CN102395359A - 治疗阿尔茨海默病和骨质疏松症以及减缓衰老 - Google Patents

治疗阿尔茨海默病和骨质疏松症以及减缓衰老 Download PDF

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CN102395359A
CN102395359A CN2010800171927A CN201080017192A CN102395359A CN 102395359 A CN102395359 A CN 102395359A CN 2010800171927 A CN2010800171927 A CN 2010800171927A CN 201080017192 A CN201080017192 A CN 201080017192A CN 102395359 A CN102395359 A CN 102395359A
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陈建宏
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Abstract

本发明公开了组合物用于治疗阿尔茨海默病、骨质疏松症、睡眠呼吸暂停、勃起功能障碍、麦卡德尔病或碳水化合物代谢障碍或者用于减缓衰老或疲劳的用途。所述组合物包含第一药剂、具有抗炎活性的第二药剂以及具有5-羟色胺活性的第三药剂，其中所述第一药剂选自氧化磷酸化抑制剂、离子载体和5’-单磷酸腺苷活化蛋白激酶激活剂。

Description

治疗阿尔茨海默病和骨质疏松症以及减缓衰老
相关申请的交叉引用
按照35U.S.C.§119(e)，本申请要求2009年3月16日提交的美国临时申请61/160,533的优先权，其内容通过引用并入本文。
背景技术
阿尔茨海默病是特征在于记忆力减退和痴呆的与年龄相关的神经疾病。骨质疏松症也是与年龄相关的疾病，其导致低骨量和骨组织丢失。需要开发治疗这两种与年龄相关疾病或另外减缓衰老的新方法。
发明内容
在一个方面，本发明的特征在于通过向需要治疗的对象施用组合物来治疗阿尔茨海默病或骨质疏松症的方法，所述组合物包含(1)第一药剂，其可以是氧化磷酸化抑制剂、离子载体(ionophore)或5’-单磷酸腺苷活化蛋白激酶(AMPK)激活剂，(2)具有抗炎活性的第二药剂，以及(3)具有或维持5-羟色胺活性的第三药剂。术语“氧化磷酸化抑制剂”指抑制氧化磷酸化的合适药剂，例如氧化磷酸化解偶联剂。离子载体是能将离子运输跨越细胞膜脂质双层的脂溶性分子。AMPK激活剂是激活AMPK使其底物(例如乙酰CoA羧化酶和丙二酰CoA脱羧酶)磷酸化的药剂。所述第一药剂的实例包括二甲双胍(例如盐酸二甲双胍)、苯乙双胍、丁双胍、麻黄素、甲状腺素、水杨酰苯胺和水杨酸。所述第二药剂可以是合适的抗炎化合物(例如非甾体抗炎化合物)。实例包括阿司匹林、双氯酚酸(例如双氯酚酸钾或双氯酚酸钠)、布洛芬(例如右布洛芬或右布洛芬赖氨酸)、吲哚美辛、对乙酰氨基酚、尼美舒利和COX-2抑制剂(例如基于一氧化氮的COX-2抑制剂)。所述第三药剂可以是具有或维持至少一种5-羟色胺活性并且当与所述第一和第二药剂组合使用时可有效治疗一种或更多种本发明靶标疾病的化合物。实例包括5-羟色胺(例如5-羟色胺硫酸盐、5-羟色胺肌酐硫酸盐复合物或5-羟色胺盐酸盐)和5-羟色胺再摄取抑制剂。一种优选的组合物包含盐酸二甲双胍、阿司匹林和5-羟色胺肌酐硫酸盐复合物。上文所述三种药剂可通过不同于其中所述的生物学机制来治疗靶标疾病。例如，二甲双胍可通过不同于抑制氧化磷酸化或激活AMPK的机制来治疗靶标疾病(例如骨质疏松症)。
上述组合物可包含5-5000mg(例如5-3000mg、5-1500mg或5-1000mg)的所述第一药剂、1-5000mg(例如1-3000mg、1-1000mg、1-500mg或1-100mg)的所述第二药剂以及0.1-1000mg(例如0.1-100mg、0.1-50mg或0.1-30mg)的所述第三药剂，或者包含与基于上述量所计算的比例相同的量。
在另一个方面中，本发明的特征在于通过向需要治疗的对象施用上述组合物来减缓衰老或疲劳的方法。
在又一个方面中，本发明的特征在于通过向需要治疗的对象施用上述组合物来治疗睡眠呼吸暂停、勃起功能障碍、麦卡德尔病(McArdledisease)或碳水化合物代谢障碍的方法。
上述组合物用于制备用于上述任何疾病和病症的药物的用途也落在本发明范围内。
下文阐述本发明一个或更多个实施方案的细节。通过说明书和权利要求书，本发明的其它特征、目的和优点将是显而易见的。
具体实施方式
本文公开了组合物用于治疗多种疾病/病症或者用于减缓衰老或疲劳的用途，所述疾病/病症例如为阿尔茨海默病、骨质疏松症、睡眠呼吸暂停、勃起功能障碍、麦卡德尔病或碳水化合物代谢障碍。所述组合物包含下文即将描述的以及美国专利申请60/885,212和12/014,932中描述的至少3种活性剂。
所述第一药剂可以是氧化磷酸化抑制剂、离子载体或腺苷5’-单磷酸活化蛋白激酶(AMPK)激活剂。除了上文所述的那些之外，所述第一药剂还可包括4，6-二硝基-邻甲酚、解偶联蛋白(例如UCP1、UCP2或UCP3)、对(三氟甲氧基)苯腙羰基氰化物、间氯苯腙羰基氰化物、C5基因产物、二硝基苯酚(例如2，4-二硝基苯酚)、肽抑制素(efrapeptin，A23871)、胍乙啶、氯丙嗪、阿米妥、司可巴比妥、鱼藤酮、孕酮、抗霉素A、萘醌、8-羟基喹啉、一氧化碳、氰化物、叠氮化物(例如NaN3)、双羟香豆素、胆红素、胆色素、麻黄碱、硫化氢、四碘甲状腺原氨酸、槲皮素、2，4-双(对氯苯胺基)嘧啶、3-磷酸甘油醛脱氢酶、寡霉素、三丁基氯化锡、金轮霉素、芦他霉素、杀黑星菌素、汞制剂(mercurials)、二环己基碳二亚胺、Dio-9、间氯苯腙丙二腈(m-chlorophenyl-hydrazonemesoxalonitrile)、离子霉素(ionomycin)、钙离子载体(例如A23187、NMDA、CA1001或恩镰孢菌素B)、增加线粒体中Ca+2浓度的化合物(例如苍术苷、米酵菌酸、毒胡萝卜素(thapsigargin)、氨基酸神经递质、谷氨酸、N-甲基-D-天冬氨酸、卡巴胆碱、离子载体、钾去极化诱导剂)、凋亡因子(即诱导凋亡的化合物)、缬氨霉素、短杆菌肽、无活菌素、尼日利亚菌素、拉沙里菌素和莫能菌素。所述第一药剂可以是AMPK激活剂(例如二甲双胍或苯乙双胍、丁双胍、5’-氨基咪唑-4-甲酰胺-核糖核苷、噻吩并吡啶酮、白藜芦醇、诺卡酮、噻唑或脂联素(adiponectin))。
所述第二药剂可包括甾体抗炎药和非甾体抗炎药。甾体抗炎药的实例包括糖皮质激素、氢化可的松、可的松、倍氯米松、双丙酸酯、倍他米松、地塞米松、泼尼松、甲基泼尼松龙、曲安西龙、醋酸氟轻松、氟氢可的松和丙酸倍氯米松。非甾体抗炎药(NSAID)的实例包括A183827、ABT963、醋氯芬酸、阿西美辛、乙酰水杨酸、AHR10037、阿氯芬酸、阿明洛芬、安吡昔康、呱氨托美丁、阿扎丙宗、阿利洛芬甲酯(atliprofen methyl ester)、AU8001、苯噁洛芬、氟灭酸苄达明、柏莫洛芬、苄哌立隆(bezpiperylon)、BF388、BF389、BIRL790、BMS347070、溴芬酸、布氯酸、异丁苯丁酸(butibufen)、BW755C、C53、C73、C85、卡洛芬、CBS1108、塞来考昔、CHF2003、氯联苯、三水杨酸胆碱镁、CHX108、西米考昔、辛诺昔康、环氯茚酸、CLX1205、COX-2抑制剂、CP331、CS502、CS706、D1367、达布非隆、地拉考昔、右旋酮洛芬、DFP、DFU、二氟尼柳、DP155、DRF4367、E5110、E6087、依尔替酸、ER34122、艾氟洛芬、依托考昔、F025、联苯乙酸乙酯、芬布芬、芬氯酸、芬克洛酸、芬克洛辛(fenclozine)、非诺洛芬、芬替酸、非普拉宗、非来那朵、氟罗布芬、氟非宁、氟舒胺、甲磺酸氟比星(flubichin methanesulfonate)、氟芬那酸、氟洛芬、氟比洛芬、FPL62064、FRL22047、FR123826、FR140423、FR188582、FS205397、呋罗芬酸、GR253035、GW406381、HAI105、HAI106、HCT2035、HCT6015、HGP12、HN3392、HP977、HX0835、HYAL AT2101、异丁芬酸、异丁普生-β-环糊精、icodulinum、IDEA070、艾拉莫德、艾瑞昔布(imrecoxib)、吲哚洛芬、IP751、伊索克酸、伊索昔康、KC764、酮洛芬、L652343、L745337、L748731、L752860、L761066、L768277、L776967、L783003、L784520、L791456、L804600、L818571、LAS33815、LAS34475、利克飞龙、LM 4108、氯布洛芬、氯诺昔康、鲁米考昔、马布洛芬、甲氯灭酸、甲氯灭酸钠、甲灭酸、美洛昔康、巯基乙胍、间卟啉、布洛芬愈创木酚酯(metoxibutropate)、咪洛芬、莫非布宗、莫苯唑酸、MX1094、萘丁美酮、萘普生钠、萘普生钠/甲氧氯普胺、NCX1101、NCX284、NCX285、NCX4016、NCX4215、NCX530、尼氟灭酸、基于一氧化氮的NSAID(NitroMed，Lexington，MA)、硝基芬酸(nitrofenac)、硝基氟吡洛芬、硝萘普生、NS398、圣罗勒油(ocimum sanctum oil)、ONO3144、奥帕诺辛、奥沙普嗪、羟吲达酸、oxpinac、羟考酮/布洛芬、羟布宗、P10294、P54、P8892、帕米格雷、帕西他沙、帕瑞考昔、PD138387、PD145246、PD164387、培比洛芬、培美酸、保泰松、吡拉唑酸、吡罗昔康、吡罗昔康β-环糊精、特戊酸吡罗昔康、吡洛芬、普拉洛芬、白藜芦醇、R-酮洛芬、R-酮咯酸、罗非考昔、RP66364、RU43526、RU54808、RWJ63556、S19812、S2474、S33516、水杨酰水杨酸、沙替格雷、SC236、SC57666、SC58125、SC58451、SFPP、SKF105809、SKF86002、水杨酸钠、舒多昔康、柳氮磺胺吡啶、舒林酸、舒洛芬、SVT2016、T3788、TA60、他美辛、他尼氟酯(talnifumate)、他唑非隆、特丁非隆、替尼达普、替诺昔康、替泊沙林、噻洛芬酸、替马考昔、替洛芬阿酯、替诺立定、硫平酸、硫噁洛芬、托芬那酸、托美汀、三氟柳、托品辛(tropesin)、TY10222、TYL0246、TYL0474、UR8962、熊果酸、伐地考昔、WAY120739、WY28342、WY41770、希莫洛芬、YS134、扎托洛芬、齐多美辛和佐美酸。
所述第三药剂包括5-羟色胺和其功能等价物。5-羟色胺的功能等价物包括5-羟色胺代谢物(例如5-羟基吲哚乙酸)、5-羟色胺转运体抑制剂(例如帕罗西汀、氟西汀、芬氟拉明、氟伏沙明、舍曲林、丙咪嗪以及WO 03/00663所公开的那些)、5-羟色胺受体2c调节剂(例如BVT933、DPCA37215、IK264、PNU22394、WAY161503、R-1065、YM348和美国专利No.3914250、WO 01/66548、WO 02/10169、WO 02/36596、WO02/40456、WO 02/40457、WO 02/44152、WO 02/48124、WO 02/51844和WO 03/033479中公开的那些)、5-羟色胺再摄取抑制剂(例如芳基吡咯烷化合物、苯基哌嗪化合物、苄基哌啶化合物、哌啶类化合物、三环γ-咔啉度洛西汀化合物、吡嗪并喹喔啉化合物、吡啶并吲哚化合物、哌啶基吲哚化合物、米那普仑、西酞普兰、舍曲林代谢物去甲基舍曲林、去甲氟西汀、西酞普兰代谢物去甲基西酞普兰、依地普仑、d，l-芬氟拉明、非莫西汀、伊福西汀、氰基度硫平、利托西汀、达泊西汀、奈法唑酮、西文氯胺、曲唑酮、米氮平、氟西汀、氟伏沙明、茚达品、茚氯嗪、米那普仑、帕罗西汀、舍曲林、西布曲明、齐美定、盐酸曲唑酮、右芬氟拉明和美国专利No.6,365,633、WO 01/27060和WO 01/162341中所公开的那些)、5-羟色胺和去甲肾上腺素再摄取抑制剂(例如文拉法辛、文拉法辛代谢物O-去甲文拉法辛、氯米帕明和氯米帕明代谢物去甲氯米帕明)、5-羟色胺IA受体拮抗剂(例如芳基哌嗪化合物、杂环稠合的苯并二噁烷类的氮杂杂环甲基衍生物或丁螺环酮)、5-羟色胺2A受体拮抗剂(例如MDL100907和法南色林)、5-羟色胺2B或2C受体拮抗剂(例如吡嗪并(氮杂)吲哚化合物或5-羟色胺能化合物)、5-羟色胺6受体拮抗剂(例如5-卤代-色胺化合物)、5-羟色胺7受体拮抗剂(例如5-卤代-色胺化合物或喹啉类化合物)、5-羟色胺多巴胺拮抗剂(例如奥氮平和齐拉西酮(ziperasidone))、单胺再摄取抑制剂(例如酰胺类)、哒嗪酮醛糖还原酶抑制剂(例如哒嗪酮化合物)、5-羟色胺能药物、5-羟色胺受体激活剂(例如甲磺酸二氢麦角碱或甲磺酸培高利特)、5-羟色胺合成的激活剂(例如维生素B1、维生素B3、维生素B6、生物素、S-腺苷甲硫氨酸、叶酸、抗坏血酸、镁、辅酶Q10或吡拉西坦)或5-羟色胺激动剂(例如芬氟拉明)。
所述第一、第二和第三药剂也可以是上述化合物的盐、前药或溶剂化物。盐可以在阴离子和药剂的带正电荷基团(例如氨基)之间形成。合适的阴离子包括氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲磺酸根、三氟乙酸根、醋酸根、氯苯氧基乙酸根、苹果酸根、对甲苯磺酸根、酒石酸根、富马酸根、谷氨酸根、葡糖醛酸根、乳酸根、戊二酸根、苯甲酸根、恩波酸根、乙醇酸根、双羟萘酸根、天门冬氨酸根、对氯苯氧异丁酸根、甲酸根、丁二酸根、环己烷羧酸根、己酸根、辛酸根(octonoate)、癸酸根、十六酸根、十八酸根、苯磺酸根、三甲氧基苯甲酸根、对甲苯磺酸根、金刚烷羧酸根、乙醛酸根、吡咯烷酮羧酸根、萘磺酸根、1-葡萄糖磷酸根、亚硫酸根、连二硫酸根和马来酸根。同样，盐也可以在阳离子和药剂的带负电荷基团(例如羧酸根)之间形成。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵阳离子例如四甲基铵离子。所述药剂还包括含季氮原子的盐。前药的实例包括酯类和其它可药用衍生物，当施用给对象时，其能转化为活性化合物。溶剂化物指活性化合物与可药用溶剂间形成的复合物。可药用溶剂的实例包括水、乙醇、异丙醇、乙酸乙酯、乙酸和乙醇胺。
上述3种活性剂是已知的药物并且公众容易获得。一些可从化学公司(例如Sigma-Aldrich，St.Louis，MO)购买。施用这些药物化合物的方案是众所周知的，必要时，可容易地重新建立。
除了所述3种必需药剂之外，本发明方法中所用的组合物还可包含一种或更多种其它活性成分。
为了实施本发明的方法，可将有效量的上述组合物经胃肠外、口服、口含、鼻腔、表面(topically)或直肠施用给需要的对象。本文所用的“有效量”指当单独施用或与一种或更多种其它活性剂组合施用时赋予对象治疗作用所需的每种活性剂的量。
如本领域技术人员所公认的，有效剂量将根据待治疗病症的类型或程度；对象的身高、体重、年龄和性别；施用途径；赋性剂用量以及可能的与另一种治疗性治疗共应用而不同。上述组合物的每日剂量可以为5-5000mg(例如10-2500或10-3000mg)的所述第一药剂、1-5000mg(例如2-1000或2-3000mg)的所述第二药剂以及0.1-1000mg(例如1-50mg)的所述第三药剂。
有需要的对象可由医护专业人员基于获得自合适诊断方法的结果来鉴定。本文所用的术语“治疗”指向患有上述疾病、所述疾病症状或易患所述疾病的对象施用上文所述的组合物，目的是赋予治疗作用，例如治愈、减轻、改变、影响、改善或预防疾病、其症状或患此疾病的倾向。本文所用的术语“减缓疲劳”指减轻、改善或缓解对象中的一种或多种疲劳症状(例如能量不足、耐久力差以及注意力缺陷)。“减缓衰老”指减轻、改善或缓解对象中衰老的有害作用(例如精力不济、记忆力减退、视觉或听力下降和关节疼痛)。
本文所述的组合物可包含可药用载体以形成药物组合物。所述载体就与组合物的活性成分相容(优选能够稳定活性成分)并且对所治疗对象无害的意义上来说必须是“可接受的”。可使用医药领域中普通技术人员公知的常规方法将本文所述的药物组合物施用给对象。
无菌注射组合物可以是在无毒胃肠外可接受的稀释剂或溶剂中的溶液或混悬剂。本文所用的术语“胃肠外”指皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸内、鞘内、病灶内或颅内注射以及任何合适的输注技术。可用的可接受载体和溶剂有甘露醇、水、1，3-丁二醇、林格氏溶液和等渗氯化钠溶液。此外，不挥发性油通常用作溶剂或混悬介质(例如合成的甘油单酯或甘油二酯)。脂肪酸例如油酸及其甘油酯衍生物用于制备注射剂，其为天然可药用油，例如橄榄油或蓖麻油，尤其是其聚氧乙烯化形式。这些油溶液或混悬剂还可包含长链醇稀释剂或分散剂、羧甲基纤维素或相似的分散剂。其它常用的表面活性剂例如吐温类或司盘类或其它类似的乳化剂或生物利用度增强剂(常用于制造可药用固体、液体或其它剂型)也可用于制剂目的。
用于口服施用的组合物可以是任何可口服的剂型，包括胶囊剂、粉末、片剂、乳剂和水混悬剂、分散剂和溶液剂。在片剂或胶囊剂的情形下，常用的载体或稀释剂包括乳糖和玉米淀粉。可添加润滑剂，例如硬脂酸镁。当水混悬剂或乳剂口服施用时，活性成分可与乳化剂或助悬剂一起混悬或溶解在油相中。必要时，可添加某些甜味剂、调味剂或着色剂。
鼻气雾剂或吸入组合物可根据药物制剂领域众所周知的技术来制备。例如，可利用本领域公知的苄醇或其它合适的防腐剂、用于提高生物利用度的吸收促进剂、氟碳化合物和/或其它增溶剂或分散剂来将这样的组合物制成盐水溶液。
用于表面施用的组合物可以软膏、凝胶、糊剂、乳剂、洗剂、泡沫剂、混合相或两亲性乳剂体系(水包油型-油包水型)的乳膏、脂质体、传递体(transfersome)、贴剂或粉末的形式制备。
上文所述的任何组合物还可以以供直肠施用的栓剂的形式施用。也可对其进行设计使组合物在肠中释放。例如，将组合物包含在固体亚单位或胶囊隔室中，所述亚单位或隔室具有包含肠溶性聚合物的基质或壁或罩，所述肠溶性聚合物在小肠或大肠的pH中溶解或分散以将药物物质在肠中释放。合适的肠溶性聚合物已在上文和美国专利5,705,189中进行了描述。
组合物可包含在饮料或食品中。实例包括茶(例如茶饮料和茶袋的内含物)、软饮料、果汁(例如水果提取物和果汁饮料)、奶、咖啡、甜食(cookies)、谷物、糖果和快餐。
可以通过体外测定对上文所述组合物治疗上文所述疾病或病症的效力进行初步筛选，然后通过动物实验和临床试验确认。对于本领域普通技术人员而言，其它方法也将是显而易见的。
无需进一步阐述，相信本领域技术人员可基于本文描述最大程度地利用本发明。本文所引用的所有出版物(包括专利和专利申请)在此均通过引用全文并入本文。
其它实施方案
本说明书中公开的所有特征可以任何组合方式相组合。本说明书中所公开的每个特征均可被起到相同、等同或相似目的的替代性特征所替代。因此，除非另外指明，否则所公开的每个特征仅仅是等同或相似特征的通用系列中的一个实例。
由上述描述可见，本领域技术人员可容易地确定本发明的必要特征，并且可在不背离其精神和范围的情形下对本发明进行各种改变、变动以使其适用于多种用途和条件。因此，其它实施方案也落在下述权利要求书的范围内。

Claims (42)

1.一种治疗疾病的方法，包括向有此需要的对象施用有效量的组合物，所述组合物包含：
选自氧化磷酸化抑制剂、离子载体和5’-单磷酸腺苷活化蛋白激酶(AMPK)激活剂的第一药剂；
具有抗炎活性的第二药剂；以及
具有或维持5-羟色胺活性的第三药剂；
其中所述疾病是阿尔茨海默病、骨质疏松症、睡眠呼吸暂停、勃起功能障碍、麦卡德尔病或碳水化合物代谢障碍。
2.权利要求1所述的方法，其中所述第一药剂是二甲双胍、苯乙双胍、丁双胍、麻黄素、甲状腺素、水杨酰苯胺或水杨酸。
3.权利要求2所述的方法，其中所述第一药剂是盐酸二甲双胍。
4.权利要求1所述的方法，其中所述第二药剂是非甾体抗炎化合物。
5.权利要求1所述的方法，其中所述第二药剂是阿司匹林、双氯酚酸、布洛芬、吲哚美辛、对乙酰氨基酚、尼美舒利或COX-2抑制剂。
6.权利要求5所述的方法，其中所述第二药剂是阿司匹林。
7.权利要求1所述的方法，其中所述第三药剂是5-羟色胺或5-羟色胺再摄取抑制剂。
8.权利要求7所述的方法，其中所述第三药剂是5-羟色胺硫酸盐、5-羟色胺肌酐硫酸盐复合物或5-羟色胺盐酸盐。
9.权利要求1所述的方法，其中所述组合物包含5-5000mg的所述第一药剂、1-5000mg的所述第二药剂以及0.1-1000mg的所述第三药剂；或者包含所述相同比例的量。
10.权利要求9所述的方法，其中所述组合物包含5-1500mg的所述第一药剂、1-1000mg的所述第二药剂以及0.1-100mg的所述第三药剂；或者包含所述相同比例的量。
11.权利要求10所述的方法，其中所述组合物包含5-1000mg的所述第一药剂、1-500mg的所述第二药剂以及0.1-50mg的所述第三药剂；或者包含所述相同比例的量。
12.权利要求1所述的方法，其中所述组合物包含盐酸二甲双胍、阿司匹林和5-羟色胺肌酐硫酸盐复合物。
13.权利要求12所述的方法，其中所述组合物包含5-5000mg的盐酸二甲双胍、1-5000mg的阿司匹林以及0.1-1000mg的5-羟色胺肌酐硫酸盐复合物；或者包含所述相同比例的量。
14.权利要求13所述的方法，其中所述组合物包含5-1500mg的盐酸二甲双胍、1-1000mg的阿司匹林以及0.1-100mg的5-羟色胺肌酐硫酸盐复合物；或者包含所述相同比例的量。
15.权利要求14所述的方法，其中所述组合物包含5-1000mg的盐酸二甲双胍、1-500mg的阿司匹林以及0.1-50mg的5-羟色胺肌酐硫酸盐复合物；或者包含所述相同比例的量。
16.权利要求1所述的方法，其中所述组合物还包含可药用载体。
17.权利要求1所述的方法，其中所述组合物包含所述第一、第二和第三药剂作为仅有的活性成分。
18.权利要求1所述的方法，其中所述第一药剂是AMPK激活剂。
19.权利要求18所述的方法，其中所述组合物包含所述第一、第二和第三药剂作为仅有的活性成分。
20.权利要求18所述的方法，其中所述AMPK激活剂选自二甲双胍、苯乙双胍、丁双胍、5’-氨基咪唑-4-甲酰胺-核糖核苷、噻吩并吡啶酮、白藜芦醇、诺卡酮、噻唑和脂联素。
21.权利要求1所述的方法，其中所述第一药剂是氧化磷酸化抑制剂或离子载体。
22.一种减缓衰老或疲劳的方法，其包括向有此需要的对象施用有效量的组合物，所述组合物包含：
选自氧化磷酸化抑制剂、离子载体和AMPK激活剂的第一药剂；
具有抗炎活性的第二药剂；以及
具有或维持5-羟色胺活性的第三药剂。
23.权利要求22所述的方法，其中所述第一药剂是二甲双胍、苯乙双胍、丁双胍、麻黄素、甲状腺素、水杨酰苯胺或水杨酸。
24.权利要求23所述的方法，其中所述第一药剂是盐酸二甲双胍。
25.权利要求22所述的方法，其中所述第二药剂是非甾体抗炎化合物。
26.权利要求22所述的方法，其中所述第二药剂是阿司匹林、双氯酚酸、布洛芬、吲哚美辛、对乙酰氨基酚、尼美舒利或COX-2抑制剂。
27.权利要求26所述的方法，其中所述第二药剂是阿司匹林。
28.权利要求22所述的方法，其中所述第三药剂是5-羟色胺或5-羟色胺再摄取抑制剂。
29.权利要求28所述的方法，其中所述第三药剂是5-羟色胺硫酸盐、5-羟色胺肌酐硫酸盐复合物或5-羟色胺盐酸盐。
30.权利要求22所述的方法，其中所述组合物包含5-5000mg的所述第一药剂、1-5000mg的所述第二药剂以及0.1-1000mg的所述第三药剂；或者包含所述相同比例的量。
31.权利要求30所述的方法，其中所述组合物包含5-1500mg的所述第一药剂、1-1000mg的所述第二药剂以及0.1-100mg的所述第三药剂；或者包含所述相同比例的量。
32.权利要求31所述的方法，其中所述组合物包含5-1000mg的所述第一药剂、1-500mg的所述第二药剂以及0.1-50mg的所述第三药剂；或者包含所述相同比例的量。
33.权利要求22所述的方法，其中所述组合物包含盐酸二甲双胍、阿司匹林和5-羟色胺肌酐硫酸盐复合物。
34.权利要求33所述的方法，其中所述组合物包含5-5000mg的盐酸二甲双胍、1-5000mg的阿司匹林以及0.1-1000mg的5-羟色胺肌酐硫酸盐复合物；或者包含所述相同比例的量。
35.权利要求34所述的方法，其中所述组合物包含5-1500mg的盐酸二甲双胍、1-1000mg的阿司匹林以及0.1-100mg的5-羟色胺肌酐硫酸盐复合物；或者包含所述相同比例的量。
36.权利要求35所述的方法，其中所述组合物包含5-1000mg的盐酸二甲双胍、1-500mg的阿司匹林以及0.1-50mg的5-羟色胺肌酐硫酸盐复合物；或者包含所述相同比例的量。
37.权利要求22所述的方法，其中所述组合物还包含可药用载体。
38.权利要求22所述的方法，其中所述组合物包含所述第一、第二和第三药剂作为仅有的活性成分。
39.权利要求22所述的方法，其中所述第一药剂是AMPK激活剂。
40.权利要求39所述的方法，其中所述组合物包含所述第一、第二和第三药剂作为仅有的活性成分。
41.权利要求39所述的方法，其中所述AMPK激活剂选自二甲双胍、苯乙双胍、丁双胍、5’-氨基咪唑-4-甲酰胺-核糖核苷、噻吩并吡啶酮、白藜芦醇、诺卡酮、噻唑和脂联素。
42.权利要求22所述的方法，其中所述第一药剂是氧化磷酸化抑制剂或离子载体。
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