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Biomed Res Int. 2016;2016:3245935. doi: 10.1155/2016/3245935. Epub 2016 Jun 26.

Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease.

Author information

1
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.
2
Geriatric Medicine-Memory Unit and Rare Disease Centre, University of Bari Aldo Moro, Bari, Italy.
3
Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.
4
Research & Development Department, Chiesi Farmaceutici, Parma, Italy.
5
Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy; Psychiatric Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
6
Physical Medicine and Rehabilitation Section, "OORR" Hospital, University of Foggia, Foggia, Italy.
7
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.
8
Psychiatric Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
9
Department of Orthogeriatrics, Rehabilitation and Stabilization, Frailty Area, E.O. Galliera NR-HS Hospital, Genova, Italy.
10
Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.

Abstract

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.

PMID:
27429978
PMCID:
PMC4939203
DOI:
10.1155/2016/3245935
[Indexed for MEDLINE]
Free PMC Article

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