ALPHA 2 AGONIST PLUS A CHOLINESTERASE INHIBITOR IN ALZHEIMERS DISEASE

AD（阿尔茨海默病）的拟胆碱治疗仅在 有限的成功。虽然一个亚组的患者有一个温和的，虽然 胆碱酯酶抑制剂的临床显著改善， 很难像左旋多巴治疗帕金森病那样有效， 甚至氟哌啶醇治疗精神分裂症很明显，一个纯粹的 AD的精神疗法的胆碱能方法是AD不是 只是胆碱能缺乏AD中去甲肾上腺素能缺陷的证据 来自研究表明LC神经元的损失，大多数 在具有最大神经皮质斑块形成的受试者中是明显的 并且与痴呆的严重程度相关。此外，去甲肾上腺素 几个大脑区域的含量减少，这种减少是 与智力衰退的更严重程度相关 AD患者因此，有令人信服的数据表明， 影响疾病的症状和疗效的严格 胆碱能途径。尽管开发了安全、更容易使用的 胆碱酯酶抑制剂，如安理申，只有一部分治疗， 患者有一定的影响。III期数据评价 Aricept的临床试验显示，62.3%的非- 因此， 因此，有必要开发替代方法。动物研究 提供令人信服的证据来支持这种替代方法， 特别是增强胆碱能和去甲肾上腺素能 活动因此，我们的总体目标是确定共同- 施用选择性α-2去甲肾上腺素能受体激动剂， 胍法辛与乙酰胆碱酯酶抑制剂安理申， 在临床上更有效地治疗阿尔茨海默氏症的认知症状 比单独施用Aricept更有效。我们建议治疗72 AD 受试者在14周双盲、安慰剂对照、平行设计中， 方案，具有额外的3周安慰剂洗脱期。受试者将 结合认知和全球的措施来对待 功能

Cholinomimetic therapies for AD (Alzheimer's disease) have met with only limited success. Although a sub-group of patients have a modest, albeit clinically significant improvement with cholinesterase inhibitors, this is hardly as a robust a treatment as L-dopa for Parkinson's disease or even haloperidol for schizophrenia. Clearly, one problem with a purely cholinergic approach to the psychotherapeutics of AD is that AD is not simply a cholinergic deficit. Evidence for a noradrenergic deficit in AD derives from studies which demonstrate a loss of LC neurons, most evident among subjects with the greatest neurocortical plaque formation and is correlated with severity of dementia. Furthermore, norepinephrine content in several brain areas is reduced and this reduction is associated with greater severity of intellectual deterioration among patients with AD. Thus, there are compelling data to indicate probably influence the symptoms of the disease and the efficacy of a strictly cholinergic approach. Despite the development of safe, easier to use cholinesterase inhibitors, such as Aricept, only a portion of treated patients have a modest effect. Evaluation of the data from Phase III trials of Aricept shows that 62.3% of substantial numbers of non- responders to a purely cholinergic approach to treatment therefore necessitate the need to develop alternative approaches. Animal studies provide convincing evidence to support such an alternative approach, particularly one which enhances both cholinergic and noradrenergic activity. Therefore, our overall aim to determine whether the co- administration of the selective alpha-2 noradrenergic receptor agonist, guanfacine, with the acetylcholinesterase inhibitor, Aricept, is clinically more effective in treating cognitive symptoms of Alzheimer's disease than administration of Aricept alone. We propose to treat 72 AD subjects in a 14 week double blind, placebo controlled, parallel design, protocol, with an additional 3 week placebo washout phase. Subjects will be treated with a combination on measures of cognitive and global functioning.