1月10日，《柳叶刀》在线发表的一项随机安慰剂对照研究显示，美金刚对年龄＞40岁的唐氏综合征患者痴呆症无效，提示对阿尔茨海默病有效的药物未必对唐氏综合征患者同样奏效。
英国伦敦国王学院的CliveBallard博士及其同事报告，这项名为“美金刚治疗年龄＞40岁的成人唐氏综合征患者的痴呆症(MEADOWS)”的试验共招募了173例受试者，结果在52周的研究中，不论是使用美金刚还是安慰剂，患者的认知功能均下降。不仅如此，虽然两组患者的认知功能下降速度相似，但安慰剂组反而降得略慢于美金刚组。
该研究的受试者为年龄≥40岁的唐氏综合征患者，或不限年龄的唐氏综合征合并痴呆症的患者，来自英国和挪威的4家学习障碍治疗中心。将受试者随机分组，给予剂量递增的美金刚治疗(8周内由5mg/d逐步增至10mg/d，之后维持在10mg/d)或安慰剂治疗。
结果显示，在校正基线评分之后，52周时安慰剂组和美金刚组患者在唐氏综合征注意力、记忆力和执行功能量表(DAMES)上的平均得分改变分别为-1.9和-5.6。两组在适应性行为量表第Ⅰ部分(-1.7vs.-10.7，针对独立功能)和第Ⅱ部分(0vs.1.0，针对富有挑战性的行为)得分的平均变化方面也无显著差异。
上述结果不受痴呆症存在与否的影响。随机分组时，两组患者各有35%被诊断为痴呆症。严重不良事件发生率也无明显的组间差异，安慰剂组和美金刚组分别为7%和11%。
痴呆症在成人唐氏综合征患者中十分常见，后者在60岁之后约有近40%会被诊断为痴呆症。而且，唐氏综合征患者在40岁之前即普遍出现有临床显著性的阿尔茨海默病样病理改变。研究者指出：“虽然从原理上讲，抗阿尔茨海默病的药物对唐氏综合征患者也应当有效，但不可否认的是这两种疾病的确存在某些重要的病理特征差异。例如，唐氏综合征患者有终身的β淀粉样蛋白复合物生成过量和多种基因调节异常，而后者中的大多数与阿尔茨海默病无关。这些差异可能使得两种疾病对同类药物产生不同反应。”
N-甲基-D-天冬氨酸受体拮抗剂美金刚已获准用于治疗中至重度阿尔茨海默病，并且在2项唐氏综合征小鼠模型研究中初显疗效。然而本项研究显示美金刚并不能给唐氏综合征患者带来益处，不论其是否已被诊断为痴呆症。研究者指出，需要开展有足够效能的随机对照试验以评估胆碱酯酶抑制剂能否治疗唐氏综合征患者的痴呆症。胆碱酯酶抑制剂已在英国获准用于唐氏综合征患者的痴呆症，但仅有很少的证据支持这一用法。
这项研究由英国伦敦国王学院发起，获得了Lundbeck的资助。Ballard博士报告称接受了由Lundbeck、杨森、诺华和Acadia提供的咨询费和演讲费，并获得了由Lundbeck和Acadia提供的酬金。其他作者报告称接受了由Lundbeck、诺华和(或)罗氏提供的咨询费、演讲费、奖金和(或)酬金，并担任Lundbeck的顾问，为诺华和卫材提供有偿专家证词，接受了由阿尔茨海默病学会和HenrySmith信托提供的资助。
该研究为今后的试验打下基础
英国伦敦大学学院精神健康系的GillLivingston博士和AndreStrydom博士在随刊述评中指出，虽然结果令人失望，但MEADOWS试验的确有助于排除对唐氏综合征合并痴呆症患者无益的治疗药物，因而避免了无谓的副作用和对医疗资源的浪费。唐氏综合征的复杂性可能意味着需要联合治疗才能改善其病理变化。研究者需要更深入地了解唐氏综合征的神经生物学机制，从而确定有效的联合治疗方案。此外，必须通过遗传学、动物和细胞学研究来确定潜在治疗手段，还需要通过确定人类认知功能所对应的动物行为模式来对实验结果加以解读。
Livingston博士曾在其他的阿尔茨海默病研究中接受Lundbeck的资助。Strydom博士参与了一项由罗氏赞助的试验，该试验旨在改善成人唐氏综合征患者的认知功能。（生物谷Bioon.com）
doi:10.1016/S0140-6736(11)61676-0
PMC:
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.
