{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T07:11:16Z","timestamp":1783149076818,"version":"3.54.6"},"reference-count":45,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T00:00:00Z","timestamp":1571616000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2019,11,26]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer\u2019s disease (AD) comparing doses in the range 150\u2013250\u200amg\/day with 8\u200amg\/day intended as a control.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>To determine how drug exposure is related to treatment response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>There are steep concentration-response relationships for steady state plasma levels in the range 0.3\u20130.8\u200ang\/ml at the 8\u200amg\/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4\u201321\u200ang\/ml produced by the high doses are not associated with any additional benefit.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Hydromethylthionine has pharmacological activity on brain structure and function at the 8\u200amg\/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16\u200amg\/day as monotherapy. A placebo-controlled trial in mild\/moderate AD is now ongoing to confirm efficacy at this dose.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3233\/jad-190772","type":"journal-article","created":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T11:50:45Z","timestamp":1571831445000},"page":"931-946","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":43,"title":["Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"72","author":[{"given":"Bjoern O.","family":"Schelter","sequence":"first","affiliation":[{"name":"TauRx Therapeutics Ltd., Singapore, Singapore"},{"name":"Institute for Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, 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