3月8日的《新英格蘭醫(yī)學(xué)雜志》(New England Journal of Medicine)上發(fā)表的一項(xiàng)隨機(jī)試驗(yàn)顯示,，在接受多奈哌齊治療后病情仍繼續(xù)加重的中重度阿爾茨海默病(AD)患者中,，與追加或轉(zhuǎn)為美金剛以及停用AD藥物治療相比,，繼續(xù)多奈哌齊(愛憶欣)治療顯示出較小但顯著的益處，表現(xiàn)為認(rèn)知和功能性預(yù)后改善,。該試驗(yàn)為期1年,，名為DOMINO(多奈哌齊和美金剛治療中重度阿爾茨海默病)研究，研究者為英國(guó)倫敦國(guó)王學(xué)院精神病學(xué)研究所的Robert Howard醫(yī)生及其合作者,。
當(dāng)AD進(jìn)展時(shí),，是繼續(xù)原有治療，還是更換治療藥物,？注意到有關(guān)這一問題的證據(jù)很少,，Howard醫(yī)生及其同事對(duì)社區(qū)中居住的295例中重度AD患者進(jìn)行了研究，這些患者已接受多奈哌齊治療2-3年,，其臨床醫(yī)生正在考慮更換治療藥物,。所有患者的簡(jiǎn)易智力狀態(tài)檢查(SMMSE)評(píng)分介于5-13分之間，SMMSE的評(píng)分范圍為0-30分,；評(píng)分越高提示認(rèn)知功能越好,。研究者將患者隨機(jī)分配到繼續(xù)多奈哌齊治療并加用安慰劑組(73例患者)、停用多奈哌齊并給予安慰劑組(73例患者),、停用多奈哌齊并改用美金剛組(76例患者)以及繼續(xù)多奈哌齊治療并加用美金剛組(73例患者),。
結(jié)果顯示,，在1年隨訪期間,，137例患者(46%)退出研究，最常見的退出原因?yàn)楦械嚼^續(xù)治療無效,。繼續(xù)多奈哌齊治療者的SMMSE評(píng)分較停用多奈哌齊者高出1.9分,。并且這些患者在護(hù)理者評(píng)估的60分Bristol日常生活活動(dòng)量表(BADLS)評(píng)分方面也較停用多奈哌齊者高出3分，提示功能受損較少,。與未使用美金剛的患者相比,，接受美金剛治療的患者SMMSE評(píng)分提高了1.2分，BADLS評(píng)分提高了1.5分,。但從任何主要或次要終點(diǎn)來看,，與單純多奈哌齊治療相比，聯(lián)合治療未提供任何有統(tǒng)計(jì)學(xué)意義的益處,。
研究者總結(jié)認(rèn)為,，對(duì)于繼續(xù)進(jìn)展的AD患者，繼續(xù)多奈哌齊治療似乎是最好的選擇，加用美金剛無顯著的進(jìn)一步獲益,。然而,，相對(duì)于患者的認(rèn)知和功能狀態(tài)的降低，多奈哌齊和美金剛治療的益處是很小的,。（生物谷 bioon.com）
doi:10.1056/NEJMoa1106668
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Donepezil and Memantine for Moderate-to-Severe Alzheimer's Disease
Robert Howard, M.D., Rupert McShane, F.R.C.Psych., James Lindesay, D.M., Craig Ritchie, M.D., Ph.D., Ashley Baldwin, M.R.C.Psych., Robert Barber, M.D., Alistair Burns, F.R.C.Psych., Tom Dening, F.R.C.Psych., David Findlay, M.B., Ch.B., Clive Holmes, Ph.D., Alan Hughes, M.B., Ch.B., Robin Jacoby, D.M., Rob Jones, M.B., Ch.B., Roy Jones, M.B., Ian McKeith, F.Med.Sc., Ajay Macharouthu, M.R.C.Psych., John O'Brien, D.M., Peter Passmore, M.D., Bart Sheehan, M.D., Edmund Juszczak, M.Sc., Cornelius Katona, M.D., Robert Hills, D.Phil., Martin Knapp, Ph.D., Clive Ballard, M.D., Richard Brown, Ph.D., Sube Banerjee, M.D., Caroline Onions, P.G.Dip., Mary Griffin, R.G.N., Jessica Adams, B.Sc., Richard Gray, M.Sc., Tony Johnson, Ph.D., Peter Bentham, M.B., Ch.B., and Patrick Phillips, Ph.D.
Background Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. Methods We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini–Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. Results Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. Conclusions In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.)
