TY - JOUR
AU - Arastoo, Mohammad
AU - Mazanetz, Michael P.
AU - Miller, Sonya
AU - Shiells, Helen
AU - Hull, Claire
AU - Robinson, Keith
AU - Storey, John M.D.
AU - Harrington, Charles
AU - Wischik, Claude M.
PY - 2023
DA - September
TI - Exploring the Anti-Hypoxaemia Effect of Hydromethylthionine: A Prospective Study of Phase 3 Clinical Trial Participants
JO - International Journal of Molecular Sciences
VL - 24
IS - 18
DO - https://doi.org/10.3390/ijms241813747
AB - 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 SpO2and 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 SpO2levels 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 SpO2occurred 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 todorbitals of heme iron, but with lower affinity than oxygen. In conclusion, HMTM can increase SpO2without 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.
PB - MDPI
UR - https://hdl.handle.net/2164/22092
KW - Coronavirus (COVID-19)
ER