牛 茜，王 蕾，曹 凱，邵 爽，郭秀花*

·論著·

·醫(yī)學(xué)循證·

膽堿酯酶抑制劑改善輕中度阿爾茨海默病患者認知療效的Meta分析

牛 茜1,2，王 蕾2，曹 凱1，邵 爽1，郭秀花1*

目的 探討4種膽堿酯酶抑制劑(多奈哌齊、加蘭他敏、石杉堿甲、卡巴拉汀)治療輕中度阿爾茨海默病(AD)患者的療效。方法 計算機檢索PubMed、EMBase、Cochrane Library、Web of Science、中國知網(wǎng)、萬方數(shù)據(jù)知識服務(wù)平臺、維普網(wǎng)、中國生物醫(yī)學(xué)網(wǎng)，檢索時限為1994年1月—2016年3月，納入關(guān)于膽堿酯酶抑制劑治療輕中度AD患者的隨機雙盲安慰劑對照試驗。對納入文獻進行數(shù)據(jù)提取和質(zhì)量評價，提取包括第一作者、發(fā)表時間、藥物、日給藥劑量、性別、年齡、觀察時間、基線簡易精神狀態(tài)評價量表(MMSE)評分、結(jié)局指標(biāo)等資料。采用RevMan 5.3軟件分析多奈哌齊、加蘭他敏、石杉堿甲、卡巴拉汀改善輕中度AD患者阿爾茨海默病評定量表-認知項目(ADAS-cog)和MMSE評分的效果。結(jié)果 共納入30篇文獻，其中多奈哌齊15篇，加蘭他敏7篇，石杉堿甲4篇，卡巴拉汀4篇。Meta分析結(jié)果顯示，多奈哌齊5 mg組、多奈哌齊10 mg組、加蘭他敏24 mg組、加蘭他敏32 mg組、卡巴拉汀12 mg組ADAS-cog評分均低于安慰劑組〔加權(quán)均數(shù)差(WMD)=-2.13，95%CI(-2.69，-1.57)，P<0.001；WMD=-2.03，95%CI(-2.80，-1.25)，P<0.001；WMD=-3.05，95%CI(-3.54，-2.55)，P<0.001；WMD=-2.64，95%CI(-3.55，-1.73)，P<0.001；WMD=-2.17，95%CI(-3.30，-1.04)，P<0.001〕。石杉堿甲400 μg組和安慰劑組ADAS-cog評分比較，差異無統(tǒng)計學(xué)意義〔WMD=-2.95，95%CI(-8.19，2.29)，P=0.270〕。多奈哌齊5 mg組、多奈哌齊10 mg組、石杉堿甲400 μg組、卡巴他汀12 mg組MMSE評分均高于安慰劑組〔WMD=1.07,95%CI(0.55,1.59)，P<0.001；WMD=1.20,95%CI(0.91,1.50)，P<0.001；WMD=2.47,95%CI(1.15,3.78)，P<0.001；WMD=1.23,95%CI(0.35,2.11)，P=0.006〕。Begg秩相關(guān)檢驗、Egger線性回歸分析，ADAS-cog納入文獻P值分別為0.511、0.755；MMSE納入文獻P值分別為0.441、0.212，未觀察到發(fā)表偏倚。結(jié)論 除石杉堿甲外，其他膽堿酯酶抑制劑治療輕中度AD患者認知功能減退效果顯著。石杉堿甲治療效果仍有待納入高質(zhì)量文獻進一步論證。

阿爾茨海默?。荒憠A酯酶抑制劑；Meta分析

牛茜，王蕾，曹凱，等.膽堿酯酶抑制劑改善輕中度阿爾茨海默病患者認知療效的Meta分析[J].中國全科醫(yī)學(xué)，2017，20(14)：1735-1742.[www.chinagp.net]

NIU Q,WANG L,CAO K,et al.Effect of cholinesterase inhibitorson on cognition of patients with mild to moderate Alzheimer′s disease:a meta-analysis[J].Chinese General Practice，2017，20(14)：1735-1742.

阿爾茨海默病(AD)是一項重大的公共衛(wèi)生問題，是引起老年癡呆最常見的神經(jīng)退行性疾病，威脅衛(wèi)生保健系統(tǒng)和國民經(jīng)濟[1]。一項發(fā)表于Lancet的流行病學(xué)系統(tǒng)綜述顯示，1990年我國AD患者為193萬，2010年達568萬，居世界第一位[2]。當(dāng)前藥物雖然可以延緩AD患者病情進展，但卻不能預(yù)防或治愈AD。膽堿酯酶抑制劑多奈哌齊、加蘭他敏、卡巴拉汀已被歐洲國家證實具有延緩AD臨床癥狀的作用[3-4]。在我國除以上3種膽堿酯酶抑制劑外，石杉堿甲也可作為改善AD患者認知功能的臨床用藥，其對真性膽堿酯酶有選擇性抑制作用，具有促進記憶再現(xiàn)和記憶保持作用[5]。

目前已有大量文獻系統(tǒng)評價3種膽堿酯酶抑制劑多奈哌齊、加蘭他敏、卡巴拉汀治療AD患者認知損害的療效及安全性，研究方法和側(cè)重點各不相同[4，6-9]。我國臨床對于石杉堿甲的廣泛使用及相關(guān)研究[10-11]也為AD治療方案的選擇提供了經(jīng)驗和依據(jù)。本研究將石杉堿甲與其他3種膽堿酯酶抑制劑(多奈哌齊、加蘭他敏、卡巴拉汀)同時進行療效評價，為臨床選擇膽堿酯酶抑制劑治療AD患者認知功能提供綜合證據(jù)。

1 資料與方法

1.1 納入與排除標(biāo)準(zhǔn) 納入標(biāo)準(zhǔn)：選取1994年1月—2016年3月公開發(fā)表的關(guān)于膽堿酯酶抑制劑治療輕中度AD患者的隨機雙盲安慰劑對照試驗，限于英文和中文兩種語言發(fā)表?；颊咝璺螦D診斷標(biāo)準(zhǔn)，簡易精神狀態(tài)評價量表(MMSE)評分10～26分，觀察時間包含12～26周，結(jié)局指標(biāo)包括阿爾茨海默病評定量表-認知項目(ADAS-cog)、MMSE。排除標(biāo)準(zhǔn)：動物實驗、臨床前試驗或生物實驗，描述性綜述、社論、會議摘要及使用不充足的方法學(xué)報道的文獻。

1.2 檢索策略 以“Alzheimer′s Disease”“cholinesterase inhibitors”“galantamine”“rivastigmine”“donepezil”“huperzine A”“randomized controlled trial”及“阿爾茨海默病”“老年癡呆”“膽堿酯酶抑制劑”“多奈哌(派)齊”“安理申(Aricept)”“利凡斯的明”“艾斯能(Exelon)”“卡巴拉汀(丁)”“加蘭他敏”“石杉堿甲”“隨機對照”“雙盲”等為關(guān)鍵詞檢索PubMed、EMBase、Cochrane Library、Web of Science、中國知網(wǎng)、萬方數(shù)據(jù)知識服務(wù)平臺、維普網(wǎng)、中國生物醫(yī)學(xué)網(wǎng)等電子數(shù)據(jù)庫，同時手動搜索相關(guān)文獻進行補充。

1.3 數(shù)據(jù)提取和質(zhì)量評價 由兩位評論員獨立提取數(shù)據(jù)，包括第一作者、發(fā)表時間、藥物、日給藥劑量、性別、年齡、觀察時間、基線MMSE、結(jié)局指標(biāo)等資料。如有爭議進行討論或由第3位評論員解決。通過RevMan 5.3軟件對納入文獻進行偏倚風(fēng)險評估得偏倚風(fēng)險圖，對文獻質(zhì)量進行評價。

1.4 統(tǒng)計學(xué)方法 采用RevMan 5.3和Stata 12.0軟件進行統(tǒng)計學(xué)分析，計量資料以加權(quán)均數(shù)差(WMD)及其95%CI表示。采用I2值及χ2檢驗探討研究間異質(zhì)性，I2≤50%，P>0.1為無統(tǒng)計學(xué)異質(zhì)性存在，采用固定效應(yīng)模型分析；否則采用隨機效應(yīng)模型分析；采用Begg秩相關(guān)檢驗和Egger線性回歸進行發(fā)表偏倚分析。以P<0.05為差異有統(tǒng)計學(xué)意義。

2 結(jié)果

2.1 文獻基本情況 初檢共獲得文獻2 513篇，通過閱讀標(biāo)題和摘要排除2 398篇，進一步根據(jù)納入與排除標(biāo)準(zhǔn)排除85篇，共納入30篇文獻[12-41]，其中多奈哌齊15篇[12-26]，加蘭他敏7篇[27-33]，石杉堿甲4篇[34-37]，卡巴拉汀4篇[38-41]。文獻篩選流程見圖1，納入文獻基本特征見表1。

表1 納入文獻基本特征

注：ADAS-cog=阿爾茨海默病評定量表-認知項目，MMSE=簡易精神狀態(tài)評價量表；-為無此數(shù)值

注：RCT=隨機對照試驗，AD=阿爾茨海默病

圖1 文獻篩選流程圖

Figure 1 Flow chart of literature screening

2.2 文獻質(zhì)量評價 19篇文獻[12,15,18,20-21,24,26-33,35,37-39,41]詳細描述了隨機分配序列的方法，10篇文獻[15，20，28-33，39，41]詳細描述分配隱藏方案，18篇文獻[12-13,15,20-22,24,26-32,37,39-41]詳細描述盲法實施情況，8篇文獻[13,15,17,26-27,30,32,41]具體報道對結(jié)局評估員實施盲法，25篇文獻[12-16，18,20-31,33,35,37-41]結(jié)局報告完整(見圖2)。

2.3 Meta分析結(jié)果

2.3.1 以ADAS-cog評分為結(jié)局指標(biāo)評估 23篇文獻[12-16,21-22,24-33,35,37-41]以ADAS-cog評分為結(jié)局指標(biāo)評估，其中多奈哌齊5 mg 5篇文獻[12-16]，各研究間無統(tǒng)計學(xué)異質(zhì)性(I2=0，P=0.63)；多奈哌齊10 mg 8篇文獻[12-14,21-22,24-26]，

注：+=低度偏倚風(fēng)險，？=偏倚風(fēng)險不確定，-=高度偏倚風(fēng)險

圖2 風(fēng)險偏倚評估結(jié)果

Figure 2 Assessment result of risk bias

各研究間有統(tǒng)計學(xué)異質(zhì)性(I2=61%，P=0.01)；加蘭他敏24 mg 6篇文獻[27-29,31-33]，各研究間無統(tǒng)計學(xué)異質(zhì)性(I2=0，P=0.57)；加蘭他敏32 mg 4篇文獻[27,29-31]，各研究間無統(tǒng)計學(xué)意義(I2=49%，P=0.12)；石杉堿甲400 μg 2篇文獻[35,37]，各研究間有統(tǒng)計學(xué)異質(zhì)性(I2=84%，P=0.01)，卡巴拉汀12 mg 4篇文獻[38-41]，各研究間有統(tǒng)計學(xué)異質(zhì)性(I2=72%，P=0.01)。采用隨機效應(yīng)模型分析，Meta分析結(jié)果顯示，多奈哌齊5 mg組ADAS-cog評分低于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=-2.13，95%CI(-2.69，-1.57)，P<0.001〕；多奈哌齊10 mg組ADAS-cog評分低于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=-2.03，95%CI(-2.80，-1.25)，P<0.001〕；加蘭他敏24 mg組ADAS-cog評分低于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=-3.05，95%CI(-3.54，-2.55)，P<0.001〕；加蘭他敏32 mg組ADAS-cog評分低于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=-2.64，95%CI(-3.55，-1.73)，P<0.001〕；石杉堿甲400 μg組和安慰劑組ADAS-cog評分比較，差異無統(tǒng)計學(xué)意義〔WMD=-2.95，95%CI(-8.19，2.29)，P=0.27〕；卡巴拉汀12 mg組ADAS-cog評分低于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=-2.17，95%CI(-3.30，-1.04)，P<0.001，見圖3〕。

2.3.2 以MMSE評分為結(jié)局指標(biāo)評估 17篇文獻[12-13,17-23,25-26,34-37,40-41]以MMSE評分為結(jié)局指標(biāo)評估，其中多奈哌齊5 mg 3篇文獻[12-13,23]，各研究間無統(tǒng)計學(xué)異質(zhì)性(I2=0，P=0.89)；多奈哌齊10 mg 10篇文獻[12-13,17-22,25-26]，各研究間無統(tǒng)計學(xué)異質(zhì)性(I2=0，P=0.63)；石杉堿甲400 μg 4篇文獻[34-37]，各研究間有統(tǒng)計學(xué)異質(zhì)性(I2=75%，P=0.008)；卡巴他汀12 mg 2篇文獻[40-41]，各研究間有統(tǒng)計學(xué)異質(zhì)性(I2=75%，P=0.04)。采用隨機效應(yīng)模型分析，Meta分析結(jié)果顯示：多奈哌齊5 mg組MMSE評分高于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=1.07,95%CI(0.55,1.59)，P<0.001〕；多奈哌齊10 mg組MMSE評分高于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=1.20,95%CI(0.91,1.50)，P<0.001〕；石杉堿甲400 μg組MMSE評分高于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=2.47,95%CI(1.15,3.78)，P<0.001〕；卡巴他汀12 mg組MMSE評分高于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=1.23,95%CI(0.35,2.11)，P=0.006，見圖4〕。

2.4 發(fā)表偏倚及敏感性分析 使用Stata 12.0軟件對ADAS-cog納入文獻進行Begg秩相關(guān)檢驗得到Z=0.66，P=0.511；進行Egger線性回歸分析得到t=0.32，P=0.755(見圖5)；對MMSE納入文獻進行Begg秩相關(guān)檢驗得到Z=0.77，P=0.441；進行Egger線性回歸分析得到t=1.30，P=0.212(見圖6)，未觀察到發(fā)表偏倚。

圖3 膽堿酯酶抑制劑和安慰劑治療輕中度AD患者ADAS-cog評分比較的森林圖

Figure 3 Forest plot of the ADAS-cog score between cholinesterase inhibitors and placebo in treating patients with mild to moderate AD

圖4 膽堿酯酶抑制劑和安慰劑治療輕中度AD患者MMSE評分比較的森林圖

Figure 4 Forest plot of the MMSE score between cholinesterase inhibitors and placebo in treating patients with mild to moderate AD

敏感性分析，以亞組為單位逐一觀察單個研究對亞組合并效應(yīng)量的影響，ADAS-cog評分中，石杉堿甲400 μg張振馨等[35]、RAFII等[37]；卡巴拉汀12 mg COREY-BLOOM等[38]會對亞組合并效應(yīng)量產(chǎn)生影響。由于石杉堿甲400 μg僅納入2篇文獻，而2篇文獻均會直接影響合并效應(yīng)量使結(jié)果發(fā)生轉(zhuǎn)變，說明由其得出的結(jié)果證據(jù)不足，需要納入更多文獻，并謹慎分析結(jié)果。剔除COREY-BLOOM等[38]研究后，卡巴拉汀12 mg組ADAS-cog評分低于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=-1.60,95%CI(-2.30，-0.90)，P<0.001〕，結(jié)果相對穩(wěn)定。MMSE評分中，石杉堿甲400 μg RAFII等[37]對亞組影響較大，將其剔除后，石杉堿甲400 μg MMSE評分高于安慰劑組，差異有統(tǒng)計學(xué)意義〔WMD=3.05,95%CI(1.83，4.27)，P<0.001〕，結(jié)果相對穩(wěn)定。

圖5 ADAS-cog評分納入文獻發(fā)表偏倚漏斗圖

圖6 MMSE評分納入文獻發(fā)表偏倚漏斗圖

3 討論

目前，膽堿酯酶抑制劑治療AD具有多年歷史，最初用于治療的他克林由于嚴(yán)重的不良反應(yīng)已經(jīng)停止使用，相繼上市的藥物有多奈哌齊、加蘭他敏、卡巴拉汀。石杉堿甲是中藥提取物，1996年在我國被批準(zhǔn)用于治療AD[42]。目前針對膽堿酯酶抑制劑多奈哌齊、加蘭他敏、卡巴拉汀治療輕中度AD認知療效，許多學(xué)者對其進行了比較研究。英國NIC研究結(jié)果顯示多奈哌齊和加蘭他敏改善認知療效顯著，但結(jié)果受到測量方法及觀察時間的限制。長期觀察結(jié)果顯示多奈哌齊或卡巴拉汀可能成為最有效的治療方法，但受到藥物使用方法的限制[4]。KOBAYASHI等[9]研究證明加蘭他敏24 mg、32 mg，卡巴拉汀12 mg，多奈哌齊5 mg、10 mg對降低AD患者ADAS-cog評分具有顯著效果。

本研究以不同膽堿酯酶抑制劑作為亞組，采用Meta分析方法比較4種膽堿酯酶抑制劑治療輕中度AD患者認知的療效。以ADAS-cog、MMSE評分為結(jié)局指標(biāo)，觀察時間為12～26周進行分析，得出多奈哌齊5 mg、多奈哌齊10 mg、加蘭他敏24 mg、加蘭他敏32 mg、卡巴拉汀12 mg均具有治療輕中度AD患者認知的療效。石杉堿甲雖納入我國治療指南，但在其他國家并未獲準(zhǔn)，故其藥物研究主要來自國內(nèi)試驗，而國外研究較少。結(jié)局變量為ADAS-cog評分的Meta分析中，只有2篇文獻[35，37]納入石杉堿甲組(1篇中文，1篇英文)，研究數(shù)量及樣本量少，且樣本來自不同國家，研究間異質(zhì)性較大，因此可能造成假陰性結(jié)果。結(jié)局變量為MMSE評分的Meta分析中，石杉堿甲亞組納入3篇中文文獻[34-36]，1篇英文文獻[37]，研究間異質(zhì)性大，觀察原始研究偏倚風(fēng)險圖，中文文獻方法學(xué)質(zhì)量低，其在隨機、分配隱藏、盲法、結(jié)局完整性均存在較高風(fēng)險，低質(zhì)量、小樣本試驗可能得出較大的干預(yù)措施療效。所以本研究MMSE評分對石杉堿甲治療效果的評價可能存在過高估計。

綜上所述，石杉堿甲療效評價由于存在研究間異質(zhì)性及偏倚風(fēng)險，需待獲得高質(zhì)量、大樣本的文獻進一步分析。本研究納入文獻的隨訪時間較短，對于藥物遠期療效需通過長期研究分析評價。盡管ADAS-cog、MMSE是評價認知功能的常用量表，但是MMSE仍然受到教育程度的影響，而ADAS-cog識別不同嚴(yán)重程度AD患者認知變化的敏感性也受到爭議。同時，本研究采用的Meta分析亞組分析為觀察性研究，而非基于隨機化比較，容易引起假陰性或假陽性結(jié)果。因此研究結(jié)果并不能作為確定的結(jié)果被提出，而需結(jié)合臨床實際對藥物的有效性進行綜合評價。

作者貢獻：牛茜進行文章的構(gòu)思與設(shè)計、撰寫論文；牛茜、王蕾進行研究的實施與可行性分析、數(shù)據(jù)收集、數(shù)據(jù)整理；牛茜、曹凱進行統(tǒng)計學(xué)處理；牛茜、邵爽進行結(jié)果的分析與解釋、論文修訂；邵爽負責(zé)文章的質(zhì)量控制及審校；郭秀花對文章整體負責(zé)，監(jiān)督管理。

本文無利益沖突。

[1]OBOUDIYAT C,GLAZER H,SEIFAN A,et al.Alzheimer′s disease[J].Semin Neurol,2013,33(4):313-329.DOI:10.1055/s-0033-1359319.

[2]CHAN K Y,WANG W,WU J J,et al.Epidemiology of Alzheimer′s disease and other forms of dementia in China,1990-2010:a systematic review and analysis[J].Lancet,2013,381(9882):2016-2023.DOI:10.1016/S0140-6736(13)60221-4.

[3]HORT J,O′BRIEN J,GAINOTTI G,et al.EFNS guidelines for the diagnosis and management of Alzheimer′s disease[J].Eur J Neurol,2010,17(10):1236-1248.DOI:10.1111/j.1468-1331.2010.03040.x.

[4]BOND M,ROGERS G,PETERS J,et al.The effectiveness and cost-effectiveness of donepezil,galantamine,rivastigmine and memantine for the treatment of Alzheimer′s disease(review of Technology Appraisal No.111):a systematic review and economic model[J].Health Technol Assess,2012,16(21):1-470.DOI:10.3310/hta16210.

[5]HA G T,WONG R K,ZHANG Y.Huperzine A as potential treatment of Alzheimer′s disease:an assessment on chemistry,pharmacology,and clinical studies[J].Chem Biodivers,2011,8(7):1189-1204.DOI:10.1002/cbdv.201000269.

[6]HERRMANN N,CHAU S A,KIRCANSKI I,et al.Current and emerging drug treatment options for Alzheimer′s disease:asystematic review[J].Drugs,2011,71(15):2031-2065.DOI:10.2165/11595870-000000000-00000.

[7]TAN C C,YU J T,WANG H F,et al.Efficacy and safety of donepezil,galantamine,rivastigmine,and memantine for the treatment of Alzheimer′s disease:a systematic review and meta-analysis[J].J Alzheimers Dis,2014,41(2):615-631.DOI:10.3233/JAD-132690.

[8]LIN J S,O′CONNOR E,ROSSOM R C,et al.Screening for cognitive impairment in older adults:a systematic review for the U.S.Preventive Services Task Force[J].Ann Intern Med,2013,159(9):601-612.

[9]KOBAYASHI H,OHNISHI T,NAKAGAWA R,et al.The comparative efficacy and safety of cholinesterase inhibitors in patients with mild-to-moderate Alzheimer′s disease:a Bayesian network meta-analysis[J].Int J Geriatr Psychiatry,2015,31(8):892-904.DOI:10.1002/gps.4405.

[10]XING S H,ZHU C X,ZHANG R,et al.Huperzine A in the treatment of Alzheimer′s disease and vascular dementia:a meta-analysis[J].Evid Based Complement Alternat Med,2014:363985.DOI:10.1155/2014/363985.

[11]YANG G,WANG Y,TIAN J,et al.Huperzine A for Alzheimer′s disease:asystematic review and meta-analysis of randomized clinical trials[J].PLoS One,2013,8(9):e74916.DOI:10.1371/journal.pone.0074916.

[12]ROGERS S L,FARLOW M R,DOODY R S,et al.A 24-week,double-blind,placebo-controlled trial of donepezil in patients with Alzheimer′s disease.Donepezil Study Group[J].Neurology,1998,50(1):136-145.

[13]ROGERS S L,DOODY R S,MOHS R C,et al.Donepezil improves cognition and global function in Alzheimer disease:a 15-week,double-blind,placebo-controlled study.Donepezil Study Group[J].Arch Intern Med,1998,158(9):1021-1031.

[14]BURNS A,ROSSOR M,HECKER J,et al.The effects of donepezil in Alzheimer′s disease-results from a multinational trial[J].Dement Geriatr Cogn Disord,1999,10(3):237-244.

[15]GREENBERG S M,TENNIS M K,BROWN L B,et al.Donepezil therapy in clinical practice:a randomized crossover study[J].Arch Neurol,2000,57(1):94-99.

[16]HOMMA A,TAKEDA M,IMAI Y,et al.Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer′s disease.A 24-week,multicenter,double-bling,placebo-controlled study in Japan.E2020 Study Group[J].Dement Geriatr Cogn Disord,2000,11(6):299-313.

[17]MOHS R C,DOODY R S,MORRIS J C,et al.A 1-year,placebo-controlled preservation of function survival study of donepezil in AD patients[J].Neurology,2001,57(3):481-488.

[18]WINBLAD B,ENGEDAL K,SOININEN H,et al.A 1-year,randomized,placebo-controlled study of donepezil in patients with mild to moderate AD[J].Neurology,2001,57(3):489-495.

[19]GAUTHIER S,FELDMAN H,HECKER J,et al.Functional,cognitive and behavioral effects of donepezil in patients with moderate Alzheimer′s disease[J].Curr Med Res Opin,2002,18(6):347-354.

[20]HOLMES C,WILKINSON D,DEAN C,et al.The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease[J].Neurology,2004,63(2):214-219.

[21]SELTZER B,ZOLNOUNI P,NUNEZ M,et al.Efficacy of donepezil in early-stage Alzheimer disease:a randomized placebo-controlled trial[J].Arch Neurol,2004,61(12):1852-1586.

[22]JOHANNSEN P,SALMON E,HAMPEL H,et al.Assessing therapeutic efficacy in a progressive disease:a study of donepezil in Alzheimer′s disease[J].CNS Drugs,2006,20(4):311-325.

[23]MAZZA M,CAPUANO A,BRIA P,et al.Ginkgo biloba and donepezil:a comparison in the treatment of Alzheimer′s dementia in a randomized placebo-controlled double-blind study[J].Eur J Neurol,2006,13(9):981-985.

[24]MAHER-EDWARDS G,DIXON R,HUNTER J,et al.SB-742457 and donepezil in Alzheimer disease:a randomized,placebo-controlled study[J].Int J Geriatr Psychiatry,2011,26(5):536-544.DOI:10.1002/gps.2562.

[25]FR?LICH L,ASHWOOD T,NILSSON J,et al.Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer′s disease:a phase Ⅱb dose-finding study[J].J Alzheimers Dis,2011,24(2):363-374.DOI:10.3233/JAD-2011-101554.

[26]HAIG G M,PRITCHETT Y,MEIER A,et al.A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer′s dementia[J].J Alzheimers Dis,2014,42(3):959-971.

[27]RASKIND M A,PESKIND E R,WESSEL T,et al.Galantamine in AD:a 6-month randomized,placebo-controlled trial with a 6-month extension.The Galantamine USA-1 Study Group[J].Neurology,2000,54(12):2261-2268.

[28]TARIOT P N,SOLOMON P R,MORRIS J C,et al.A 5-month,randomized,placebo-controlled trial of galantamine in AD.The Galantamine USA-10 Study Group[J].Neurology,2000,54(12):2269-2276.

[29]WILCOCK G K,LILIENFELD S,GAENS E.Efficacy and safety of galantamine in patients with mild to moderate Alzheimer′s disease:multicentre randomised controlled trial.Galantamine International-1 Study Group[J].BMJ,2000,321(7274):1445-1449.

[30]ROCKWOOD K,MINTZER J,TRUYEN L,et al.Effects of a flexible galantamine dose in Alzheimer′s disease:a randomised,controlled trial[J].J Neurol Neurosurg Psychiatry,2001,71(5):589-595.

[31]WILKINSON D,MURRAY J.Galantamine:a randomized,double-blind,dose comparison in patients with Alzheimer′s disease[J].Int J Geriatr Psychiatry,2001,16(9):852-857.

[32]BRODATY H,COREY-BLOOM J,POTOCNIK F C,et al.Galantamine prolonged-release formulation in the treatment of mild to moderate Alzheimer′s disease[J].Dement Geriatr Cogn Disord,2005,20(2/3):120-132.

[33]ROCKWOOD K,FAY S,SONG X,et al.Attainment of treatment goals by people with Alzheimer′s disease receiving galantamine:a randomized controlled trial[J].CMAJ,2006,174(8):1099-1105.

[34]劉福根,方雍生,高之旭,等.石杉堿甲片治療Alzheimer病的隨機對照雙盲試驗[J].藥物流行病學(xué)雜志，1995,4(4):196-198. LIU F G,FANG Y S,GAO Z X,et al.Double-blind control treatment of Huperzine-A and placebo in 28 patients with Alzheimer disease[J].Chinese Journal of Pharmacoepidemiol，1995,4(4):196-198.

[35]張振馨，王新德，陳清棠，等.石杉堿甲治療阿爾茨海默病的有效性和安全性的多中心雙盲隨機對照試驗[J].中華醫(yī)學(xué)雜志，2002,82(14):941-944.DOI:10.3760/j:issn:0376-2491.2002.14.003. ZHANG Z X,WANG X D,CHEN Q T,et al.Clinical efficacy and safety of huperzine A in treatment of mind to moderate Alzheimer disease,a placebo controlled,double-blind,randomized trial[J].National Medical Journalof China，2002,82(14):941-944.DOI:10.3760/j:issn:0376-2491.2002.14.003.

[36]陽初玉,呂澤平,鄭陳光.石杉堿甲治療輕中度阿爾茨海默病的有效性及安全性研究[J].中國臨床康復(fù),2003,7(31):4258-4259.DOI:10.3321/j.issn:1673-8225.2003.31.010. YANG C Y,LYU Z P,ZHENG C G.Efficacy and reliability of huperzine A in mild and moderate Alzheimer′s disease[J].Chinese Journal of Clinical Rehabilitation，2003,7(31):4258-4259.

[37]RAFII M S,WALSH S,LITTLE J T,et al.A phase Ⅱ trial of huperzine A in mild to moderate Alzheimer disease[J].Neurology,2011,76(16):1389-1394.DOI:10.1212/WNL.0b013e318216eb7b.

[38]COREY-BLOOM J,ANAND R,VEACH J.A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate),a new acetylcholinesterase inhibitor,in patients with mild to moderately severe Alzheimer′s disease[J].Int J Geriatr Psy,1998,1(2):55-65.

[39]R?SLER M,ANAND R,CICIN-SAIN A,et al.Efficacy and safety of rivastigmine in patients with Alzheimer′s disease:international randomised controlled trial[J].BMJ,1999,318(7184):633-638.

[40]FELDMAN H H,LANE R,Study 304 Group.Rivastigmine:a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer′s disease[J].J Neurol Neurosurg Psychiatry,2007,78(10):1056-1063.

[41]WINBLAD B,CUMMINGS J,ANDREASEN N,et al.A six-month double-blind,randomized,placebo-controlled study of a transdermal patch in Alzheimer′s disease-rivastigmine patch versus capsule[J].Int J Geriatric Psychiatry,2007,22(5):456-467.

[42]徐紅冰,王曉平,劉皋林.石杉堿甲的藥理研究及臨床應(yīng)用[J].世界臨床藥物,2014,35(1):60-63. XU H B,WANG X P,LIU G L.Pharmacological studies and clincal application of huperzine A[J].World Clinical Drugs，2014,35(1):60-63.

(本文編輯：賈萌萌)

Effect of Cholinesterase Inhibitorson on Cognition of Patients with Mild to Moderate Alzheimer′s Disease:a Meta-analysis

NIUQian1,2,WANGLei2,CAOKai1,SHAOShuang1,GUOXiu-hua1*

1.SchoolofPublicHealth,CapitalMedicalUniversity,Beijing100069,China2.BeixiaguanCommunityHealthServicesCenter,Beijing100081,China

Objective To discuss the effect of cholinesterase inhibitors (donepezil,galanthamine,huperzine A,rivastigmine) on the treatment of patients with mild to moderate Alzheimer′s Disease (AD).Methods From January 1994 to March 2016,PubMed,EMBase,Cochrane Library,Web of Science,CNKI,Wanfang Data Knowledge Service Platform,VIP Network,and China Biomedical Network was searched by computer retrieval to enroll randomized,double-blind,placebo-controlled trials of cholinesterase inhibitors treating patients with mild to moderate AD.Data extraction and quality evaluation were conducted to the included literatures.The data including the first author,the time of publication,medicine,one-day dose,gender,age,the time of observation,the baseline MMSE and the outcome indicators were extracted.RevMan 5.3 software was used to analyze the effect of donepezil,galanthamine,huperzine A,and rivastigmine on improving the scores of Alzheimer′s Disease Assessment Scale-cognitive Subscale(ADAS-cog) and mini-mental state examination(MMSE) among patients with AD.Results We enrolled 30 literatures totally,of which 15 on donepezil,7 on galanthamine,4 on huperzine A and 4 on rivastigmine.Meta-analysis showed that the ADAS-cog scores of the group of 5 mg donepezil,group of 10 mg donepezil,group of 24 mg galanthamine,group of 32 mg galantamine and group of 12 mg rivastigmine were lower than those of the placebo group〔WMD=-2.13，95%CI(-2.69，-1.57),P<0.001;WMD=-2.03,95%CI(-2.80,-1.25),P<0.001;WMD=-3.05,95%CI(-3.54,-2.55),P<0.001;WMD=-2.64,95%CI(-3.55,-1.73),P<0.001;WMD=-2.17,95%CI(-3.30,-1.04),P<0.001〕.There was no significant difference in the ADAS-cog score between group of 400 μg huperzine A and the placebo group 〔WMD=-2.95,95%CI(-8.19,2.29),P=0.270〕.The MMSE scores of the group of 5 mg donepezil,group of 10 mg donepezil,group of 400 μg huperzine A and group of 12 mg rivastigmine were higher than those of the placebo group〔WMD=1.07,95%CI(0.55,1.59),P<0.001;WMD=1.20,95%CI(0.91,1.50),P<0.001;WMD=2.47,95%CI(1.15,3.78),P<0.001;WMD=1.23,95%CI(0.35,2.11)，P=0.006〕.Begg rank correlation test and Egger linear regression test showed thatPvalue of the literatures included in ADAS-cog scale was 0.511 and 0.755 respectively;Pvalue of the literatures included in MMSE scale was 0.441 and 0.212 respectively.No publication bias was observed.Conclusion Except for huperzine A,other cholinesterase inhibitors have significant effect on the treatment of cognitive decline among patients with mild to moderate AD.The treatment effect of huperzine A needs to be further demonstrated by including high quality literatures.

Alzheimer disease;Cholinesterase inhibitors;Meta-analysis

R 745.7

A

10.3969/j.issn.1007-9572.2017.14.017

2016-07-29；

2017-02-25)

1.100069北京市，首都醫(yī)科大學(xué)公共衛(wèi)生學(xué)院

2.100081北京市海淀區(qū)北下關(guān)社區(qū)衛(wèi)生服務(wù)中心

*通信作者：郭秀花，教授；E-mail：guoxiuh@ccmu.edu.cn

*Correspondingauthor:GUOXiu-hua,Professor;E-mail:guoxiuh@ccmu.edu.cn