Methylthioninium (MT) is a tau aggregation inhibitor with therapeutic potential in Alzheimer’s disease (AD). MT exists in equilibrium between reduced [leucomethylthioninium (LMT)] and oxidized (MT+) forms; as the chloride salt [methylthioniniumchloride (MTC)], it is stabilized in its MT+ form. While the results of a phase 2 study of MTC in 321 AD subjects identified a 138 mg MT/day dose as the minimum effective dose, the 228 mg MT/day dose lacked efficacy. The authors hypothesized that the lack of a dose response may reflect differences in redox processing of MT at different levels in the gut. The synthesis of a novel chemical entity, LMTX (providing LMT in a stable anhydrous crystalline form), enabled a systematic comparison of the pharmacokinetic properties of MTC and LMTX in preclinical and clinical studies. The quantity of MT released in water or gastric fluid within 60 minutes proved to be an important determinant of clinical efficacy. There was also a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered as MTC.
See article at J Pharmacol Exp Ther 2015, 352:110–118.
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