Galimberti Daniela, Scarpini Elio
a Neurology Unit, Department of Pathophysiology and Transplantation , University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico , Milan , Italy.
Expert Opin Investig Drugs. 2016 Oct;25(10):1181-7. doi: 10.1080/13543784.2016.1216972. Epub 2016 Aug 5.
To date, pharmacological treatment of Alzheimer's disease (AD) includes Acetylcholinesterase Inhibitors (AChEIs) for mild-to-moderate AD, and memantine for moderate-to-severe AD. AChEIs reversibly inhibit acetylcholinesterase (AChE), thus increasing the availability of acetylcholine in cholinergic synapses, enhancing cholinergic transmission. These drugs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease.
On the wake of successful clinical trials which lead to the marketing of AChEIs donepezil, rivastigmine and galantamine, many compounds with AChEI properties have been developed and tested mainly in Phase I-II clinical trials in the last twenty years. Here, we review clinical trials initiated and interrupted, and those ongoing so far.
Despite many clinical trials with novel AChEIs have been carried out after the registration of those currently used to treat mild to moderate AD, none so far has been successful in a Phase III trial and marketed. Alzheimer's disease is a complex multifactorial disorder, therefore therapy should likely address not only the cholinergic system but also additional neurotransmitters. Moreover, such treatments should be started in very mild phases of the disease, and preventive strategies addressed in elderly people.
迄今为止，阿尔茨海默病（AD）的药物治疗包括用于轻度至中度AD的乙酰胆碱酯酶抑制剂（AChEIs），以及用于中度至重度AD的美金刚。AChEIs可逆性抑制乙酰胆碱酯酶（AChE），从而增加胆碱能突触中乙酰胆碱的可用性，增强胆碱能传递。这些药物可提供短期症状缓解，但无法明显阻止疾病进展。
在成功的临床试验促使多奈哌齐、卡巴拉汀和加兰他敏等AChEIs上市之后，过去二十年间已研发并主要在I-II期临床试验中测试了许多具有AChEI特性的化合物。在此，我们回顾已启动并中断的以及迄今仍在进行的临床试验。
尽管在目前用于治疗轻度至中度AD的药物注册之后已开展了许多针对新型AChEIs的临床试验，但迄今为止尚无一项在III期试验中取得成功并上市。阿尔茨海默病是一种复杂的多因素疾病，因此治疗可能不仅应针对胆碱能系统，还应针对其他神经递质。此外，此类治疗应在疾病的极轻微阶段开始，并针对老年人制定预防策略。
