Panza Francesco, Solfrizzi Vincenzo, Seripa Davide, Imbimbo Bruno P, Lozupone Madia, Santamato Andrea, Zecca Chiara, Barulli Maria Rosaria, Bellomo Antonello, Pilotto Alberto, Daniele Antonio, Greco Antonio, Logroscino Giancarlo
Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy; Department of Clinical Research in Neurology, University of Bari Aldo Moro, "Pia Fondazione Cardinale G. Panico", Tricase, Lecce, Italy; Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.
Geriatric Medicine-Memory Unit and Rare Disease Centre, University of Bari Aldo Moro, Bari, Italy.
Biomed Res Int. 2016;2016:3245935. doi: 10.1155/2016/3245935. Epub 2016 Jun 26.
The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. 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 (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.
针对大脑中β-淀粉样蛋白积聚的药物在阿尔茨海默病（AD）的多项II/III期临床试验中失败，这激发了人们对针对tau蛋白病变的替代治疗方法的兴趣与日俱增，这些方法包括针对tau蛋白磷酸酶/激酶、主动和被动免疫以及抗tau蛋白聚集的方法。最先进的tau蛋白聚集抑制剂（TAI）是亚甲蓝（MT），一种在还原形式（无色亚甲蓝）和氧化形式（MT(+)）之间处于平衡状态的药物。在一项针对321例轻度至中度AD患者的为期24周的II期临床试验中对亚甲蓝进行了研究，该试验未能在轻度AD患者中显示出显著的积极效果，尽管长期观察（50周）和生物标志物研究表明可能有益。138毫克/天的剂量对中度受影响的AD患者的认知能力以及轻度受影响患者的脑血流量显示出潜在益处。更多的临床证据将来自正在进行的大型III期试验，该试验使用一种新形式的TAI（称为TRx0237）治疗AD和额颞叶痴呆的行为变异型，这种新形式在更高剂量下具有更高的生物利用度且毒性更低。最近，基于临床使用的水杨酸衍生物双水杨酸酯在动物研究中取得的令人印象深刻的结果，人们正在积极探索tau蛋白乙酰化抑制剂。
