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医药导报
医药导报, 2017, 36(7): 761-767
doi: 10.3870/j.issn.1004-0781.2017.07.010
口服银杏叶提取物制剂治疗轻度认知功能障碍Meta分析*
Meta-Analysis of Oral Preparation of Ginkgo Biloba Extract in The Treatment of Mid Cognitive Impairment
曾佩佩1,, 黎红丹1, 刘泰2,
1.广西中医药大学研究生学院,南宁 530023
2.广西中医药大学第一附属医院脑病科,南宁 530023
ZENG peipei,, LI hongdan, LIU tai,
1.School of Graduate,Guangxi University of Chinese Medicine, Nanning 530023,China
2.Department of Encehalopathy, the First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning 530023,China
通信作者 刘泰(1959-),男,广西桂林人,主任医师,教授,学士,研究方向:神经系统疾病。电话:0771-5848502,E-mail:liutai590216@163.com。

作者简介 曾佩佩(1990-),女,广西桂林人,在读硕士,研究方向:脑血管病的中医诊治研究。E-mail:294905673@qq.com。
基金资助: 广西卫计委资助项目(S201410-01)
中图分类号: R286     文献标识码: A     文章编号: 1004-0781(2017)07-0761-07
摘要:

目的 评价口服银杏叶提取物EGB761治疗轻度认知功能障碍(MCI)的疗效及安全性。方法 计算机检索PubMed、Embase、Cochrane Library、CNKI、WanFang和VIP等数据库,查找口服银杏叶提取物治疗MCI的随机对照试验。对纳入文献进行质量评价,采用RevMan5.2版软件进行Meta分析。结果 共纳入7个研究,共计815例患者。Meta分析结果显示:口服银杏叶提取物制剂3,6,12个月在改善MCI患者简易智能量表(MMSE)评分方面优于对照组[MD=1.81,95%CI(0.02,3.60),P=0.05;MD=1.96,95%CI(1.48,2.43),P<0.000 01;MD=1.79,95%CI(0.99,2.58),P<0.000 1];口服银杏叶提取物制剂6,12个月在改善MCI患者画钟试验(CDT)评分方面优于对照组[MD=0.43,95%CI(0.30,0.57),P<0.000 01;MD=0.57,95%CI(0.39,0.75),P<0.000 01];口服银杏叶提取物制剂治疗6及12个月,其预防MCI患者转化为痴呆的疗效优于对照组[RR=0.27,95%CI(0.06,1.27),P=0.10;RR=0.32,95%CI(0.16,0.63),P=0.001]。结论 口服银杏叶提取物制剂治疗MCI的临床有效性及预防痴呆的发生率优于空白对照。
关键词: 银杏叶提取物 ; 银杏叶片 ; 认知功能障碍 ; 轻度 ; Meta分析

Abstract:

Objective To evaluate the efficacy and safety of oral ginkgo biloba extract EGB761 in patients with mild cognitive impairment. Methods They searched PubMed,Embase,the Cochrane Library ,CNKI,Wanfang and VIP databases for randomly controlled trials of oral ginkgo biloba extract for mild cognitive impairment.After assessed the quality of studies included,RevMan5.2 software was used to analyze data. Results Seven studies which including 815 patients were involved by our inclusion criteria.The results of meta-analysis showed,compared with the control group,ginkgo biloba was superior in improving mild cognitive impairment patients' MMSE level[MD=1.81,95%CI(0.02,3.60),P=0.05;MD=1.96,95%CI(1.48,2.43),P<0.000 01;MD=1.79,95%CI(0.99,2.58),P<0.000 1] after treated three months、six months and twelve months. Ginkgo biloba was also superior in improving mild cognitive impaimant patients.CDT level[MD=0.43,95%CI(0.30,0.57),P<0.000 01;MD=0.57,95%CI(0.39,0.75),P<0.000 01] after treated six months and twelve months.The effect of preventing MCI patients into dementia was better than that of the control group[RR=0.27,95%CI(0.06,1.27),P=0.10;RR=0.32,95%CI(0.16,0.63),P=0.001]after treated six months and twelve months. Conclusion Oral preparation of ginkgo biloba extract in the treatment of MCI clinical efficacy and prevention of dementia occurrence rate was better than that of blank control group.
Key words: extract ; Tablets ; Cognitive impairment ; mild ; Meta-analysis

轻度认知功能障碍(mild cognitive impairment,MCI)是介于正常人和痴呆患者之间的一种认知下降状态,是指患者存在认知领域障碍,但不影响日常生活,目前普遍认为MCI是阿尔茨海默病(Alzheimer's disease,AD)发病的预警信号[1]。近年来,随着我国人口老龄化进程加快,MCI患病率逐年升高[2]。据统计,每年有10%~15%MCI患者转化为痴呆。因此,对MCI患者进行早期干预,预防或延缓MCI进一步向痴呆转化受到广泛关注[3]。银杏叶是银杏科植物银杏的干燥叶,现代药理学研究表明,其含有天然活性黄酮及萜类内酯等成分,能显著提高海马超氧化物歧化酶(SOD)活性,抑制胆碱酯酶的活力,提高患者记忆力,达到有效预防AD的功效[4]。标准银杏叶提取物EGB761黄酮糖苷含量24%,萜类化合物含量6%,银杏苦内脂含量3.1%,白果内酯含量2.9%,其中黄酮糖苷是其主要活性成分,是广泛应用于痴呆及认知障碍治疗的一种提取物制剂[5]。但是目前国际上开展的预防性随机对照试验表明,银杏叶提取物EGB761改善患者的认知水平较安慰药组无明显差异,对其能否预防MCI发展为AD存在争议[6-8]。针对银杏叶提取物EGB761改善认知功能的不确定性,笔者采用Cochrane系统评价的方法对相关的随机对照试验进行全面评价,以明确银杏叶提取物EGB761治疗轻度认知功能障碍的疗效及安全性,从而为临床决策提供循证医学证据。

1 资料与方法
1.1 纳入与排除标准

1.1.1 研究类型 随机对照试验,无论是否使用盲法,文献语种限定为英语和中文。

1.1.2 研究对象 符合2012年《中国痴呆诊疗指南》中MCI诊断标准,存在主观、客观的记忆或其他认知功能损害,日常生活能力基本保留的个体,年龄、性别不限,简易智能量表(mini-mental stata examination,MMSE)分值24~27分,日常生活能力量表评分<26分。

1.1.3 干预措施 治疗组采用基础治疗+银杏叶提取物,对照组单用基础治疗,两组基础治疗相同且不能含有改善认知的药物。

1.1.4 结局指标 MMSE、画钟试验(clock drawing tesk,CDT)、痴呆转化率。

1.2 检索策略

计算机检索PubMed、Embase、Cochrane Library、CNKI、WanFang和VIP中关于银杏叶提取物治疗MCI的随机对照试验,时限限定为建库至2016年3月23日,检索词包括“银杏叶提取物”“轻度认知功能障碍”“ginkgo biloba”和“mild cognitive impairment”。手工检索会议资料及未发表的研究。根据各数据库的检索特点制定相应的检索策略。

1.3 资料的提取

由2位研究者根据纳入与排除标准筛选文献后,制定数据与资料提取表,提取相应的资料与数据,相互核查数据,如有分歧则通过讨论或与第3位研究者共同协商解决。提取的资料包括:①文献的基本特征(作者、发表年限、样本量);②文献研究的质量指标(随机分配方法、分配方案隐藏、盲法、数据完整性、选择性报告结果及其他);③干预措施实施情况;④结局指标及数据。

1.4 方法质量学评价

根据Cochrane Handbook 5.1.0提供的偏倚风险评估对纳入的文献进行质量评价。偏倚风险的维度包括:①随机分配方案的产生;②分配方案的隐藏;③对研究对象和研究人员采用盲法;④对结果评价者采用盲法;⑤结果数据的不完整性;⑥选择性报告结果;⑦其他。根据评价标准可评价为“高风险偏倚”“低风险偏倚”和“不清楚”[9]。以“分配方案的隐藏”为例,若文中详细描述了采用内“中心分配(包括网络、药房控制随机)”或“相同外形的顺序编号的药物容器”或“顺序编号、密封、不透明的信封”进行方案隐藏,则评定该项为“低风险偏倚”;若文中描述按照“使用摊开的随机分配表”或“出生日期”或“病历号”或“就诊顺序”或“其他明确的非隐藏过程”方案进行分配,则评定为“高偏倚风险”;若没有足够信息判定为低风险或高风险,则判定为“不清楚”。其他各项详细评定方法参照Cochrane手册。

1.5 统计学方法

采用RevMan5.2软件进行Meta分析,计量资料统计效应量采用均数差(MD)及其95%可信区间(CI)表示,计数资料采用比值比(OR)或相对危险度(RR)及其95%CI为统计量。采用χ2检验分析各研究间的异质性,当P>0.1,I2<50%时,各研究间无异质性,采用固定效应模型合并效应量;当P<0.1,I2>50%时,则各研究结果存在统计学异质性,分析其异质性产生的来源,排除临床异质性的影响后采用随机效应模型合并效应量;当P<0.1,I2>75%时,对可能产生异质性的因素进行亚组分析或敏感性分析,或只进行描述性分析。

2 结果
2.1 文献检索结果

共检索出文献241篇,首先通过Endnote软件,排除重复文献67篇,再阅读文章题目及摘要,排除非临床实验(包括综述、动物试验、专家经验等)、无对照试验、未使用随机分组试验、数据无法提取的研究,剩余12篇文献获取全文。其中4篇文献为同一研究数据重复发表,选取其中1篇纳入Meta分析,其余3篇排除;1篇文献干预措施为银杏叶分散片,其剂型与纳入标准有分歧;1篇文献对照组为安慰药对照,与纳入标准中空白对照分歧,均排除。最终纳入7个试验[10-16],共815例患者。见图1。


图1 文献检索框架图

Fig.1 Flow chart of the literature retrieval

2.2 纳入研究的质量评价及一般情况

纳入研究均提到采用随机分组,其中4个研究提到采用随机数字表进行随机分配。所有纳入研究均未描述盲法的实施、随机分配方案的隐藏及失访退出情况,具体见表1。根据Cochrane系统评价偏倚风险维度对文献进行质量评估,结果见图2。

表1 纳入文献质量评价
Tab.1 Quality assessment on the included literatures
文献第一作者
与发表年		 随机
方法		 分配
隐藏		 盲法 数据是
否完整		 选择性
报道结果		 其他
肖世源2011[10] 随机 未提及 未提及 是 不清楚 不清楚
李文英2013[11] 随机数字表 未提及 未提及 是 不清楚 不清楚
董振华2012[12] 随机数字表 未提及 未提及 是 不清楚 不清楚
王蓓芸2012[13] 随机 未提及 未提及 是 不清楚 不清楚
韩自力2016[14] 随机数字表 未提及 未提及 是 不清楚 不清楚
夏讯2013[15] 随机数字表 未提及 未提及 是 不清楚 不清楚
张超2013[16] 随机 未提及 未提及 是 不清楚 不清楚

表1 纳入文献质量评价

Tab.1 Quality assessment on the included literatures


图2 纳入文献偏移风险评价

Fig.2 Risk assessment on the bias of the included literatures

所有研究治疗组和对照组均给予相同基础治疗,包括健康教育、适度运动、营养支持及基础疾病的治疗,包括降压、降糖、抗血小板聚集等治疗。所有基础治疗均对认知功能无改善作用,对研究结果不产生影响。治疗组在对照组基础上给予银杏叶片治疗,其为银杏叶提取物(EGB761)的口服制剂,生产厂家及服用剂量不限。疗程为3个月~1年,每日服用剂量120~240 mg,其中2个试验[11,15]为120 mg,5个试验[10,12-14,16]为240 mg。所有试验均对MMSE进行评定,4个试验[10-12,15]对CDT进行评定,5个试验[11-12,14-16]对痴呆转化率进行评定。2个试验[14-15]报道未发生不良事件,其余5个试验[10-13,16]均未报道不良事件情况。文献基本情况见表2所示。

表2 纳入文献分析
Tab.2 Analysis on the included literatures
文献第一作者
与发表年		 治疗组 对照组 干预措施 疗程/
个月		 观测指标
例 治疗组 对照组
肖世源2011[10] 54 44 EGB761,240 mg+基础治疗 基础治疗 6 ①②
李文英2013[11] 35 34 EGB761,120 mg+基础治疗 基础治疗 3 ①②③
董振华2012[12] 58 55 EGB761,240 mg+基础治疗 基础治疗 6,12 ①②③
王蓓芸2012[13] 45 42 EGB761,240 mg+基础治疗 基础治疗 12 ①
韩自力2016[14] 60 60 EGB761,240 mg+基础治疗 基础治疗 6,12 ①③
夏讯2013[15] 123 122 EGB761,120 mg+基础治疗 基础治疗 6,12 ①②③
张超2013[16] 43 40 EGB761,240 mg+基础治疗 基础治疗 3,6 ①③

①.MMSE;②.CDT;③.dementia conversion rate;EGB 761.ginkgo biloba extract

①.MMSE;②.CDT;③.痴呆转化率;EGB 761.银杏叶提取物

表2 纳入文献分析

Tab.2 Analysis on the included literatures

2.3 Meta分析结果

2.3.1 MMSE评分 试验均报道了银杏叶片与空白对照治疗MCI患者的MMSE评分,治疗疗程分别为3,6,12个月。亚组分析结果显示,疗程为3及12个月的研究结果间有统计学异质性(P=0.02,I2=83%;P=0.20,I2=33%;P=0.01,I2=72%),其异质性可能与各研究中患者的认知障碍程度构成比差异有关,故采用随机效应模型进行Meta分析。结果显示,疗程3个月合并效应量[MD=1.81,95%CI(0.02,3.60),P=0.05];疗程6个月合并效应量[MD=1.96,95%CI(1.48,2.43),P<0.000 01];疗程为12个月合并效应量[MD=1.79,95%CI(0.99,2.58),P<0.0001]。结果表明,银杏叶片改善MCI患者MMSE评分优于对照组,但疗程为3及12个月的研究结果间存在统计学异质性,需客观看待研究结论(图3)。


图3 治疗后两组MMSE评分的Meta分析森林图

Fig.3 Forest plot of meta-analysis on MMSE scores of the two groups after treatment

2.3.2 CDT评分 4个实验[10-12,15]报道了银杏叶片与空白对照治疗MCI患者的CDT评分,治疗疗程分别为6,12个月。亚组分析结果显示,各研究无统计学异质性(P=0.99,I2=0%;P=0.35,I2=0%),故采用固定效应模型进行合并分析。结果显示,疗程3个月合并效应量[MD=0.43,95%CI(0.30,0.57),P<0.000 01];疗程6个月合并效应量[MD=0.57,95%CI(0.39,0.75),P<0.00001]。结果表明银杏叶片改善MCI患者的CDT评分优于对照组,具体结果见图4。


图4 治疗后两组CDT评分的Meta分析森林图

Fig.4 Forest plot of meta-analysis on CDT scores of the two groups after treatment

2.3.3 痴呆转化率 5个试验[11-12,14-16]报道了银杏叶片与空白对照治疗MCI患者的痴呆转化率,治疗疗程分别为6,12个月。亚组分析结果显示各研究无统计学异质性(P=0.58,I2=0%;P=0.98,I2=0%),故采用固定效应模型进行合并分析。结果显示,疗程6个月合并效应量[RR=0.27,95%CI(0.06,1.27),P=0.10];疗程12个月合并效应量[RR=0.32,95%CI(0.16,0.63),P=0.001]。结果见图5。表明银杏叶片治疗MCI患者痴呆转化率低于对照组。


图5 治疗后两组痴呆转化率的Meta分析

Fig.5 Forest plot of meta-analysis on dementia conversion rate of the two groups after treatment

3 讨论

目前证据显示,口服银杏叶提取物制剂改善MCI患者的认知功能优于空白对照组,治疗后治疗组痴呆发病率亦较对照组低,对于MCI患者发展为痴呆有一定的预防作用。本次Meta分析结果与HALIL等[17]、GAVRILOVA等[18]的研究结果一致,银杏叶提取物治疗MCI患者有效,是MCI治疗的理想药物。为银杏叶提取物预防MCI发展为痴呆提供了循证医学证据[19]。但本研究存在一定的局限性,样本量大小,方法质量学偏低,随机分组方法描述过于简单,所有实验均未对分配方案的隐藏、盲法情况进行描述,存在一定的选择偏倚、实施偏倚及测量偏倚。由于不同地域在测量量表的选择与疗效的评定上存在一定差异,导致可以合并的数据不多,可能导致一定的临床异质性存在。只有2个试验报道未发生不良事件,其余5个试验均未报道不良事件,故银杏叶提取物治疗MCI的安全性尚不能得出结论。

综上所述,银杏叶提取物改善MCI患者认知功能及预防其发展为痴呆有一定疗效,但纳入文献的研究质量和研究方案设计存在诸多问题,导致试验质量存在一定问题。因此尚需要开展更多设计合理的多中心大样本且随访时间足够长的随机对照试验验证其疗效及安全性。

The authors have declared that no competing interests exist.
参考文献
[1] MAGAKI S,MUELLER C,DICKSON C,et al.Increased production of inflammatory cytokines in mild cognitive impairment[J].Expgerontol,2007,42(3):233-240.
Recent studies indicate that chronic inflammation plays a pathogenic role in both the central nervous system (CNS) and periphery in Alzheimer's disease (AD). We have screened for cytokines differentially produced by peripheral blood mononuclear cells (PBMCs) isolated from subjects with mild cognitive impairment (MCI) and mild AD subjects who had progressed from MCI using a commercially available cytokine array. Following determination of expressed cytokines, we quantified levels of the proinflammatory cytokines TNF-alpha, IL-6, and IL-8, and the anti-inflammatory cytokine IL-10 using flow cytometry. We have found a significant increase in the levels of IL-6, IL-8, and IL-10 produced by PBMCs stimulated for 24 h with phytohemagglutinin (PHA) in MCI subjects compared to healthy elderly controls. However, in PBMCs stimulated for 48 h with lipopolysaccharide (LPS), lower TNF-alpha/IL-10, IL-6/IL-10, and IL-8/IL-10 ratios were seen in MCI subjects. There were no differences in plasma levels of IL-8 between aged controls, MCI, and mild AD, and the levels of circulating IL-6 and IL-10 were below detection limits. Our data indicate that changes in cytokine production by PBMCs may be detected early in MCI, and an alteration of the immune response may precede clinical AD.
DOI:10.1016/j.exger.2006.09.015      PMID:1868444      URL    
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[2] TANG E Y,BRAVNE C,ALBANESE E,et al.Mild cognitive impairment definitions:more evolution than revolution[J].Neurodegener Dis Manag,2015,5(1):11-17.
Early identification of those at higher risk of dementia may play a part in secondary prevention and has received great clinical and research interest. Mild cognitive impairment (MCI) is a construct originally proposed to identify those who fall between normal cognitive aging and dementia. Clinical and research utility and validity of MCI are hotly debated. New MCI criteria proposed include the recent construct of mild neurocognitive disorder in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, MCI criteria proposed by the National Institute on Aging-Alzheimer's Society and criteria elaborated by the International Working Group. This article aims to discuss whether these definitions provide clearer conceptualization of MCI and to highlight implications for research.
DOI:10.2217/nmt.14.42      PMID:25711450      URL    
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[3] NIE H,XU Y,LIU B,et al.The prevalence or mild cognitive impairment about elderly population in china:a meta-analysis[J].Int J Geriatr Psych,2011,26(6):558-563.
Dementia has been a major public health problem and mild cognitive impairment is considered the pre-dementia syndrome in recent years. However, there has not yet been a systematic analysis of the prevalence of mild cognitive impairment in China.The aim of this study was to analyse the prevalence of mild cognitive impairment among the population aged 60 years and older in China.Epidemiological investigations on mild cognitive impairment in China published in journals were identified manually and online by using CBMDISK, ChongqingVIP database and CNKI database. Those reported in English journals were identified using MEDLINE. Selected studies had to describe an original study defined by strict screening and diagnlstic criteria. The fixed effects model or random effects model was employed according to statistical test for homogeneity.Twenty-two studies were selected, the statistical information of which was collected for systematic analysis. The results showed that the pooled prevalence of MCI for the elderly population was 12.7% (95% CI: 9.7-16.5%). In eastern and western China, the prevalence of MCI was 9.6 and 14.7%, respectively. There was a higher prevalence of MCI in the illiterate elderly population than in those who received years of education.The prevalence of MCI affected by sex, age,education, which was lower in eastern than that in western China.
DOI:10.1002/gps.2579      PMID:20878675      URL    
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[4] 王雪梅. 银杏叶主要成分药理研究进展[J].亚太传统医药,2014,10(18):59-60.
归纳整理近3年来国内银杏叶提取物药理研究的文献,以我国银杏叶为研究对象,查阅国内外银杏叶提取物防治中枢神经系统、心脑血管、肝脏、肾脏等疾病研究资料,并进行分类概述。从银杏叶提取物的药理作用、作用机制等对银杏叶的药理作用进行综述,为银杏叶的临床应用提供参考依据。
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[5] 汪素娟,康安,狄留庆,等.银杏叶提取物主要活性成分药动学研究进展[J].中草药,2013,44(5):626-631.
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[6] STEVEN T,ANNETTE F,DIANE G,et al.The Ginkgo evaluation of memory(GEM) study :design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia[J].Contemp Clin Trials,2006,27(3):238-253.
The epidemic of late life dementia, prominence of use of alternative medications and supplements, and initiation of efforts to determine how to prevent dementia have led to efforts to conduct studies aimed at prevention of dementia. The GEM (Ginkgo Evaluation of Memory) study was initially designed as a 5-year, randomized double-blind, placebo-controlled trial of Ginkgo biloba , administered in a dose of 120 mg twice per day as EGb761, in the prevention of dementia (and especially Alzheimer's disease) in normal elderly or those with mild cognitive impairment. The study anticipates 8.5 years of participant follow-up. Initial power calculations based on estimates of incidence rates of dementia in the target population (age 75+) led to a 3000-person study, which was successfully recruited at four clinical sites around the United States from September 2000 to June 2002. Primary outcome is incidence of all-cause dementia; secondary outcomes include rate of cognitive and functional decline, the incidence of cardiovascular and cerebrovascular events, and mortality. Following screening to exclude participants with incident dementia at baseline, an extensive neuropsychological assessment was performed and participants were randomly assigned to treatment groups. All participants are required to have a proxy who agreed to provide an independent assessment of the functional and cognitive abilities of the participant. Assessments are repeated every 6months. Significant decline at any visit, defined by specific changes in cognitive screening scores, leads to a repeat detailed neuropsychological battery, neurological and medical evaluation and MRI scan of the brain. The final diagnosis of dementia is achieved by a consensus panel of experts. Side effects and adverse events are tracked by computer at the central data coordinating center and unblinded data are reviewed by an independent safety monitoring board. Studies such as these are necessary for this and a variety of other potential protective agents to evaluate their effectiveness in preventing or slowing the emergence of dementia in the elderly population.
DOI:10.1016/j.cct.2006.02.007      PMID:16627007      URL    
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[7] BETH E,ELLEN S,MICHELLE C,et al.Ginkgo biloba for preventing cognitive decline in older adults[J].JAMA,2009,302(24):2663-2670.
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[8] STEVAN T,JEFF D,ANNETTE L,et al.Ginkgo biloba for prevention of dementia[J].JMMA,2008,300(19):2253-2262.
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[9] HIGGINS J P T,GREEN S.Cochrane handbook for systematic reviews of interventions version 5.1.0 [EB/OL].The Cochrane Collaboration,2011(2011-03)[2015-1-4]..
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[10] 肖世源,张春燕,李践一,等.银杏叶片G(斯泰隆)治疗轻度认知功能障碍的临床研究[J].中成药,2011,33(5):751-754.
目的观察银杏叶片G（斯泰隆）治疗轻度认知功能损害（MCI）的疗效。方法将98例患者随机分为空白对照组44例和治疗组54例,在给予一般同一基础保健支持的情况下,空白对照组不给予任何治疗,治疗组给予银杏叶片G（斯泰隆）,19.2 mg,3次/d,口服,共治疗6个月。结果银杏叶片G能显著提高MMSE、画钟试验（P〈0.01）;而对照组简易智能状态检查（MMSE）、画钟试验无明显进步也无明显退步（P〉0.05）。对MMSE的总有效率为74.07%,较空白对照组的34.09%有明显提高（P〈0.01）,对画钟试验的总有效率为66.67%,较空白对照组的40.91%有提高（P〈0.05）。结论银杏叶片G治疗轻度认知障碍有一定的疗效。
DOI:10.1007/s10570-010-9464-0      URL    
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[11] 李文英,田大虎,闫稳平,等.银杏叶片对高尿酸血症患者认知功能障碍的疗效观察[J].世界中医药,2013,8(1):48-50.
目的:观察银杏叶片对具有高尿酸血症的轻度认知障碍(mild congnitive impairment,MCI)患者认知功能的影响.方法:选取69例高尿酸血症合并MCI患者,随机分为治疗组(35例)和对照组(34例),2组均给 予基础治疗,为口服别嘌呤醇0.1g/次,3次/d,治疗组加服银杏叶片,每次1片,每天3次,连续服用3个月.检测2组治疗前、治疗后的简易精神状态检 查(mini-mental state examination,MMSE)积分、画钟试验(clock drawing task,CDT)积分、MMSE疗效、CDT疗效及痴呆转化率.结果:2组治疗前MMSE、CDT积分比较,差异无统计学意义(P>0.05). 与本组治疗前比较,治疗组治疗后各指标均升高,且高于对照组,差异均有统计学意义(P<0.05).治疗组MMSE、CDT总有效率(MMSE为 74.3%,CDT为68.6%)均高于对照组(MMSE为41.2%,CDT为38.2%),差异均有统计学意义(P<0.01).治疗组痴呆转 化率(5.71%)低于对照组(17.6%),差异有统计学意义(P<0.05).结论:银杏叶片3个月干预MCI患者,能够较好地改善认知功能, 并初步观察到能降低痴呆的转化率.
DOI:10.3969/j.issn.1673-7202.2013.01.018      URL    
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[12] 董振华,张春燕,蒲斌红,等.银杏叶片对轻度认知障碍患者认知功能的影响[J].中国中西医结合杂志,2012,32(9):1208-1211.
目的 观察银杏叶片对轻度认知障碍(mild congnitive impairment,MCI)患者认知功能的影响.方法 选取113例2009年9月-2011年2月就诊于复旦大学附属华东医院中医认知障碍专科门诊(58例)、同济大学附属东方医院中医门诊(34例)及上海市枫林街道社区卫生服务中心(21例)MCI患者,采用随机数字表法分为治疗组(58例)和对照组(55例),两组均给予基础治疗,治疗组在此基础上加服银杏叶片,每次1片,每天3次,连续服用1年.检测两组治疗前、治疗半年及1年的简易精神状态检查( mini-mental state examination,MMSE)积分、画钟试验(clock drawing task,CDT)积分、MMSE疗效、CDT疗效及痴呆转化率.结果 两组治疗前MMSE、CDT积分比较,差异无统计学意义(P＞0.05).与本组治疗前比较,治疗组治疗半年及1年各指标均升高,且高于对照组同期,差异均有统计学意义(P ＜0.01,P＜0.05),治疗半年及1年MMSE、CDT积分比较,差异无统计学意义(P＞0.05).治疗组治疗半年及1年MMSE、CDT总有效率(MMSE分别为67.24％、65.52％,CDT分别为62.07％、60.34％)均高于对照组同期(MMSE分别为36.36％、30.91％,CDT分别为34.55％、30.91％),差异均有统计学意义(P＜0.01)；治疗组两个时间点MMSE、CDT总有效率比较,差异无统计学意义(P＞0.05).治疗组治疗半年及1年痴呆转化率(分别为1.72％、5.17％)均低于对照组同期(分别为9.09％、14.55％),差异均有统计学意义(P＜0.05).结论 银杏叶片1年期干预MCI患者,能够较好地改善认知功能,并初步观察到能降低痴呆的转化率.
DOI:10.7661/CJIM.2012.9.1208      URL    
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[13] 王蓓芸,钟远,燕虹.银杏叶片治疗老年轻度认知功能障碍患者的临床疗效及事件相关电位P300的变化[J].中国老年学杂志,2012,32(12):2495-2496.
目的 探讨银杏叶片治疗轻度认知功能障碍(MCI)患者的临床疗效及事件相关电位(ERP) P300的变化.方法 选取87例MCI患者,随机分为银杏叶片治疗组(治疗组)和对照组,观察治疗前后简易精神状况检查表( MMSE)和临床疗效的变化和事件相关电位(ERP) P300,并与对照组进行比较.结果 治疗后治疗组与治疗前及对照组比较,MMSE分值提高(P＜0.01,P ＜0.05),P300电位波幅提高(P＜0.01,P＜0.05),潜伏期缩短(P＜0.01,P ＜0.05).结论 银杏叶片治疗能够显著改善老年MCI患者认知功能及脑电活动状态.
DOI:10.3969/j.issn.1005-9202.2012.12.023      URL    
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[14] 韩自力. 银杏叶片治疗轻度认知障碍的临床疗效观察[J].实用心脑肺血管病杂志,2016,24(1):91-94.
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[15] 夏讯. 银杏叶提取物对轻度认知功能损害的影响[J].浙江中西医结合杂志,2013,23(11):876-879.
目的：观察银杏叶提取物对轻度认知功能损害（MCI）的影响。方 法：MCI患者245例，随机分为治疗组（n=123）与对照组（n=122），两组均予基础治疗，治疗组加用银杏叶提取物40mg，1天3次，口服。两 组治疗前、治疗6个月及1年行简易精神状态检查（MMSE）与画钟试验（CDT）。监测治疗前后两组红细胞乙酰胆碱（RBC-Ach）及红细胞乙酰胆碱酯 酶（RBC-AchE）活性。结果：治疗6个月及1年，治疗组MMSE、CDT积分均显著提高，且均高于同期对照组（P<0.01）；与治疗前比 较，治疗1年治疗组RBC-Ach含量显著升高（P<0.01），且高于对照组（P<0.01）；治疗组RBC-AchE活性水平显著下降 （P<0.01），且低于对照组（P<0.01）。结论：银杏叶提取物能显著改善MCI患者认知功能，降低AD转化率，可能与其改善中枢胆碱 能系统功能有关。
DOI:10.3969/j.issn.1005-4561.2013.11.004      URL    
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[16] 张超,冯娟,李红娟,等.银杏叶提取物治疗帕金森病轻度认知障碍疗效的观察[J].中国现代医生,2013,51(31):109-111.
目的观察银杏叶提取物（EGB）对帕金森病合并轻度认知功能障碍（PD—MCI）患者认知功能的影响。方法根据2012年国际运动障碍协会颁布的PD—MCI诊断标准，自温岭市第一人民医院神经内科门诊及病房、康复科病房应用MoCA量表筛选出PD—MCI患者83例，随机分为治疗组（43例）及对照组（40例），两组均给予基础治疗，治疗组另外给予银杏叶提取物进行治疗，疗程共6个月，治疗前、治疗后3个月及6个月分别进行简易精神状态量表（MMSE）及蒙特利尔认知评估（MoCA）积分测量，分析比较两组治疗3个月、6个月后的MMSE及MoCA积分变化、治疗有效率及痴呆转化情况。结果治疗组3个月及6个月后MMSE及MoCA量表评分较治疗前均增高（P〈0．05），治疗组3个月及6个月后MMSE及MoCA量表评分均高于对照组同期（P〈0．05），治疗组3个月及6个月后MMSE及MoCA有效率均高于对照组同期（P〈0．05，P〈0．01），治疗组6个月MMSE及MoCA有效率比3个月增高（P〈0．05），两组3个月及6个月痴呆转化率比较无明显差异（P〉0．05）。结论银杏叶提取物可以在6个月内持续改善PD—MCI患者认知功能，疗效随着时间的延长而增加。
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[17] HALIL M,CANKURTARAN M,YAVUZ B B,et al.No alteration in the PFA-100 in vitro bleeding time induced by the ginkgo biloba special,EGB761,in elderly patients with mild cognitive impairment[J].Blood Coagul Fibbin,2005,16(5):349-353.
EGb 761 is widely used in the management of mild cognitive impairment in the elderly population. Elucidation of the effects of EGb 761 on primary haemostasis via PFA-100 could represent an important step for better understanding of the haemostatic safety of EGb 761. The purpose of this prospective study is to assess the effects of Ginkgo biloba special extract, EGb 761, on PFA-100 in vitro bleeding time in elderly patients with mild cognitive impairment. A total of 40 elderly patients aged 65-79 years who were referred for geriatric assessment and who were diagnosed as having mild cognitive impairment were included. Patients were started on 80 mg EGb-761 three times daily. The complete set of PFA-100 in vitro bleeding time and coagulation parameters including prothrombin time, activated partial thromboplastin time and International Normalized Ratio were assessed before and on the seventh day of treatment with EGb 761. There was no statistically significant prolongation in PFA-100 in vitro bleeding time or coagulation parameters in patients receiving EGb 761 after 7 days. The data about the safety of EGb 761 from the point of primary haemostasis in our elderly patient population with mild cognitive impairment casts hope for the future management of this 'difficult-to-treat' population with the promising Ginkgo extracts.
DOI:10.1097/01.mbc.0000172695.62363.57      PMID:15970719      URL    
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[18] GAVRILOVA S I,PREUSS U W,WONG J W M,et al.Efficacy and safety of Ginkgo biloba extract EGB761 in mild cognitive impairment with neuropsychiatric symptoms:a randomized,placebo-controlled,double-blind,multi-center trial[J].Int J Geriatr Psych,2014,29(10):1087-1095.
The study was conducted to explore the effects of EGb 761 (Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany) on neuropsychiatric symptoms (NPS) and cognition in patients with mild cognitive impairment (MCI).One hundred and sixty patients with MCI who scored at least 6 on the 12-item Neuropsychiatric Inventory (NPI) were enrolled in this double-blind, multi-center trial and randomized to receive 24065mg EGb 761 daily or placebo for a period of 2465weeks. Effects on NPS were assessed using the NPI, the state sub-score of the State-Trait Anxiety Inventory and the Geriatric Depression Scale. Further outcome measures were the Trail-Making Test (A/B) for cognition and global ratings of change. Statistical analyses followed the intention-to-treat principle.The NPI composite score decreased by 7.065±654.5 (mean, standard deviation) points in the EGb 761-treated group and by 5.565±655.2 in the placebo group (p65=650.001). Improvement by at least 4 points was found in 78.8% of patients treated with EGb 761 and in 55.7% of those receiving placebo (p65=650.002). Superiority of EGb 761 over placebo (p65<650.05) was also found for the State-Trait Anxiety Inventory score, the informants' global impression of change, and both Trail-Making Test scores. There were statistical trends favoring EGb 761 in the Geriatric Depression Scale and the patients' global impression of change. Adverse events (all non-serious) were reported by 37 patients taking EGb 761 and 36 patients receiving placebo.EGb 761 improved NPS and cognitive performance in patients with MCI. The drug was safe and well tolerated.
DOI:10.1002/gps.4103      PMID:24633934      URL    
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[19] TAN M S,YU J T,TAN C C,et al.Efficacy and adverse effects of ginkgo biloba for cognitive impairment and aementia:a systematic review and meta-analysis[J].JAD,2015,43(2):589-603.
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关键词（key words）
银杏叶提取物
银杏叶片
认知功能障碍
轻度
Meta分析
extract
Tablets
Cognitive impairment
mild
Meta-analysis
作者
曾佩佩
黎红丹
刘泰
ZENG peipei
LI hongdan
LIU tai