CN114786668A - 用于治疗抑郁症的环丝氨酸和锂的组合疗法 - Google Patents
用于治疗抑郁症的环丝氨酸和锂的组合疗法 Download PDFInfo
- Publication number
- CN114786668A CN114786668A CN202080080304.7A CN202080080304A CN114786668A CN 114786668 A CN114786668 A CN 114786668A CN 202080080304 A CN202080080304 A CN 202080080304A CN 114786668 A CN114786668 A CN 114786668A
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- Prior art keywords
- lithium
- cycloserine
- pharmaceutically acceptable
- acceptable salt
- combination
- Prior art date
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Abstract
本发明涉及用于预防或治疗抑郁症的环丝氨酸和锂的组合疗法。与各自单独施用相比,根据本发明的环丝氨酸和锂的组合施用具有非常优异的预防或治疗抑郁症的效果,从而有效地用作用于抗抑郁药的组合疗法。
Description
技术领域
本发明涉及用于治疗抑郁症的环丝氨酸和锂的组合疗法。
背景技术
抑郁症是一种无论客观情况如何都会发生的情绪病理学现象。患者的生活全都被情绪低落、兴趣下降和快感缺失所覆盖,并且受到精神锻炼的匮乏、悲观的感觉和绝望困扰。其因为激发自杀而是一种导致自杀企图的疾病,并且体现为各种身体症状,诸如食欲下降、失眠、便秘、无性欲等。抑郁症最近已经成为一种严重的社会问题。
大部分目前的抗抑郁药具有提高中枢5-羟色胺或去甲肾上腺素突触中的神经递质浓度的药理作用。广泛使用的抗抑郁药可以根据提高神经递质浓度的机理分类为三环抗抑郁药(TCA)、单胺氧化酶抑制剂(MAOI)、选择性5-羟色胺再摄取抑制剂(SSRI)等。虽然这些常规抗抑郁药是相对有效的,但是在一些情况下,可能出现严重的副作用和不满足预期的作用。存在大量的对抗抑郁药响应不佳(Thase等人,2001)、具有高复发率(Frank等人,1991)以及由于严重副作用而不能服用药物(Gumnick和Nemeroff,2000)的患者。TCA诸如丙咪嗪(imipramine)、地昔帕明(desipramine)等具有严重的副作用,诸如低血压、心功能不全等。最广泛使用的SSRI诸如氟西汀(fluoxetine)、舍曲林(sertraline)等引起恶心、胃肠出血、性功能障碍等。
环丝氨酸(D-环丝氨酸;DCS)是一种以商品名Seromycin批准的抗生素物质,并且已知其是关于神经系统的NMDA受体的部分激动剂。Seromycin胶囊(其是作为药物使用的环丝氨酸)每日口服施用两次。其药物浓度考虑体重、医疗状况、seromycin血清水平等来决定,并且不应超过1,000mg/天。
在锂盐中,碳酸锂(Li2CO3)已经被批准用于治疗双相障碍(躁郁症)。已知锂作用于神经元中的Na+/K+ATP酶,改变神经递质的释放,影响cAMP浓度,并且阻止肌醇代谢,由此消耗并且抑制神经元。
如上所述,已知环丝氨酸和锂盐能够分别通过不同的机理作用于中枢神经系统,但是根本不知道组合使用所述药物能够有效地治疗抑郁症。
发明内容
技术问题
本发明的一个目的是提供一种用于治疗抑郁症的环丝氨酸和锂的组合疗法。
问题的解决方案
在本发明中,本发明人首次证实,与各自单独施用相比,当将环丝氨酸和锂组合施用时,显著改善了预防或治疗抑郁症的效果。
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)锂或其药用盐。
在药物组合物中,环丝氨酸可以是D-环丝氨酸,并且锂的药用盐可以是碳酸锂、氯化锂、乙酸锂、硫酸锂、柠檬酸锂、乳清酸锂、葡糖酸锂或它们的组合。
在药物组合物中,(i)环丝氨酸或其药用盐与(ii)锂或其药用盐的重量比可以是10:5至10:1,并且具体地,约2.5:1或约5:1。药物组合物可以分别包含10至50mg的环丝氨酸或其药用盐和2.5至10mg的锂或其药用盐。
在药物组合物中,药物组合物可以是口服施用的。
在另一个方面,本发明提供了一种用于预防或治疗抑郁症的组合,所述组合包含:(i)包含环丝氨酸或其药用盐的第一制备物;和(ii)包含锂或其药用盐的第二制备物。
在组合中,第一制备物和第二制备物可以同时施用或在不同时间施用。另外,组合可以是包含第一制备物和第二制备物的组合制备物,并且具体地可以是口服施用的组合制备物。
在又一个方面,本发明提供了一种用于预防或治疗抑郁症的锂的佐剂药物组合物,所述佐剂药物组合物包含环丝氨酸或其药用盐。
在又一个方面,本发明提供了一种用于预防或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)锂或其药用盐。
发明的有益效果
与各自单独施用相比,根据本发明的环丝氨酸和锂的组合施用具有非常优异的预防或治疗抑郁症的效果,从而有效地用作用于抗抑郁药的治疗疗法或组合制备物。
附图说明
图1示出了根据D-环丝氨酸和锂盐的组合治疗的小鼠中的强迫游泳测试(FST)的结果;以及
图2示出了分别根据D-环丝氨酸、锂盐以及它们的组合治疗的小鼠中的旷场测试(OFT)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实施例提供,并且在确定本领域技术人员众所周知的技术或构造的详细描述可能不必要地使本发明的要点不清楚的情况下,可以省略其详细描述,并且因此本发明不限于此。在下述权利要求的描述之内以及在由此解释的等同范围之内,可以对本发明进行各种改进和应用。
另外,本说明书中使用的术语是用于适当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人员的目的或者本发明所属领域的习惯等而不同。因此,这些术语的定义应当基于在整个本说明书中的内容来确定。在整个本说明书中,当一个部分“包括”一个组分时,除非另外指明,否则这意味着所述部分还可以包括其他组分,而不是排除其他组分。
除非另外定义,否则本发明中使用的所有技术术语以本领域普通技术人员在本发明的相关领域中通常理解的相同含义使用。另外,在本说明书中描述了优选的方法或样品,但是与其类似的那些或其等同物也被包括在本发明的范围内。本说明书中描述的所有出版物的内容都通过引用并入本发明中。
本发明人证实,与各自单独施用相比,根据本发明的环丝氨酸和锂盐的组合施用具有非常优异的治疗抑郁症的效果,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)锂或其药用盐。
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]
锂盐是GSK-3抑制剂系列药物中的一种。除了作为GSK-3抑制剂的锂以外,GSK3抑制剂的实例可以包括:无机原子,诸如锌和钨(包括其药用盐);ATP竞争性抑制剂,诸如靛玉红(indirubin)、6-BIO、海曼辛(hymenialdisine)、二溴坎萨林(dibromocantharelline)、美迪宁(meridianin)、氨基嘧啶、芳基吲哚马来酰亚胺、噻唑、保罗酮(paullone)和阿罗辛(aloisine);非ATP竞争性抑制剂,诸如曼扎明(manzamine)、呋喃并倍半萜烯(furanosesquiterpene)、噻二唑烷二酮(thiadiazolidindione)、卤代甲基酮和L803-mts,等等(参见Eldar-Finkelman,Hagit和Ana Martinez,“GSK-3抑制剂:对CNS的临床前和临床关注(GSK-3inhibitors:preclinical and clinical focus on CNS)”,Frontiers inmolecular neuroscience 4(2011):32)。
然而,甚至对于本发明所属领域的技术人员来说也非常难以预测的是,当上述GSK-3抑制剂的锂盐与环丝氨酸组合施用时,在抑郁症的治疗中显示出累加的治疗效果。然而,本发明人进行了作为GSK-3抑制剂之一的锂或其药用盐与环丝氨酸在小鼠模型中的组合疗法,结果,首次证实了该组合疗法在抑郁症的治疗方面有效,分别与锂盐或环丝氨酸的治疗效果相比,其具有非常优异的效果(图1至2)。
在本发明中,药用盐是指在制药行业中常用的盐,并且例如,可以包括无机离子的盐,诸如钠、钾、钙、镁、锂、铜、锰、锌、铁等的盐,无机酸的盐,诸如盐酸、磷酸、硫酸等的盐,并且除此以外,还可以包括有机酸的盐,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,以及氨基酸的盐,诸如赖氨酸、精氨酸、胍等的盐。另外,药用盐可以包括有机离子的盐,诸如四甲基铵、四乙基铵、四丙基铵、四丁基铵、苄基三甲基铵、苄索铵(benzethonium)等的盐,其可以用于药物反应、纯化和分离过程。然而,本发明中表示的盐的类型不限于以上列出的盐。
例如,锂的优选药用盐可以包括但不限于碳酸锂、氯化锂、乙酸锂、硫酸锂、柠檬酸锂、乳清酸锂和葡糖酸锂。
在本发明的一个示例性实施方案中,证实了环丝氨酸和锂盐的组合施用在实验动物的行为测试诸如强迫游泳测试(FST)等中显示出非常优异的结果(图1至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。抑郁症可以是单次发作或复发的重度抑郁症,或者伴有恐惧症的焦虑症或抑郁症,或者躁郁症,诸如I型双相障碍、II型双相障碍或循环障碍。
在本发明的药物组合物中,(i)环丝氨酸或其药用盐与(ii)锂或其药用盐的重量比可以是10:5至10:1,并且具体地,约2.5:1或约5:1。药物组合物可以分别包含10至50mg的环丝氨酸或其药用盐和2.5至10mg的锂或其药用盐。在一个示例性实施方案中,药物组合物可以包含10至50mg的D-环丝氨酸和2.5至10mg的碳酸锂。具体地,药物组合物可以包含12.5至25mg的D-环丝氨酸/5mg碳酸锂。本发明人证实,当环丝氨酸和锂盐以上述重量比组合施用时,组合疗法在治疗抑郁症方面特别有效(图1至2)。
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预防或治疗抑郁症的实际效果的药物剂量。合适的总每日剂量可以由主治医师在合适的医疗判断范围内确定。优选的是根据各种因素对于特定患者不同地应用特定的治疗有效量,所述因素包括要实现的反应的类型和程度,要组合施用的药物的类型和用量,在一些情况下是否使用其他制备物所使用的特定组成,患者的年龄、体重、总体健康状态、性别和饮食,施用时间,施用途径,治疗持续时间,以及医疗领域中众所周知的类似因素。
本发明的药物组合物可以每天一次至数次地分次施用。例如,环丝氨酸或其药用盐和锂或其药用盐可以基于小鼠分别以0.2至50mg/kg和0.1至100mg/kg的剂量施用,并且具体地,相对于1mg/kg的锂或其药用盐,可以施用2至7.5mg/kg的环丝氨酸或其药用盐。
在本发明的实施例中证实,作为将环丝氨酸和锂盐以各种剂量范围施用至实验动物(例如,小鼠)的结果,在组合施用约2.5mg/kg或5mg/kg的D-环丝氨酸和约1mg/kg的碳酸锂的组中,强迫游泳测试(FST)结果得到显著改善(图1)。
因此,可以考虑在本发明中证实的向小鼠施用的最佳剂量、小鼠-人剂量响应关系和无可见不良作用水平(NOAEL)等换算人中的优选剂量。剂量换算因数可以通过使用文献中描述的人等效剂量(HED)计算法表示(参见FDA,US.“行业指南,估计成年健康志愿者的初始临床试验中的最大安全起始剂量(Guidance for Industry,Estimating the maximumsafe starting dose in initial clinical trials for therapeutics in adulthealthy volunteers)”,FDA编辑(2005))。上述文献中提出的小鼠-人剂量换算因数为12.3,并且通过将在小鼠中确定的药物的剂量(A)除以换算因数得到A/12.3(mg/kg)的剂量。通常,为体重60kg的成人制备一片药片。如果将A/12.3(mg/kg)的值乘以60kg,则得到约5×A(mg)的剂量,其是人的剂量。因此,参照在本发明的实施例中确定的D-环丝氨酸和碳酸锂的最佳小鼠剂量比,可以得到向人施用的优选药物剂量。
因此,本发明的药物组合物中包含的D-环丝氨酸和碳酸锂的剂量分别优选为10至50mg和2.5至10mg,并且更优选地,施用12.5至25mg的D-环丝氨酸/5mg碳酸锂。本发明人还证实,与D-环丝氨酸和碳酸锂的剂量组高于上述范围的情况相比,治疗抑郁症的效果在上述范围内最大化。这首次证实了当以比用于D-环丝氨酸或碳酸锂的单一制备物的剂量低得多的剂量组合施用D-环丝氨酸和碳酸锂时,治疗抑郁症的效果得到改善。
本发明的药物组合物可以口服施用或胃肠外施用,并且优选口服施用。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组合使用。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、心境稳定剂、抗精神病药、苯二氮类药物或它们的组合组合用于抑郁症的有效治疗。
本发明的药物组合物可以包含药用载体、赋形剂和/或稀释剂以用于施用。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、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、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使用本领域众所周知的方法制备成药物制剂。在制剂的制备中,可以将活性成分与载体混合或用载体稀释,或者包封在容器形式的载体中。当本发明的药物组合物被制备成用于口服施用的制剂时,例如,药物组合物可以被配制为片剂、糖锭、锭剂、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,所述方法包括将治疗有效量的(i)环丝氨酸或其药用盐和(ii)锂或其药用盐施用至患者。在另一个方面,本发明提供了(i)环丝氨酸或其药用盐和(ii)锂或其药用盐在制备用于预防或治疗抑郁症的药物中的用途。环丝氨酸、锂、盐等与上述相同。
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,所述组合包含:(i)包含环丝氨酸或其药用盐的第一制备物;和(ii)包含锂或其药用盐的第二制备物。
在本发明中,术语“组合”是指两种以上活性物质在制剂中的组合以及在治疗中彼此以指定间隔施用的活性物质的单独制剂的意义上的组合。因此,当关于本发明进行描述时,术语“组合”包括两种以上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,并且可以具体地选择碳酸锂作为锂的药用盐。
在本发明的组合中,第一制备物中的环丝氨酸或其药用盐的剂量和第二制备物中的锂或其药用盐的剂量可以分别是10至50mg和2.5至10mg,并且更优选地,施用12.5至25mg的D-环丝氨酸/5mg碳酸锂。在本发明的组合中,第一制备物和/或第二制备物可以分别胃肠外施用或口服施用,并且优选地可以口服施用。
在本发明的组合中,第一制备物和第二制备物可以同时施用或在不同时间施用。
本发明的组合可以是包含第一制备物和第二制备物的组合制备物,并且具体地可以是口服施用的组合制备物。
在本发明的组合中,第一制备物中包含的环丝氨酸或其药用盐与第二制备物中包含的锂或其药用盐的重量比可以是10:5至10:1,并且具体地,约2.5:1或约5:1。在此情况下,第一制备物中包含的环丝氨酸或其药用盐的剂量和第二制备物中包含的锂或其药用盐的剂量可以分别是10至50mg和2.5至10mg,并且更优选地,施用12.5至25mg的D-环丝氨酸/5mg碳酸锂。
在一个方面,本发明提供了一种用于预防或治疗抑郁症的锂的佐剂药物组合物,所述佐剂药物组合物包含环丝氨酸或其药用盐。
在本发明中,术语“佐剂”是指其中虽然作为辅剂单独施用的药物的预防或治疗效果相对较低,但是当与其他中枢神经系统药物组合施用时,预防或治疗抑郁症的效果得到显著改善的用途。
在组合物中,环丝氨酸可以是D-环丝氨酸,并且可以具体地选择碳酸锂作为锂的药用盐。
在用于预防或治疗抑郁症的锂的佐剂药物组合物中,环丝氨酸或其药用盐的重量可以是用于预防或治疗抑郁症的锂或其药用盐的重量的2至10倍,或2.25至7.5倍,并且具体地,约2.5倍、5倍或7.5倍。在此情况下,用于预防或治疗抑郁症的锂的佐剂药物组合物中包含的环丝氨酸或其药用盐可以具有约10至50mg的重量,这可以将用于预防或治疗抑郁症的锂或其药用盐的重量减少至约2.5至10mg。
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,环丝氨酸和锂或其药用盐可以原样加入,或可以与其他食品或食品成分一起使用,并且可以根据常规方法适当地使用。除了活性成分以外,组合物还可以包含食品可接受的食品补充添加剂,并且活性成分的混入量可以根据使用目的(预防、保健或治疗)适当地确定。
本发明的食品组合物可以包括保健功能食品。本发明中使用的术语“保健功能食品”是指使用具有对人体有用的功能的原料或成分以片剂、胶囊、散剂、颗粒剂、液体丸剂等形式制造和加工的食品。此处,术语“功能”是指获得对保健用途有用的效果,诸如调控营养物、对人体的结构和功能的生理作用等。
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,本发明的包含环丝氨酸和/或锂作为活性成分的组合物可以通过根据本领域技术人员的选择将其他合适的佐剂成分和保健功能食品中可以含有的已知添加剂混合来制备。可以加入的食品的实例可以包括肉类、香肠、面包、巧克力、糖果、零食、糕点、比萨饼、拉面、其他面条、口香糖、乳制品(包括冰淇淋)、各种汤类、饮料、茶、饮品、酒精饮料、复合维生素等,并且食品可以通过将根据本发明的提取物作为主要组分加入到榨出的果汁、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物同样适用,只要它们彼此不矛盾即可。
将通过以下实施例更详细地描述本发明。然而,这些实施例仅提供用于具体表现本发明的内容,并且本发明不限于此。
<实施例1>根据环丝氨酸和锂的组合施用的强迫游泳测试(FST)结果
为了测试根据本发明的药物组合物的施用的减轻抑郁症的效果,对小鼠进行强迫游泳测试(FST)。为了衡量对不可避免地发生的急性应激的应对策略的FST是常用于衡量抗抑郁药效果的动物行为实验。
为了证实通过D-环丝氨酸(DCS)和锂的组合施用减轻抑郁症的效果,将10ml/kg的制备物施用至所有小鼠组(C57BL6)。对各组小鼠进行施用:载剂(DW,对照组,n=22),DCS2.5(DCS 2.5mg/kg,单一治疗组,n=6),DCS 5(DCS 5mg/kg,单一治疗组,n=6),Li2CO3 1(Li2CO3 1mg/kg,单一治疗组,n=6),DCS 1+Li2CO3 1(DCS 1mg/kg和Li2CO3 1mg/kg,组合治疗组,n=13),DCS 2.5+Li2CO3 1(DCS 2.5mg/kg和Li2CO3 1mg/kg,组合治疗组,n=14),DCS5+Li2CO3 1(DCS 5mg/kg和Li2CO3 1mg/kg,组合治疗组,n=14),DCS 10+Li2CO3 1(DCS10mg/kg和Li2CO3 1mg/kg,组合治疗组,n=14)。在1小时后,对小鼠进行衡量抑郁症样行为的强迫游泳测试(FST)。
具体地,将各组小鼠分别置于3L Pyrex烧杯(直径13cm,高24cm)中,并且将烧杯用27.5±1.5℃的水灌至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。不动时间定义为小鼠在不挣扎的情况下漂浮或者仅进行为了保持小鼠头部高于水面所需的运动时所花费的RNR时间。
结果,与用载体施用的对照组相比,用DCS或Li2CO3单独施用的各组未显示出统计显著性,而在用DCS和LiCl组合施用后一小时内进行FST的组显示出不动的明显减少(图1和2)。另外,显示出甚至在组合施用DCS和Li2CO3后一周,不动仍明显减少(图1)。
另外,作为旷场测试的结果,证实了其不影响动物的活动,诸如实验中小鼠在预定时间段(15分钟)内移动的距离(图2)。这证明了在FST实验结果中证实的以特定比率组合施用的组的不动时间减少不是由相应组的活动增加造成的。
上述结果表明,环丝氨酸和锂的组合施用可以作为抗抑郁药有效地用作用于预防或治疗抑郁症效果的组合疗法。
Claims (15)
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)锂或其药用盐。
3.根据权利要求1所述的药物组合物,其中锂的药用盐是碳酸锂。
4.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)所述锂或其药用盐的重量比为10:5至10:1。
5.根据权利要求4所述的药物组合物,其中将(i)10至50mg的所述环丝氨酸或其药用盐和(ii)2.5至10mg的所述锂或其药用盐施用至人。
6.根据权利要求5所述的药物组合物,其中将12.5至25mg的D-环丝氨酸/5mg碳酸锂施用至人。
7.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口服施用的。
8.一种用于预防或治疗抑郁症的组合,所述组合包含:
(i)包含环丝氨酸或其药用盐的第一制备物;和
(ii)包含锂或其药用盐的第二制备物。
9.根据权利要求8所述的组合,其中所述第一制备物和所述第二制备物同时施用或在不同时间施用。
10.根据权利要求8所述的组合,其中所述组合是包含所述第一制备物和所述第二制备物的组合制备物。
11.根据权利要求10所述的组合,其中所述组合是口服施用的组合制备物。
12.一种用于预防或治疗抑郁症的锂的佐剂药物组合物,所述佐剂药物组合物包含环丝氨酸或其药用盐。
13.一种用于预防或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)锂或其药用盐。
14.一种用于预防或治疗抑郁症的方法,所述方法包括将治疗有效量的(i)环丝氨酸或其药用盐和(ii)锂或其药用盐施用至患者。
15.(i)环丝氨酸或其药用盐和(ii)锂或其药用盐的组合在制备用于预防或治疗抑郁症的药物中的用途。
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