CN115515578A - 用于治疗抑郁症的环丝氨酸和己酮可可碱联合疗法 - Google Patents
用于治疗抑郁症的环丝氨酸和己酮可可碱联合疗法 Download PDFInfo
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- CN115515578A CN115515578A CN202180033305.0A CN202180033305A CN115515578A CN 115515578 A CN115515578 A CN 115515578A CN 202180033305 A CN202180033305 A CN 202180033305A CN 115515578 A CN115515578 A CN 115515578A
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- pentoxifylline
- cycloserine
- pharmaceutically acceptable
- acceptable salt
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Abstract
本发明提供一种用于预防或治疗抑郁症的复合组合物,其包含(i)环丝氨酸或其药用盐和(ii)己酮可可碱或其药用盐。所述复合组合物可以有效地用作抗抑郁药。
Description
技术领域
本发明涉及用于治疗抑郁症的环丝氨酸和己酮可可碱的联合疗法。
背景技术
应激是指由外部刺激引起的有机体中的有害反应或变化。通常,当对活体的刺激超过一定程度时,就会产生有害作用。此时,活体在对某种威胁的反应中会引起紧张性头痛、偏头痛、高血压、消化不良、疲劳、疼痛、脱发和皮肤粗糙(无论何种类型的刺激),如果其长期持续存在,则将非特异性全身适应综合征(general adaptive syndrome)诸如引起各种神经官能症和胃溃疡定义为应激(Selye,1958,Longmans Green and Co.)。根据最近的几份报告,已知超过90%的疾病是由应激引起的。最近,韩国保健福祉部(the Ministry ofHealth and Welfare of Korea)也将应激归类为一种新的疾病代码。具体地,已报道了由应激引起的各种疾病,包括精神障碍诸如抑郁症、消化系统病症诸如胃神经机能不良(gastraneuria)和十二指肠溃疡、内分泌病症诸如应激性甲状腺机能亢进、皮肤病症诸如应激性黄褐斑或痤疮以及心血管病症诸如心律失常或心绞痛。
抑郁症是一种无论客观情况如何都会发生的情绪病理现象。患者的全部生活都被情绪低落、兴趣减弱和快感缺乏(anhedonia)所覆盖,并且变得深陷于精神锻炼匮乏、悲观感觉和绝望。其是一种导致自杀企图的疾病,因为自杀是有动机的,并且表现为各种各样的身体症状诸如食欲下降、失眠、便秘、性欲缺乏等。抑郁症最近已成为一个严重的社会问题。
大多数的当前抗抑郁药具有增加中枢5-羟色胺或去甲肾上腺素突触中神经递质浓度的药理作用。广泛使用的抗抑郁药可以根据增加神经递质浓度的机制而分为三环抗抑郁药(TCA;tricyclic antidepressant)、单胺氧化酶抑制剂(MAOI;monoamine oxidaseinhibitor)、选择性5-羟色胺再摄取抑制剂(SSRI;selective serotonin reuptakeinhibitor)等。尽管这些常规抗抑郁药相对有效,但是在一些情况下,可能会出现严重的副作用和不符合预期的效果。许多患者对抗抑郁药反应不佳(Thase等人2001)、具有高复发率(Frank等人1991)以及由于严重的副作用而无法服用药物(Gumnick和Nemeroff 2000)。TCA诸如丙咪嗪(imipramine)、地昔帕明(desipramine)等具有严重的副作用如低血压、心功能障碍等。最广泛使用的SSRI诸如氟西汀(fluoxetine)、舍曲林(sertraline)等会引起恶心、胃肠道出血、性功能障碍等。
D-环丝氨酸(D-cycloserin;DCS)是一种以商品名Seromycin获批的抗生素物质,并且已知是关于神经系统的NMDA受体的部分激动剂。Seromycin胶囊(其是用作药物的环丝氨酸)经口施用,每天两次。其药物浓度考虑到体重、身体状况、seromycin血清水平等来确定,并且不应超过1,000mg/天。
另一方面,己酮可可碱(pentoxifylline)已知用于循环系统疾病(诸如外周血管疾病)、降低血液粘度和改善血液流动、抗血栓形成作用等,并且其可以用于与中枢神经系统相关的脑循环障碍。己酮可可碱经口施用,每天2-3次,并且一次可以施用约400mg。
已知环丝氨酸和己酮可可碱分别通过不同的机制作用于中枢神经系统,但是尚无联合使用上述药物来治疗抑郁症的已知情形。
发明内容
技术问题
本发明的一个目的是提供根据环丝氨酸和己酮可可碱的联合施用而用于预防或治疗抑郁症的用途。
本发明的另一个目的是提供根据环丝氨酸和己酮可可碱的联合施用而用于改善抑郁症的用途。
技术方案
在本发明中,发明人证实了,当环丝氨酸和己酮可可碱联合施用时,与各自单个施用相比,显著改善了抗抑郁效果。
在一个方面,本发明提供了一种用于预防或治疗抑郁症的药物组合物,所述药物组合物包含:(i)环丝氨酸或其药用盐;和(ii)己酮可可碱或其药用盐作为活性成分。
在药物组合物中,环丝氨酸可以是D-环丝氨酸。
在药物组合物中,(i)环丝氨酸或其药用盐与(ii)己酮可可碱或其药用盐的重量比可以为1:1至1:12,并且具体地1:2至1:8。
药物组合物可以经口施用,并且每种活性成分可以同时施用或在不同时间施用。例如,药物组合物可以是其中每种活性成分同时施用的联合制剂。
在另一个方面,本发明提供了一种用于改善抑郁症的食品组合物,所述食品组合物包含:(i)环丝氨酸或其药用盐;和(ii)己酮可可碱或其药用盐。
有利效果
根据本发明的环丝氨酸和己酮可可碱的联合施用与各自单个施用相比具有优异的抑郁症减轻效果,由此有效地用作抗抑郁药。
附图说明
图1示出了依赖于D-环丝氨酸和己酮可可碱的联合治疗的小鼠强迫游泳测试(FST)的结果。
图2示出了依赖于D-环丝氨酸和己酮可可碱的联合治疗的小鼠悬尾测试(TST)的结果。
具体实施方式
在下文中,将参照附图以本发明的示例性实施方案的形式详细描述本发明。然而,以下示例性实施方案作为本发明的示例呈现,并且在其中确定本领域技术人员熟知的技术或配置的详细描述可能不必要地使本发明的主旨模糊不清的情况下,可以省略其详细描述,并且因此本发明不限于此。本发明可以在所附描述的权利要求的描述内以及由此解释的等效范围内进行各种修改和应用。
另外,本说明书中使用的术语是用于适当地表达本发明的优选实施方案的术语,其可以根据使用者或操作者的意图或者本发明所属领域的习惯等而变化。因此,这些术语的定义应该基于整个本说明书的内容来建立。在整个说明书中,当一个部分“包含”一个组分时,除非另有说明,否则其意指该部分还可以包含其他组分,而不是排除其他组分。
除非另有定义,否则本发明中使用的所有技术术语均以与本发明相关领域中的本领域普通技术人员通常理解的相同含义使用。另外,本说明书中描述了优选的方法或样品,但是与其相似的方法或样品或者它们的等效物均包含在本发明的范围内。在本说明书中通过引用描述的所有出版物的内容都结合到本发明中。
本发明人确认了环丝氨酸和己酮可可碱的联合施用与各自单个施用相比具有显著优异的抗抑郁效果,并且完成了本发明。
在一个方面,本发明提供了一种用于预防或治疗抑郁症的药物组合物,所述药物组合物包含:(i)环丝氨酸或其药用盐;和(ii)己酮可可碱或其药用盐。
在本发明的药物组合物中,环丝氨酸可以是由下式1表示的D-环丝氨酸:
[式1]
在另一个方面,己酮可可碱是属于黄嘌呤衍生物的非选择性PDE抑制剂,并且在机制上区别于属于竞争性PDE抑制剂的药物,例如PDE1抑制剂(例如长春西汀(vinpocetine))、PDE2抑制剂(例如EHNA(赤型-9-(2-羟基-3-壬基)腺嘌呤)、BAY 60-7550(2-[(3,4-二甲氧基苯基)甲基]-7-[(1R)-1-羟乙基]-4-苯基丁基)-5-甲基-咪唑并[5,1-f][1,2,4]三嗪-4(1H)-酮)、羟吲哚、PDP(9-(6-苯基-2-氧代己-3-基)-2-(3,4-二甲氧基苄基)-嘌呤-6-酮)))、PDE3抑制剂(例如阿那格雷(anagrelide,)、西洛他唑(cilostazol)、依诺昔酮(enoximone)、氨力农(inamrinone)、米力农(milinone)、匹莫苯(pimobendan))、PDE4抑制剂(例如阿普斯特(apremilast)、屈他维林(drotaverine)、异丁司特(ibudilast)、木犀草素(luteolin)、日中花碱(mesembrine)、吡拉米司特(piclamilast)、罗氟司特(roflumilast)、咯利普兰(rolipram))、PDE5抑制剂(例如阿伐那非(avanafil)、双嘧达莫(dipyridamole)、淫羊藿苷(icariin)、西地那非(sildenafil)、他达拉非(tadalafil)、乌地那非(udenafil)、伐地那非(vardenafil))、PDE6抑制剂、PDE7抑制剂(例如喹唑啉)、PDE8抑制剂、PDE9抑制剂、PDE10抑制剂(例如罂粟碱(papaverine))、PDE11抑制剂、PDE12抑制剂或它们的组合。
另外,己酮可可碱区别于属于非选择性PDE抑制剂的其他黄嘌呤衍生物,诸如咖啡因、副黄嘌呤(paraxanthine)、可可碱(theobromine)和茶碱(theophylline)。
在本发明的一个示例性实施方案中,证实了D-环丝氨酸和己酮可可碱的联合施用在治疗抑郁症中显示是有效的(图1和2)。
在本发明中,药用盐是指制药工业中常用的盐,并且例如可以包括无机离子诸如钠、钾、钙、镁、锂、铜、锰、锌、铁等的盐,无机酸诸如盐酸、磷酸、硫酸等的盐,并且除此之外,还可以包括有机酸诸如抗坏血酸、柠檬酸、酒石酸、乳酸、马来酸、丙二酸、富马酸、乙醇酸、琥珀酸、丙酸、乙酸、乳清酸、葡糖酸、乙酰水杨酸等的盐,以及氨基酸盐诸如赖氨酸、精氨酸、胍等。另外,药用盐可以包括可以用于药物反应、纯化和分离过程的有机离子诸如四甲基铵、四乙基铵、四丙基铵、四丁基铵、苄基三甲基铵、苯乙铵(benzethonium)等的盐。然而,本发明中所指的盐的类型不限于上面列出的盐。
在本发明中,通过进行强迫游泳测试(FST)和悬尾测试(TST)(它们是以动物模型为对象的抗抑郁功效测试),证实了环丝氨酸和己酮可可碱联合组合物的不动(immobility)减少效果。因此,本发明的联合组合物可以有用地用作预防或治疗抑郁症的组合物。另外,根据FST和TST测试的结果,预期本发明的联合组合物被有用地用作用于焦虑症(例如,恐慌症(panic disorder)、强迫症、创伤后应激障碍、急性应激障碍、疑病症(hypochondriasis)、分离性障碍(dissociative disorder))的治疗剂。
在本发明的一个示例性实施方案中,证实了环丝氨酸和己酮可可碱的联合施用在实验动物中在行为测试诸如强迫游泳测试(FST)、悬尾测试(TST)等中显示出显著优异的结果(图1和2)。因此,本发明的药物组合物可以有效地用于预防或治疗抑郁症或焦虑症。
在本发明的药物组合物中,(i)环丝氨酸或其药用盐与(ii)己酮可可碱或其药用盐的重量比可以为1:1至1:12,并且更具体地1:2至1:8。例如,药物组合物可以在制剂中分别包含50至250mg的环丝氨酸和100至600mg的己酮可可碱,但不限于此。在一个实施方案中,药物组合物可以在制剂中包含100至400mg己酮可可碱/约50mg D-环丝氨酸。
本发明的药物组合物可以以治疗有效量施用。治疗有效量是指发挥有效抗抑郁效果的药物剂量。合适的总日剂量可以由主治医师在适当的医学判断范围内确定。优选的是根据各种因素对特定患者不同地应用特定治疗有效量,这些因素包括要实现的反应的类型和程度、要联合施用的药物的类型和量、使用的特定组合物(是否在某些情况下使用其他制剂)、患者的年龄、体重、一般健康状况、性别和饮食、施用时间、施用途径、治疗持续时间以及医学领域众所周知的类似因素。
本发明的药物组合物可以以一天一次至数次的分剂量施用。例如,环丝氨酸或其药用盐和己酮可可碱或其药用盐可以基于小鼠以这样的剂量施用:约10至120mg/kg(更具体地约20至80mg/kg)己酮可可碱(Pen)/约10mg/kg DCS剂量,证实了在该范围剂量中以上述DCS:Pen重量比,强迫游泳测试(FST)和悬尾测试(TST)的结果得到显著改善(图1和2)。
因此,考虑到本发明中确认的对小鼠施用的最佳剂量、小鼠-人剂量反应关系和未观察到的不良作用水平(NOAEL)等,可以转换为人的优选剂量。剂量转换因子可以利用文献中描述的人体等效剂量(HED)计算方法来表示(参见FDA,US.“Guidance for Industry,Estimating the maximum safe starting dose in initial clinical trials fortherapeutics in adult healthy volunteers(工业指南,估算用于成年健康志愿者中的治疗的初始临床试验中的最大安全起始剂量).”FDA,ed(2005))。上述文献中建议的小鼠-人剂量转换因子为12.3,并且A/12.3(mg/kg)的剂量是通过将在小鼠中确定的药物的剂量(A)除以转换因子而得出的。通常,一个片剂是为体重60kg的成年人制作的。如果将A/12.3(mg/kg)的值乘以60kg,则得出约5×A(mg)的剂量,即人体剂量。因此,参考本发明实施例中确定的D-环丝氨酸和己酮可可碱的最佳小鼠剂量比,可以得出对人施用的优选药物剂量。在一个示例性实施方案中,本发明的联合组合物可以分别包含50至250mg的D-环丝氨酸和100至600mg的己酮可可碱。例如,联合制剂中的D-环丝氨酸和己酮可可碱可以分别为50至100mg和100至400mg。
本发明的药物组合物可以经口施用或肠胃外施用,并且优选地经口施用。另外,本发明的药物组合物可以与一种或多种中枢神经系统药物联合使用。例如,药物组合物可以与另外的药物抗抑郁药、草药抗抑郁药、抗惊厥药、情绪稳定剂、抗精神病药、苯二氮类药物或它们的组合联合使用,以用于有效治疗抑郁症。
本发明的药物组合物可以包括药用载体、赋形剂和/或稀释剂以进行施用。载体、赋形剂和/或稀释剂的实例可以包括但不限于乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。
本发明的药物组合物可以利用本领域熟知的方法制备成药物制剂。在制剂的制备中,活性成分可以与载体混合或用载体稀释,或者封装在载体中(以容器形式)。当本发明的药物组合物制备成用于经口施用的制剂时,例如,药物组合物可以配制成片剂、锭剂、糖锭、水溶性或油性混悬剂、散剂或颗粒剂、乳剂、硬胶囊或软胶囊、糖浆或酏剂。
在一个方面,本发明提供了一种用于预防或治疗抑郁症的方法,所述方法包括向患者施用治疗有效量的(i)环丝氨酸或其药用盐和(ii)己酮可可碱或其药用盐。在另一个方面,本发明提供了(i)环丝氨酸或其药用盐和(ii)己酮可可碱或其药用盐在制备抗抑郁药中的用途。环丝氨酸、己酮可可碱和抑郁症与如上所述的相同。
在一个方面,本发明提供了一种用于预防或治疗抑郁症的组合,所述组合包括:(i)包含环丝氨酸或其药用盐的第一制剂;和(ii)包含己酮可可碱或其药用盐的第二制剂。
在本发明中,术语“组合”是指制剂中的两种或更多种活性物质的组合,以及在治疗中彼此以特定间隔施用的活性物质的单独制剂意义上的组合。因此,当结合本发明描述时,术语“组合”包括两种或更多种治疗有效化合物的共同施用的临床实现。
在本发明的组合中,环丝氨酸可以是D-环丝氨酸。
在本发明的组合中,第一制剂可以包含50至250mg的环丝氨酸或其药用盐,并且第二制剂可以包含100至600mg的己酮可可碱或其药用盐。更具体地,第一制剂可以包含50至100mg的环丝氨酸或其药用盐,并且100至400mg的己酮可可碱。
在本发明的组合中,第一制剂和/或第二制剂可以分别是肠胃外或经口施用的,并且优选地可以是经口施用的。
在本发明的组合中,第一制剂和第二制剂可以同时施用或在不同时间施用。
本发明的组合物可以是药物组合物或食品组合物。当组合物用作食品组合物时,可以直接添加环丝氨酸和己酮可可碱或其药用盐,或者可以与其他食品或食品成分一起使用,并且可以按照常规方法适当使用。除了活性成分之外,组合物还可以包含食品可接受的食品补充添加剂,并且所混合的活性成分的量可以根据使用目的(预防、保健或治疗性治疗)而适当确定。
本发明的食品组合物可以包含保健功能食品。本发明中使用的术语“保健功能食品”是指使用对人体具有有用功能性的原料或成分,以片剂、胶囊、散剂、颗粒剂、液体丸剂等的形式制造和加工的食品。此处,“功能性”是指对人体的结构和功能获得用于保健用途的有用效果诸如控制营养、生理作用等。
另外,对本发明的组合物可以使用的保健食品的类型没有限制。此外,可以通过混合其他合适的佐剂成分和可以包含在保健功能食品中的已知添加剂(取决于本领域技术人员的选择)来制备本发明的包含环丝氨酸和/或己酮可可碱作为活性成分的组合物。可以添加的食品的实例可以包括肉、香肠、面包、巧克力、糖果、零食、糖食、比萨、拉面、其他面条、口香糖、乳制品(包括冰淇淋)、各种汤、饮料、茶、饮品、酒精饮料、维生素复合物等,并且食品可以通过将根据本发明的提取物作为主要组分添加到榨汁、茶、果冻、果汁等中来制备。
在本发明的组合物、治疗方法和用途中描述的所有事项均同等地适用,只要它们彼此不矛盾即可。
本发明将通过以下实施例更详细地进行描述。然而,提供这些实施例仅用于具体体现本发明的内容,并且本发明不限于此。
<实施例1>根据环丝氨酸和己酮可可碱的联合施用的强迫游泳测试(FST)结果
为了测试根据施用本发明的复合组合物的减轻抑郁症的效果,对小鼠进行强迫游泳测试(FST)。FST(其用于测量不可避免地发生的急性应激的应对策略)是一种通常用于测量抗抑郁效果的动物行为实验。
为了证实通过D-环丝氨酸(DCS)和己酮可可碱(Pen)的联合施用来减轻抑郁症的效果,将小鼠的每个组经口施用媒介物(DW 5ml/kg)、DCS(以10mg/kg单独施用)、己酮可可碱(以80mg/kg单独施用)和DCS+己酮可可碱(DCS 10mg/kg和己酮可可碱10、20、80、160mg/kg的联合治疗组)。在施用之后,对小鼠进行测量抑郁症样行为的强迫游泳测试(FST)。
具体地,将每个小鼠组(C57BL/6)分别置于3L Pyrex烧杯(直径为13cm,高度为24cm)中,并且将烧杯用26℃的水填充直至9cm的深度。强迫所有小鼠游泳6分钟,并且在实验的最后4分钟测量不动时间。不动时间被定义为在没有挣扎或仅进行将小鼠的头部保持在水面上方所需的运动的情况下在小鼠漂浮时所用的RNR时间。
作为结果,与施用媒介物的对照组相比,单独施用单一DCS或己酮可可碱的每个组在不动方面没有显示出显著差异,但是在联合施用了DCS和己酮可可碱后一小时内经历FST的组显示出不动的显著降低(图1)。特别地,本发明人已发现,当联合治疗组中的DCS和己酮可可碱的重量比为1:1至1:12(具体地1:2至1:8)时,抗抑郁效果最大化。
<实施例2>根据环丝氨酸和己酮可可碱的联合施用的悬尾测试(TST)结果
为了测试根据施用本发明的复合组合物的减轻抑郁症的效果,使小鼠经历悬尾测试(TST)。TST(其用于测量啮齿动物模型中的应激)是基于实验动物在面对短期、不可逆应激时面临不动姿势的行为。在本发明的技术领域中,TST被用来测量抗抑郁药的效果。
为了确认通过联合施用D-环丝氨酸(DCS)和己酮可可碱(Pen)来减轻抑郁症的效果,将单独的DCS、Pen或复合组合物施用至所有的小鼠组(C57BL6)。对小鼠的每个组施用媒介物(DW 5ml/kg)、DCS(以10mg/kg单独施用)、己酮可可碱(以80mg/kg单独施用)和DCS+己酮可可碱(DCS 10mg/kg和己酮可可碱10、20、80、160mg/kg的联合治疗组)。在1小时后,对小鼠进行测量抑郁症样行为的悬尾测试(TST)。
具体地,准备一个长度为7cm的胶带,并且将一端附接至每个组中的小鼠的尾巴,而将另一端附接至所准备的用于悬挂小鼠的TST工具(宽度为60cm,长度为11.5cm,高度为55cm)的上杆。小鼠一经悬挂就开始实验,并且在实验开始后6分钟测量不动时间。不动时间被定义为小鼠在没有挣扎其腿的情况下所花费的时间量。如果在做了一个大动作之后,腿像秋千一样移动(即使腿没有动),则该时间也包括在内。
作为结果,与施用媒介物的对照组相比,施用单独的DCS或Pen的每个组并未显示出统计显著性,但是在联合施用了DCS和Pen后一小时内经历TST的组显示出不动的显著降低(图2)。特别地,继实施例1之后,本发明人再次确认了当联合治疗组中的DCS和己酮可可碱的重量比为1:1至1:12(具体地1:2至1:8)时,抗抑郁效果最大化。
Claims (8)
1.一种用于预防或治疗抑郁症的药物组合物,所述药物组合物包含:
(i)环丝氨酸或其药用盐;和
(ii)己酮可可碱或其药用盐。
3.根据权利要求1所述的药物组合物,其中(i)所述环丝氨酸或其药用盐与(ii)所述己酮可可碱或其药用盐的重量比为1:1至1:12。
4.根据权利要求3所述的药物组合物,其中(i)所述环丝氨酸或其药用盐与(ii)所述己酮可可碱或其药用盐的重量比为1:2至1:8。
5.根据权利要求1所述的药物组合物,其中所述药物组合物是经口施用的。
6.根据权利要求1所述的药物组合物,其中(i)环丝氨酸或其药用盐和(ii)己酮可可碱或其药用盐是同时施用的或者在不同时间施用的。
7.根据权利要求1所述的药物组合物,其中所述组合物是包含(i)环丝氨酸或其药用盐和(ii)己酮可可碱或其药用盐的联合制剂。
8.一种用于改善抑郁症的食品组合物,所述食品组合物包含:
(i)环丝氨酸或其药用盐;和
(ii)己酮可可碱或其药用盐。
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