1月10日,，《柳葉刀》在線發(fā)表的一項隨機(jī)安慰劑對照研究顯示,，美金剛對年齡＞40歲的唐氏綜合征患者癡呆癥無效，提示對阿爾茨海默病有效的藥物未必對唐氏綜合征患者同樣奏效,。
英國倫敦國王學(xué)院的CliveBallard博士及其同事報告,，這項名為“美金剛治療年齡＞40歲的成人唐氏綜合征患者的癡呆癥(MEADOWS)”的試驗共招募了173例受試者，結(jié)果在52周的研究中,，不論是使用美金剛還是安慰劑,，患者的認(rèn)知功能均下降。不僅如此,，雖然兩組患者的認(rèn)知功能下降速度相似,，但安慰劑組反而降得略慢于美金剛組。
該研究的受試者為年齡≥40歲的唐氏綜合征患者,，或不限年齡的唐氏綜合征合并癡呆癥的患者,，來自英國和挪威的4家學(xué)習(xí)障礙治療中心,。將受試者隨機(jī)分組，給予劑量遞增的美金剛治療(8周內(nèi)由5mg/d逐步增至10mg/d,，之后維持在10mg/d)或安慰劑治療,。
結(jié)果顯示,，在校正基線評分之后,，52周時安慰劑組和美金剛組患者在唐氏綜合征注意力、記憶力和執(zhí)行功能量表(DAMES)上的平均得分改變分別為-1.9和-5.6,。兩組在適應(yīng)性行為量表第Ⅰ部分(-1.7vs.-10.7,，針對獨立功能)和第Ⅱ部分(0vs.1.0，針對富有挑戰(zhàn)性的行為)得分的平均變化方面也無顯著差異,。
上述結(jié)果不受癡呆癥存在與否的影響,。隨機(jī)分組時，兩組患者各有35%被診斷為癡呆癥,。嚴(yán)重不良事件發(fā)生率也無明顯的組間差異,，安慰劑組和美金剛組分別為7%和11%。
癡呆癥在成人唐氏綜合征患者中十分常見,，后者在60歲之后約有近40%會被診斷為癡呆癥,。而且，唐氏綜合征患者在40歲之前即普遍出現(xiàn)有臨床顯著性的阿爾茨海默病樣病理改變,。研究者指出：“雖然從原理上講,，抗阿爾茨海默病的藥物對唐氏綜合征患者也應(yīng)當(dāng)有效，但不可否認(rèn)的是這兩種疾病的確存在某些重要的病理特征差異,。例如,，唐氏綜合征患者有終身的β淀粉樣蛋白復(fù)合物生成過量和多種基因調(diào)節(jié)異常，而后者中的大多數(shù)與阿爾茨海默病無關(guān),。這些差異可能使得兩種疾病對同類藥物產(chǎn)生不同反應(yīng),。”
N-甲基-D-天冬氨酸受體拮抗劑美金剛已獲準(zhǔn)用于治療中至重度阿爾茨海默病，并且在2項唐氏綜合征小鼠模型研究中初顯療效,。然而本項研究顯示美金剛并不能給唐氏綜合征患者帶來益處,，不論其是否已被診斷為癡呆癥。研究者指出,，需要開展有足夠效能的隨機(jī)對照試驗以評估膽堿酯酶抑制劑能否治療唐氏綜合征患者的癡呆癥,。膽堿酯酶抑制劑已在英國獲準(zhǔn)用于唐氏綜合征患者的癡呆癥，但僅有很少的證據(jù)支持這一用法,。
這項研究由英國倫敦國王學(xué)院發(fā)起,，獲得了Lundbeck的資助。Ballard博士報告稱接受了由Lundbeck,、楊森,、諾華和Acadia提供的咨詢費和演講費，并獲得了由Lundbeck和Acadia提供的酬金。其他作者報告稱接受了由Lundbeck,、諾華和(或)羅氏提供的咨詢費,、演講費、獎金和(或)酬金,，并擔(dān)任Lundbeck的顧問,，為諾華和衛(wèi)材提供有償專家證詞，接受了由阿爾茨海默病學(xué)會和HenrySmith信托提供的資助,。
該研究為今后的試驗打下基礎(chǔ)
英國倫敦大學(xué)學(xué)院精神健康系的GillLivingston博士和AndreStrydom博士在隨刊述評中指出,，雖然結(jié)果令人失望，但MEADOWS試驗的確有助于排除對唐氏綜合征合并癡呆癥患者無益的治療藥物,，因而避免了無謂的副作用和對醫(yī)療資源的浪費,。唐氏綜合征的復(fù)雜性可能意味著需要聯(lián)合治療才能改善其病理變化。研究者需要更深入地了解唐氏綜合征的神經(jīng)生物學(xué)機(jī)制,，從而確定有效的聯(lián)合治療方案,。此外，必須通過遺傳學(xué),、動物和細(xì)胞學(xué)研究來確定潛在治療手段,，還需要通過確定人類認(rèn)知功能所對應(yīng)的動物行為模式來對實驗結(jié)果加以解讀。
Livingston博士曾在其他的阿爾茨海默病研究中接受Lundbeck的資助,。Strydom博士參與了一項由羅氏贊助的試驗,，該試驗旨在改善成人唐氏綜合征患者的認(rèn)知功能。（生物谷Bioon.com）
doi:10.1016/S0140-6736(11)61676-0
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PMID:
Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial
Marisa Hanney, PhD, Vee Prasher, MD, Nicola Williams, MSc, Emma L Jones, DPhil, Prof Dag Aarsland, PhD, Anne Corbett, PhD, Dale Lawrenc, MRCPsych, Ly-Mee Yu, PhD, Stephen Tyrer, FRCPsych, Prof Paul T Francis, PhD, Tony Johnson, PhD, Roger Bullock, MRCPsych, Prof Clive Ballard, MDa, on behalf of the MEADOWS trial researchers
Summary
Background
Prevalence of Alzheimer's disease in people with Down's syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimer's disease. Evidence to support treatment with Alzheimer's drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Down's syndrome.
Methods
In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Down's syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Down's syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898.
Findings
We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of ?4·1 (95% CI ?13·1 to 4·8) in DAMES scores, ?8·5 (–20·1 to 3·1) in ABS I scores, and 2·0 (–7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77).
Interpretation
There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Down's syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimer's disease are not necessarily effective in this group of patients.
