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Research ArticleNeuropharmacology

Complex Disposition of Methylthioninium Redox Forms Determines Efficacy in Tau Aggregation Inhibitor Therapy for Alzheimer’s Disease

Thomas C. Baddeley, Jennifer McCaffrey, John M. D. Storey, John K. S. Cheung, Valeria Melis, David Horsley, Charles R. Harrington and Claude M. Wischik
Journal of Pharmacology and Experimental Therapeutics January 2015, 352 (1) 110-118; DOI: https://doi.org/10.1124/jpet.114.219352
Thomas C. Baddeley
Department of Chemistry (T.C.B., J.M.D.S.), School of Medicine and Dentistry (J.K.S.C., V.M., D.H., C.R.H., C.M.W.),University of Aberdeen, Aberdeen, United Kingdom; and Salamandra LLC, Washington, DC (J.M.)
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Jennifer McCaffrey
Department of Chemistry (T.C.B., J.M.D.S.), School of Medicine and Dentistry (J.K.S.C., V.M., D.H., C.R.H., C.M.W.),University of Aberdeen, Aberdeen, United Kingdom; and Salamandra LLC, Washington, DC (J.M.)
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John M. D. Storey
Department of Chemistry (T.C.B., J.M.D.S.), School of Medicine and Dentistry (J.K.S.C., V.M., D.H., C.R.H., C.M.W.),University of Aberdeen, Aberdeen, United Kingdom; and Salamandra LLC, Washington, DC (J.M.)
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John K. S. Cheung
Department of Chemistry (T.C.B., J.M.D.S.), School of Medicine and Dentistry (J.K.S.C., V.M., D.H., C.R.H., C.M.W.),University of Aberdeen, Aberdeen, United Kingdom; and Salamandra LLC, Washington, DC (J.M.)
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Valeria Melis
Department of Chemistry (T.C.B., J.M.D.S.), School of Medicine and Dentistry (J.K.S.C., V.M., D.H., C.R.H., C.M.W.),University of Aberdeen, Aberdeen, United Kingdom; and Salamandra LLC, Washington, DC (J.M.)
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David Horsley
Department of Chemistry (T.C.B., J.M.D.S.), School of Medicine and Dentistry (J.K.S.C., V.M., D.H., C.R.H., C.M.W.),University of Aberdeen, Aberdeen, United Kingdom; and Salamandra LLC, Washington, DC (J.M.)
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Charles R. Harrington
Department of Chemistry (T.C.B., J.M.D.S.), School of Medicine and Dentistry (J.K.S.C., V.M., D.H., C.R.H., C.M.W.),University of Aberdeen, Aberdeen, United Kingdom; and Salamandra LLC, Washington, DC (J.M.)
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Claude M. Wischik
Department of Chemistry (T.C.B., J.M.D.S.), School of Medicine and Dentistry (J.K.S.C., V.M., D.H., C.R.H., C.M.W.),University of Aberdeen, Aberdeen, United Kingdom; and Salamandra LLC, Washington, DC (J.M.)
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Abstract

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 a chloride salt [methylthioninium chloride (MTC), “methylene blue”], it is stabilized in its MT+ form. Although the results of a phase 2 study of MTC in 321 mild/moderate AD subjects identified a 138-mg MT/day dose as the minimum effective dose on cognitive and imaging end points, further clinical development of MT was delayed pending resolution of the unexpected lack of efficacy of the 228-mg MT/day dose. We hypothesized that the failure of dose response may depend on differences known at the time in dissolution in simulated gastric and intestinal fluids of the 100-mg MTC capsules used to deliver the 228-mg dose and reflect previously unsuspected 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), has 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 in retrospect to be an important determinant of clinical efficacy. A further factor was a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered in the MT+ form as MTC. A model is presented to account for the complexity of MT absorption, which may have relevance for other similar redox molecules.

Footnotes

    • Received August 19, 2014.
    • Accepted October 14, 2014.
  • This research was supported by TauRx Therapeutics Ltd. (Singapore).

  • dx.doi.org/10.1124/jpet.114.219352.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 352 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 1
1 Jan 2015
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Research ArticleNeuropharmacology

Methylthioninium Redox Forms for Alzheimer’s Treatment

Thomas C. Baddeley, Jennifer McCaffrey, John M. D. Storey, John K. S. Cheung, Valeria Melis, David Horsley, Charles R. Harrington and Claude M. Wischik
Journal of Pharmacology and Experimental Therapeutics January 1, 2015, 352 (1) 110-118; DOI: https://doi.org/10.1124/jpet.114.219352

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Research ArticleNeuropharmacology

Methylthioninium Redox Forms for Alzheimer’s Treatment

Thomas C. Baddeley, Jennifer McCaffrey, John M. D. Storey, John K. S. Cheung, Valeria Melis, David Horsley, Charles R. Harrington and Claude M. Wischik
Journal of Pharmacology and Experimental Therapeutics January 1, 2015, 352 (1) 110-118; DOI: https://doi.org/10.1124/jpet.114.219352
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