CN109803547A - 含有脱辅基水母素和维生素d的组合物及其使用方法 - Google Patents
含有脱辅基水母素和维生素d的组合物及其使用方法 Download PDFInfo
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- CN109803547A CN109803547A CN201780059049.6A CN201780059049A CN109803547A CN 109803547 A CN109803547 A CN 109803547A CN 201780059049 A CN201780059049 A CN 201780059049A CN 109803547 A CN109803547 A CN 109803547A
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Abstract
本发明提供了含有脱辅基水母素和维生素D的组合物及其用于治疗与钙失衡和维生素D缺乏相关的症状和病症的方法,这些症状和病症涉及例如睡眠质量、精力质量、情绪质量、记忆质量或疼痛。
Description
相关申请的交叉引用
本申请要求2016年9月23日提交的美国临时申请62/398,669的权益,其在此完整引入以供所有目的。
关于联邦资助研究或开发的声明
无。
技术领域
本发明一般涉及用于维持钙平衡的组合物。特别是,本发明涉及含有脱辅基水母素和维生素D的组合物,用于预防和/或减轻与钙失衡和维生素D缺乏相关的疾病或症状。
背景技术
钙是人体第五大富含元素,主要存在于骨中。体内99%以上的钙储存于骨骼中,其与溶于体液和软组织例如血液的剩余1%钙稳定交换。该交换的控制主要由内分泌***指导,其感知血浆中离子化钙的浓度并指导钙交换以维持该关键平衡。组织间隙液和软组织中1%的钙中仅一小部分是离子化和可溶性的。体液和组织中剩下的钙与蛋白质,尤其是钙结合蛋白(CaBP)相结合。已知CaBP的作用是维持钙平衡。
由于身体需要特定的钙离子浓度来进行必要的生理过程,钙平衡的维持对于身体健康至关重要。医疗界理解血浆和体液中恰当的钙浓度对于身体功能是关键的,包括但不限于神经元兴奋性、肌肉收缩、膜渗透性、细胞***、激素分泌和骨矿物化。钙平衡的打破,即钙失衡与许多疾病、综合征和病况相关,包括但不限于癌症、心脏病和神经退行性疾病。
过去,钙通道拮抗剂(其封闭细胞内部和组织间隙液之间的钙流动)被广泛用作药物制剂,用于预防钙相关病症,包括高血压、绞痛、哮喘、偏头痛和神经功能恶化。例如,发现尼嘧地平(nimidopine)能通过减少导致神经恶变的钙失衡而改善痴呆中的症状学和认知功能。然而,许多这些钙通道拮抗剂有不良副作用,包括但不限于不适、液体潴留、胃灼热、心律不齐、头晕、胃不适,且在极少情况下导致昏迷、发热和过度出血。
尽管有这些进展,仍然需要能减轻或预防钙失衡的新替代治疗。特别是,需要与先前药物相比副作用减少的药物或营养组合物,如果被发现,它们能满足医学和营养健康界经久以来的需要。
发明概述
本发明提供了有利于减轻和/或预防与钙失衡和维生素D缺乏相关的症状或疾病的组合物。这些组合物包括脱辅基水母素和维生素D联合可接受的载体,通过各种途径施给对象。
因此,本发明涉及含有有效量的脱辅基水母素和维生素D,联合可接受运载体的组合物。在一些实施方式中,本发明涉及包括有效量的脱辅基水母素和维生素D,联合可接受运载体的营养组合物。在一些实施方式中,营养组合物除了脱辅基水母素和维生素D包括至少一种其他被认为提供营养益处的成分,例如免疫增强剂、抗炎剂、抗氧化剂、抗病毒剂或其混合物。在一些实施方式中,脱辅基水母素和维生素D组合物以单位剂型提供,选自片剂、胶囊、溶液、悬液、糖浆、饮料、口服或眼科制剂或注射剂。
在另一个方面,本发明涉及一种治疗与钙失衡和维生素D缺乏有关的症状或病症的方法,包括对需要这种治疗的对象施用有效量的脱辅基水母素和维生素D。
本发明的方法用于治疗各种与钙失衡和维生素D缺乏相关的症状或病症,包括但不限于睡眠质量、精力质量、情绪质量、疼痛和记忆质量。在一些实施方式中,钙失衡和维生素D缺乏与神经元兴奋性、肌肉收缩、膜渗透性、细胞***、激素分泌、骨矿物化、或缺血后的细胞死亡生理上相关。在这些方法中,脱辅基水母素和维生素D优选以营养组合物形式施予对象。
在另一个实施方式中,本发明包括脱辅基水母素和维生素D制备营养组合物的用途,用于在施用所述营养组合物的对象内治疗与钙失衡和维生素D缺乏相关的症状或病症。用这些组合物治疗的示范性症状或病症包括与睡眠、精力、情绪、疼痛或记忆相关的那些。
因此,本发明还包括用脱辅基水母素和维生素D治疗对象内与钙失衡和维生素D缺乏相关的症状或病症,包括与对象内例如睡眠、精力、情绪、疼痛或记忆相关的那些症状或病症。
本发明提供了各种相较于现有组合物和方法的优点,其中对对象的心理和生理健康提供了整体改善。
在阅读了说明书和权利要求后,本发明的其他目标、特征和优势是显而易见的。
附图说明
图1提供了一张图表,显示对于第0日到第90日,评分从基线开始的改变百分数,来自以下方面:睡眠、精力、情绪、疼痛和整体健康的综合质量。
图2描述了一张图表,显示56个参与者每天摄取脱辅基水母素(10mg)的数据。参与者的评估从第8天开始到第30天。记忆研究在30天后显示统计学显著的改善(hp<0.05)。57%的参与者有整体记忆改善,51%有记忆保留改善,84%有记住驾驶方向的改善,66%有单词回忆改善。N=56;66%女性,34%男性,平均年龄=56岁;范围为20-78岁。
图3显示了来自标准化认知功能检查表的评分从第0日到第90日的相对基线水平的改善百分数。
图4描述了AQ(脱辅基水母素)和维生素D在大鼠下丘脑切片中的神经保护作用。
发明详述
I.概述
在描述本发明的材料和方法前,应理解本发明不限于特定方法和所述材料,其可以变化。还应理解,本文所用术语的目的仅是描述具体实施方式,不应用来限制本发明的范围,本发明的范围仅受所附权利要求书的限制。
必须注意到,本文和所附权利要求书所用的单数形式“一个”、“一种”和“所述”包括复数含义,除非上下文另有明确说明。同样,术语“一个”(或“一种”)、“一个或多个”和“至少一个”在本文中可互换使用。还应当注意,术语“包括”、“包含”、和“具有”可以互换使用。
除非另外定义,否则,本文中所使用的所有技术和科学术语都具有本发明所属领域普通技术人员通常所理解的同样含义。虽然可采用与本文所述类似或等同的任何方法和材料实施或测试本发明,但在此描述的是优选的方法和材料。本文特别提到的全部出版物和专利都在此出于所有目的引入以供参考。
II.发明
水母素是最初从发光水母和其他海洋生物中分离得到的光蛋白。水母素复合物包括22,285道尔顿的脱辅基水母素蛋白,分子氧和发光体腔肠素。当3个Ca2离子与该复合物结合时,腔肠素被氧化成腔肠酰胺(coelentermide),伴随释放二氧化碳和蓝光。水母素不由细胞输出或分泌,也不在细胞内区室化或螯合。因此,已用水母素测定来检测相当长期的Ca2变化。在一些实验***中,水母素的发光能在细胞上样后的许多小时乃至许多天内被检测。还已知水母素并不破坏细胞功能或胚胎发育。
由于其Ca2依赖性发光,水母素复合物被广泛用作胞内Ca2指征。维多利亚多管发光水母(Aequorea victoria)水母素已被特别用于:(1)分析单个肾上腺嗜铬细胞对烟碱胆碱激动剂的分泌反应;(2)澄清Ca2释放在心肌损伤中的作用;(3)证明授精过程中的Ca2大量释放;(4)研究发育中的鸡成肌细胞中肌浆网C2泵表达调控;和(5)校准注射体积小到3皮升的微量滴定管。
脱辅基水母素的分子量约为22kDa。通过还原脱辅基水母素中的二硫键,可用脱辅基水母素产生水母素。负荷钙的脱辅基水母素维持作为含有结合底物的未反应光蛋白的相同紧凑骨架和总体折叠模式。
从维多利亚多管水母常规纯化水母素需要费力的提取过程,有时会得到十分混杂或对经研究的生物体有毒的制备物。两吨水母通常产生约125mg的纯化光蛋白。相反,优选通过纯化来自基因改造的大肠杆菌的脱辅基水母素,然后体外重新与纯腔肠素构建水母素复合物来制备重组水母素。已经描述了本发明所用的脱辅基水母素,且本领域技术人员能通过已知的纯化方案和/或合成法商业获得它。S.Inouye,S.Zenno,Y.Sakaki,和F.Tsuji.脱辅基水母塑的高水平表达和纯化(High level expression and Purification ofapoaequorin).(199 1)Protein Expression and Purification 2,122-126。
维生素D是一组脂溶性甾醇,其负责引起钙、铁、镁、磷和锌的肠道吸收。身体通过皮肤接触来自阳光的紫外线反应产生维生素D。其还被发现存在于天然食物例如鱼、鱼肝油、蛋白,以及增强乳和谷物制品中。在饮食补剂中,维生素D的两种最常见的化合物形式是维生素D3(胆钙化醇)和维生素D2(麦角钙化醇)。
维生素D是脂溶性维生素,其是生物学惰性的,必需在体内经历两次羟化才能活化。第一次羟化发生在肝脏内,将维生素D转化为25-羟基维生素[25(OH)D],也称作骨化二醇。第二次羟化主要在肾脏内,形成生理活性的1,25-二羟基维生素D[1,25(OH)2D],也称作骨化三醇。维生素D的活性形式骨化三醇作为激素在血液中循环,调节血液流中的钙和磷浓度,促进骨骼的健康生长和重建。
维生素D促进钙吸收,维持恰当的血清钙和磷浓度,实现正常的骨矿物化,预防低血钙性抽搐。其也被成骨细胞和破骨细胞用于骨骼生长和骨骼重建。也已显示它在细胞生长、神经肌肉和免疫功能的调节和减少炎症中起作用。
本发明涉及对对象施用含脱辅基水母素和维生素D的组合物,以纠正或维持对象内的钙平衡和维生素D水平。维生素D缺乏可引起钙失衡。应理解,血浆和体液中离子钙浓度的维持对于许多身体功能是关键的,包括但不限于神经元兴奋性、肌肉收缩、膜渗透性、细胞***、激素分泌、骨矿物化,或预防缺血后的细胞死亡。钙平衡的破坏,即钙失衡理解为导致和/或牵涉到许多疾病、综合征和病况。这些疾病、综合征和病况包括与睡眠质量、精力质量、情绪质量和记忆质量以及疼痛感知相关的那些。CaBP的研究认识到,它们在维持恰当的离子钙水平中起到保护因子作用。
理解维生素D水平的维持对于钙吸收,细胞生长、神经肌肉和免疫功能的调节,以及炎症减轻是关键的。维生素D缺乏通常与佝偻病相关,这是一种骨组织不能正确矿物化,导致骨柔软和骨骼变形的疾病。医学院指南提供了维生素D的推荐膳食供给量(RDA)是对于1-70岁的成人600国际单位(IU),对于大于70岁的成人800IU以优化骨骼健康。
在一些实施方式中,本发明的方法包括联合施用脱辅基水母素和维生素D,以治疗钙失衡,延缓钙失衡的进程,预防钙失衡的发生,预防和/或治疗钙失衡复发以及治疗维生素D缺乏。在其他实施方式中,本发明提供了方法,包括施用脱辅基水母素和微生物D,联合一种或多种其他具有已知治疗或营养价值的药物。脱辅基水母素和维生素D的特别优选的应用是治疗一种或多种与睡眠、精力、情绪和记忆质量以及疼痛感知有关的症状和疾病。
本文所用术语“治疗”包括预防性以及失调缓解性治疗。本文所用的术语“减少”、“减轻”、“阻抑”和“抑制”具有其通常理解上的减少或减轻的意义。本文所用术语“发展”表示范围或严重程度的增加、前进、生长或恶化。本文所用术语“复发”表示疾病在缓解后重新发生。
本文所用的术语“施用”指使得病人、组织、器官或细胞与脱辅基水母素和维生素D接触。本文所用的施用可以在体外,即在试管中;或在体内,即在活生物体例如人的细胞或组织中实现。在优选的实施方式中,本发明包括向患者或对象给予本发明中有用的组合物。本文等价使用的“病人”或“对象”指哺乳动物,优选是人,其:(1)具有钙失衡相关病症和/或维生素D缺乏,可通过施用脱辅基水母素和维生素D医治或治疗;或(2)对钙失衡相关疾病和/或维生素D缺乏敏感,可通过施用脱辅基水母素和维生素D预防。
本文所用术语“有效量”和“治疗有效量”指足以产生所需治疗响应而没有过度不良副作用(如毒性、刺激性或过敏性响应)的活性试剂的量。显然,具体的“有效量”将随着所治疗的特定病症,患者的身体状况,被治疗的动物的类型,治疗的持续时间,并行治疗的性质(如果有的话)以及所用的具体制剂和化合物或其衍生物的结构等因素而不同。在这种情况下,如果导致以下一种或多种情况,该量被认为是治疗有效的:(1)预防钙失衡相关疾病和/或维生素D缺乏;和(2)逆转或稳定钙失衡相关疾病和/或维生素D缺乏。本领域普通技术人员使用常规实验可以容易地确定最佳有效量。
在一些对对象口服给药的组合物中,脱辅基水母素与至少一种可接受运载体以约10-50mg/剂的形式配制成优选胶囊形式的剂量,对于对象的推荐剂量是约20mg/天。在对对象口服给药的一些优选组合物中,维生素D(以D3胆钙化醇的形式)与脱辅基水母素联合配制,其剂量是约25-75mcg/剂,对对象的推荐剂量是约50mcg/天。
本发明的组合物包括液体或冻干或其他干燥的制剂,包括各种缓冲内含物(例如Tris-Hcl、乙酸盐、磷酸盐)的稀释剂,pH和离子强度,添加剂例如白蛋白或明胶,以防止吸附到表面,去污剂(例如Tween20、Tween80、Pluronic F68、胆酸盐),增溶剂(例如甘油、聚乙二醇),抗氧化剂(例如抗坏血酸、偏亚硫酸氢钠),防腐剂(例如硫柳汞,苯甲醇,对羟基苯甲酸酯),膨胀物质或张力调节剂(例如乳糖,甘露糖醇),聚合物例如聚乙二醇对蛋白质的共价附着,与金属离子的络合,或物质掺入到聚合物化合物(例如聚乳酸、聚乙醇酸、或水凝胶)的颗粒制剂内或上,或脂质体、微乳液、层状结构或多层微囊、血影或原生质球上。这些组合物将影响生理状态、溶解度、稳定性、体内释放速率和体内清除速率。受控或持续释放组合物包括亲脂储库(例如脂肪酸、蜡、油)中的制剂。
本发明还包括施用有聚合物(例如泊洛沙姆或泊洛沙胺)包裹的颗粒组合物的方法。组合物的其他实施方式包括颗粒形式的保护包衣,蛋白酶抑制剂或渗透增强剂,用于各种给药途径,包括胃肠外、肺内、鼻内和口腔。在一些实施方式中,组合物通过胃肠外、胃粘膜、经粘膜、肌肉内、静脉内、皮内、皮下、腹膜内、心室内、颅内或肿瘤内给药。
此外,本文所用的“药学上可接受的运载体”对于本领域技术人员是熟知的,包括但不限于0.0141M和优选0.05M的磷酸缓冲液或0.9%盐水。另外,这些药学上可接受的运载体可以是水性或非水性溶液、悬液和乳液。非水性溶剂的示例是丙二醇,聚乙二醇,植物油如橄榄油,和可注射的有机酯如油酸乙酯。水性运载体包括水、醇溶液/水溶液、乳液或悬液,包括盐水和缓冲介质。
肠胃外载剂包括氯化钠溶液,林格氏右旋糖,右旋糖和氯化钠,乳酸林格氏液和不挥发油。静脉内载体包括流体和营养补充剂、电解质补充剂如基于林格氏右旋糖的那些,等。也可以存在防腐剂和其他添加剂,例如抗菌剂,抗氧化剂,调整剂(collating agent),惰性气体等。
可根据本发明给药的受控或持续释放组合物包括亲脂储库(例如脂肪酸、蜡、油)中的制剂。本发明还包括颗粒组合物,其被聚合物(例如泊洛沙姆或泊洛沙胺)包裹,以及与针对组织特异性受体,配体或抗原的抗体偶联,或与组织特异性受体的配体偶联的化合物。
根据本发明给药的其他组合物的实施方式包括颗粒形式的保护包衣,蛋白酶抑制剂或渗透增强剂,用于各种给药途径,包括腹膜内、肺内、鼻内、眼科和口腔。
已知通过水溶性聚合物(例如聚乙二醇、聚乙二醇和聚丙二醇的共聚物、羧甲基纤维素、糊精、聚乙烯醇、聚乙烯吡咯烷醇或聚脯氨酸)的共价结合改性的化学实体在静脉注射后,显示相比相应的未经修饰的化合物显著更长的血液半衰期。这样的修饰还可提高化学实体在水性溶液中的溶解度,减少聚集,增强化合物的物理和化学稳定性,并大大减少化合物的免疫原性和反应性。结果,可通过相较于未经修饰实体,以较低频率和较低剂量施用这样的聚合物-实体加合物,实现理想的体内生物活性。
在本发明的另一个方法中,组合物可通过控释***传递。例如,药物可通过静脉输注、可移植等渗泵、透皮贴片、脂质体、或其他给药形式给药。在一个实施方式中,可使用泵。在另一个实施方式中,可以使用聚合物材料。在另一个实施方式中,可将控释***置于治疗目标,即大脑附近,因此仅需要全身剂量的一部分。
组合物可包含脱辅基水母素和维生素D,或可进一步包括药学可接受的运载体,可以是固体或液体形式,例如片剂、粉末、胶囊、丸剂、溶液、悬液、酏剂、糖浆、饮料、乳液、凝胶、乳膏、眼科制剂、或栓剂,包括直肠和尿道栓剂。药学上可接受的运载体还包括树胶、淀粉、糖、纤维素材料及其混合物。含有脱辅基水母素和维生素D的组合物可通过例如丸剂的皮下移植施给病人。在另一个实施方式中,提供丸剂用于在一段时间内受控释放脱辅基水母素和/或维生素D。还可通过静脉内、动脉内、肌肉内注射液体,口腔施用液体或固体,或通过局部给药施用组合物。还可通过使用直肠栓剂或尿道栓剂实现给药。
本发明可施用的组合可通过已知的溶解、混合、造粒或制片技术制备。对于口腔给药,脱辅基水母素或其生理上耐受的衍生物例如盐、酯、N-氧化物等和/或维生素D或其生理上耐受的衍生物例如盐、酯、N-氧化物等与为此目的习惯的添加剂混合,例如载剂、稳定剂或惰性载体,并通过习惯的方法转化成适合的给药形式,例如片剂、包衣片剂、硬或软明胶胶囊、水性、醇性或油性溶液。
合适的惰性载剂的例子是常规的片剂基底,例如乳糖、蔗糖或玉米淀粉,联合粘合剂例如***胶、玉米淀粉、明胶,以及崩解剂例如玉米淀粉、马铃薯淀粉、海藻酸,或润滑剂例如硬脂酸或硬脂酸镁。
合适的油性载剂或溶剂的例子是植物或动物油,例如葵花籽油或鱼肝油。组合物可同时作为干和湿颗粒起效。对于胃肠外给药(皮下、静脉内、动脉内、或肌肉内注射),化学实体或其生理上耐受的衍生物例如盐、酯、N-氧化物等如所需,与对于该目的习惯或适于该目的的物质(例如增溶剂或其他助剂)一起转化成溶液、悬液或排出物。
例子是无菌液体例如水和油,加入或不加入表面活性剂和其他药学上可接受的佐剂。油的例子是石油、动物、植物或合成来源的油,例如花生油、大豆油或矿物油。一般水、盐水、水性葡萄糖和相关的糖溶液,以及甘醇如丙二醇或聚乙二醇是优选的液体运载体,特别对于可注射溶液而言。
含有活性成分的组合物的制备是本领域熟知的。这些组合物可制备成传递到鼻咽的气溶胶,或作为可注射剂,例如液体溶剂或悬液;然而也可制成适合在注射前溶于或悬于液体的固体形式。也可将该组合物乳化。活性治疗成分通常与赋形剂混合,后者是药学上可接受的,并与活性成分相容。合适的赋形剂包括例如水、盐水、葡萄糖、甘油、乙醇等或其任何组合。另外,组合物可含有少量辅助物质,例如湿润或乳化剂,pH缓冲剂,以增强活性组分的效力。
活性成分可作为中和的药学上可接受的盐形式配制在组合物中。药学上可接受的盐包括酸加成盐,其用无机酸(例如盐酸或磷酸)或有机酸(例如乙酸、草酸、酒石酸、扁桃酸等)形成。用游离羧基形成的盐还可源自无机碱例如钠、钾、铵、钙、或铁的氢氧化物,和有机碱例如异丙胺、三甲胺、2-乙基氨基乙醇、组氨酸、普鲁卡因等。
对于体表外用,使用例如软膏、凝胶、滴剂等,将脱辅基水母素或其生理上耐受的衍生物和/或维生素D或其生理上耐受的衍生物与生理学可接受的稀释剂,加入或不加入药学运载体以溶液、悬液或乳液制备或施用。
在本发明的另一个方法中,可在囊泡,例如脂质体中传递活性成分(见Langer,Science 249:1527-1533(1990);Treat等,《感染性疾病和癌症治疗中的脂质体》(Liposomes in the Therapy of Infectious Disease and Cancer),Lopez-Berestein和Fidler(编),Liss,N.Y.,第353-365页(1989))。
脱辅基水母素和/或维生素D的盐是优选的药学上可接受的盐。然而,其他盐也可用于制备本发明的组合物或其药学上可接受的盐。合适的药学上可接受的盐包括酸加成盐,其可通过例如混合脱辅基水母素和/或维生素D的溶液与药学上可接受的酸溶液混合来形成,所述酸例如盐酸、硫酸、甲磺酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、草酸、柠檬酸、酒石酸、碳酸或磷酸。
另外,本文所述的含脱辅基水母素和维生素D的组合物可以营养组合物形式提供,其中脱辅基水母素和维生素D预防各种有害钙失衡相关病症和维生素D缺乏的发生,或使其减少或稳定。本说明书所用的术语“营养”或“营养组合物”指食品或食品部分,其提供医疗健康益处,包括预防和/或治疗疾病。本发明的营养组合物可仅包含作为活性成分的脱辅基水母素和维生素D,或也可以进一步包含(与以下混合)包括维生素、辅酶、矿物质、草药、氨基酸等通过提高该物质的总摄取补充饮食的饮食补剂。
因此,本发明提供了对病人提供营养益处的方法,包括步骤:对病人施用含有脱辅基水母素和维生素D的营养组合物。这样的组合物通常包括“营养学上可接受的运载体”,其在本文中指任何适合口腔给药的运载体,包括上文所述的适合口腔途径的药学上可接受的运载体。在一些实施方式中,本发明的营养组合物包括饮食补剂,其在功能基础上定义为包括免疫增强剂、抗炎剂、抗氧化剂、抗病毒剂或其混合物。
免疫增强剂和/或抗病毒剂可用于加速伤口愈合和促进免疫功能;它们包括金光菊,或紫锥花(Echinacea)属的草药提取物,茴香属(Sambuca)的草药提取物和白毛茛(Goldenseal)提取物。黄芪(Astragalus)属的草药以其天然或加工形式也是有效的免疫增强剂。黄芪刺激骨髓中的干细胞和淋巴组织活性免疫细胞的发育。锌及其生物活性盐,例如甘油磷酸锌和乙酸锌也在治疗普通感冒中作为免疫增强剂。
抗氧化剂包括天然的含硫氨基酸大蒜素,其能提高血液中抗氧化酶的水平。草药或草药提取物例如含有大蒜素的大蒜也是有效的抗氧化剂。儿茶素和含有儿茶素的草药例如绿茶的提取物也是有效的抗氧化剂。黄芪属的提取物也显示抗氧化活性。生物类黄酮例如槲皮素、陈皮苷、茴香苷及其混合物也是有效的抗氧化剂。生物类黄酮的主要益处是保护维生素C在体内不被氧化。这使得身体能有更多维生素C或抗坏血酸使用。
生物类黄酮例如槲皮素也是有效的抗炎剂,也在本发明的组合物中如此使用。抗炎草药补剂和衍生自植物或草药的抗炎化合物也可在本发明的组合物中用作抗炎剂。这些包括菠萝蛋白酶(bromolain),一种在菠萝中发现的蛋白酶;荨麻提取物和茶;姜黄(tumeric)提取物或姜黄素(curcumin),一种分离自姜黄的黄色颜料。可用于本发明的其它补剂可以是姜,其源自姜属(Zingiber)的草药。其已被发现因化合物例如姜酚和相关化合物姜烯酚等具有强心剂活性,还能在头晕和前庭疾病的治疗中提供益处。姜也能有效治疗恶性和其他胃疾病。
帮助重建软组织结构,特别是重建软骨的补剂在治疗关节炎和其他关节疾病的组合物中也是有用的。葡糖胺,硫酸葡糖胺、软骨素可衍生自许多来源,例如麋鹿鹿茸。海洋液体复合物,ω-3脂肪酸复合物,以及鱼油也已知对于治疗与关节炎相关的疼痛是有用的。
用于治疗偏头痛的补剂包括小白菊和银杏(Gingko biloba)。小白菊中的主要活性成分是倍半萜小白菊内酯,其抑制***素的分泌,后者通过血管中的血管痉挛作用导致疼痛。小白菊也显示抗炎性质。由于其血小板稳定和抗血管痉挛作用,鱼油也能用于治疗偏头痛。草药银杏也通过稳定动脉和促进血液循环帮助治疗偏头痛。
虽然上文所列的一些补剂已由于其药物效果被描述,在本发明中也可利用其他补剂,其效果也被详细记载在科学文献中。
本发明可根据下面描述和公开化学物、仪器、统计分析和方法学的非限制性例子得到更全面的理解,这些化学物、仪器、统计分析和方法学在可能与本发明联用的出版物中被报道。本说明书引用的所有参考文献都应看作对本领域技术水平的指示。本文中所有内容均不应解释为承认本发明不是先于这些公开内容的在先发明。
实施例:
实施例1经九十(90)天施用脱辅基水母素导致测试对象改善的生活质量。
该分析(对32位病人经90天的开放标签研究)显示了睡眠、精力、情绪、疼痛、一般健康状况的总体质量提高。表现的改变通过标准化检查表测定。这些包括定量的认知测试、睡眠指标、头痛指标和生活质量问卷调查的评估。研究显示改善的表现。没有参与者由于不良事件中断研究。
图1所示的结果显示,所提到的领域的评分从基线的改善百分数;我们排除了记忆评分用于另一张图表。此处的分析在图上标为1、2、3、4和5,对于第0日至第90日作图。图表显示睡眠、精力、情绪、疼痛和一般健康的总体质量提高。基线来自研究前的时期。
实施例2经三十(30)天施用脱辅基水母素导致测试对象改善的生活质量。
该研究是在30天时间段内对56个参与者的开放标签研究。通过记忆筛选工具测试表现上的改变。如图2所示,研究早在第8日就显示了改善的记忆表现,而在第30日显示了统计上更高的改善。没有参与者由于不良事件中断研究。
实施例3经九十(90)天施用脱辅基水母素导致测试对象改善的认知。
本分析(32个参与者的开放标签研究)显示认知能力的提高。表现的改变通过标准化认知检查表测定。该研究显示,认知早在第8日即得到改善,但在第30日,以及第60-90日有统计上更高的改善。没有参与者由于不良事件中断研究。图3所示的结果显示认知水平评分相较基线有显著的百分数增加。注意:51%以上的参与者有认知能力的提高。
实施例4含脱辅基水母素和维生素D的组合物的给药
对病人施用含脱辅基水母素和维生素D的组合物,其为胶囊形式,含有脱辅基水母素和维生素D3的混合物。组合物含有50mcg维生素D3(D3胆钙化醇形式)和20mg脱辅基水母素。营养组合物装载在营养学上可接受的植物胶囊(植物纤维素、水)中。组合物还含有微晶纤维素、糖、和少量:***树胶(***胶)、酪蛋白胨、玉米淀粉、乳糖、硬脂酸镁(植物来源)、中链甘油三酯(植物油)、盐、大豆蛋白胨、DL-α-生育酚、磷酸三钙和水。每日摄取一粒胶囊提供推荐剂量。这样的剂量含有约250%的维生素D推荐日摄取量。适用于本发明的维生素D来自BASF,以“干维生素D3 100GFP/HP”出售。单一剂量也可配制成含有其他量的脱辅基水母素,包括含有10mg或40mg脱辅基水母素的单剂。
实施例5AQ(脱辅基水母素)和维生素D在大鼠下丘脑切片中的神经保护作用评估
实验数据中的一个亚组的最初结果显示切片中经5分钟氧葡萄糖耗竭(OGD图4;左上图)后的显著细胞死亡,以及不经过5分钟OGD的很少细胞死亡(图4;右上图)。AG在下丘脑中的直接注射导致更少的死亡和正在死亡的细胞(即染成蓝色的细胞)。哺以补充有维生素D(0.0125mg/kg)的饮食(约10天)的大鼠也显示具有更少的死亡或正在死亡的细胞。AG和维生素D的组合可进一步减少细胞死亡数量(图4,左下图)。对照切片(没有经过OGD的)并不根据处理条件而有所改变。
应理解,本文所述的实施例和实施方式仅用于说明目的,本领域技术人员应了解据此作出的各种修饰或改变,且它们包括在本申请的主旨和权益以及所附权利要求书的范围内。本文引用的所有出版物、专利和专利申请通过引用全文纳入本文以用于所有目的。
Claims (18)
1.一种治疗与钙失衡和维生素D缺乏中至少一种相关的症状或病症的组合物,包含:(a)有效量的脱辅基水母素;(b)有效量的维生素D;和(c)可接受的运载体。
2.如权利要求1所述的组合物,其中组合物的形式是单位剂量,其含有所述有效量的脱辅基水母素和维生素D。
3.如权利要求2所述组合物,其特征在于,(a)单位剂量中脱辅基水母素的有效量是约10mg到约50mg;和(b)单位剂量中维生素D的有效量是约25mcg到约75mcg。
4.如权利要求3所述组合物,其特征在于,(a)单位剂量中脱辅基水母素的有效量是约20mg;和(b)单位剂量中维生素D的有效量是约50mcg。
5.如权利要求1-4中任一项所述的组合物,其特征在于,维生素D是D3胆钙化醇形式。
6.如权利要求1-5中任一项所述的组合物,所述单位剂量是胶囊。
7.如权利要求1-6中任一项所述的组合物,所述组合物是营养组合物。
8.一种治疗与钙失衡和维生素缺乏中至少一种相关的症状或病症的方法,包括对需要所述治疗的对象施用有效量的权利要求1-7中任一项所述的组合物。
9.如权利要求8所述的方法,其中所述症状或病症与睡眠相关,对所述对象施用组合物改善对象的睡眠质量。
10.如权利要求8所述的方法,其中所述症状或病症与精力相关,对所述对象施用组合物改善对象的精力质量。
11.如权利要求8所述的方法,其中所述症状或病症与情绪相关,对所述对象施用组合物改善对象的情绪质量。
12.如权利要求8所述的方法,其中所述症状或病症与疼痛相关,对所述对象施用组合物减轻对象的疼痛。
13.如权利要求8所述的方法,其中所述症状或病症与记忆相关,对所述对象施用组合物改善对象的记忆质量。
14.如权利要求8所述的方法,其特征在于,所述症状或病状与神经元兴奋性、肌肉收缩、膜渗透性、细胞***、激素分泌、骨矿物化、或缺血后的细胞死亡有关。
15.用脱辅基水母素和维生素D制备营养组合物的用途,用于在施用所述营养组合物的对象内治疗与钙失衡和维生素D缺乏中至少一种相关的症状或病症。
16.用脱辅基水母素和维生素D制备营养组合物的用途,用于在施用所述营养组合物的对象内治疗与睡眠、精力、情绪、疼痛或记忆相关的症状或病症。
17.脱辅基水母素和维生素D,用于治疗与对象内钙失衡和维生素D缺乏中至少一种相关的症状或病症。
18.脱辅基水母素和维生素D,用于在施用所述营养组合物的对象内治疗与睡眠、精力、情绪、疼痛或记忆相关的症状或病症。
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