School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZP, UK.
Scottish Biologics Facility, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZP, UK.
Int J Mol Sci. 2023 Sep 6;24(18):13747. doi: 10.3390/ijms241813747.
Methylthioninium chloride (MTC) is a standard treatment for methaemoglobinaemia. A preparation of reduced MTC has been reported to increase blood oxygen saturation (SpO) 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 SpO 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 SpO 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 SpO 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 orbitals of heme iron, but with lower affinity than oxygen. In conclusion, HMTM can increase SpO 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.
甲硫氨酸氯化物（MTC）是治疗高铁血红蛋白血症的标准疗法。据报道，一种还原型 MTC 制剂可提高严重 COVID-19 患者的血氧饱和度（SpO）并降低呼吸频率。我们在两项阿尔茨海默病的 3 期临床试验中开发了一种具有良性安全性特征的稳定型还原甲硫氨酸（羟甲基甲硫氨酸甲磺酸盐，HMTM）。本前瞻性研究的目的是确定口服 HMTM 对轻度低氧血症（非 COVID-19 引起）患者的 SpO 和高铁血红蛋白（metHb）水平的影响。18 名参与者随机接受 4、75、100 或 125 mg 剂量的 HMTM 单剂量治疗，基线时 SpO 水平低于 94%。患者在 4 小时后、2 周和 6 周后每天两次常规接受脉搏血氧饱和度监测。4 小时内 SpO 显著升高约 3%，并在 2 周和 6 周内持续升高，且无剂量差异。2 至 6 周期间，metHb 水平略有剂量依赖性升高（0.060-0.162%）。最低能量计算化学表明，HMT 可以通过从 HMT 的中心氮原子向血红素铁的轨道捐赠一对电子，与 heme 铁结合在 2.10 Å 以内，但亲和力低于氧。总之，HMTM 可以通过充当血红素铁的强可置换场配体来增加 SpO 而不降低 metHb。我们假设这促进了血红素从低氧亲和力 T 态向更高亲和力 R 态的转变。HMTM 有可能成为低氧血症的辅助治疗方法。
