该蛋白的低水平是由于内含子GAA重复序列的扩增，导致降低的mRNA水平。FRDA患者表现出线粒体酶顺乌头酸酶活性的降低。顺乌头酸酶负责柠檬酸盐向异柠檬酸盐的转化，即Krebs(也称作柠檬酸或三羧酸循环)中的第一步。认为人类患者中的Frataxin缺乏主要导致三羧酸循环中的缺陷。
最近的工作证实，血液酮体的升高(对禁食的正常应答)可以增加线粒体柠檬酸盐和异柠檬酸盐水平，从而克服在FRDA中发现的顺乌头酸酶的阻断。基于酮体的疗法可以为该类患者群体提供有效治疗。
GLUT1-缺陷型癫痫
GLUT1-缺陷型癫痫的特征在于幼儿期发作、延缓发育和具有精神发育迟滞的后天获得的小头畸形。GLUT1-缺陷型癫痫源自GLUT1基因中的几种类型的突变。葡萄糖运载体1(GLUT1)是负责将葡萄糖从血流运输到脑的主要蛋白。在标准的饮食条件下，脑几乎完全依赖于血糖来获取能量。但是，在有些情况(诸如饥饿)下，酮体可以提供不同于葡萄糖的能量来源。酮体不依赖于GLUT1来运输进脑，因此可以在GLUT1-缺陷型综合征中提供能量。酮体疗法因此变成这些患者的终生治疗的实用方法。
矮妖精貌综合征和Rabson-Mendenhall综合征
矮妖精貌综合征和Rabson-Mendenhall综合征是特征在于胰岛素抵抗性、持续的高血糖症和生长迟缓的罕见疾病。患者很少活到20岁以后。这些综合征源自胰岛素受体基因的突变，所述突变降低了胰岛素的受体亲和力。现有的治疗由施用递增剂量的胰岛素(多达数千单位/天)组成。由于胰岛素与其受体的结合差，该治疗仅产生微弱的结果。已经证实，酮体会模仿胰岛素的刺激PDH多酶复合物的作用，从而增加Krebs三羧酸循环代谢物水平，增加ATP形式的能量输出，并提高代谢效率。酮富集的或生酮的饮食可以证实对这些疾病的有效治疗。
其它疾病和综合征
大量的其它疾病和综合征与降低的代谢有关。这些疾病包括冠状动脉绕道移植术(CABG)、痴呆、与年龄有关的记忆缺陷、麻醉诱发的记忆丧失、外伤性脑损伤、亨廷顿病和许多其它疾病。显然，代谢干预可以帮助患有这些疾病折磨的人群。
未满足的需求
尽管基于酮体的疗法可能适用于这些疾病，现有的方法是不实用的或不充分的。生酮饮食需要连续性严格遵守低碳水化合物摄入，这使得病患们难以依从。
在1979年，Birkhahn等人((Birkhahn,McMenamy等人1979))描述了乙酰乙酸的单甘油酯(他们将其称作“单乙酰乙酸甘油酯(monoacetoacetin)”(MA))的合成。在以后的研究(1986)中，Birkhahn、McMemany和Border将单乙酰乙酸甘油酯静脉内注射给大鼠，以检查单乙酰乙酸甘油酯是否是合适的替代能量源(Birkhahn,Askari等人1986)。
Hirakawa等人延伸了Birkhahn的工作，对单乙酰乙酸甘油酯进行了其它研究。在2004公开的研究中，Sawai等人检查了单乙酰乙酸甘油酯作为几个胃癌细胞系的细胞培养物的能源的作用(Sawai,Yashiro等人2004)(Takahata,Ohira等人2004)。
可以看出，公开的现有技术都没有涉及单乙酰乙酸甘油酯用于治疗神经性障碍的用途，所述神经性障碍例如阿尔茨海默病、帕金森病、弗里德赖希共济失调症(FRDA)、GLUT1-缺陷型癫痫、矮妖精貌综合征和Rabson-Mendenhall综合征、冠状动脉绕道移植术(CABG)、痴呆、麻醉诱发的记忆丧失、与年龄有关的记忆缺陷、外伤性脑损伤、亨廷顿病或帕金森病。单乙酰乙酸甘油酯可以用于治疗这些疾病，是本发明的新发现。
Birkhahn等发明人提交了关于相关化合物的几个专利申请。标题为“Parenteralnutrientsbasedonwatersolubleglycerolbisacetoacetates”的美国专利5,420,335于1995年5月30日获得授权。标题为“Nutritivewatersolubleglycerolestersofhydroxybutyricacid”的美国专利5,693,850于1997年12月2日获得授权。发明人RichardVeech的一系列专利和专利申请涉及用于治疗神经变性疾病的类似化合物，它们包括美国专利6323237、6316038和6207856以及几个专利申请，包括US2004/0266872、US2004/0171671和US2006/0280721。但是，应当指出，Veech的专利教导，由于无论“1,3-丁二醇(其形成乙酰乙酸酯)还是甘油(它是葡萄糖的前体)都不是正常的氧化还原对D-β-羟基丁酸酯的一部分”，且“应当施用生理比例的酮。否则，在整个动物中，肝会根据其自身的线粒体游离的[NAD+]/[NADH]来调节酮的比例。如果施用异常比例的酮，病理学后果是明显的可能性”。参见，例如，US2004/0171671的第[0054]段。
因此，可以看出，本发明证实了，在缺乏羟基丁酸或其对应盐的来源的情况下施用的单乙酰乙酸甘油酯和其它乙酰乙酸酯，可以用于有效地治疗神经变性疾病。因此，可以解决上面讨论的未满足的需求。
本文引用的所有美国专利和专利申请都通过引用整体并入本文。本文引用的那些专利和专利申请的部分列表包括，例如，2007年7月31日提交的USSN60/953,074,“GenomictestinginAlzheimer'sdiseaseandotherdiseasesassociatedwithreducedneuronalmetabolism”；2007年5月14日提交的USSN60/917,886,“InhibitorsofAcetyl-CoACarboxylaseforTreatmentofHypometabolism”；2005年5月3日提交的USSN11/123,706,“MethodforReducingLevelsofDiseaseAssociatedProteins”；2006年6月15日提交的USSN11/424,429,“MethodToReduceOxidativeDamageAndImproveMitochondrialEfficiency”；2005年8月25日提交的USSN10/546,976,“Novel-ChemicalEntitiesandMethodsfortheirUseinTreatmentofMetabolicDisorders”；2001年5月1日提交的USSN09/845,741；2004年12月28日提交的USSN10/152,147，现在的美国专利号6,835,750；2004年12月22日提交的USSN11/021,920；2006年1月13日提交的USSN11/331,673；2006年12月14日提交的USSN11/611,114；和2007年6月29日提交的USSN11/771,431。
附图说明
图1A至1D显示了施用不同量的单乙酰乙酸甘油酯的小鼠中β-羟基丁酸酯的血液水平(mM)随时间(小时)的变化。
图2显示了在尸体解剖时具有更高的起始BHB水平和更大的TH+神经元数量的动物之间的关系。
发明内容
本发明包括治疗与代谢减退有关的疾病的方法，该方法包括：以有效升高患者的血中酮体水平的量，向患有与代谢减退有关的疾病的患者施用包含有效量的式I化合物的组合物:
其中R独立地表示羟基或乙酰乙酸的酯、或其药学上可接受的盐，其中所述组合物缺乏D-β-羟基丁酸或其对应盐的来源。
在另一个实施方案中，患者的血液中的升高水平的酮体是在D-β-羟基丁酸酯和乙酰乙酸酯的正常生理比例的范围内。可能与代谢减退有关的疾病包括阿尔茨海默病、帕金森病、弗里德赖希共济失调、GLUT1-缺陷型癫痫、矮妖精貌综合征和Rabson-Mendenhall综合征、冠状动脉绕道移植术、痴呆、麻醉诱发的记忆丧失、与年龄有关的记忆缺陷或亨廷顿病。在一个实施方案中，式I化合物以在0.1g/kg/天至10g/kg/天范围内的剂量给药。
在一个实施方案中，在给药后约2小时，患者的血中酮体水平从0.2mM升高至20mM。在一个实施方案中，式I是单乙酰乙酸甘油酯。
本发明的方法还包括如下另外的步骤：测定哺乳动物的载脂蛋白E状态，且如果哺乳动物是载脂蛋白E4(-)，则选择该哺乳动物用于治疗。在其它实施方案中，施用第二种组合物，其中所述组合物包含碳水化合物源。在一个实施方案中，所述碳水化合物源是葡萄糖。在另一个实施方案中，所述组合物另外包含碳水化合物源。所述碳水化合物源可以是葡萄糖。
具体实施方式
对诸如阿尔茨海默病、帕金森病、弗里德赖希共济失调症(FRDA)、GLUT1-缺陷型癫痫、矮妖精貌综合征和Rabson-Mendenhall综合征、冠状动脉绕道移植术(CABG)、痴呆、麻醉诱发的记忆丧失、与年龄有关的记忆缺陷、外伤性脑损伤、亨廷顿病和许多其它疾病的治疗，存在巨大需求。例如，阿尔茨海默病的现有治疗几乎不能减缓或治疗该疾病。酮体前体，诸如本发明的组合物(包括如本发明所述的单乙酰乙酸甘油酯化合物)的应用，将满足极大的未获满足的药学需求。
发明人以前已经证实，口服施用中链甘油三酯(MCT)对酮病的诱导可改善可能的轻度至中度阿尔茨海默病患者的认知性能(美国专利6,835,750；Reger,2004#136)。但是，该治疗需要施用大量MCT，且可能造成一些肠不适。在本申请中，发明人公开了一项新的发明，该发明解决了许多与施用MCT有关的问题。
本发明描述了通过以有效升高患者的血中酮体水平的量，对哺乳动物施用包含有效量的式I化合物的组合物，以诱导高酮血症:
其中R独立地表示羟基或乙酰乙酸的酯、或乙酰乙酸的前体、或其药学上可接受的盐，其中所述组合物缺乏D-β-羟基丁酸或其对应盐的来源。式I的化合物也可用作治疗与代谢减退有关的疾病的方法。在一个实施方案中，本发明包括口服和静脉内施用单乙酰乙酸甘油酯(3-氧代丁酸2,3-二羟丙酯)。在另一个实施方案中，本发明包括二乙酰乙酸甘油酯(乙酰乙酸酯的二甘油酯)。在另一个实施方案中，本发明包括乙酰乙酸的三甘油酯。根据式I的化合物会升高哺乳动物中的循环酮体水平，且可以用于治疗神经变性疾病和代谢减退障碍。
在有些实施方案中，与代谢减退有关的疾病可以是下述任一种：阿尔茨海默病、帕金森病、弗里德赖希共济失调、GLUT1-缺陷型癫痫、矮妖精貌综合征和Rabson-Mendenhall综合征、冠状动脉绕道移植术、痴呆、麻醉诱发的记忆丧失、与年龄有关的记忆缺陷、外伤性脑损伤或亨廷顿病。在一个实施方案中，要治疗的与代谢减退有关的疾病是阿尔茨海默病。
制备单乙酰乙酸甘油酯和其它化合物的方法是本领域已知的。
本发明人已经证实，当口服施用时，单乙酰乙酸甘油酯会升高血清酮体，尤其是β-羟基丁酸酯(β-HB)。令人惊奇地，已经证实，施用乙酰乙酸的前体，诸如在体内分解成乙酰乙酸的单乙酰乙酸甘油酯，可有效地治疗神经障碍，尽管本领域的教导指出，在没有其对应的氧化还原对D-β-羟基丁酸酯来源的情况下施用乙酰乙酸前体会导致病理学后果。
酮体在脑神经元的发育和健康中起关键作用。许多研究已经证实，对于发育哺乳动物新生儿的脑而言优选的底物是酮体(综述参见参考文献(Edmond,1992#43))。大量证据表明，成年人脑(甚至在老年人中)以浓度依赖性的方式使用酮体。酮体在脑中补充葡萄糖的能力，已经被用于治疗脑的低葡萄糖可用性病症。GLUT-1是一种组分性葡萄糖运载体，其将葡萄糖运输进中枢神经系统(CNS)。脑的高葡萄糖需求要求，存在Glut-1基因的2个功能拷贝。如果Glut-1的单个拷贝是无功能的，这会导致GLUT-1缺乏综合征。在发育过程中产生的低葡萄糖水平导致婴幼儿(癫痫)发作、延缓发育和小头畸形。通过施用生酮饮食来增加血清酮水平，可以部分地缓解这些征状。
这些化合物可以模仿增加脂肪酸的氧化的作用，包括但不限于，式I的化合物，诸如单乙酰乙酸甘油酯。乙酰乙酸的前体包括当施用时直接产生乙酰乙酸酯的化合物。这样的化合物通过可以如下方式产生乙酰乙酸：通过作用于前体化合物以释放乙酰乙酸的酶的作用，或通过pH、温度或机械作用的变化。这样的化合物包括但不限于，乙酰乙酸的二聚体、三聚体或其它寡聚体；乙酰乙酸的酯和糖类(包括其它连接诸如酰胺和硫键)。
本发明的组合物对酮病的诱导会减轻与葡萄糖的利用降低有关的病症，是发明人的新发现。
关于癫痫，现有技术提供了生酮饮食的描述，其中脂肪含量高，且碳水化合物是有限的。总之，这种饮食的原理是，在其中碳水化合物水平缺乏或有限的高度管理的饮食的背景下，大量脂肪(长链或中链甘油三酯)的摄入，可以增强血酮水平。认为碳水化合物和胰岛素的限制会预防脂肪组织中的再酯化。不同于现有技术，本发明提供并要求保护在生酮饮食的背景之外施用式I化合物(例如，单乙酰乙酸甘油酯)。此外，下面的实施例部分提供了包含碳水化合物的示例性制剂。
在有些实施方案中，本发明的化合物可以与碳水化合物源共同施用，或与碳水化合物源共同配制。碳水化合物源可以包括超过一类碳水化合物。碳水化合物或糖类通常是简单分子，它们是具有许多添加的羟基的直链醛或酮，在不构成醛或酮官能团的一部分的每个碳原子上通常添加一个羟基。碳水化合物可以是单糖、二糖、多糖和/或寡糖。适用于本发明的碳水化合物是这样的碳水化合物，其在哺乳动物中消化后，至少能产生作为单糖的碳水化合物的一部分。在一个实施方案中，碳水化合物是单糖，且任选地是葡萄糖、果糖和/或半乳糖。在另一个实施方案中，碳水化合物是二糖，且任选地是蔗糖和/或乳糖。
从药物组合物制剂可以衍生出其它益处，所述制剂包括第一种组合物和/或第二种组合物，其包括代谢助剂。代谢助剂包括维生素、矿物质、抗氧化剂和其它有关的化合物。这样的化合物可以选自包括但不限于下述物质的列表：抗坏血酸、生物素、骨化三醇、钴胺、叶酸、烟酸、泛酸、维生素B6、视黄醇、视黄醛(维生素A)、视黄酸、核黄素、硫胺、α-生育酚、植物甲萘醌、多异戊烯甲萘醌、钙、镁、钠、铝、锌、钾、铬、钒、硒、磷、锰、铁、氟、铜、钴、钼、碘。因此，选自代谢助剂、增加酮体水平的化合物和三羧酸循环中间体的成分的组合，将证实有益于与降低的代谢有关的疾病的治疗和预防，所述疾病包括阿尔茨海默病、帕金森病、TBI、亨廷顿病和癫痫。
可以在根据需要或根据希望的基础上，施用本发明的组合物。本发明的组合物可以每月给药1次、每周1次、每天1次、或每天超过1次。类似地，可以隔日、隔周或隔月、每3天、每3周或每3月、每4天、每4周或每4月等给药。可以每天给药多次。当用作普通饮食需求的补充物时，可以将组合物直接施用给哺乳动物，或以其它方式与每日膳食或饮料相接触或混合。当用作每日膳食或饮料时，施用技术是本领域技术人员已知的。也可以在定期基础上进行施用，例如，作为哺乳动物的治疗方案的一部分。治疗方案可以包括，使哺乳动物定期摄入可有效增强如上定义的特征的量的本发明的组合物。定期摄入可以是每天1次，或每天2、3、4或更多次，在每天或每周的基础上。类似地，定期施用可以是隔天或隔周、每3天或每3周、每4天或每4周、每5天或每5周、每6天或每6周，且在这样的方案中，施用可以是每天多次。定期施用的目的是，给哺乳动物提供最佳剂量的本发明的任意组合物，如本文所例证的。
在一个实施方案中，本文提供的组合物预期用于“长期”消耗，在本文中有时称为“延长的”期间。本文使用的“长期施用”通常是指超过1个月的时期。超过2、3或4个月的时期构成本发明的一个实施方案。也包括包含更长时期(包括超过5、6、7、8、9或10个月)的实施方案。也包括超过11个月或超过1年的时期。也预见到超过1、2、3、4、5、6、7、8、10、12、14、16、18、20或更多年的长期使用。在有些情况下，预见到，患者会在他的余生中在上文讨论的定期基础上继续消耗本发明的组合物。本文使用的“定期基础”表示至少每周施用或消耗组合物。也包括更频繁的施用或消耗，诸如每周2次或3次。也包括这样的方案，其包括至少每天1次消耗。技术人员会理解，所达到的几种酮体或一种特定酮体在血液(尿或脑脊髓液)中的水平，可以是确定施用频率的有价值的度量。无论是否在本文中特别地例证，允许将测量的化合物的血液水平维持在可接受的范围内的任意频率，被认为在本文中是有用的。技术人员会理解，施用频率将随消耗或施用的组合物而变化，有些组合物可能需要更高或更低频率的施用，以维持希望的测量化合物(例如，酮体)的血液水平。
通常，有效量是这样的量，其有效地：(1)减少要治疗的疾病的征状，或(2)诱导药理学变化，该变化与治疗要治疗的疾病有关。例如，对于阿尔茨海默病，有效量包括这样的量，其有效地：增加认知评分；减缓痴呆的进展；或增加受影响的患者的预期寿命。有效量也表示可有效地实现特定生物学结果的本文所述的化合物或组合物的量。通过至少一个神经心理学测验的改善结果，可以评估对一些前述病症的治疗的有效性，所述测验例如包括本领域已知的用于评估与代谢减退有关的疾病的任意神经心理学测验，所述疾病包括阿尔茨海默病、帕金森病、弗里德赖希共济失调、GLUT1-缺陷型癫痫、矮妖精貌综合征和Rabson-Mendenhall综合征、冠状动脉绕道移植术、痴呆、麻醉诱发的记忆丧失、与年龄有关的记忆缺陷或亨廷顿病。这样的神经心理学测验的实例包括ADAS-cog、细微精神状态检查(MMSE)、Stroop色-字干扰任务(StroopColorWordInterferenceTask)、Wechsler记忆量表-III的逻辑记忆子测验(LogicalMemorysubtestoftheWechslerMemoryScale-III)、临床医生的痴呆评级和以临床医生的访视为基础的变化印象。治疗前述病症的有效性包括：脑的适当生理活性的提高，诸如智力稳定性、记忆/回忆能力、解决问题的能力、推理能力、思考能力、判断能力、学习能力、理解力、直觉、觉知、注意力，它们可以通过本领域合适的任意方式来测量。
个体的任意上述类别或特定类型的性质或功能的下降，通常是性质或功能的改善或增强的对立面。本发明的组合物的“有效量”(如上面的讨论的)可以是预防下降、减少下降的程度或速率、或延迟下降的发作或进展、或改善以前的下降所需的量。可以相对于没有接受治疗的群体，考虑下降的预防、减少或延迟。也可以在单个基础上，或在有些实施方案中，在群体基础上，测量和考虑下降的预防、减少或延迟。
在一个优选的实施方案中，生酮化合物被提供在组合物的施用方便的制剂中，所述制剂包括装入多个容器中的剂量单位。生酮化合物(诸如monoacetoacetein)的剂量优选地以有效量施用，从而产生足以增加患有与代谢减退有关的疾病的患者的认知能力的酮体浓度，所述疾病诸如上面讨论的阿尔茨海默病、帕金森病、弗里德赖希共济失调、GLUT1-缺陷型癫痫、矮妖精貌综合征和Rabson-Mendenhall综合征、冠状动脉绕道移植术、痴呆、麻醉诱发的记忆丧失、与年龄有关的记忆缺陷、外伤性脑损伤或亨廷顿病。
在一个实施方案中，口服施用生酮化合物。在另一个实施方案中，静脉内施用生酮化合物。例如，单乙酰乙酸甘油酯和/或其它生酮化合物制品的口服施用是本领域已知的。
在一个实施方案中，本发明的任意组合物增加哺乳动物或患者中至少一类酮体的循环浓度。在一个实施方案中，循环酮体是D-β-羟基丁酸酯。在另一个实施方案中，循环酮体是正常氧化还原对D-β-羟基丁酸酯/乙酰乙酸酯的等摩尔混合物。在一个实施方案中，肝根据其自身的线粒体游离的[NAD+]/[NADH]来调节酮的比例。在施用后的多个时间点，可以测量循环的多种酮体(或一种酮体)的量，且在一个实施方案中，在预测接近血液中的峰浓度的时间进行测量，但是也可以在预测的血药浓度峰值水平之前或之后测量循环酮体。在有些实施方案中，测量的循环酮体可以是D-β-羟基丁酸酯；乙酰乙酸酯；或二者。然后任选地调节在这些离开峰的时间测量的这些物质中的任一种的量，以反映在预测的峰时间的预测水平。在一个实施方案中，预测的峰时间是在约2小时。循环血药浓度的峰值和时间可以随本领域技术人员已知的因素而变化，包括本领域技术人员已知的个体消化速率，食物、饮料等的共摄入或先摄入或后摄入。
在一个实施方案中，物质D-β-羟基丁酸酯达到的血中浓度峰值是约0.05毫摩尔(mM)至约50mM。测定D-β-羟基丁酸酯的血中浓度是否在血液中升高到约0.05至约50mM的另一种方式是，测定D-β-羟基丁酸酯的尿排泄，其中与上述血中浓度相对应的水平是在约5毫克/分升(mg/dL)至约160mg/dL的范围内。在其它实施方案中，D-β-羟基丁酸酯的血中浓度峰值升高到约0.15至约2mM、约0.15至约0.3mM。在其它实施方案中，D-β-羟基丁酸酯的血中浓度峰值升高到至少约0.05mM、至少约0.1mM、至少约0.15mM、至少约0.2mM、至少约0.5mM、至少约1mM、至少约2mM、至少约2.5mM、至少约3mM、至少约4mM、至少约5mM、至少约10mM、至少约20mM、至少约30mM、至少约40mM、至少约50mM。在另一个实施方案中，至少一类酮体的循环浓度是约0.1mM的水平；在0.1-50mM的范围内，在0.2-20mM的范围内，在0.3-5mM的范围内，和在0.5-2mM的范围内。
本发明组合物中化合物的剂量的有效量，即能升高有效量的酮体浓度的化合物，在有些实施方案中即第一种组合物，是本领域技术人员显而易见的，且可以通过测定在血液中产生的酮体的量方便地确定。在能升高酮体水平的化合物是单乙酰乙酸甘油酯的情况下，在一个实施方案中，单乙酰乙酸甘油酯的剂量是在0.05g/kg/天至10g/kg/天的单乙酰乙酸甘油酯的范围内。在另一个实施方案中，剂量是在0.25g/kg/天至5g/kg/天的单乙酰乙酸甘油酯的范围内。在另一个实施方案中，剂量是在0.5g/kg/天至2g/kg/天的单乙酰乙酸甘油酯的范围内。在其它实施方案中，剂量是在约0.1g/kg/天至约2g/kg/天的范围内。在其它实施方案中，单乙酰乙酸甘油酯的剂量是至少约0.05g/kg/天、至少约0.1g/kg/天、至少约0.15g/kg/天、至少约0.2g/kg/天、至少约0.5g/kg/天、至少约1g/kg/天、至少约1.5g/kg/天、至少约2g/kg/天、至少约2.5g/kg/天、至少约3g/kg/天、至少约4g/kg/天、至少约5g/kg/天、至少约10g/kg/天、至少约15g/kg/天、至少约20g/kg/天、至少约30g/kg/天、至少约40g/kg/天、和至少约50g/kg/天。
方便的单位剂量容器和/或制剂包括片剂、胶囊、锭剂、含片、硬糖、营养条、营养饮料、计量喷雾剂、乳剂和栓剂、以及其它。组合物可以与药学上可接受的赋形剂诸如明胶、油和/或其它药学活性剂相组合。例如，组合物可以有利地与不同于本发明化合物的其它治疗剂或预防剂相组合和/或联合使用。在许多情况下，与本发明化合物联合施用能增强这些药剂的效能。例如，本发明化合物可以有利地与抗氧化剂、能增强葡萄糖利用效率的化合物及其混合物联合使用(参见例如Goodman等人，1996)。
在一个优选的实施方案中，给人受试者直接静脉内输注本发明的组合物，例如单乙酰乙酸甘油酯，达到治疗和预防与代谢减退有关的疾病所需的水平。静脉内使用的溶液的制备是本领域技术人员熟知的。
其它代谢助剂包括增加能量的化合物，例如辅酶CoQ-10、肌酸、L-肉碱、正乙酰基-肉碱、L-肉碱衍生物、及其混合物。这些化合物能通过多种方式增加能量生产。肉碱会增加脂肪酸的代谢。CoQ-10用作线粒体内电子传递过程中的电子载体。因此，将这些化合物加入本发明的组合物诸如单乙酰乙酸甘油酯，会增加代谢效率，特别是在缺乏营养的个体中。
即使同时消耗大量的碳水化合物，施用本发明的组合物，诸如单乙酰乙酸甘油酯，也会导致酮体水平升高(综述参见(Odle1997)；也参见2001年9月21日提交的美国临时专利申请系列号60/323,995，“DrugTargetsforAlzheimer'sDiseaseandOtherDiseasesAssociatedwithDecreasedNeuronalMetabolism”)。申请人的方案的优点是显然的，因为不需要小心地监视饮食，且顺应性更加简单。
在一个实施方案中，本发明包括共同施用本发明的组合物，诸如含有单乙酰乙酸甘油酯和L-肉碱或L-肉碱的衍生物的组合物。因而，在本发明中，本发明的组合物(含有例如单乙酰乙酸甘油酯)与增加所述单乙酰乙酸甘油酯的利用性所需的剂量的L-肉碱相组合。L-肉碱和单乙酰乙酸甘油酯的剂量随宿主的状况、递送方法和本领域技术人员已知的其它因素而变化，且其量足以使血酮水平升高到治疗和预防本文定义的代谢减退疾病所需的程度。可用于本发明中的L-肉碱的衍生物包括但不限于，癸酰肉碱、己酰(hexanoyl)肉碱、己酰肉碱、月桂酰肉碱、辛酰肉碱、硬脂酰肉碱、肉豆蔻酰肉碱、乙酰-L-肉碱、O-乙酰-L-肉碱和棕榈酰-L-肉碱。在一个实施方案中，本发明提供了这样的制剂，其包含单乙酰乙酸甘油酯和肉碱的混合物，以提供升高的血酮水平。这种制剂的性质依赖于施用的持续时间和途径。这种制剂含有0.05g/kg/天至10g/kg/天的单乙酰乙酸甘油酯和0.05mg/kg/天至10mg/kg/天的肉碱或其衍生物。在一个实施方案中，单乙酰乙酸甘油酯的剂量是在0.05g/kg/天至10g/kg/天的单乙酰乙酸甘油酯的范围内。更优选地，剂量是在0.25g/kg/天至5g/kg/天的单乙酰乙酸甘油酯的范围内。更优选地，剂量是在0.5g/kg/天至2g/kg/天的单乙酰乙酸甘油酯的范围内。在有些实施方案中，肉碱或肉碱衍生物的剂量是在0.05g/kg/天至10g/kg/天的范围内。更优选地，肉碱或肉碱衍生物的剂量是在0.1g/kg/天至5g/kg/天的范围内。更优选地，肉碱或肉碱衍生物的剂量是在0.5g/kg/天至1g/kg/天的范围内。剂量根据例如制剂和/或宿主，在必要时做出变动。
在一个实施方案中，所述组合物包含这样的制剂，其包含与1-2000mg肉碱相组合的1-500g单乙酰乙酸甘油酯。单乙酰乙酸甘油酯的量可以是至少约1g、至少约10g、至少约50g、至少约100g、至少约150g、至少约200g、至少约250g、至少约300g、至少约400g。肉碱的量可以是至少约1mg、至少约50mg、至少约100mg、至少约250mg、至少约500mg、至少约1000mg、至少约1250mg或至少约1500mg。一种甚至更优选的制剂包含与500mgL-肉碱相组合的用50g单甘油酯和甘油二酯乳化的50g单乙酰乙酸甘油酯。这种制剂的耐受性较好，并在健康的人受试者中诱导高酮血症3-4小时。
在另一个实施方案中，本发明还包括测定患者的基因型或特定等位基因。该方法可以另外包括，基于测定结果，选择进行治疗的患者。在一个实施方案中，测定患者的载脂蛋白E基因的等位基因。在有些实施例中，发明人教导，当用本发明的组合物(包括单乙酰乙酸甘油酯)诱导酮体水平升高时，非-E4载体的表现比含有E4等位基因的那些更好。另外，含有E4等位基因的那些具有更高的空腹酮体水平，且该水平在2小时时间间隔中持续升高。因此，E4载体可能需要更高的酮水平或增加存在的酮体的利用能力的试剂。因此，在含有E4等位基因的那些的一个实施方案中，施用的剂量包括与增加脂肪、单乙酰乙酸甘油酯或酮体的利用率的试剂相组合的单乙酰乙酸甘油酯的剂量。增加脂肪酸的利用率的试剂的实例可以选自、但不限于：非甾体抗炎药(NSAID)、抑制素药(诸如和)和贝特类(如本文别处所讨论的)。
在本发明的另一个实施方案中，其它益处可以源自这样的药物组合物制剂，其包含能升高患者中的酮体浓度的化合物(诸如单乙酰乙酸甘油酯)和其它治疗剂，例如，抗阿尔茨海默病药、抗糖尿病药、能增加脂类的利用率的药剂、抗动脉粥样硬化药、抗高血压药、抗炎药、减肥药、及其组合。在一个实施方案中，其它治疗剂是在阿尔茨海默病、帕金森病、外伤性脑损伤、亨廷顿病或癫痫的治疗中使用的药剂。
在本发明的一些方法中，使用各种常规方法，将本发明的生酮化合物和治疗剂、或第一种组合物和第二种组合物施用给哺乳动物(例如，人，男性或女性)。本文提及的每种组合物的施用，可以是在根据现有方案、推荐方案或本领域关于该组合物和/或化合物已知的方案的剂型和给药计划中。在该实施方案中，本发明的生酮化合物和治疗剂的施用，是根据个体特异性的方案和/或给药计划，但是以使本发明的生酮化合物和治疗剂在特定哺乳动物中的施用在特定治疗计划中至少部分地重叠的方式进行。在一个实施方案中，本发明的生酮化合物和治疗剂的施用在治疗计划中基本上重叠。在一个实施方案中，第一种和第二种组合物的治疗计划充分重叠，以实现本文指出的有益效果。
本发明的生酮化合物和治疗剂也可以一起用于同一口服剂型中或同时服用的分开的口服剂型中。上述组合物可以在单次剂量或多次剂量中施用，每日1-4次。可能适当的是，患者从低剂量组合开始，并逐渐增加到高剂量组合。
实施例
下面提供的实施例仅用于例证目的，无意限制本发明的范围。
实施例1
小鼠药代动力学(PK)研究
发明人检查了小鼠口服(po)和腹膜内(ip)施用单乙酰乙酸甘油酯后的不同时间点的血中酮体水平。
使用6-7周龄的ICR雄性小鼠。每只小鼠体重在20-30克之间。每笼圈养3只动物，并在给药前顺应至少3天。给小鼠施用单次口服剂量(范围为2.5、5和10ml/kg)的化合物或单次腹膜内剂量(1g/kg)。在15、30、60和180分钟时麻醉动物来收集血液。通过心脏穿刺收集全血(～0.4ml)，并收集到肝素钠抗凝血药(肝素钠,1:9比例)中。在13,000rpm离心血液8分钟，以分离血浆。将血浆转移到预标记的、颜色编码的埃彭道夫管中，并在-70℃冷冻。观察动物的毒性症状，并记录临床观察。按照生产商的指导(StanBioInc.)，使用β-羟基丁酸酯检测试剂盒，测定β-羟基丁酸酯(BHB)的血浆水平。
单乙酰乙酸甘油酯(在本文中也称作AC-0523)导致循环BHB水平在早至15分钟时的显著增加(参见图1A-D)。
实施例2
使用单乙酰乙酸甘油酯升高大鼠模型的血清酮水平
给Sprague-Dawley大鼠饲喂标准的商业大鼠食物。顺应15天后，给2组大鼠饲喂含有l-5g/kg/天的单乙酰乙酸甘油酯的实验饮食。对照组保持标准的等热量食物。
每天测量每只大鼠的重量。每天收集尿样，并通过酶测定法分析3-羟基丁酸酯。在饲喂实验饮食5天后，使大鼠安乐死，收集血样，并通过标准的酶技术分析3-羟基丁酸酯、乙酰乙酸酯和丙酮。
通过酶方法，测量在安乐死时收集的大鼠血浆中的酮体浓度。发现对照组显示出正常的3-羟基丁酸酯和乙酰乙酸酯的浓度，为约0.02-0.07mM。发现饲喂单乙酰乙酸甘油酯的大鼠具有升高的3-羟基丁酸酯、乙酰乙酸酯和丙酮浓度。这些结果表明，饲喂单乙酰乙酸甘油酯的大鼠在它们的血液中具有升高的酮体水平。
通过GC-MS测得，饲喂单乙酰乙酸甘油酯的大鼠的尿中的3-羟基丁酸酯浓度分别是约1-10mM。3-羟基丁酸酯在对照大鼠的尿中不可检出。这些结果表明，单乙酰乙酸甘油酯的口服剂量会升高血液和尿中的酮体浓度。
实施例3
在MPTP损伤的小鼠中的神经保护作用
为了测试AC-0523的可能的治疗潜力，进行了小规模实验来检查AC-0523在帕金森病(PD)小鼠模型中的潜在神经保护作用。1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)会阻断线粒体电子传递链的复合物I(NADH-泛醌氧化还原酶)，并造成PD的典型征状和多巴胺能神经元的缺失。
全身注射的MPTP在转化成MPP+后，会造成黑质纹状体多巴胺(DA)神经末梢的缺失和最终的纹状体多巴胺能神经元的死亡。该神经病理学模仿人PD患者的多巴胺去神经支配的纹状体的状况，并产生活动过度和姿势不稳。进行酪氨酸羟化酶(TH)(该酶负责催化多巴胺产生)的测定和SNc中含有TH的细胞的定量，以测量纹状体多巴胺能神经变性的程度。酪氨酸羟化酶是多巴胺能神经纤维的可靠标志物，已经发现，其在人PD患者和该疾病的动物模型中都降低。
使用了平行试验组的设计。在设施中顺应后，在Rotarod和活动任务中测试受试者。在测试处理的第二天，所有受试者开始为期8天的腹膜内施用MPTP或盐水。在MPTP或盐水处理之前15分钟和之后2.75小时，受试者接受实验化合物或盐水。在处理的第1天和第9天，抽血，用于随后的β-羟基丁酸酯的监测。在处理第11天，使所有动物安乐死，并在少量实验动物上进行组织学检查。
AC-0523保护表达酪氨酸羟化酶(TH)的细胞免于MPTP毒性。用AC-0523处理的动物具有(111±20)的“TH+神经元”的平均密度，这与用盐水处理的动物(111±11)相当，且高于用MPTP处理的动物(78±12)(参见下表)。
一般而言，具有更高起始BHB水平的动物在尸体解剖时具有更大量的TH+神经元，再次证实了AC-0523在这些条件下是神经保护性的(参见图2中的关系)。
MPTP结论
AC-0523在MPTP-处理的受试者中的神经保护作用得到了支持。也施用AC-0523的MPTP-处理的小鼠的SNc中的TH-阳性细胞数高于仅接受盐水或AC-1202的MPTP-处理的小鼠，且与没有接受MPTP的小鼠相当。尾状壳核中的TH密度在用MPTP和盐水处理的动物中是最低的，而在接受MPTP和AC0523的受试者中是最高的。
实施例4
评价单乙酰乙酸甘油酯在阿尔茨海默病中的安全性、耐受性和有效性
在患有可能的轻度至中度的阿尔茨海默病的受试者中施用单乙酰乙酸甘油酯，每天1次，持续90天。使用随机、双盲、安慰剂对照、平行的、多中心设计。在多达4周的筛选期之后，受试者接受化合物2或安慰剂90天，继之以2周清除期。
研究受试者是100位门诊患者，他们被诊断为患有可能的轻度至中度严重度的阿尔茨海默病。在方案的双盲期，50位受试者接受活性药物，50位受试者接受安慰剂。
单乙酰乙酸甘油酯或匹配安慰剂每天给药1次，持续90天。在90天给药期结束后，受试者具有2周的研究药物清除期。每位受试者观察5次：在筛选时、基线、和基线后45、90和104天。检查不良事件、生命特征、重量、身体检查、12-引导ECGs、实验室检验。主要结果度量是：阿尔茨海默病评估量表-认知分量表(ADAS-Cog),阿尔茨海默病合作研究-临床医生的总体印象改变(ADCS-CGIC)和细微精神状态检查(MMSE)。发现，用单乙酰乙酸甘油酯处理的受试者将表现出一个或多个结果量度的改善，包括ADAS-Cog、ADCS-CGIC或MMSE。
在第0天(基线)、第45天和第90天，在剂量前和剂量后2小时测量β-羟基丁酸酯水平。还在筛选时和在清除期结束时(第104天)，测量β-羟基丁酸酯Cmin水平。在提供许可的受试者中测量载脂蛋白E基因型。预见到，用化合物2处理的受试者将表现出升高的血清酮体水平。
实施例5
营养饮料和其它制剂
A.立即可饮的饮料。使用下述的成分制备立即可饮的饮料：乳化的单乙酰乙酸甘油酯5-100g/饮料、L-肉碱250-1000mg/饮料和多种调味剂和用于增加适口性、稳定性等的其它成分。
B.粉末化的饮料。可以将单乙酰乙酸甘油酯制备成干燥的形式，可用于食物条和粉末化的饮料制品中。粉末化的饮料可以由下面的组分制备：干燥的乳化的单乙酰乙酸甘油酯10-50g、L-肉碱250-500mg、蔗糖8-15g、糊精-麦芽糖复合剂1-5g、调味剂0-1g。
C.食物条。食物条由下述物质组成：干燥的乳化的单乙酰乙酸甘油酯0.1-50g、L-肉碱250-500mg、甘油1-5g、玉米糖浆固体5-25g、可可粉2-7g、包衣料15-25g。
D.明胶胶囊。使用下述的成分制备硬或软明胶胶囊：单乙酰乙酸甘油酯0.1-1000mg/胶囊、L-肉碱250-500mg/胶囊，淀粉NF0-600mg/胶囊；淀粉可流动粉末0-600mg/胶囊；有机硅流体350厘沱0-20mg/胶囊。混合各成分，过筛，装入胶囊中。
E.片剂。使用下述的成分制备片剂:单乙酰乙酸甘油酯0.1-1000mg/片；L-肉碱250-500mg/片；微晶纤维素20-300mg/片；淀粉0-50mg/片；硬脂酸镁或硬脂酸0-15mg/片；烟熏化的二氧化硅0-400mg/片；胶体二氧化硅0-1mg/片和乳糖0-100mg/片。混合各成分，进行压制，形成片剂。
F.混悬液。使用下述的成分制备混悬液:0.1-1000mg单乙酰乙酸甘油酯；250-500mgL-肉碱；羧甲基纤维素钠50-700mg/5ml；苯甲酸钠0-10mg/5ml；纯化水5ml；以及矫味剂和着色剂(根据需要)。
G.肠胃外溶液。通过在10体积％的丙二醇和水中搅拌1.5重量％的单乙酰乙酸甘油酯和L-肉碱，制备肠胃外组合物。用氯化钠使溶液等渗，并灭菌。
提供的本发明的说明书是用于解释和描述目的，而无意穷尽本发明或将本发明限制为公开的形式。本发明的范围仅由下面的权利要求书限定。本领域普通技术人员显而易见多种修饰和变化。为了最好地解释本发明的原理、实际应用、和使本领域普通技术人员理解本发明的具有适合预期的特定用途的不同修饰的不同实施方案，选择并描述了在附图中描述和显示的实施方案。
Claims (5)
1.单乙酰乙酸甘油酯在制备用于治疗患者中的帕金森病的药物中的应用，其中所述组合物缺乏D-β-羟基丁酸的来源。
2.权利要求1的应用，其中单乙酰乙酸甘油酯以在0.1g/kg/天至10g/kg/天范围内的剂量给药。
3.权利要求1的应用，其中所述患者的血中酮体水平在给药后约2小时从0.2mM升高至20mM。
4.权利要求1的应用，其中施用第二种组合物，其中所述组合物包含碳水化合物源。
5.权利要求4的应用，其中所述碳水化合物源是葡萄糖。
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2009
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- 2009-07-02 CN CN2009801286361A patent/CN102105071A/zh active Pending
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| CA2729622A1 (en) | 2010-01-07 |
| AU2016238886A1 (en) | 2016-10-20 |
| KR20110043648A (ko) | 2011-04-27 |
| WO2010003114A1 (en) | 2010-01-07 |
| KR101734152B1 (ko) | 2017-05-11 |
| JP5674652B2 (ja) | 2015-02-25 |
| EP2303036A1 (en) | 2011-04-06 |
| US9125881B2 (en) | 2015-09-08 |
| CN102105071A (zh) | 2011-06-22 |
| CA2729622C (en) | 2017-07-25 |
| JP2011526929A (ja) | 2011-10-20 |
| US20110178032A1 (en) | 2011-07-21 |
| AU2016238886B2 (en) | 2018-07-05 |
| AU2009266869A1 (en) | 2010-01-07 |
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