Exploring the Anti-Hypoxaemia Effect of Hydromethylthionine: A Prospective Study of Phase 3 Clinical Trial Participants

Author:

Arastoo Mohammad12,Mazanetz Michael P.34,Miller Sonya5,Shiells Helen5,Hull Claire5ORCID,Robinson Keith6ORCID,Storey John M. D.45,Harrington Charles R.15ORCID,Wischik Claude M.15

Affiliation:

1. School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZP, UK

2. Scottish Biologics Facility, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZP, UK

3. NovaData Solutions Ltd., 15 Monreith Rd, Newlands, Glasgow G43 2NX, UK

4. Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, UK

5. TauRx Therapeutics Ltd., 395 King Street, Aberdeen AB24 3FX, UK

6. Syneos Health, LLC, Morrisville, NC 27560, USA

Abstract

Methylthioninium chloride (MTC) is a standard treatment for methaemoglobinaemia. A preparation of reduced MTC has been reported to increase blood oxygen saturation (SpO2) and lower respiratory rates in patients with severe COVID-19. We have developed a stable form of reduced methylthionine (hydromethylthionine-mesylate, HMTM) having a benign safety profile in two Phase 3 trials in Alzheimer’s disease. The aim of this prospective study was to determine the effects of oral HMTM on SpO2 and methaemoglobin (metHb) levels in a cohort of patients with mild hypoxaemia not due to COVID-19. Eighteen participants randomised to a single dose of 4, 75, 100 or 125 mg doses of HMTM had SpO2 levels below 94% at baseline. Patients were routinely monitored by pulse oximetry after 4 h, and after 2 and 6 weeks of twice daily dosing. Significant ~3% increases in SpO2 occurred within 4 h and were sustained over 2 and 6 weeks with no dose differences. There were small dose-dependent increases (0.060–0.162%) in metHb levels over 2 to 6 weeks. Minimum-energy computational chemistry revealed that HMT can bind within 2.10 Å of heme iron by donating a pair of electrons from the central nitrogen of HMT to d orbitals of heme iron, but with lower affinity than oxygen. In conclusion, HMTM can increase SpO2 without reducing metHb by acting as a strong displaceable field ligand for heme iron. We hypothesise that this facilitates a transition from the low oxygen affinity T-state of heme to the higher affinity R-state. HMTM has potential as an adjunctive treatment for hypoxaemia.

Funder

TauRx Therapeutics Ltd., Singapore

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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