楊華 郭忠偉 李霞 張江濤 馮斌
鹽酸美金剛聯(lián)合鹽酸多奈哌齊對中重度阿爾茨海默病患者精神行為癥狀的療效觀察
楊華 郭忠偉 李霞 張江濤 馮斌
目的 評價鹽酸美金剛聯(lián)合鹽酸多奈哌齊對阿爾茨海默?。ˋD)伴發(fā)精神行為癥狀(BPSD)的療效及安全性。 方法 將符合標準的80例AD患者隨機分為研究組和對照組,每組40例,治療組患者服用鹽酸美金剛和鹽酸多奈哌齊,對照組患者單用鹽酸多奈哌齊。鹽酸美金剛起始劑量為5mg/d,每周遞增5mg,4周末增至20mg/d;鹽酸多奈哌齊起始劑量為5mg/d,4周末增至10mg/d;觀察12周。治療前及治療12周末,分別采用癡呆行為量表(BEHAVE-AD)評價精神行為癥狀、日常生活能力量表(ADL)判定患者日常生活活動能力、臨床總體印象量表(CGI)評定患者總體變化情況。 結(jié)果 治療12周末,研究組BEHAVE-AD減分較對照組更顯著(8.1±3.30, 9.2±2.80,t=-3.317,P<0.01),ADL減分更顯著(28.1±2.35,29.3±2.63,t=2.097,P<0.05),CGI評分分別為(3.43±0.82和4.37± 0.85),差異有統(tǒng)計學意義(t=-5.413,P<0.01)。 結(jié)論 鹽酸美金剛聯(lián)合鹽酸多奈哌齊治療BPSD的療效優(yōu)于單用鹽酸多奈哌齊。
阿爾茨海默病 精神和行為癥狀 鹽酸多奈哌齊 鹽酸美金剛
癡呆的行為和心理癥狀(Behavioral and psychological symptoms of dementia,BPSD)決定著患者及照料者的生活質(zhì)量,同時也構(gòu)成了照料者的主要應激來源,也是患者住院的主要原因[1],由于典型或非典型抗精神病藥物可大大增加阿爾茨海默?。ˋlzheimer Disease,AD)患者的心血管事件風險[2],故限制了其在臨床上的應用。鹽酸多奈哌齊為乙酰膽堿酯酶抑制劑(acetylcholinesterase inhibitor,AChEI),可逆性抑制腦中乙酰膽堿酯酶的活性而增加神經(jīng)遞質(zhì)乙酰膽堿的濃度,一定程度上控制BPSD[3]。鹽酸美金剛是N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid receptor,NMDA)受體拮抗劑,通過非競爭性阻斷NMDA受體,降低谷氨酸引起的NMDA受體過度興奮,對妄想、激越、易激惹有較好療效[4]。本文旨在觀察兩藥聯(lián)用治療BPSD療效。
1.1 一般資料 2009至2011年入住我院老年科的AD患者80例。入組標準:(1)符合美國神經(jīng)病學會、語言障礙和卒中-老年性癡呆和相關(guān)疾病學會(The Alzheimer’s Disease and Related DisordersAssociation,NINCDS/ ADRDA)制定的AD“可能”診斷標準[5];(2)年齡65~80歲;(3)簡易精神狀態(tài)檢查(Mini-mental state examination,MMSE):5~12分;(3)Hachinski缺血量表(Hachinski Inchemic Score,HIS)評分≤4分;(4)癡呆行為量表(BEHAVE-AD)評分≥8分[6];(5)頭顱CT或MR示腦萎縮;(6)入組前4周未服用鹽酸多奈哌齊(商品名:安理申,日本衛(wèi)材(中國)藥業(yè)有限公司)和鹽酸美金剛(商品名:易倍申,丹麥靈北公司)。排除標準:(1)伴有嚴重的軀體疾病,合并心、肝、腎和造血系統(tǒng)等嚴重原發(fā)性疾?。唬?)過敏體質(zhì)及對膽堿類藥物、鹽酸美金剛過敏者;(3)其他疾病引起的癡呆。組間性別構(gòu)成、年齡、病程以及受教育程度等差異均無統(tǒng)計學意義。80例患者采用隨機數(shù)字表法分為服用鹽酸美金剛聯(lián)合鹽酸多奈哌齊組(治療組)與鹽酸多奈哌齊組(對照組)。兩組患者一般情況比較見表1。
表1 兩組患者一般情況比較
由表1可見,兩組患者一般情況差異均無統(tǒng)計學意義(均P>0.05)。
1.2 方法
1.2.1 服藥方法 鹽酸美金剛第1周為每天5mg(晨服),第2周每天10mg(每次5mg,2次/d),第3周每天15mg(早上10mg,下午5mg),第4周開始以后服用維持劑量每天20mg(每次10mg,2次/d);鹽酸多奈哌齊起始劑量為5mg/d,4周末增至10mg/d。觀察時間為12周。
1.2.2 評定方法 分別于治療前與治療后第12周末采用癡呆行為量表(BEHAVE-AD)評價精神行為。BEHAVE-AD共有25項條目,包含偏執(zhí)和妄想觀念、幻覺、行為紊亂、攻擊行為、日夜節(jié)律紊亂、情感障礙、焦慮和恐懼7個分量表,每項條目按癥狀嚴重程度為0~3分,4級評分。另外,還有一項總評條目,按總體印象為0~3分,4級評分)。日常生活能力量表(Activies of daily living,ADL)用于判定患者日常生活活動能力。臨床總體印象量表(Clinical Global Impression,CGI)評定患者總體變化情況。每周對藥物不良反應采用藥物不良反應作用量表(Treatment Emergent Symptom Scale,TESS)評價。治療前及治療后每2周復查血常規(guī)、生化常規(guī)和心電圖。由2位不知分組治療情況的評定者分別作評定。1.2.3 統(tǒng)計學處理 采用SPSS15.0軟件處理。計量資料用表示,組間比較采用t檢驗。
2.1 兩組AD患者治療前后BEHAVE-AD評分比較見表2。
表2 兩組AD患者治療前后BEHAVE-AD評分比較
由表2可見,治療后兩組AD患者BEHAVE-AD評分均有明顯下降,但研究組下降更明顯。
2.3 兩組AD患者治療前后ADL評分比較 見表3。
表3 兩組AD患者治療前后ADL評分比較
由表3可見,治療后兩組AD患者ADL評分均有明顯下降,但研究組下降更明顯。
2.4 兩組AD患者治療12周末CGI評分比較 治療12周末研究組和對照組CGI評分分別為3.43±0.82和4.37±0.85,差異有統(tǒng)計學意義(t=-5.413,P<0.01)。
2.5 兩組AD患者不良反應比較 兩組發(fā)生不良發(fā)生率相近,癥狀均輕微,差異無統(tǒng)計學意義(P>0.05),見表4。
表4 兩組AD患者不良反應比較(例)
BPSD的發(fā)病機制復雜,與病前性格、不同腦區(qū)腦結(jié)構(gòu)改變、代謝異常和神經(jīng)遞質(zhì)失調(diào)有關(guān)[7-8]。臨床對BPSD藥物治療分為病因與對癥治療。研究顯示,AChEI和NMDA能在一定程度上改善BPSD癥狀[9-10],但是,AChEI和NMDA在改善BPSD具體臨床癥狀方面各有自己的優(yōu)勢。Gauthier等[11]為了明確鹽酸多奈哌齊對中重度癡呆患者精神行為癥狀的療效,進行了一項為期24周隨機、雙盲、安慰劑對照研究,盡管NPI評分降低,但主要體現(xiàn)在抑郁、焦慮、情感淡漠因子,對激越癥狀沒有改善[12]。Gauthier等[13]在一項匯總分析中,發(fā)現(xiàn)鹽酸美金剛治療中重度癡呆患者的精神和行為癥狀,在治療12、24、48周后,NPI評分明顯降低,與安慰劑組比較有統(tǒng)計學差異,尤其是幻覺、妄想、激越、易激惹亞量表評分改善更明顯。Wilcock等[14]報道鹽酸美金剛對伴有激惹、幻覺或妄想的中重度老年性癡呆患者治療觀察,與安慰劑對照,觀察12周、24周、48周,應用美金剛12周末,有55.3%患者癥狀緩解,24周末有61.0%患者癥狀緩解,而安慰劑組緩解率分別為44.4%和44.8%,且治療組激越、幻覺、妄想亞量表評分較安慰劑組有統(tǒng)計學差異。
那么,美金剛聯(lián)合鹽酸多奈哌齊干預BPSD是否有更好臨床療效?本文觀察結(jié)果顯示,治療12周末,研究組和對照組BEHAVE-AD評分均有明顯下降,但研究組下降更明顯,與對照組比較差異有統(tǒng)計學意義(P<0.01);CGI評分差異有統(tǒng)計學意義(P<0.01);研究組對ADL改善較對照組更顯著(P<0.01)。這說明鹽酸多奈哌齊聯(lián)合鹽酸美金剛能進一步改善患者的精神行為癥狀,提高日常生活能力。分析原因可能如下:(1)鹽酸多奈哌齊和鹽酸美金剛對BPSD亞癥狀療效各有針對性,聯(lián)合使用后,治療效果疊加;(2)BPSD是在認知功能障礙背景下大腦功能失調(diào)的結(jié)果[1]。最近研究顯示激越癥狀與工作記憶密切相關(guān)[16],因此改善認知在一定程度上可改善BPSD。研究顯示美金剛聯(lián)合鹽酸多奈哌齊較單一應用鹽酸多奈哌齊能使認知功能更能進一步獲益[17-18];(3)膽堿能神經(jīng)功能在BPSD發(fā)生、發(fā)展中起著重要作用[19]。美金剛聯(lián)合鹽酸多奈哌齊較單一應用鹽酸多奈哌齊刺激大腦皮質(zhì)和海馬乙酰膽堿的釋放更明顯[20];(4)正電子發(fā)射成像(PET)[21]、磁共振波譜分析技術(shù)(MRS)[22]、彌散張量成像(DTI)[23]功能影響學研究發(fā)現(xiàn),BPSD與腦功能關(guān)系密切,BPSD亞臨床癥狀與腦區(qū)不同代謝物異?;蚬δ芟嚓P(guān)。而鹽酸多奈哌齊和美金剛對AD患者不同腦區(qū)功能和代謝物的影響又具有各自特點[25-27]。因此,推斷聯(lián)合應用鹽酸多奈哌齊和美金剛較單一使用鹽酸多奈哌齊更能全面改善腦功能,從而更有效改善BPSD;(5)激越和精神病性癥狀與phospho-tau相關(guān)[28]。美金剛能減輕phospho-tau[29];(6)BPSD是突觸喪失直接作用的結(jié)果[30]。NMDA及NMDA受體在神經(jīng)突觸功能喪失過程中起著關(guān)鍵性作用[31]。美金剛能減輕NMDA毒性,鹽酸多奈哌齊通過NMDA Receptor調(diào)節(jié)突觸可塑性[33]。因此,鹽酸多奈哌齊聯(lián)合美金剛突觸可塑性調(diào)節(jié)具有協(xié)調(diào)作用,可能增加對BPSD的治療作用。
本研究結(jié)果顯示,聯(lián)合用藥不良反應發(fā)生率與單一用藥相當,與國外單一用藥不良反應基本一致[34]。癥狀均輕微,經(jīng)相應對癥處理后好轉(zhuǎn),并沒有因不良反應而脫落病例。但觀察12周后,研究組BEHAVE-AD評分雖然由治療前的13.7±2.73降低到8.1±3.30,且減分較對照組顯著,但BEHAVE-AD平均分仍>8分,仍有32.5 %(13/40)患者BPSD沒有緩解,說明兩者聯(lián)用并不能完全消除BPSD。
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Combination of memantine and donepezil in treatment of patients with Alzheimer disease
Alzheimer Disease Behavioral and psychological symptoms DonepezilMemantine
2012-04-05)
(本文編輯:田云鵬)
310012 杭州,浙江省立同德醫(yī)院老年科
【 Abstract】Objective To evaluate the efficacy and safety of combination of memantine and donepezil in treatment of patients with Alzheimer disease (AD).Methods Eighty patients with AD were randomly assigned to receive combination of memantine (starting dose 5 mg/d,5 mg weekly increments,20 mg/d after 4 weeks)and donepezil(starting dose 5 mg/d,10 mg/d after 4 weeks)(combination group,n=40)or donepezil alone(control group,n=40)for 12 weeks.The behavioral and psychological symptoms,activities of daily living and clinical global impression were evaluated with Behavioral Pathology in Alzheimer's Disease Rating Scale(BEHAVE-AD),Activities of Daily Living Inventory(ADL)and Clinical Global Impression Scale(CGI)before and after treatment.Results At the end of week 12,the scores of BEHAVE-AD and ADL were lower in combination treatment group than those in control group(8.1±3.30 vs 9.2±2.80,t=-3.317,P=0.002)and(28.1±2.35 vs 29.3±2.63,t=2.097,P<0.05), respectively.The CGI score in combination group was better than that in control group (3.43±0.82 vs 4.37±0.85,t=-5.413,P<0.01).Six patients(15.0%)in combination group and 5 patients(12.5%)in control group developed mild adverse effects respectively.Conclusion Combination of memantine and donepezil achieves better efficacy than donepezil alone in treatment of patients with Alzheimer disease.