CN111450217A - 一种治疗帕金森病痴呆的中药组合物及其制备方法 - Google Patents
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Abstract
一种治疗帕金森病痴呆的中药组合物，由以下重量份数的原料药制成：熟地、五味子、仙灵脾、蚕蛾、肉苁蓉、巴戟天、龟板、黄柏、太子参、牡蛎、吴茱萸、远志、益智仁、分心木、狗脊、蜈蚣、天花粉、络石藤、透骨草、千年健、皂角刺、壁虎、珍珠、菊花、川芎、鹿茸、蜂蜜。本发明能有效改善脑神经功能，促进神经代谢以及减轻细胞损伤，也能有效改善帕金森病相关症状，而且使用简便、安全可靠、成本低、疗效明显；且中药组方合理，提取制备工艺科学先进，符合车间大批量生产，质量标准严格可控。
Description
技术领域
本发明属于医药类技术领域，尤其涉及一种治疗帕金森病痴呆的中药组合物及其制备方法。
背景技术
帕金森病(PD)是一种神经系统退行性病变，主要有运动不协调、认知功能、自主神经功能障碍和神经精神异常等临床表现，随着病程的进展，患者认知功能和日常生活能力呈进行性下降，认知功能障碍表现越来越明显，主要有注意力、执行力、记忆力、视空间能力的改变，认知功能障碍会逐渐发展为帕金森病痴呆，帕金森病痴呆发生率约为20％-60％，帕金森病最主要的病理改变是中脑黑质多巴胺能神经元的变性死亡，由此而引起纹状体DA含量显著性减少而致病。导致这一病理改变的确切病因目前仍不清楚，遗传因素、环境因素、年龄老化、氧化应激等均可能参与PD多巴胺能神经元的变性死亡过程，此外有证据表明，在帕金森病痴呆患者脑组织中β淀粉样蛋白过度表达和积聚，与阿尔茨海默病的发病机制相似，计算机断层显像发现，Aβ的沉积与帕金森病痴呆患者的认知功能下降存在相关性，长期大多数伴发认知功能损伤的PD患者将进一步发展为痴呆，给社会和家庭带来巨大的负担。
中医认为，帕金森病痴呆的基本病机为髓海不足，正如《医林改错》所云“年高无记性者，脑髓渐空”。颤病者，多年迈久病，气血虚弱，肝肾亏虚，而致精少神昏、脑失所养，而见健忘、发呆等症。气血不足，精血亏虚，髓海失充，继而导致风、痰、瘀等变证丛生，日久导致痰瘀互结，各脏腑气血衰弱，元神昏赣，筋脉失养，肢体失控。因此，我们认为，帕金森病痴呆病位在髓海，本虚标实之证，临床常见的头摇肢颤、头晕耳鸣、记忆不清，甚则神呆、言语失序、啼笑无常等皆为精亏髓减，痰瘀互结之象。
目前，帕金森病痴呆治疗药物较少，虽然有一些药物应用在一定程度上缓解了患者的认知障碍，但长期药物治疗效果不明显，有时还会加剧患者痴呆、运动症状的波动，对愈后造成不良影响。
发明内容
本发明的目的在于提供一种治疗帕金森病痴呆的中药组合物，同时提供其制备方法是本发明的又一发明目的。
为实现上述发明目的，本发明采取以下技术方案：
一种治疗帕金森病痴呆的中药组合物，由以下重量份数的原料药制成：熟地20～40份、五味子10～20份、仙灵脾20～40份、蚕蛾5～15份、肉苁蓉20～40份、巴戟天10～20份、龟板20～40份、黄柏10～20份、太子参10～20份、牡蛎20～40份、吴茱萸10～20份、远志10～20份、益智仁10～20份、分心木20～40份、狗脊20～40份、蜈蚣10～20份、天花粉10～20份、络石藤20～40份、透骨草10～20份、千年健20～40份、皂角刺10～20份、壁虎10～20份、珍珠10～20份、菊花5～10份、川芎5～10份、鹿茸5～10份、蜂蜜5～10份。
所述的治疗帕金森病痴呆的中药组合物的制备方法，包括以下步骤：
1)将熟地、五味子、仙灵脾、蚕蛾、巴戟天、龟板、黄柏、太子参、牡蛎、吴茱萸、远志、益智仁、分心木、狗脊、天花粉、络石藤、透骨草、千年健、皂角刺、菊花、川芎、肉苁蓉混合粉碎，得粉末A，将蜈蚣、珍珠、壁虎、鹿茸粉碎，过七号筛，得粉末B；
2)将粉末A加水提取，所得提取液经过滤、浓缩得浸膏，所得浸膏经喷雾干燥制粒得干燥颗粒，将粉末B和干燥颗粒粉碎，过120目筛，混合得粉末C；
3)将蜂蜜加水使其70℃时的相对密度为1.30-1.40，并于70℃下与粉末C混合，制丸块，搓丸条，制丸粒，干燥即得，谓之熄颤健脑丸。
步骤2)中，所述粉末A制成浸膏的具体操作为：粉末A采用连续回流法提取，共回流提取两次，每次回流提取前加水，每克药材加水6-10ml，沸后回流提取25-35min；将得到的提取液用纱布过滤，合并过滤后的提取液，用旋转蒸发仪蒸发浓缩即得浸膏。
所用纱布的孔径为0.70-0.90毫米。
步骤2)中得到的浸膏含水量为55-65％时停止蒸发浓缩。
现有帕金森病痴呆治疗缺乏针对性药物，单纯用治疗老年性痴呆的药物虽然可以改善智能障碍，但对帕金森病缺乏疗效，帕金森病痴呆患者常因年老体弱，人过中年，脾胃逐渐受损，肝肾亏虚，精气暗衰，筋脉失于濡养；久病必有瘀，本发明中药组合物—熄颤健脑丸，采用活血化瘀以生新，激发人体“肾属性”，使“骨髓之精”、“脏腑之精”得充，从而起到修复、重建脏腑之效；补益药配渗泄药，使补而不壅滞；滋阴药配助阳药，使阴得阳而化生；活血药配补血药，活血而不伤血；兼顾先天与后天。
本发明熄颤健脑丸是近几年来临床治疗帕金森病痴呆的新药，不仅能有效改善脑神经功能，促进神经代谢以及减轻细胞损伤，也能有效改善帕金森病相关症状，而且使用简便、安全可靠、成本低、疗效明显。
本发明熄颤健脑丸的功效：补肾益精、熄颤健脑、化瘀生新，故命名熄颤健脑丸。
药理作用为：具有脑保护作用、抗细胞凋亡、抗纤维化、抗炎、改善神经功能、抗氧化、抗衰老、增强免疫力、熄颤健脑、镇静、催眠、抗惊厥、抗血栓等作用。
病机分析：所治之证乃精亏髓减，痰瘀互结证则肝木不生，致使肝肾阴液精血亏虚，不足以濡养筋脉，从而导致虚风内动，则头摇肢颤、持物不稳；肾精不足则见腰膝酸软，头晕耳鸣，善忘；肾司二便，故见小便不畅；肾生精，精生髓，脑为聚髓之处，肾精不足则脑髓不得充，则见神志、失眠障碍；舌淡红，苔薄白，脉沉细无力，皆为精亏髓减之征。治当以补肾益精、养阴息风、化瘀生新。
临床表现：头摇肢颤，不可自主，持物不稳，步态障碍，步距小，腰膝酸软、头晕耳鸣，神呆、言语失序、善忘，言语謇涩，啼笑反常，小便不畅，寤寐颠倒，舌淡红，苔薄白，脉沉细无力。西医病：帕金森病伴有注意力、执行力、记忆力、视空间能力障碍，认知功能障碍、帕金森病痴呆。
注意事项：湿热蕴结慎用此方。
与现有技术相比，本发明的有益效果如下：
本发明熄颤健脑丸是针对精亏髓减，痰瘀互结证型的帕金森病痴呆的具有中医特色中成药。方中熟地、肉苁蓉(酒制)共用可大补精血，使精亏得补，阴精充沛；鹿茸、仙灵脾共同温补肾阳，使阳生髓充；远志、益智仁可以健脾益智，醒神开窍，使脑安神灵、陆药共担补肾益精、益智止颤共为君；太子参补中气、固后天，使后天精血生化有源，蜈蚣、蚕蛾通络息风以止颤、缓拘急，天花粉、皂角刺祛痰通络，气血调畅，神安助智；五味子、巴戟天其质润能养，为补肾阳、益精血之良药；分心木、狗脊可以强筋骨、健腰膝、益精填髓，舒筋活络；共为臣药；吴茱萸、络石藤、透骨草、千年健、菊花熄风通络减颤；黄柏、龟板、牡蛎、珍珠重镇安神，滋阴潜阳，清虚热防补肾益髓药太过，致使内生他邪；川芎活血化瘀，壁虎破血逐瘀，二药行气血。生新血，即可引血上冲脑窍，又可防补益太过而生瘀血，上述诸味药合用，共起填精增髓、养阴息风、活血化瘀生新之效。
本发明配方按新药申报的要求进行中药的药材提取、制备工艺、质量标准等研究，以期进一步提高中药产品的质量，从而保证人们用药的安全性和有效性。对熟地、五味子、仙灵脾、蚕蛾、肉苁蓉、巴戟天、龟板、黄柏、太子参、牡蛎、吴茱萸、远志、益智仁、分心木、狗脊、蜈蚣、天花粉、络石藤、菊花、川芎、鹿茸、透骨草、千年健、皂角刺的提取工艺进行正交考察，优化提取条件，并根据药物剂型的特点对片剂制备工艺进行研究；对产品理化及剂型按要求进行考察，采用薄层色谱法以对照药材和对照品作为对照，对方中熟地、五味子、仙灵脾、蚕蛾、肉苁蓉、巴戟天、龟板、黄柏、太子参、牡蛎、珍珠、吴茱萸、远志、益智仁、分心木、狗脊、进行了薄层定性鉴别研究；根据药材特点，采用原子吸收、原子荧光对部分元素进行考察；用高效液相色谱法对其中的主要有效成分地黄素、山茱萸苷、没食子酸、五味子素、甜菜碱、环木菠萝烷三萜、黄酮类、甾醇、三萜皂苷、小檗碱、党参苷、石松碱等进行了含量测定及色谱鉴别研究，并结合紫外测定总氨基酸含量；同时，根据研究制定的草案，对制剂的长期、加速稳定性进行考察。优选出了方中药味的提取、合理的制剂成型工艺，有效的建立了方中药味的质量控制方法。
因此，本发明中药组方合理，提取制备工艺科学先进，符合车间大批量生产，质量标准严格可控。
具体实施方式
下面结合具体实施方式对本发明做进一步说明。
实施例1
一种治疗帕金森病痴呆的中药组合物，由以下重量份数的原料药制成：熟地30份、五味子15份、仙灵脾30份、蚕蛾10份、肉苁蓉25份、巴戟天15份、龟板25份、黄柏15份、太子参15份、牡蛎30份、吴茱萸15份、远志15份、益智仁15份、分心木30份、狗脊30份、蜈蚣15份、天花粉15份、络石藤30份、透骨草15份、千年健30份、皂角刺15份、壁虎15份、珍珠15份、菊花8份、川芎8份、鹿茸8份、蜂蜜8份。
其制备方法，包括以下步骤：
1)将熟地、五味子、仙灵脾、蚕蛾、巴戟天、龟板、黄柏、太子参、牡蛎、吴茱萸、远志、益智仁、分心木、狗脊、蜈蚣、天花粉、络石藤、透骨草、千年健、皂角刺、菊花、川芎、肉苁蓉混合均匀粉碎，得粉末A，将蜈蚣、珍珠、壁虎、鹿茸均匀粉碎，然后过七号筛，得粉末B；
2)将粉末A加水提取，所得提取液经过滤、浓缩得浸膏，所得浸膏经喷雾干燥制粒得干燥颗粒，将粉末B和干燥颗粒粉碎，过120目筛，混合均匀得粉末C；步骤2)中，所述粉末A制成浸膏的具体操作为：粉末A采用连续回流法提取，共回流提取两次，每次回流提取前加水，每克药材加水8ml，沸后回流提取30min；将得到的提取液用纱布(孔径为0.85毫米)过滤，合并过滤后的提取液，用旋转蒸发仪蒸发浓缩即得浸膏；步骤2)中得到的浸膏含水量为60％时停止蒸发浓缩；
3)将蜂蜜加水使其70℃时的相对密度为1.38，然后在70℃下与粉末C混合，制丸块，搓丸条，制丸粒，干燥即得，谓之熄颤健脑丸。
实施例2
一种治疗帕金森病痴呆的中药组合物，由以下重量份数的原料药制成：熟地20份、五味子10份、仙灵脾20份、蚕蛾5份、肉苁蓉20份、巴戟天10份、龟板20份、黄柏10份、太子参10份、牡蛎20份、吴茱萸10份、远志10份、益智仁10份、分心木20份、狗脊20份、蜈蚣10份、天花粉10份、络石藤20份、透骨草10份、千年健20份、皂角刺10份、壁虎10份、珍珠10份、菊花5份、川芎5份、鹿茸5份、蜂蜜5份。
其制备方法同实施例1，不同之处在于，
步骤2)中，所述粉末A制成浸膏的具体操作为：粉末A采用连续回流法提取，共回流提取两次，每次回流提取前加水，每克药材加水6ml，沸后回流提取25min；所用纱布的孔径为0.70毫米；得到的浸膏含水量为55％时停止蒸发浓缩；步骤3)中，将蜂蜜加水使其70℃时的相对密度为1.30。
实施例3
一种治疗帕金森病痴呆的中药组合物，由以下重量份数的原料药制成：熟地40份、五味子20份、仙灵脾40份、蚕蛾15份、肉苁蓉40份、巴戟天20份、龟板40份、黄柏20份、太子参20份、牡蛎40份、吴茱萸20份、远志10～20份、益智仁20份、分心木40份、狗脊40份、蜈蚣20份、天花粉20份、络石藤40份、透骨草20份、千年健40份、皂角刺20份、壁虎20份、珍珠20份、菊花10份、川芎10份、鹿茸10份、蜂蜜10份。
其制备方法同实施例1，不同之处在于，
步骤2)中，所述粉末A制成浸膏的具体操作为：粉末A采用连续回流法提取，共回流提取两次，每次回流提取前加水，每克药材加水10ml，沸后回流提取35min；所用纱布的孔径为0.90毫米；得到的浸膏含水量为65％时停止蒸发浓缩；步骤3)中，将蜂蜜加水使其70℃时的相对密度为1.40。
下面结合实验数据说明本发明的有益效果：
实验例1：本发明熄颤健脑丸对精亏髓减，痰瘀互结证型金森病痴呆临床研究
1、研究对象
2017年6月20日至2018年12月30日，纳入本研究的60例患者，均来自于河南中医药大学第三附属医院脑病科门诊及病房，均符合本研究精亏髓减，痰瘀互结证型金森病痴呆患者的纳入标准。
2、诊断标准
参考《中国帕金森病的诊断标准(2016版)》由中华医学会神经病学分会帕金森病及痴呆运动障碍学组制订。
3、分组情况
将符合上述诊断标准的患者60例，按照就诊先后进行编号，从1号至60号，录入EXCEL软件，利用“RAND”函数生成60个随机数并与序号对应，按照生成的随机数进行升序排列，则前30个序号为治疗组，后30个序号为对照组。因患者依从性差，治疗组脱落1例，最终收集符合诊断的患者为59例，即治疗组29例，对照组30例。
4、治疗方案
对照组：口服多巴丝肼片基础上服用天智颗粒治疗，服药周期为9周；多巴丝肼片(规格：左旋多巴200mg与盐酸苄丝肼50mg，国药准字号H10930198，生产厂家：上海罗氏公司有限公司)，一日3次，每次口服125mg，一周后改为250mg，一日3次。
治疗组：在口服多巴丝肼片基础上服用熄颤健脑丸，服药疗程为9周，多巴丝肼片联合熄颤健脑丸，熄颤健脑丸(由河南中医大学第三附属医院药剂科提供)，每次3丸，一日三次。
3周为一个疗程，共连续3个疗程。
5、评定内容
观察两组患者在治疗前后不同时间的中医证候评分、日常生活能力(UPDRSⅡ评分)、运动症状(UPDRSⅢ)、日常生活质量(PDQ-39)的积分变化情况。
6、疗效评定
参考《颤证(帕金森病)中医诊疗方案(2015年版)》，进行本研究的疗效评定。疗效指数采用尼莫地平法，计算方法为：(治疗前总积分-治疗后总积分)/治疗前总积分×100％＝疗效；中医证候临床疗效评定标准：基本痊愈：中医临床症状、体征消失或基本消失，疗效≥80％；显效：中医临床症状、体征明显改善，疗效≥50％；有效：中医临床症状、体征均有所改善，疗效≥20％；无退步：中医症状、体征无明显改善，亦无加重，疗效≤20％；无效恶化：中医临床症状、体征无明显改善，甚至加重，疗效≤0％。
7、统计学分析
采用SPSS22.0统计软件对本研究收集的资料进行统计学处理及分析，数据分为计数资料与计量资料，计数资料采用χ2检验，病情程度比较采用等级资料的秩和检验。计量资料以均数±标准差
表示，先进行正态性检验，若符合正态性，则进行方差齐性检验，二者同时满足，组内比较选用重复测量资料的方差分析，组间比较选用独立样本t检验；若不满足正态性，则采用非参数检验。其中检验水准α＝0.05。
8、结果：
8.1病情程度比较
两组病情程度比较结果见表1，经秩和检验，z＝-0.614，P＝0.539>0.05，两组有差异无统计学意义。
表1两组患者治疗前病情程度(H-Y分级)
注：与对照组比较P>0.05。
8.2中医证候比较
两组治疗前中医证候评分经独立样本t检验，t＝0.516，P＝0.608>0.05，提示两组存在差异，无统计学意义，详见表2。
表2两组患者治疗前中医证候评分的比较
| 例数 | 治疗前 | t | P |
| 29 | 19.58±3.51 | / | / |
| / | / | 0.516 | 0.608 |
| 30 | 19.13±3.22 | / | / |
注：与对照组比较P>0.05。
8.3日常生活能力(UPDRSⅡ)评分情况
两组治疗前日常生活能力评分经独立样本t检验，t＝0.521,P＝0.605>0.05,提示两组存在差异，无统计学意义，详见表3。
表3两组患者治疗前日常生活能力评分的比较
| 组别 | 例数 | 治疗前 | t | P |
| 治疗组 | 29 | 36.55±5.96 | / | / |
| / | / | / | 0.521 | 0.605 |
| 对照组 | 30 | 35.63±5.86 | / | / |
注：与对照组比较P>0.05。
8.4运动症状(UPDRSⅢ)评分情况
两组治疗前运动症状评分经独立样本t检验，t＝0.597,P＝0.553>0.05，提示两组有差异，无统计学意义，详见表4。
表4两组患者治疗前运动症状评分的比较
| 组别 | 例数 | 治疗前 | t | P |
| 治疗组 | 29 | 36.55±5.96 | / | / |
| / | / | / | 0.597 | 0.553 |
| 对照组 | 30 | 35.73±3.22 | / | / |
注：与对照组比较P>0.05。
8.5生活质量评分情况
两组治疗前日常生活质量评分经独立样本t检验，t＝0.459,P＝0.648>0.05，提示两组存在差异，无统计学意义，详见表8。
表5两组患者治疗前生活质量评分的比较
| 组别 | 例数 | 治疗前 | t | P |
| 治疗组 | 29 | 64.82±11.43 | ||
| 0.459 | 0.648 | |||
| 对照组 | 30 | 63.53±10.20 |
注：与对照组比较P>0.05。
8.6临床研究结果
8.6.1中医证候评分比较
中医证候评分方面组内比较采用重复测量方差分析，治疗组与对照组各自在其治疗前后不同时间的整体比较有统计学意义(F＝347.451，P＝0.00<0.05)，且随时间的增长，其差异愈显著，治疗前后时间变化与组别之间的关系比较存在的交互效应，差异有统计学意义(F＝21.122，P＝0.000<0.01)，即治疗组的中医症候评分整体优于对照组；从不同时间点的治疗组与对照组相互对比，在治疗3周时，治疗组与对照组的证候评分比较无统计学意义(P＝0.145>0.05)，而在治疗6周与9周后，两组评分均具有显著差异有统计学意义(P＝0.000<0.05)，见表6所示。
表6中医证候评分比较
| 组别 | 例数 | 治疗前 | 治疗3周后 | 治疗6周后 | 治疗9周后 |
| 治疗组 | 29 | 19.58±3.51 | 16.34±2.59＊# | 12.86±2.01＊# | 8.96±1.84＊# |
| 对照组 | 30 | 19.13±3.22 | 17.40±2.87＊ | 14.86±2.38＊ | 12.83±2.60＊ |
注：与同组治疗前比较＊P<0.05；治疗3周后，与对照组比较＊#P>0.05；治疗6周后与治疗9周后，与对照组比较＊#P<0.05。
8.6.2中医证候总有疗效率的比较
两组中医证候积分量表的疗效比较，经χ2检验，χ2＝4.069，P＝0.044<0.05，两组有差异有统计学意义，观察者总有效率为86.20％，对照组为63.33％，说明治疗组优于对照组，见表7。
表7两组中医证候总有效率的比较
| 组别 | 例数 | 临床痊愈 | 显效 | 有效 | 无效 | 总有效率(％) |
| 治疗组 | 29 | 3 | 13 | 9 | 4 | 86.20％ |
| 对照组 | 30 | 1 | 3 | 15 | 11 | 63.33％ |
注：与治疗前比较P<0.05。
8.6.3日常生活能力(UPDRSⅡ)评分的比较
日常生活能力评分方面组内比较采用重复测量方差分析，两组在治疗前后不同时间的整体比较具有统计学意义(F＝183.737，P＝0.000<0.05)，随时间的增长，差异越显著，治疗前后时间与组别之间存在交互效应(F＝19.766,P＝0.000<0.05)，即说明治疗组的日常生活能力(UPDRSⅡ)评分优于对照组。采用独立样本t检验发现，不同时间点两组相互比较，在治疗3周后，两组日常生活能力评分比较无统计学意义(P＝0.859>0.05)；而在治疗6周后两组评分比较差异有统计学意义(P＝0.005<0.05)；治疗9周后，两组评分均具有统计学意义(P＝0.003<0.05)(具体见表8)。
表8日常生活能力(UPDRSⅡ)评分的比较
| 组别 | 例数 | 治疗前 | 治疗3周后 | 治疗6周后 | 治疗9周后 |
| 治疗组 | 29 | 17.17±3.88 | 15.96±3.58＊# | 12.65±3.01＊# | 11.06±2.25＊# |
| 对照组 | 30 | 16.73±3.98 | 16.13±3.65＊ | 15.03±3.15＊ | 13.13±2.88＊ |
注：与同组治疗前比较＊P<0.05；治疗3周后，与对照组比较＊#P>0.05；治疗6周后与治疗9周后，与对照组比较＊#P<0.05。
8.6.4运动症状(UPDRSⅢ)评分的比较
运动症状评分方面采用组内比较采用重复测量方差分析，两组在治疗前后不同时间的整体比较具有统计学意义(F＝664.156，P＝0.000<0.05)，随时间的增长，差异越显著，治疗前后时间与组别之间存在交互效应(F＝18.956,P＝0.000<0.05)，提示治疗组的运动症状整体优于对照组。
采用独立样本t检验对不同时间点两组相互比较，在治疗3周后，两组运动症状评分比较无统计学意义(P＝0.325>0.05)；而在治疗6周后具有统计学意义(P＝0.039<0.05)；治疗9周后，治疗组与对照组评分均具有统计学意义(P＝0.005<0.05)。
表9运动症状(UPDRSⅢ)评分比较
| 组别 | 例数 | 治疗前 | 治疗3周后 | 治疗6周后 | 治疗9周后 |
| 治疗组 | 29 | 36.55±5.96 | 30.65±5.50＊# | 25.89±4.58＊# | 21.58±3.88＊# |
| 对照组 | 30 | 35.63±5.86 | 32.26±5.67＊ | 28.66±5.43＊ | 24.83±4.66＊ |
注：与同组治疗前比较＊P<0.05；治疗3周后，与对照组比较＊#P>0.05；治疗6周后与治疗9周后，与对照组比较＊#P<0.05。
8.6.5日常生活质量(PDQ-39)评分的比较
两组分别在治疗前与治疗9周后进行生活质量评分比较，统计学方法分析采用配对t检验进行组内比较；两组在治疗9周后进行生活质量评分比较，统计学方法分析采用独立样本t检验进行组间比较。采用配对t检验对治疗组与对照组治疗前与治疗后9周后生活质量评分比较，治疗组：治疗前后比较，差异均有统计学意义(P＝0.000<0.05)；对照组：治疗前后比较，差异均有统计学意义(P＝0.000<0.05)。经独立样本t检验分析发现：治疗组在治疗9周后的生活治疗评分明显优于对照组，差异具有统计学意义(P＝0.000<0.05)。提示：两组的治疗方法对于患者的生活质量恢复均有效果，治疗组明显优于对照组。见表10。
表10日常生活质量(PDQ-39)评分的比较
| 组别 | 例数 | 治疗前 | 治疗9周后 |
| 治疗组 | 29 | 64.82±11.43 | 44.68±8.45＊# |
| 对照组 | 30 | 63.53±10.20 | 49.96±9.11＊ |
注：与同组治疗前比较＊P<0.05；与对照组比较#P<0.05。
9、安全性评价不良结果发生处理
在本课题研究期间，两组患者血常规、肝功能、肾功能、心电图等安全性指标均未出现异常反应；两组患者均未出现相关的毒副作用或者异动症、开关效应等不良并发症。
10、研究小结：
经过为期9周的治疗，通过对两组患者的中医证候量表、日常生活能力量表(UPDRSⅡ)、运动症状量表(UPDRSⅢ)和日常生活质量量表(PDQ-39)的评价，显示两组患者临床症状均有改善，随着治疗时间的增长，疗效更为明显，且对两组总有效率比较，治疗组为86.20％，对照组为63.33％，经统计学分析差异有统计学意义，说明治疗组疗效均优于对照组。
10.1中医证候量表评分：治疗组与对照组在治疗前后均存在显著性差异(P<0.05)，说明治疗均有疗效；治疗3周后，治疗组与对照组评分比较，无统计学意义(P>0.05)；治疗6周、9周后，两组比较均具有显著差异(P<0.05)。
10.2日常生活能力量表(UPDRSⅡ)评分：两组患者在治疗后均较治疗前有显著性差异(P<0.05)，提示两组治疗均有疗效；治疗3周后两组评分比较(P>0.05)，无明显差异；治疗6周、9周后，治疗组与对照组评分比较均具有明显差异(P<0.05)。
10.3运动功能量表(UPDRSⅢ)评分：两组患者在治疗后均较治疗前有显著性差异。(P<0.05)，提示治疗均有疗效；治疗3周后，治疗组与对照组评分比较(P>0.05)，两组无明显差异；治疗6周、9周后，两组评分比较均存在显著差异(P<0.05)。
10.4日常生活质量量表(PDQ-39)评分：两组患者在治疗后均较治疗前有显著性差异(P<0.05)，提示两组治疗均有疗效；通过对治疗后两组的评分进行统计学分析，两组存在差异有统计学意义(P<0.05)。
11结论
熄颤健脑丸对精亏髓减，痰瘀互结证型金森病痴呆患者可提高认知能力，有效缓解患者运动症状，改善中医证候，提高患者生活质量，具有较好的临床疗效，且安全、无副作用。
实验例2：熄颤健脑丸对帕金森病痴呆患者认知功能及脑脊液IL-6,IL-1β,TNF-α、IFN-γ水平影响
1、诊断标准：
帕金森病诊断符合中华医学会神经病学分会帕金森病及运动障碍学组《中国帕金森病治疗指南(第三版)中帕金森病的相关诊断标准，简易智能状态检查量表(MMSE)评分为轻中度痴呆(10-20分)；排除严重肝肾功能障碍、心脑血管疾病、其他原因引起的痴呆、重度认知功能障碍及意识障碍、有精神异常、不能配合研究或完成量表评分者。患者及家属签署知情同意书，并自愿参与本次研究。
2、分组：河南中医药大学第三附属医院脑病科门诊及病房的66例帕金森病痴呆患者随机分为治疗组70例和对照组70例，两组年龄、性别、BMI、病程、合并症、Hoehn Yahr分级、帕金森病综合评分量表(UPDRS)评分比较差异无统计学意义(P均>0.05)，具有可比性。
3、治疗用药：对照组：多巴丝肼片联合复方苁蓉益智胶囊，多巴丝肼片一日3次，每次口服125mg，一周后改为250mg，一日3次。复方苁蓉益智胶囊，每次3粒，一日三次口服。治疗组：多巴丝肼片联合熄颤健脑丸，熄颤健脑丸(由河南中医大学第三附属医院药剂科提供)，每次3丸，一日三次。
3周为一个疗程，共连续3给疗程。
4、观察指标
①两组治疗前后MMSE评分：该评分包括定向力、回忆力、语言能力和计算力等内容，总分为27-30分为正常，<27分为认知功能障碍，得分越高则认知功能越好。
②组治疗前后的生活满意度量表(LSIB)评分、帕金森病生活质量评分量表(PDQ)评分。
③组治疗前后脑脊液IL-6,IL-1β,TNF-αIFN-γ的变化：采用免疫酶联法(ELISA)，按照说明书由检验科专人操作。
5、研究结果：
5.1两组治疗前后认知功能相关指标比较
表11两组治疗前后认知功能相关指标比较(一)
表12两组治疗前后认知功能相关指标比较(二)
治疗后MMSE评分中定向力、语言能力、和计算力及总分均显著提高(P均<0.OS)，且观察组上述指标改善情况均显著优于对照组(P均<0.05)。
2 2组治疗前后LSIB及PDQ评分比较
表13 2组治疗前后LSIB及PDQ评分比较
2组治疗后LSIB,PDQ评分均显著改善(P均<0.05)，治疗组上述指标改善情况显著优于对照组(P均<0.OS)。
3 2组治疗前后脑脊液IL-6,IL-1β,TNF-α、IFN-γ水平比较
表14 2组治疗前后脑脊液IL-6,IL-1β水平比较
表14 2组治疗前后脑脊液TNF-α、IFN-γ水平比较
结论：本发明熄颤健脑丸能够改善帕金森病痴呆患者的认知功能及生活质量，提高生活满意度，且安全可靠，其机制可能与抑制机体IL-6,IL-1β,TNF-α、IFN-γ水平有关。
实验例3：熄颤健脑丸对帕金森病大鼠模型MAPK/ERK1/2及MAPK/JNK信号通路的影响
方法：选用健康SD大鼠60只，均为雄性。随机将60只大鼠分为正常组、对照组、模型组和治疗组(大、中、小剂量组)。模型组与治疗组经颈背部注射鱼藤酮(注射剂量1mg/kg)，共注射14天(连续注射7天后休息1天，造模共15天)。假手术组给予相同剂量的DMSO和生理盐水混合液(注射剂量同造模大鼠)。造模结束后，治疗组按生理盐水配置成20mg/ml,40mg/ml,60mg/ml,按体重1ml/100g.d灌胃，共15天。其余三组按1ml/100g.d生理盐水灌胃，1次/d，直到实验结束。各组疗程结束后对所有大鼠进行行为学评价及敞箱实验。并采用免疫组化法和免疫蛋白印迹法检测大鼠黑质区酪氨酸羟化酶(TH)、磷酸化的细胞外信号调节蛋白激酶1/2(p-ERK1/2)、磷酸化的c-Jun氨基末端激酶(p-c-Jun)阳性细胞表达情况及蛋白含量。
结果：各组大鼠的行为学表现存在差异，各组敞箱实验评分存在差异，正常组与模型组及模型组与治疗中高剂量组结果均有显著统计学意义(P<0.05)。各组免疫组化法和免疫蛋白印迹法检测结果存在差异。与正常组相比，模型组大鼠黑质区TH阳性细胞表达及蛋白表达均降低(p＜0.05)，p-ERK1/2、p-c-Jun阳性细胞表达及蛋白表达显著增加(p＜0.05)，与模型组相比，治疗中高剂量组大鼠黑质区TH阳性细胞表达及蛋白表达增加(p＜0.05)，p-ERK1/2、p-c-Jun阳性细胞表达及蛋白表达显著增加(p＜0.05)。正常组与假手术组各实验结果差别均不显著(p＞0.05)。
结论：熄颤健脑丸可能通过调节鱼藤酮诱导的帕金森病模型大鼠体内MAPK/ERK1/2及MAPK/JNK信号通路，降低p-ERK1/2、p-c-Jun在鱼藤酮诱导的帕金森模型大鼠黑质区的表达，对帕金森病模型大鼠帕金森症状及整体状况起到一定的改善作用。
实验例4：熄颤健脑丸对帕金森病模型大鼠行为学和细胞凋亡研究
目的：观察熄颤健脑丸对帕金森病模型大鼠行为学和凋亡相关基因Bcl-2、Bax、Caspase3蛋白含量，为熄颤健脑丸治疗帕金森病痴呆提供理论依据。
方法：帕金森病模型采用向大鼠黑质纹状体部位注射6-羟基多芭胺(6-OHDA)的方法制备。选择健康大鼠为空白组。将造模成功大鼠随机分为模型组、熄颤健脑丸低剂量组、熄颤健脑丸中剂量组、熄颤健脑丸高剂量组和美多芭组。每天给予相应药物或水喂养，共喂养4周，期间用阿扑吗啡诱导大鼠行为学的改变，观察并记录。采用免疫组化法测定帕金森病模型大鼠黑质纹状体内多芭胺能神经元凋亡相关的Bcl-2、Bax和Caspase3蛋白的表达。
结果：1、帕金森病模型大鼠行为学改变：空白组未见旋转行为改变，低剂量组旋转次数虽有所改变，但与模型组相比无统计学意义(P﹥0.05)。中剂量组与高剂量组、模型组和美多芭组相比，帕金森病模型大鼠旋转次数改变均无统计学意义(P﹥0.05)，高剂量组与美多芭组相比无统计学意义(P﹥0.05)。2、帕金森病模型大鼠黑质纹状体内Bcl-2、Bax和Caspase3蛋白的表达：低剂量组Bcl-2与模型组比较，差异有统计学意义(P<0.05)，Bax和Caspase3蛋白的表达与模型组比较，均无统计学意义(P﹥0.05)。与中剂量组、高剂量组比较，均有统计学意义(P<0.05或P<0.01)。中剂量组与模型组和空白组比较，Bcl-2、Bax和Caspase3蛋白的表达均有所改变，差异具有统计学意义(P<0.05)，与高剂量组相比，Bcl-2和Bax蛋白的表达有统计学差异(P<0.05)。Caspase3蛋白表达差异无统计学意义(P﹥0.05)。高剂量组Bcl-2、Bax和Caspase3蛋白的表达与模型组组比较，均具有统计学意义(P<0.05或P<0.01)，Bcl-2、Bax与空白组比较无统计学差异(P﹥0.05)，Caspase3与空白组比较有统计学差异(P<0.05)。美多巴组Bcl-2、Bax和Caspase3蛋白的表达与空白组和模型组比较，均有统计学意义(P<0.05)或(P<0.01)。
结论：熄颤健脑丸改变帕金森病模型大鼠行为学异常，其机制可能与提高Bcl-2蛋白表达，降低Bax和Caspase3的蛋白表达来抑制多芭胺能神经元的凋亡有关。
临床案例
病例1
贾某，女，40岁，山西盂县人，病案号：24017，2014年7月6日以“头晕、吞咽困难，四肢僵硬，走路不稳1年余”为主诉。1年前在休息时突然出现头晕、四肢无力、饮水呛咳、吞咽困难，伴恶心，无头痛、呕吐，急至盂县人民医院求治，查头颅CT示：正常，按脑梗死给予抗凝、改善循环、营养神经等药物应用后，治疗效果不佳。上述症状加重，后留置鼻饲管，长期鼻饲饮食，期间间断口服药物、康复治疗，疗效一般，为求系统中西医诊治，特求治于我院。诊断：帕金森病，中医：颤证肝肾阴虚、痰淤互阻，给予熄颤健脑丸(河南中医药大学第三附属医院制剂室)，一天三次，每次3丸。多巴丝肼片一日3次，每次口服125mg，一周后改为250mg，一日3次。连用2月，患者成功拔除鼻饲管，经口进食可以满足营养供给，走路基本正常，随访6个月无异常。
病例2
李某69岁帕金森病3年，双上肢、下肢活动慢并伴有静止性震颤、肌强直、震颤3年，舌颤、眼球震颤、张口困难、说话不清、伴有碎步、走路不稳，生活基本失去了自理能力，查头颅CT示：正常，口服美多芭、金刚烷胺、卡佐双多巴等效果不明显，为求系统中西医诊治，特求治于我院。诊断：帕金森病，中医：颤证肝肾阴虚、痰淤互阻，给予熄颤健脑丸(河南中医药大学第三附属医院制剂室)，一天三次，每次2丸。多巴丝肼片一日3次，每次口服125mg，一周后改为250mg，一日3次。10天后明显好转，连用2月，患者走路基本正常，震颤消失，随访6个月无异常。
Claims (5)
1.一种治疗帕金森病痴呆的中药组合物，其特征在于，由以下重量份数的原料药制成：熟地20～40份、五味子10～20份、仙灵脾20～40份、蚕蛾5～15份、肉苁蓉20～40份、巴戟天10～20份、龟板20～40份、黄柏10～20份、太子参10～20份、牡蛎20～40份、吴茱萸10～20份、远志10～20份、益智仁10～20份、分心木20～40份、狗脊20～40份、蜈蚣10～20份、天花粉10～20份、络石藤20～40份、透骨草10～20份、千年健20～40份、皂角刺10～20份、壁虎10～20份、珍珠10～20份、菊花5～10份、川芎5～10份、鹿茸5～10份、蜂蜜5～10份。
2.权利要求1所述的治疗帕金森病痴呆的中药组合物的制备方法，其特征在于，包括以下步骤：
1）将熟地、五味子、仙灵脾、蚕蛾、巴戟天、龟板、黄柏、太子参、牡蛎、吴茱萸、远志、益智仁、分心木、狗脊、天花粉、络石藤、透骨草、千年健、皂角刺、菊花、川芎、肉苁蓉混合粉碎，得粉末A，将蜈蚣、珍珠、壁虎、鹿茸粉碎，过七号筛，得粉末B；
2）将粉末A加水提取，所得提取液经过滤、浓缩得浸膏，所得浸膏经喷雾干燥制粒得干燥颗粒，将粉末B和干燥颗粒粉碎，过120目筛，混合均匀得粉末C；3）将蜂蜜加水使其70℃时的相对密度为1.30-1.40，并于70℃下与粉末C混合，制丸块，搓丸条，制丸粒，干燥即得。
3.如权利要求2所述的治疗帕金森病痴呆的中药组合物的制备方法，其特征在于，步骤2）中，所述粉末A制成浸膏的具体操作为：粉末A采用连续回流法提取，共回流提取两次，每次回流提取前加水，每克药材加水6-10ml，沸后回流提取25-35min；将得到的提取液用纱布过滤，合并过滤后的提取液，用旋转蒸发仪蒸发浓缩即得浸膏。
4.如权利要求3所述的治疗帕金森病痴呆的中药组合物的制备方法，其特征在于，所用纱布的孔径为0.70-0.90毫米。
5.如权利要求2所述的治疗帕金森病痴呆的中药组合物的制备方法，其特征在于，步骤2）中得到的浸膏含水量为55-65%时停止蒸发浓缩。
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| CN1840639A (zh) * | 2006-01-23 | 2006-10-04 | 张德全 | 一种滋补保健药酒 |
| CN105535429A (zh) * | 2015-12-29 | 2016-05-04 | 河南中医学院 | 一种治疗帕金森病的中药及其制备方法 |
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| CN1840639A (zh) * | 2006-01-23 | 2006-10-04 | 张德全 | 一种滋补保健药酒 |
| CN105535429A (zh) * | 2015-12-29 | 2016-05-04 | 河南中医学院 | 一种治疗帕金森病的中药及其制备方法 |
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