title: Tau-directed approaches for the treatment of Alzheimer's disease: focus on leuco-methylthioninium.
abstract: 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.
authors.affiliation: a Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences , IRCCS 'Casa Sollievo della Sofferenza' , San Giovanni Rotondo , Foggia , Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Seripa
authors.affiliation: b Geriatric Medicine-Memory Unit and Rare Disease Centre , University of Bari Aldo Moro , Bari , Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Solfrizzi
authors.affiliation: c Research & Development Department , Chiesi Farmaceutici , Parma , Italy.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
authors.affiliation: d Institute of Neurology , Catholic University of Sacred Heart , Rome , Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Daniele
authors.affiliation: e Physical Medicine and Rehabilitation Section, 'OORR' Hospital , University of Foggia , Foggia , Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Santamato
authors.affiliation: f Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs , University of Bari Aldo Moro , Bari , Italy.
authors.forename: Madia
authors.initials: M
authors.lastname: Lozupone
authors.affiliation: g Department of Medical Science, Section of Internal and Cardiopulmonary Medicine , University of Ferrara.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Zuliani
authors.affiliation: a Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences , IRCCS 'Casa Sollievo della Sofferenza' , San Giovanni Rotondo , Foggia , Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Greco
authors.affiliation: f Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs , University of Bari Aldo Moro , Bari , Italy.|h Department of Clinical Research in Neurology , University of Bari Aldo Moro, 'Pia Fondazione Cardinale G. Panico' , Tricase , Lecce , Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Logroscino
authors.affiliation: a Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences , IRCCS 'Casa Sollievo della Sofferenza' , San Giovanni Rotondo , Foggia , Italy.|f Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs , University of Bari Aldo Moro , Bari , Italy.|h Department of Clinical Research in Neurology , University of Bari Aldo Moro, 'Pia Fondazione Cardinale G. Panico' , Tricase , Lecce , Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Panza
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D002986:Clinical Trials as Topic; D006801:Humans; D008751:Methylene Blue / Q000627:therapeutic use*; D016875:tau Proteins / Q000187:drug effects*
chemical_list: D016875:tau Proteins; D008751:Methylene Blue
keywords: Alzheimer’s disease; TRx0237; dementia; immunotherapy; leuco-methylthioninium; methylthioninium; microtubule-stabilizing agents; tau aggregation inhibitors; tau phosphorylation inhibitors; tau protein