CN112494509A - 一种防治阿尔茨海默症的组合物及应用 - Google Patents
一种防治阿尔茨海默症的组合物及应用 Download PDFInfo
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Abstract
本发明公开了一种防治阿尔茨海默症的组合物及应用,所述的组合物由以下重量份数的组分组成:胞磷胆碱1~1000份、尿苷酸1~500份、N‑乙酰神经氨酸1~300份、磷脂酰丝氨酸1~300份、维生素E1~50份、维生素B60.1~5份、维生素B120.1~5份、叶酸0.1~5份。本发明所提供的组合物能够有效解决现有技术中AD症状无特效药,现有药物毒副作用大的问题,本发明通过对脑部物质代谢和AD病理机制的研究,从加强脑部营养,降低同型半胱氨酸的含量,提高乙酰胆碱含量,进而预防和干预早期AD症状。
Description
技术领域
本发明属于医药健康研究技术领域,具体涉及一种防治阿尔茨海默症的组合物及应用。
背景技术
阿尔茨海默病(Alzheimer's disease,AD)是一种慢性中枢神经系统退行性疾病,是老年性痴呆中最为常见的一种类型。主要临床症状为显著的记忆丧失思维定向、理解、计算、学习、语言和判断等能力不同程度障碍,以及相应的人格和行为改变。AD分为家族遗传型AD(familial Alzheimer's disease,FAD)和散发型AD(sporadic Alzheimer'sdisease,SAD)两种,其中SAD占AD患者总数的95%以上。AD以发病年龄为依据分为发病早于65岁的早发型AD(early-onset Alzheimer's disease,EOAD)和发病迟于65岁的迟发型AD(late-onset Alzheimer's disease,LOAD),在EOAD中以FAD为主,在LOAD则以SAD为主。AD从发现报道至今已有百余年,虽然针对AD的发病机制进行了大量研究,也取得了丰硕的研究成果,提出了多种假说,但任何一种假说都难以完全解释AD的确切发病机制。针对AD病程缓慢和不可逆转的特点,目前国际上形成的AD治疗基本共识:AD的防治重点应当前移。因此,AD的早期诊断与干预成为当前国际AD研究的重点和热点。
目前临床用于AD治疗的药物包括胆碱酯酶抑制剂和NMDAR体拮抗剂两大类。
2014年12月,美国FDA批准了一种联合胆碱酯酶抑制剂多奈哌齐和NMDAR拮抗剂美金刚的胶囊制剂,用于治疗AD。(1)胆碱酯酶抑制剂:胆碱酯酶抑制剂通过抑制胆碱酯酶活性,降低ACh的降解速度,增加突触ACh含量,激活尼古T和毒蕈碱受体,发挥改善认知的功能,在临床上除AD外,胆碱酯酶抑制剂也用于治疗其他形式的痴呆,包括血管性痴呆、混合型痴呆和路易体痴呆。但临床发现,胆碱酯酶抑制剂不能改善AD的神经精神症状。(2)NMDAR拮抗剂:Glu是存在于大脑海马与新皮质区的兴奋性神经递质,在学习、记忆和认知过程中发挥重要作用。AD脑中神经细胞外会有过量Glu累积,导致兴奋性毒性作用,因此通过阻断NMDAR可以减轻Glu过度兴奋导致的神经损伤。该类药物主要以美金刚(akatinolmemantine)为代表,该药也是FDA批准的首个用于中、重度AD临床治疗的药物。但据报道,美金刚也具有导致思维混乱和眩晕等不良反应。(3)联合用药:2014年,美国FDA批准了以多奈哌齐和美金刚联合组成固定剂量组方的胶囊制剂namzaric,用于临床治疗中至重度AD。随机对照研究显示,两者合用比单独使用胆碱酯酶抑制剂表现出更为显著的临床疗效,是目前AD治疗最有效的方法。这一应用体现了通过多个靶点联合用药的策略,具有重要意义。但上述药物(包括胆碱酯酶抑制剂和NMDAR拮抗剂)均属于改善症状(symptomatic therapy)药物,用药后具有短期改善患者症状的作用,但无法延缓和阻止病情进展恶化。因此开发针对疾病病理的治疗(disease-modifying therapy,DMT)药物是当前的关注重点。但自2003年以来,迄今还无一个抗AD新药获得FDA批准。
丰富充足的营养在改善认知障碍中起着重要作用。由于老人身体机能的下降,消化吸收功能减退,营养不良现象在老年人群中普遍存在,其能够加速AD病程。因此,营养素补充在治疗AD方面具有较大的潜力,且具有有效性和低毒性的特点,所以越来越受到国内外学者的重视。同时,脑部物质代谢的深入研究,通过补充外源性脑部营养物质,加强乙酰胆碱的积累、降低同型半胱氨酸(可以使早老性痴呆症的发生率加倍)也是对抗AD的一种积极策略。因此,脑部物质代谢研究出发,开发能激活人体细胞和细胞能量的营养物质配方,对有效的防治阿尔茨海默病或衰老的药物已是本领域研究者的关注热点。
发明内容
发明目的:本发明所要解决的技术问题是针对现有技术的不足,提供一种防治阿尔茨海默症的组合物。
本发明还要解决的技术问题是提供上述组合物的应用。
为了解决上述第一个技术问题,本发明公开了一种防治阿尔茨海默症的组合物,由以下重量份数的组分组成:
其中,所述的胞磷胆碱是一种内源性活性物质,是生物细胞膜性结构物质合成的中间物,胞磷胆碱在肠道水解为胆碱和胞嘧啶后进入血液循环系统,穿过血脑屏障在中枢神经系统内重合成胞磷胆碱,胞磷胆碱在中枢神经系统中也可以转化为乙酰胆碱,所以胞磷胆碱作为脑代谢激活剂,能够促进脑细胞呼吸,改善脑功能,增强上行网状结构激活系统的功能,促进苏醒,降低脑血管阻力。因此补充外源性胞磷胆碱可以从代谢调控的角度提升脑部乙酰胆碱的含量,改善认知功能障碍。有研究发现,胞二磷胆碱能够强化学习记忆及改善动物学习记忆障碍的报道。也有研究发现,应用胞二磷胆碱后,AD大鼠顶叶皮层老年斑表达无明显减少,神经元中β-分泌酶与γ-分泌酶水平无明显下降。提示胞二磷胆碱不具有通过抑制分泌酶的表达而减少Aβ产生,从而减少老年斑表达的作用。关于胞二磷胆碱在分泌酶的基因表达、转录、翻译过程中具体作用的机制尚需要进一步研究。
其中,所述的尿苷酸(UMP)作为脑膜磷脂生物合成的重要化合物,研究发现口服UMP可显著增加啮齿动物的大脑磷脂-磷脂酰胆碱(PtdCho)的水平。PtdCho能提供胆碱促进乙酰胆碱(ACh)的合成。有动物实验研究发现,UMP给药也有影响老年和幼龄大鼠纹状体和纹状体细胞外液中的乙酰胆碱水平,说明尿苷酸可以增强胆碱能功能,可能通过增加脑磷脂水平,改善AD症状。
其中,所述的N-乙酰神经氨酸(唾液酸)是哺乳类动物神经细胞膜的天然组成成分,其可与碳水化合物和脂质组成的酸性酯糖,透过血脑屏障,与神经细胞膜结合,引起膜功能变化,有感知、传递细胞内外信息的功能,参与细胞的识别、粘着、生长、分化以及细胞信息传递过程,细胞间的识别的能力;还能加速损伤神经组织再生、修复、促进神经支配功能修复,加速神经细胞的重塑性,改善细胞膜稳定性,,抑制Ap-蛋白引起的细胞激肽的释放。
其中,所述的磷脂酰丝氨酸(PS)又称复合神经酸,是脑部磷脂群重要的活性物质,其功能主要是改善神经细胞功能,调节神经脉冲的传导,增进大脑记忆功能,由于其具有很强的亲脂性,吸收后能够迅速通过血脑屏障进入大脑,起到舒缓血管平滑肌细胞,增加脑部供血的作用。有临床研究显示,PS作为一种抗痴呆药物可改善行为和认知表现,且无明显副作用,因此许多国家都已广泛应用PS补充剂来治疗衰老引发的痴呆症及老年记忆损失。
其中,所述的尿苷酸(UMP)、N-乙酰神经氨酸(唾液酸)和磷脂酰丝氨酸(PS)相辅相成,共同协同作用,进一步提高AD的改善水平。
优选地,所述的组合物由以下重量份数的组分组成:
进一步优选地,所述的组合物由以下重量份数的组分组成:
更进一步优选地,所述的组合物由以下重量份数的组分组成:
其中,上述组合物的剂型为胶囊剂、丸剂、颗粒剂、片剂和口服液中的任意一种。
其中,上述剂型的制备方法为向组合物加入制剂成型所需的辅料,按照制备药物制剂的常规方法制成。
为了解决上述第二个技术问题,本发明公开了上述组合的应用。
其中,所述的应用为在制备防治阿尔茨海默症药物中的应用,或在制备防治阿尔茨海默症保健品中的应用,或在制备防治阿尔茨海默症功能性食品中的应用。
其中,所述的阿尔茨海默症为早期阿尔茨海默症,即发病年龄早于65岁的早发型阿尔茨海默症。
有益效果:与现有技术相比,本发明具有如下优势:
(1)本发明所提供的组合物能够有效解决现有技术中AD症状无特效药,现有药物毒副作用大的问题,本发明通过对脑部物质代谢和AD病理机制的研究,从加强脑部营养,降低同型半胱氨酸的含量,提高乙酰胆碱含量,进而预防和干预早期AD症状。
(2)现有药物均属于改善症状药物,用药后具有短期改善患者症状的作用,但无法延缓和阻止病情进展恶化,而本发明所提供的组合物能够有效降低同型半胱氨酸的含量,从而延缓、阻止病情进展的恶化。
(3)本发明所提供的组合物可使P301L小鼠的跳台及避暗潜伏期明显缩短,即被动学习记忆能力显著提高;组合物干预后,P301L八臂迷宫的总探究时间明显缩短,工作记忆及参考记忆错误次数减少,即空间学习记忆能力明显提高;P301L小鼠血清中同型半胱氨酸含量降低,改善P301L小鼠部分关键脑区的连接水平。上述动物实验结果提示,给阿尔茨海默病动物模型P301L小鼠补充适量的本发明的组合物,能够显著改善阿尔茨海默症tau样病变相关的认知功能减退。
(4)经动物实验证实,本发明的组合物具有改善阿尔茨海默症小鼠的空间学习能力和空间探索能力,且血清中同型半胱氨酸含量降低。上述动物实验结果提示,给阿尔茨海默病动物模型小鼠补充适量的本发明的组合物,能够显著改善阿尔茨海默症tau样病变相关的认知功能减退。通过人群测试,该组合物能够明显改善阿尔茨海默病人群的记忆力。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明,本发明的上述和/或其他方面的优点将会变得更加清楚。
图1为实施例1和对比例中被动逃避实验的结果图。
图2为实施例1和对比例中水迷宫实验的结果图。
图3为实施例1和对比例中半胱氨酸浓度。
图4为实施例1,以及实施例4~7中被动逃避实验和水迷宫实验的结果图。
图5为实施例1,以及实施例4~7中半胱氨酸浓度。
具体实施方式
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得,同型半胱氨酸采用东软医疗同型半胱氨酸(HCY)检测试剂盒进行检测。
本发明所用的实验小鼠为表达P301L突变的转人tau基因小鼠,按照中山大学刘静硕士的学位论文提供的方法由集萃药康定制(刘静,表达P301L突变的tau转基因小鼠模型的建立,2007年),以下简称为P301L小鼠,能够很好地模拟NFTs这一病理现象及认知功能减退症状。
下面通过具体实施例对本发明作进一步的说明。
实施例1
按照日食用量:胞磷胆碱:490mg,尿苷酸:240mg,N-乙酰神经氨酸:152mg,磷脂酰丝氨酸:148mg,维生素E:24mg,维生素B6:1mg,维生素B12:0.45mg,叶酸:0.55mg配置该组合物5g,辅料为微晶纤维素。
制备方法:将上述原料按重量由小到大逐级混合并充分混匀,溶于生理盐水制成灌胃工作液,浓度为100mg/mL。
对比例1
按照日食用量:胞磷胆碱:490mg,尿苷酸:240mg,维生素E:24mg,维生素B6:1mg,维生素B12:0.45mg,叶酸:0.55mg配置该组合物5g,辅料为微晶纤维素。制剂方法同实施例1。
对比例2
按照日食用量:胞磷胆碱:490mg,尿苷酸:240mg,N-乙酰神经氨酸:152mg,维生素E:24mg,维生素B6:1mg,维生素B12:0.45mg,叶酸:0.55mg配置该组合物5g,辅料为微晶纤维素。制剂方法同实施例1。
对比例3
按照日食用量:胞磷胆碱:490mg,尿苷酸:240mg,磷脂酰丝氨酸:148mg,维生素E:24mg,维生素B6:1mg,维生素B12:0.45mg,叶酸:0.55mg配置该组合物5g,辅料为微晶纤维素。制剂方法同实施例1。
对比例4
按照日食用量:胞磷胆碱:490mg,N-乙酰神经氨酸:152mg,磷脂酰丝氨酸:148mg,维生素E:24mg,维生素B6:1mg,维生素B12:0.45mg,叶酸:0.55mg配置该组合物5g,辅料为微晶纤维素。制剂方法同实施例1。
实施例2:效果评价
6~7月龄SPF级P301L小鼠30只,雌雄各半,按体重随机分为阳性对照组(P301L)、实施例1和对比例1~3的组合物干预组,以同月龄同源野生型C57BL/6J小鼠为阴性对照组(Control)。组合物组小鼠每日每公斤体重以灌胃方式给予一定量的灌胃工作液(以20g小鼠为例,灌胃体积为0.15mL),P301L组和Control组小鼠每日灌胃等体积生理盐水。干预四周后,跳台和避暗实验检测小鼠的被动逃避学习记忆;水迷宫实验检测小鼠的空间学习记忆能力;采用全自动生化分析仪检测小鼠血清中同型半胱氨酸含量。
结果显示:
(1)被动逃避实验中,与Control组比较,P301L组小鼠的跳台与避暗潜伏期显著缩短;组合物组小鼠跳台与避暗潜伏期明显延长,且潜伏期实施例1>对比例2>对比例3>对比例4>对比例1(图1)。
(2)水迷宫实验中,组合物作用于P301L小鼠的水迷宫行为学实验的结果可以看出,与P301L小鼠对比,补充组合物的小鼠能够快速定位平台并有效改善AD症状;在水迷宫实验中,补充组合物的小鼠,在24h和72h穿越平台的目标象限的次数均优于P301L小鼠;补充组合物的小鼠,在24h内和72h内穿越目标平台区域的次数均优于P301L小鼠,且效果实施例1>对比例2>对比例3>对比例1和对比例4(图2)。
(3)同型半胱氨酸含量检测结果显示,与Control组比较,P301L组小鼠血清中的同型半胱氨酸表达升高;补充组合物的小鼠的同型半胱氨酸含量明显降低(图3)。上述实验结果表明,给予P301L转基因小鼠补充适量本发明的组合物可明显改善认知功能减退症状。实验证明,实施例1的组合物效果由于另外三种组合物,实施例1>对比例2>对比例3>对比例1和对比例4。
实施例3
对实施例1中的组合物配方进行毒理实验。设4个剂量组,溶媒对照组,组合物高剂量组15g/kg,组合物中剂量组7.5g/kg,组合物低剂量组3.75g/kg。使用SD健康大鼠,16只动物分为4组,每组4只,雌雄各半。所有动物采用口服灌胃。溶媒对照组采用实验动物饮用水上下午给药,给药体积2mL/100g体重/次。组合物高剂量组上下午给药,给药体积2mL/100g体重/次;组合物中剂量组单次给药,给药体积2mL/100g体重;组合物低剂量组单次给药,给药体积1mL/100g体重。
15g/kg组合物单次经口给药会造成动物大范围死亡,主要症状:15g/kg组合物大鼠出现了水样稀便,12g/kg和6g/kg组合物组大鼠出现软便,该组合物的动物症状表现严重程度呈一定的剂量依赖性。
根据本次试验结果,实施例1组合物对大鼠经口单次给药最小致死量(MLD)为15g/kg(相当于人等效剂量2.38g/kg),最大耐受量(MTD)>7.5g/kg(相当于人等效剂量1.19g/kg)。另外,根据本次试验有限数据估算:实施例1组合物LD50=10.442g/kg,根据OECD急毒相关原则,实施例1组合物LD50都远大于2000mg/kg,因此,该组合物无严重急性中毒的危险性。
实施例4
按照日食用量:胞磷胆碱:1000mg,尿苷酸:500mg,N-乙酰神经氨酸:300mg,磷脂酰丝氨酸:300mg,维生素E:40mg,维生素B6:2mg,维生素B12:2mg,叶酸:2mg配置该组合物5g,辅料为微晶纤维素。
将上述原料按重量由小到大逐级混合并充分混匀,溶于生理盐水制成灌胃工作液,浓度为100mg/mL。
实施例5
按照日食用量:胞磷胆碱:700mg,尿苷酸:400mg,N-乙酰神经氨酸:200mg,磷脂酰丝氨酸:200mg,维生素E:40mg,维生素B6:2mg,维生素B12:2mg,叶酸:2mg配置该组合物5g,辅料为微晶纤维素。
将上述原料按重量由小到大逐级混合并充分混匀,溶于生理盐水制成灌胃工作液,浓度为100mg/mL。
实施例6
按照日食用量:胞磷胆碱:300mg,尿苷酸:200mg,N-乙酰神经氨酸:100mg,磷脂酰丝氨酸:100mg,维生素E:10mg,维生素B6:0.1mg,维生素B12:0.1mg,叶酸:0.1mg配置该组合物5g,辅料为微晶纤维素。
将上述原料按重量由小到大逐级混合并充分混匀,溶于生理盐水制成灌胃工作液,浓度为100mg/mL。
实施例7
按照日食用量:胞磷胆碱:100mg,尿苷酸:20mg,N-乙酰神经氨酸:10mg,磷脂酰丝氨酸:10mg,维生素E:5mg,维生素B6:0.1mg,维生素B12:0.1mg,叶酸:0.1mg配置该组合物5g,辅料为微晶纤维素。
将上述原料按重量由小到大逐级混合并充分混匀,溶于生理盐水制成灌胃工作液,浓度为100mg/mL。
实施例8:效果评价
6~7月龄SPF级P301L小鼠40只,雌雄各半,按体重随机分为阳性对照组(P301L)、实施例1和实施例4~7的组合物干预组,以同月龄同源野生型C57BL/6J小鼠为阴性对照组(Control)。组合物组小鼠每日每公斤体重以灌胃方式给予一定量的灌胃工作液(以20g小鼠为例,灌胃体积为0.15mL),P301L组和Control组小鼠每日灌胃等体积生理盐水。干预四周后,跳台和避暗实验检测小鼠的被动逃避学习记忆;水迷宫实验检测小鼠的空间学习记忆能力;采用全自动生化分析仪检测小鼠血清中同型半胱氨酸含量;
结果显示:
(1)被动逃避实验中,与Control组比较,P301L组小鼠的跳台与避暗潜伏期显著缩短;组合物组小鼠跳台与避暗潜伏期明显延长,且呈现剂量正相关性(实施例4>实施例5>实施例1>实施例6>实施例7),但剂量超过实施例1使用剂量后,避暗潜伏期并不能明显提升,因此优选实施例1配方方案(图4)。
(2)水迷宫实验中,组合物作用于P301L小鼠的水迷宫行为学实验的结果可以看出,与P301L小鼠对比,补充组合物的小鼠能够快速定位平台并有效改善AD症状;在水迷宫实验中,补充组合物的小鼠,在24h和72h穿越平台的目标象限的次数均优于P301L小鼠;补充组合物的小鼠,在24h内和72h内穿越目标平台区域的次数均优于P301L小鼠,且呈现剂量正相关性(实施例4>实施例5>实施例1>实施例6>实施例7),但剂量超过实施例1使用剂量后,24h和72h穿越平台的目标象限的次数和目标平台次数并不能明显提升,因此优选实施例1配方方案(图4)。
(3)同型半胱氨酸含量检测结果显示,与Control组比较,P301L组小鼠血清中的同型半胱氨酸表达升高;补充组合物的小鼠的同型半胱氨酸含量明显降低(图5)。上述实验结果表明,给予P301L转基因小鼠补充适量本发明的组合物可明显改善认知功能减退症状。实验证明,补充组合物效果明显,且呈现剂量正相关性(实施例4>实施例5>实施例1>实施例6>实施例7),但剂量超过实施例1使用剂量后,同型半胱氨酸并不能明显降低,基本趋于正常水平,因此优选实施例1配方方案(图5)。
实施例9
通过人群试服实施例1的组合物,试用人员(未经药物治疗的轻度AD患者),受试16周后,患者的记忆力、睡眠状况得到改善,且无任何不适,说明该组合是有效的。更多临床实验需要进一步开展。
本发明提供了一种防治阿尔茨海默症的组合物及应用的思路及方法,具体实现该技术方案的方法和途径很多,以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。本实施例中未明确的各组成部分均可用现有技术加以实现。
Claims (8)
5.根据权利要求1~4中任意一项所述的组合物,其特征在于,所述组合物的剂型为胶囊剂、丸剂、颗粒剂、片剂和口服液中的任意一种。
6.权利要求1~4中任意一项所述的组合物在制备防治阿尔茨海默症药物中的应用。
7.权利要求1~4中任意一项所述的组合物在制备防治阿尔茨海默症保健品中的应用。
8.权利要求1~4中任意一项所述的组合物在制备防治阿尔茨海默症功能性食品中的应用。
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