CN108366977A - 用于慢性炎症的姜黄素和白藜芦醇 - Google Patents
用于慢性炎症的姜黄素和白藜芦醇 Download PDFInfo
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Abstract
姜黄素和白藜芦醇的组合能够防止小胶质细胞参与脑中的炎症通路。因此,这种组合能够减轻/预防继发于例如肥胖症、糖尿病、损伤和感染的病症的脑炎症。该组合还可以减轻慢性疼痛。
Description
发明简述
本发明涉及姜黄素和白藜芦醇的组合用来减轻慢性炎症,特别是(其中炎症主要由小胶质细胞介导的)脑中慢性炎症的用途,以及减轻脑和脊髓所感知到的慢性疼痛的用途。已发现所述组合对小胶质细胞的作用是协同的,因此可用于控制、减轻和预防慢性炎症,例如与糖尿病、低烧、肥胖症、高血压、运动用力(athletic exertion)和慢性神经病相关的慢性炎症。
背景技术
已知姜黄素和白藜芦醇的组合在治疗某些癌症如肺癌方面具有一定的协同作用。参见例如Malhotra等人2014PLoS ONE 9(4)e93820,其中发现该组合调控ser 15处的p53磷酸化并因此增强减缓癌细胞生长的凋亡。
已知姜黄素和白藜芦醇单独使用而不是组合使用时,均具有抗氧化作用,如Derochette等人2013Chemico-Biological Interactions 206:186-193中所讨论的。此处,发现姜黄素比白藜芦醇更好地调节NADPH氧化酶活性,因为姜黄素还充当氧自由基清除剂。发现白藜芦醇仅具有氧自由基清除活性,而不能像姜黄素那样容易进入细胞。类似地,Cordini等人2014Eur.J.Pharmaceutics and Biopharmaceutics 88:178-185显示:当用作抗癌疗法时,两种活性物的共包封改善了它们的抗氧化活性。
姜黄素和白藜芦醇都已被提议作为阿尔茨海默病治疗中的单一活性成分。参见Villaflores等人2012Taiwanese J Obstetrics and Gynecology51:515-525。此外,由于姜黄素的抗氧化活性,已公开了其展示出对各种其他神经疾病的活性,所述神经疾病包括多发性硬化症、帕金森病、癫痫、脑损伤、年龄相关性神经变性、精神***症、海绵状脑病(Crutzfeldt Jacob aka C-J疾病)、神经性疼痛和抑郁症。白藜芦醇可通过SIRT-1通路充当神经保护剂。
小胶质细胞(microglia)是脑和脊髓中的一类细胞。它们在中枢神经***中的功能与外周免疫***中的巨噬细胞大致类似。参见例如Loane等人2010Neurotherapeutics 7(4):366-377。小胶质细胞能够通过吞噬作用清除细胞碎片和/或毒性物质,从而维持中枢神经***的微环境。其细胞表面具有针对各种生长因子、细胞因子和受损细胞释放的其他因子的许多受体。响应于这种刺激,小胶质细胞可以释放促炎分子,包括趋化因子,其可以引起神经元细胞死亡。小胶质细胞的短期激活被认为对中枢神经***的健康有益,然而长期激活可能是有害的。
存在许多以下情况,其中慢性炎症(通常继发于另一种病症如肥胖症或糖尿病)会对神经组织产生不利影响。在这些情况下,中枢神经***在其它方面是健康的(即没有神经元病症,例如阿尔茨海默病、痴呆症、多发性硬化症、帕金森病、癫痫症、脑损伤、年龄相关的神经变性、精神***症或海绵状脑病)、但正在经受脑组织慢性炎症或有经受脑组织慢性炎症风险的人会希望保护这些组织,在血脑屏障被致更易渗透的情况下尤为如此。
小胶质细胞还与慢性疼痛的产生有关。参见例如Giron等人2015Pain ManagementNursing(待刊文章,2015年5月8日在线发表)1-13。被激活的小胶质细胞可以释放各种炎性分子。在引发疼痛反应的损伤已经愈合之后,疼痛状况可长时间持续。目前,没有不具有副作用和/或成瘾的风险的、专注于单独的慢性疼痛的合适的治疗,希望具有这样的治疗剂。
发明详述
根据本发明,已发现:姜黄素和白藜芦醇的组合能够作为抗炎剂协同作用于小胶质细胞。因此,本发明的一个方面是姜黄素和白藜芦醇的组合用于保护脑组织(特别是小胶质细胞)免于激活,从而减轻或预防慢性炎症的用途。在本发明的优选方面,所经受的慢性炎症来自以下这些类别之一:
a)继发于糖尿病或肥胖症,
b)由于低水平脑创伤(例如由于接触性运动、跌倒而经受的脑创伤,或其他轻微头部损伤)所致;或者
c)由于低烧或感染(例如流感、窦炎或脑膜炎)所致,
d)伴有与血脑屏障渗漏同时发生的高血压相关炎症。
重要的是,明确不属于本发明的一部分的是姜黄素和白藜芦醇的组合用来预防、治疗和/或减轻任何以下疾病的症状的用途:癌症、阿尔茨海默病、多发性硬化症、帕金森病、癫痫症、脑损伤、年龄相关的神经变性、精神***症、海绵状脑病(C-J疾病)、神经性疼痛和抑郁症。此外,还明确排除该组合用于在患有任何上述疾病的人中治疗由于糖尿病、肥胖症、低水平脑创伤、低烧或高血压导致的慢性炎症的用途。
本发明的另一方面是姜黄素和白藜芦醇的组合用来预防、治疗或减轻慢性疼痛的感觉的用途。已知随着时间的推移,阿片类(opiod)止痛药会失去效力。因此,本发明的另一方面是联合施用姜黄素和白藜芦醇的组合以帮助维持阿片类的有效性和/或预防、治疗或减轻慢性疼痛的感觉,前提条件是有此需要的人没有患:癌症、阿尔茨海默病、多发性硬化症、帕金森病、癫痫、脑损伤、年龄相关性神经变性、精神***症、海绵状脑病(C-J疾病)或抑郁症。
本发明的另一方面是姜黄素和白藜芦醇的组合用来帮助保持正常血脑屏障(BBB)功能的用途,因为该组合对小胶质细胞具有协同抗炎作用,这有助于维持BBB的完整性。
作为高血压疗法的辅助物,这一点尤其重要。因此,本发明的另一方面是姜黄素和白藜芦醇的组合用来控制高血压患者的炎症的用途。
附图简述
图1.姜黄素C3提取物(0-30nM)抑制LPS刺激的原代小胶质细胞的炎性细胞因子释放。基于制造商记录的C3提取物中姜黄素的百分比来计算姜黄素的浓度。图1A:姜黄素C3处理>10nM(18μg/mL)显著抑制PGE2释放和IL-1β释放(图1B)。图1C:显著抑制IL-6释放需要至少20nM(50μg/mL)的姜黄素C3浓度。图1D:姜黄素C3浓度>5nM(12.5μg/mL)显著抑制TNF-α释放。通过单因素方差分析(1-way ANOVA)和随后的Tukey事后检验确定了各处理之间的显著差异(p<0.05)。方差分析参数***每个图表内。误差线表示SEM。
图2.白藜芦醇(0-250μM)仅抑制LPS刺激的原代小胶质细胞的PGE2表达。图2A:白藜芦醇在75μM和250μM时显著抑制PGE2释放,但未检测到对TNF-α(图2B)和IL-1β(图2C)释放的显著效果。通过单因素方差分析和随后的Tukey事后检验确定了各处理之间的显著差异(p<0.05)。方差分析参数***每个图表内。误差线表示SEM。
图3.白藜芦醇和姜黄素C3提取物在其各自IC50值下的组合抑制原代小胶质细胞的PGE2释放并很可能具有协同作用。白藜芦醇(2.25μM)、姜黄素C3(7nM;14.4μg/mL)和白藜芦醇(2.25μM)+姜黄素C3(7nM)的组合抑制PGE2释放,其中组合相较于单独的化合物具有显著更强的作用。通过单因素方差分析和随后的Tukey事后检验确定了各处理之间的显著差异(p<0.05)。没有共同字母的棒(bar)显著不同。显示50%抑制的虚线以突出单独化合物相较于组合的响应。方差分析参数***每个图表内。误差线表示SEM。
图4.白藜芦醇(2.25μM)+姜黄素C3(7nM)组合的协同作用分析检测到了强大的协同作用。相对于计算的组合指数值绘制受影响部分(Fa,即90%抑制=0.9)。所有计算值均<0.1,指示两种化合物具有非常强的协同效应,平均浓度指数值为0.04。白藜芦醇和姜黄素C3的剂量减少指数(DRI)值分别确定为42.76和21.86。因此,白藜芦醇浓度降低43%(即1.3μM)和姜黄素C3浓度降低22%(即6.5nM)在组合时仍然具有协同效应。
在说明书和权利要求全文中使用时,适用以下定义:
“慢性疼痛”是持续超过12周的疼痛。
“急性炎症”通常是由细菌病原体或受损组织引起的。其通常持续几天,但可导致慢性炎症。
“慢性炎症”的主要特征在于其持续性和缺乏清楚的判断(resolution)。其可以由不可降解的病原体、病毒感染、持续性异物或自身免疫反应引起。其在组织不能战胜损伤剂的效果时发生。
在本申请中使用的“健康个体”具体指没有任何以下疾病/病症的人:癌症、阿尔茨海默病、多发性硬化症、帕金森病、癫痫症、脑损伤、年龄相关性神经变性、精神***症、海绵状脑病(C-J疾病)和抑郁症。
“在其它方面健康的个体”意指所述个体患有待通过施用本发明的组合来治疗或改善的疾病/病症,但不同时具有任何以下疾病/病症:癌症、阿尔茨海默病、多发性硬化症、帕金森病、癫痫、脑损伤、年龄相关性神经变性、精神***症、海绵状脑病(C-J疾病)和抑郁症。
剂量
用于人体的姜黄素和白藜芦醇的组合的剂量范围为1mg/天至1000mg/天。优选地,组合的范围为25-500mg/天,更优选地,所述范围为100-200mg/天。在本发明的一些方面中,以150mg/天施用组合。
姜黄素:白藜芦醇的比例应该是具有协同效应的比例。这是一个相当宽泛的比例,最低可达1:138且最高可达1:6250。为了便于制造,范围应该在1:100至100:1之间,优选50:1至1:50,更优选从-1:10至10:1。也可以设想1:1的比例(例如每种150-500mg)。
上述剂量优选每天施用一次,但如果期望的话,可将剂量分成2或3个方便的较小剂量以在一整天施用。
为了获得最佳结果,应该连续服用姜黄素和白藜芦醇的组合至少一周,优选至少4周,并且可以服用更长时间。
形式
根据本发明的营养组合物、饮食组合物和/或药物组合物可以是适用于施用给人体的任何盖伦形式(galenic form),尤其是经口施用中常规的任何形式,例如固体形式,如作为食物或饲料(用的添加剂/补充剂)、食物或饲料预混物、强化的食物或饲料、片剂、丸剂、颗粒剂、锭剂、胶囊和泡腾配制剂(如粉末和片剂),或液体形式,如溶液、乳剂或悬浮液的形式,例如作为饮料、糊剂和油悬浮液。糊剂可以被包封在硬壳胶囊或软壳胶囊中,从而该胶囊的基质为例如(鱼、猪、家禽、牛)明胶、植物蛋白或木质素磺酸盐。其它应用形式的例子是用于经皮、肠胃外、或可注射施用的形式。饮食和药物组合物可以是受控(延迟)释放的配制剂的形式。根据本发明的饮食组合物可以进一步含有保护性水状胶质(例如树胶、蛋白质、改性淀粉)、粘合剂、成膜剂、包封剂/材料、壁/壳材料、基质化合物、包衣、乳化剂、表面活性剂、增溶剂(油、脂肪、蜡、卵磷脂等)、吸附剂、载体、填料、共化合物(co-compound)、分散剂、润湿剂、加工助剂(溶剂)、流平剂、掩味剂、增重剂、凝胶化剂(jellifying agents)、凝胶形成剂、抗氧剂和抗微生物剂。
适合含有白藜芦醇和姜黄素的组合的食物的例子是谷物棒、乳制品(如酸奶)和烘焙产品,如蛋糕和饼干。强化食品的例子是谷物棒和烘焙产品,如面包、面包卷、硬面包圈、蛋糕和饼干。饮食补充剂的例子是片剂、丸剂、颗粒剂、锭剂、胶囊和泡腾配制剂,无酒精饮品的形式(如软饮、果汁、柠檬水(lemonade)、近水(near-water)饮品、茶和基于乳的饮品),液体食品的形式,如汤和乳制品(牛奶什锦早餐(muesli)饮品)。饮料也是合适的。饮料包括无酒精饮品和酒精饮品以及待加入饮用水中的液体制剂以及液体食品。无酒精饮品例如是软饮、运动饮料、果汁、蔬菜汁(例如番茄汁)、柠檬水、茶和基于乳的饮品。液体食品是例如汤和乳制品(例如,牛奶什锦早餐饮品)。
除了白藜芦醇和姜黄素的组合外,根据本发明的药物组合物可以进一步包含常规的药物添加剂和佐剂、赋形剂或稀释剂,这包括但不限于:水、任何来源的明胶、植物胶质、木质素磺酸盐、云母、糖、淀粉、***胶、植物油、聚亚烷基二醇、增香剂、防腐剂、稳定剂、乳化剂、缓冲剂、润滑剂、着色剂、润湿剂、填料等。载体材料可以是适于经口/非肠道/可注射施用的有机或无机的惰性载体材料。
糖尿病相关的炎症
糖尿病(或糖尿病前期状态,如高血糖症)的一个经常被忽视的方面是慢性炎症,其也可以存在于脑中。通过使用姜黄素和白藜芦醇的组合,可以减少并/或消除脑炎症的量。因此,本发明的一个方面是白藜芦醇和姜黄素的组合来减少继发于糖尿病的脑和/或其他神经组织中炎症的量的用途。另一方面是控制、减轻或改善继发于糖尿病的脑和/或其他神经组织的急性或慢性炎症的症状的方法,所述方法包括向患有糖尿病的人施用白藜芦醇和姜黄素的组合,前提条件是所述人是在其它方面健康的人。
本发明的另一方面是白藜芦醇和姜黄素的组合的下述用途:通过向有患糖尿病风险的健康人施用所述组合来预防脑和/或其他神经组织中继发的炎症、使所述炎症减轻至最低程度、延迟所述炎症的发作和/或减少所述炎症的量。
与肥胖症相关的炎症
肥胖者,无论是否同时患有糖尿病,都可能经受慢性炎症,包括脑和神经组织中的炎症。因此,本发明的另一方面是姜黄素和白藜芦醇的组合来预防或减轻或消除继发于肥胖症或糖尿病并发肥胖症的脑和/或神经组织中的炎症的用途。本发明的另一方面是减轻继发于肥胖症的脑或神经组织中的炎症的方法,所述方法包括向肥胖的人施用白藜芦醇和姜黄素的组合,前提条件是所述人是在其它方面健康的人。
对于有发生脑和神经组织的炎症的风险但尚未具有这种炎症的人,特别是超重的人,本发明的另一方面是降低发生继发于肥胖症的脑和神经组织的炎症的风险的方法,所述方法包括向在其它方面健康的人施用姜黄素和白藜芦醇的组合。
继发于轻微脑创伤的炎症
遭受不足以引起脑震荡或意识丧失的一次或多次轻微头部损伤(即一次或多次轻微损害)的人也可能会经受脑和神经组织的炎症,尽管可能没有明显的损伤迹象。即使佩戴了防护头盔,也会发生炎症。有这些类型损伤风险的人的例子包括:
·运动员,特别是参与有身体接触或有跌倒或撞击头部风险的运动的运动员。这些运动的例子包括:拳击、摔跤、足球、橄榄球、武术、滑冰、滑雪、自行车运动、体操、马术等。
·具有可能使他们暴露于轻微头部损伤的工作的人,例如建筑业中的人、特技演员、军事人员、救援人员、消防员、警察等,或
·由于另一种医学状况而导致其平衡受损且有跌倒风险的人,包括体弱老人或癫痫患者。
因此,本发明的另一方面是白藜芦醇和姜黄素的组合在有遭受轻微头部损伤风险的人中预防、改善或降低继发于轻微头部创伤的脑和其他神经组织的发炎的风险。本发明的另一个方面是降低继发于轻微头部损伤的脑和其他神经组织的发炎的风险的方法,所述方法包括向有遭受所述损伤风险的在其它方面健康的人施用姜黄素和白藜芦醇的组合。
继发于发烧的炎症
遭受低烧的人经常经受脑炎症。虽然这种类型的短期疾患可能不是特别严重,但长期低烧可导致慢性炎症。例如,遭受长期鼻窦炎或其他***反应的人可能经受脑或其他神经组织中的炎症。也可能影响脑的其他疾病/病症是直接影响脑和神经组织本身的那些疾病,如脑膜炎。施用给患脑膜炎的人能够减轻相关的炎症。
因此,本发明的另一方面是减轻继发于低烧或脑膜炎的脑炎症的方法,所述方法包括向有此需要的人施用姜黄素和白藜芦醇的组合,前提条件是所述人没有患癌症、阿尔茨海默病、多发性硬化、帕金森病、癫痫、脑损伤、年龄相关性神经变性、精神***症、海绵状脑病(C-J疾病)和/或抑郁症。本发明的另一方面是使用姜黄素和白藜芦醇的组合来减轻继发于低热或脑膜炎的脑炎症。
经受慢性疼痛的人
虽然慢性疼痛本身在学术上不是疾病,但它可能会使人衰弱。此外,随着时间的推移,阿片类往往会失去效力。本发明的另一方面是白藜芦醇和姜黄素的组合来改善或缓解有此需要的人的慢性疼痛的用途,所述人没有患癌症、阿尔茨海默病、多发性硬化症、帕金森病、癫痫症、脑损伤、年龄相关性神经变性、精神***症、海绵状脑病(C-J疾病)和/或抑郁症。因此,本发明还包括减轻慢性疼痛的方法,所述方法包括向有此需要的人施用白藜芦醇和姜黄素的组合,前提条件是所述人没有患伴随的癌症、阿尔茨海默氏病、多发性硬化症、帕金森病、癫痫症、脑损伤、年龄相关的神经变性、精神***症、海绵状脑病(C-J疾病)和/或抑郁症。
继发于高血压的炎症
高血压可干扰BBB的完整性并因此参与炎症通路。因此,本发明的另一方面是姜黄素和白藜芦醇的组合在患有高血压但在其他方面身体健康的人中的用途。本发明的一部分是减轻患有高血压的人的脑和神经组织中的炎症的方法,所述方法包括施用白藜芦醇和姜黄素的组合,前提条件是所述人没有患伴随的癌症、阿尔茨海默氏病、多发性硬化症、帕金森病、癫痫症、脑损伤、年龄相关的神经变性、精神***症、海绵状脑病(C-J疾病)和/或抑郁症。
保护血脑屏障
本发明的另一方面是姜黄素和白藜芦醇的组合用来保护有BBB渗漏风险的人的BBB的用途,所述人例如遭受伴随血脑屏障渗漏发生的糖尿病、肥胖症、低水平脑创伤、低烧或高血压相关的炎症或有遭受所述炎症风险的人。因此,本发明的另一个方面是保护BBB免于渗漏的方法,所述方法包括向正在经受BBB渗漏或有经受BBB渗漏风险的人施用姜黄素和白藜芦醇的组合,前提条件是所述人在其它方面是健康的。
展示以下非限制性实施例以更好地阐释本发明。
实施例
实施例1
材料和方法
小胶质细胞的收获和培养。涉及动物的所有实验均经在Bolder Biopath,Inc.(Boulder,CO)设立的动物管理委员会(Animal Care and Use Committee)批准。原代小胶质细胞培养物来源于通过剖腹产取自定时怀孕的母体(dams)(Charles River)的E22Sprague Dawley大鼠幼仔的新皮质组织。简而言之,在Hibernate EB(Brain Bits;Springfield,IL)中分离幼仔脑皮质。然后将样品转移到Hibernate E(不含Ca;BrainBits;Springfield,IL)中并用新鲜的Hibernate E(-Ca)洗涤两次。接着将组织在含有0.5%胰蛋白酶(Sigma)的Hibernate E(-Ca)中于37℃下消化15分钟。移除上覆溶液,并通过用含有20%热灭活的胎牛血清(FBS;Hyclone)的Hibernated E(-Ca)洗涤沉降的组织来淬灭胰蛋白酶反应。
将组织研磨成单细胞,并通过70-μm细胞过滤器过滤悬浮液。使用台盼蓝(0.4%;Fisher Scientific)和Countess自动化细胞计数器(Life Technologies,Grand Island,NY)测定时,细胞数量和生存力始终高于95%。在含有100μg/mL青霉素、100μg/mL链霉素、0.5ng/mL两性霉素(CellnTec)和1mM丙酮酸钠的HiGlutaXL Dulbecco改良Eagle培养基(Dulbecco’s Modified Eagle Medium;DMEM,4.5g/L葡萄糖,加上谷氨酰胺;HyClone)中,以8x 106个细胞/烧瓶将细胞接种到T-75烧瓶(VWR)中。于在体外的第3天更换培养基,细胞在烧瓶中时每4-5天加料(fed)一次。于在体外的第14天,以5ng/mL的终浓度添加小鼠粒细胞巨噬细胞集落刺激因子(mGM-CSF;R&D Systems;Minneapolis,MN)以刺激小胶质细胞分化。
细胞刺激和细胞因子测定。每2周一次从饲养层培养物上的培养基中分离小胶质细胞,并接种到96孔板(75000个细胞/孔;VWR)中的DMEM、10%FBS和100μg/mL青霉素、100μg/mL链霉素、0.5ng/mL两性霉素中。铺板后24小时,用姜黄素C3提取物(0-50μg/mL;0-25nM;Sabinsa;Langen Hessen,Germany)、白藜芦醇(0-250μM;ResVida;DSM NutritionalProducts)或其组合处理细胞。然后,持续另外24小时,之后用脂多糖(LPS;100ng/mL;Sigma)刺激细胞。刺激后24小时,收集上清液用于细胞因子测定。将上清液储存在-20℃直至进行测定。通过ELISA(Cayman Chemical)测量上清液中***素E2(PGE2)的浓度。通过多重ELISA(Quansys Biosciences;Logan,UT)测定上清液中肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)的浓度。然后将数据归一化为对单独LPS的对照响应的百分比。
协同作用的计算。根据Chou-Talay的经典等效线图方程和中效原理并根据Choi等人(2013)1的方法来确定由白藜芦醇与姜黄素C3的组合产生的协同作用。该原理基于质量作用定律,由Talay和Chou2开发,以将生物化学和生物物理学的主要理论Michaelis-Menten,Hill,Heanderson-Hasselbach和Schatchard方程统一为检测药物组合时的累加效应、协同效应和拮抗效应的定量定义。使用ComboSyn软件3(ComboSyn,Inc.Paramus,NJ)进行计算。简而言之,绘制每种药物的剂量-响应曲线以计算其各自的IC50值。然后在协同计算中将IC50值用作相对Dm(具有50%效应的剂量)值。通过计算组合指数(CI)值来证实协同作用。CI值接近1表示累加效应,而CI<1表示协同效应。当CI>1时,指示拮抗效应。还报告了剂量减少指数(DRI)值,这是每种化合物在组合给予时与单独每种药物的剂量相比的潜在倍数剂量减少的量度。
Claims (4)
1.一种减轻脑炎症的方法,所述方法包括:
向正在经受脑或神经组织中的炎症或有经受所述炎症风险的人施用有效协同量的白藜芦醇和姜黄素的组合,所述炎症由选自以下的病症引起:
继发于糖尿病的炎症,
继发于肥胖症的炎症,
由于低水平脑创伤导致的炎症,
由于低烧或感染导致的炎症,
继发于高血压的炎症和
慢性疼痛,
前提条件是所述人没有任何以下疾病:癌症、阿尔茨海默病、多发性硬化症、帕金森病、癫痫、脑损伤、年龄相关性神经变性、精神***症、海绵状脑病(C-J疾病)或抑郁症。
2.根据权利要求1所述的方法,其中以1-1000mg/天的剂量施用所述白藜芦醇和姜黄素。
3.白藜芦醇和姜黄素的组合联合用于减轻或预防正在经受任何以下病症或有任何以下病症风险的人中的脑和神经***的炎症的用途:
继发于糖尿病的炎症,
继发于肥胖症的炎症,
由于低水平脑创伤导致的炎症,
由于低烧或感染导致的炎症,
继发于高血压的炎症和
慢性疼痛。
4.根据权利要求3所述的用途,其中用量为1-1000mg/天,优选约25-500mg/天,更优选100-200mg/天。
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