Drug candidates in clinical trials for Alzheimer's disease.
Drug candidates in clinical trials for Alzheimer's disease.
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DOI：
10.1186/s12929-017-0355-7
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发表时间：
2017-07-19
影响因子：
11
通讯作者：
Fu WM
中科院分区：
文献类型：
--
作者：
Hung SY;Fu WM
阿尔茨海默病（AD）是老年痴呆症的一种主要形式，其特征是进行性记忆和神经元丧失以及认知障碍。 AD 是全世界最常见的神经退行性疾病，影响着五分之一的 85 岁以上老年人。最近的治疗方法受到 AD 的五种神经病理学特征的强烈影响：乙酰胆碱缺乏、谷氨酸兴奋毒性、β 淀粉样蛋白的细胞外沉积（Aβ 瘟疫）、神经元内神经原纤维缠结 (NTF) 的形成和神经炎症。 AD 中乙酰胆碱 (ACh) 浓度降低会导致认知和行为功能逐渐显着丧失。目前的 AD 药物美金刚和乙酰胆碱酯酶抑制剂 (AChEI) 通过增强胆碱能信号传导来缓解其中一些症状，但它们并不能治愈。自2003年以来，没有新药被批准用于治疗AD。本文重点介绍当前针对 AD 神经病理学发现的临床试验研究，包括乙酰胆碱反应、谷氨酸传输、Aβ 清除、tau 蛋白沉积和神经炎症。这些研究包括乙酰胆碱酯酶抑制剂、神经递质受体激动剂和拮抗剂、β-分泌酶 (BACE) 或 γ-分泌酶抑制剂、针对 Aβ 清除或 tau 蛋白的疫苗或抗体，以及抗炎化合物。正在进行的针对 Aβ 肽（crenezumab、gantenerumab 和 aducanumab）被动免疫疗法的 III 期临床试验似乎很有希望。使用小分子阻断 5-HT6 血清素受体（intepirdine）、抑制 BACE 活性（E2609、AZD3293 和 verubecestat）或减少 tau 聚集（TRx0237）目前也处于 III 期临床试验中。我们在这里系统地回顾了最近临床试验的结果，以对治疗和预防 AD 的新型治疗化合物进行全面回顾。
Alzheimer’s disease (AD) is a major form of senile dementia, characterized by progressive memory and neuronal loss combined with cognitive impairment. AD is the most common neurodegenerative disease worldwide, affecting one-fifth of those aged over 85 years. Recent therapeutic approaches have been strongly influenced by five neuropathological hallmarks of AD: acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of amyloid-β (Aβ plague), formation of intraneuronal neurofibrillary tangles (NTFs), and neuroinflammation. The lowered concentrations of acetylcholine (ACh) in AD result in a progressive and significant loss of cognitive and behavioral function. Current AD medications, memantine and acetylcholinesterase inhibitors (AChEIs) alleviate some of these symptoms by enhancing cholinergic signaling, but they are not curative. Since 2003, no new drugs have been approved for the treatment of AD. This article focuses on the current research in clinical trials targeting the neuropathological findings of AD including acetylcholine response, glutamate transmission, Aβ clearance, tau protein deposits, and neuroinflammation. These investigations include acetylcholinesterase inhibitors, agonists and antagonists of neurotransmitter receptors, β-secretase (BACE) or γ-secretase inhibitors, vaccines or antibodies targeting Aβ clearance or tau protein, as well as anti-inflammation compounds. Ongoing Phase III clinical trials via passive immunotherapy against Aβ peptides (crenezumab, gantenerumab, and aducanumab) seem to be promising. Using small molecules blocking 5-HT6 serotonin receptor (intepirdine), inhibiting BACE activity (E2609, AZD3293, and verubecestat), or reducing tau aggregation (TRx0237) are also currently in Phase III clinical trials. We here systemically review the findings from recent clinical trials to provide a comprehensive review of novel therapeutic compounds in the treatment and prevention of AD.
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影响因子：
5.3
作者：
Bulic B;Ness J;Hahn S;Rennhack A;Jumpertz T;Weggen S
通讯作者：
Weggen S
影响因子：
14
作者：
Doody, Rachelle Smith;Tariot, Pierre N.;Graham, Stephen M.
通讯作者：
Graham, Stephen M.
影响因子：
168.9
作者：
Holmes, Clive;Boche, Delphine;Nicoll, James A. R.
通讯作者：
Nicoll, James A. R.
DOI：
10.1186/alzrt269
发表时间：
2014
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Cummings JL;Morstorf T;Zhong K
通讯作者：
Zhong K
影响因子：
2.1
作者：
Arai, Heii;Suzuki, Hideo;Yoshiyama, Tamotsu
通讯作者：
Yoshiyama, Tamotsu