title: Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease.
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.
authors.affiliation: 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.).
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Baddeley
authors.affiliation: 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.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: McCaffrey
authors.affiliation: 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.).
authors.forename: John M D
authors.initials: JM
authors.lastname: Storey
authors.affiliation: 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.).
authors.forename: John K S
authors.initials: JK
authors.lastname: Cheung
authors.affiliation: 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.).
authors.forename: Valeria
authors.initials: V
authors.lastname: Melis
authors.affiliation: 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.).
authors.forename: David
authors.initials: D
authors.lastname: Horsley
authors.affiliation: 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.).
authors.forename: Charles R
authors.initials: CR
authors.lastname: Harrington
authors.affiliation: 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.) cmw@taurx.com.
authors.forename: Claude M
authors.initials: CM
authors.lastname: Wischik
mesh_terms: D065966:Absorption, Physicochemical; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004435:Eating; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008751:Methylene Blue / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010084:Oxidation-Reduction; D066263:Protein Aggregation, Pathological / Q000188:drug therapy*; D055815:Young Adult; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D016875:tau Proteins; D008751:Methylene Blue