用于治疗阿尔茨海默病的靶向tau蛋白方法：聚焦于亮甲硫鎓。
Tau-directed approaches for the treatment of Alzheimer's disease: focus on leuco-methylthioninium.
作者信息
Seripa Davide, Solfrizzi Vincenzo, Imbimbo Bruno P, Daniele Antonio, Santamato Andrea, Lozupone Madia, Zuliani Giovanni, Greco Antonio, Logroscino Giancarlo, Panza Francesco
机构信息
a Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences , IRCCS 'Casa Sollievo della Sofferenza' , San Giovanni Rotondo , Foggia , Italy.
b Geriatric Medicine-Memory Unit and Rare Disease Centre , University of Bari Aldo Moro , Bari , Italy.
出版信息
Expert Rev Neurother. 2016;16(3):259-77. doi: 10.1586/14737175.2016.1140039.
Small molecular weight compounds able to inhibit formation of tau oligomers and fibrils have already been tested for Alzheimer's disease (AD) treatment. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT(+)). MT chloride (also known as methylene blue) was investigated in a 24-week Phase II study in 321 mild-to-moderate AD patients at the doses of 69, 138, and 228 mg/day. This trial failed to show significant positive effects of MT in the overall patient population. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected patients and cerebral blood flow in mildly affected patients. A follow-up compound (TRx0237) claimed to be more bioavailable and less toxic than MT, is now being developed. Phase III clinical trials on this novel TAI in AD and in the behavioral variant of frontotemporal dementia are underway.
能够抑制tau寡聚体和原纤维形成的小分子化合物已被用于阿尔茨海默病（AD）治疗的测试。最先进的tau聚集抑制剂（TAI）是亚甲蓝（MT），一种以还原形式（无色亚甲蓝）和氧化形式（MT(+)）处于平衡状态的药物。在一项针对321名轻至中度AD患者的为期24周的II期研究中，对氯化MT（也称为亚甲蓝）进行了69、138和228毫克/天剂量的研究。该试验未能在总体患者群体中显示出MT的显著积极效果。138毫克/天的剂量对中度受影响患者的认知表现和轻度受影响患者的脑血流量显示出潜在益处。一种后续化合物（TRx0237）据称比MT具有更高的生物利用度和更低的毒性，目前正在研发中。关于这种新型TAI在AD和额颞叶痴呆行为变异型中的III期临床试验正在进行。
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