May Mangafodipir or Other SOD Mimetics Contribute to Better Care in COVID-19 Patients?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by massive inflammation of the arterial endothelium accompanied by vasoconstriction and widespread pulmonary micro thrombi. As a result, due to the destruction of nitric oxide (•NO) by inflammatory superoxide (O2•-), pulmonary •NO concentration ceases, resulting in uncontrolled platelet aggregation and massive thrombosis, which kills the patients. Introducing •NO by inhalation (INO) may replace the loss of endothelium-derived •NO. The first results from clinical trials with INO in SARS-CoV-2 patients show a rapid and sustained improvement in cardiopulmonary function and decreased inflammation. An ongoing phase III study is expected to confirm the method's efficacy. INO may hence become a first line treatment in SARS-CoV-2 patients. However, due to the rapid inactivation of •NO by deoxyhemoglobin to nitrate, pulmonary administration of •NO will not protect remote organs. Another INO-related pharmacological approach to protect SARS-CoV-2 patients from developing life-threatening disease is to inhibit the O2•--driven destruction of •NO by neutralizing inflammatory O2•-. By making use of low molecular weight compounds that mimic the action of the enzyme manganese superoxide dismutase (MnSOD). The MnSOD mimetics of the so-called porphyrin type (e.g., AEOL 10150), salen type (e.g., EUK-8) and cyclic polyamine type (e.g., M40419, today known as GC4419 and avasopasem manganese) have all been shown to positively affect the inflammatory response in lung epithelial cells in preclinical models of chronic obstructive pulmonary disease. The Manganese diPyridoxyL EthylDiamine (MnPLED)-type mangafodipir (manganese dipyridoxyl diphosphate-MnDPDP), a magnetic resonance imaging (MRI) contrast agent that possesses MnSOD mimetic activity, has shown promising results in various forms of inflammation, in preclinical as well as clinical settings. Intravenously administration of mangafodipir will, in contrast to INO, reach remote organs and may hence become an important supplement to INO. From the authors' viewpoint, it appears logical to test mangafodipr in COVID-19 patients at risk of developing life-threatening SARS-CoV-2. Five days after submission of the current manuscript, Galera Pharmaceuticals Inc. announced the dosing of the first patient in a randomized, double-blind pilot phase II clinical trial with GC4419 for COVID-19. The study was first posted on ClinicalTrials.gov (Identifier: NCT04555096) 18 September 2020.

Calmangafodipir [Ca4Mn(DPDP)5], mangafodipir (MnDPDP) and MnPLED with special reference to their SOD mimetic and therapeutic properties.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) participate in pathological tissue damage. Mitochondrial manganese superoxide dismutase (MnSOD) normally keeps ROS and RNS in check. During development of mangafodipir (MnDPDP) as a magnetic resonance imaging (MRI) contrast agent, it was discovered that MnDPDP and its metabolite manganese pyridoxyl ethyldiamine (MnPLED) possessed SOD mimetic activity. MnDPDP has been tested as a chemotherapy adjunct in cancer patients and as an adjunct to percutaneous coronary intervention in patients with myocardial infarctions, with promising results. Whereas MRI contrast depends on release of Mn(2+), the SOD mimetic activity depends on Mn(2+) that remains bound to DPDP or PLED. Calmangafodipir [Ca4Mn(DPDP)5] is stabilized with respect to Mn(2+) and has superior therapeutic activity. Ca4Mn(DPDP)5 is presently being explored as a chemotherapy adjunct in a clinical multicenter Phase II study in patients with metastatic colorectal cancer.

Mangafodipir as a cardioprotective adjunct to reperfusion therapy: a feasibility study in patients with ST-segment elevation myocardial infarction.

AIMS: The aim of the present study was to examine the feasibility of applying the catalytic antioxidant mangafodipir [MnDPDP, manganese (Mn) dipyridoxyl diphosphate] as a cardioprotective adjunct to primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation (STE) myocardial infarction (STEMI). Both MnDPDP and a metabolite (Mn dipyridoxyl ethyldiamine) possess properties as mitochondrial superoxide dismutase mimetics and iron chelators, and combat oxidative stress in various tissues and conditions. METHODS AND RESULTS: The study tested MnDPDP (n = 10) vs. saline placebo (n = 10), given as a brief intravenous (i.v.) infusion prior to balloon inflation during pPCI in patients with STEMI. Mangafodipir was well tolerated and did not affect heart rate or blood pressure. Despite longer ischaemic time (205 vs. 144 min, P = 0.019) in the MnDPDP group, plasma biomarker releases were identical for the two groups. With placebo vs. MnDPDP, mean STE resolutions were 69.8 vs. 81.9% (P = 0.224) at 6 h and 73.1 vs. 84.3% (P = 0.077) at 48 h. Cardiac magnetic resonance revealed mean infarct sizes of 32.5 vs. 26.2% (P = 0.406) and mean left ventricular (LV) ejection fractions of 41.8 vs. 47.7% (P = 0.617) with placebo vs. MnDPDP. More LV thrombi were detected in placebo hearts (5 of 8) than MnDPDP-treated hearts (1 of 10; P = 0.011). CONCLUSIONS: Mangafodipir is a safe drug for use as an adjunct to reperfusion therapy. A tendency to benefit of MnDPDP needs confirmation in a larger population. The study revealed important information for the design of a Phase II trial.

Analyzing equilibrium water exchange between myocardial tissue compartments using dynamical two-dimensional correlation experiments combined with manganese-enhanced relaxography.

Water compartments were identified and equilibrium water exchange was studied in excised rat myocardium enriched with intracellular manganese (Mn(2+)). Standard relaxographic measurements were supplemented with diffusion-T(2) and T(1)-T(2) correlation measurements. In nonenriched myocardium, one T(1) component (800 ms) and three T(2) components (32, 120, and 350 ms) were identified. The correlation measurements revealed fast- and slow-diffusing water fractions with mean diffusion coefficients of 1.2 x 10(-5) and 3.0 x 10(-5) cm(2) s(-1). The two shortest T(2) components, which had different diffusivities, both originated from water in intracellular compartments. A component with longer relaxation time (T(1) approximately equal 2200 ms; T(2) approximately equal 1200 ms), originating from extra-tissue water, was also observed. The presence of this component may lead to erroneous estimations of water exchange rates from multiexponential relaxographic analyses of excised tissues. The tissue T(1) value is strongly reduced with increasing enrichment of Mn(2+), and eventually a second tissue T(1) component emerges, indicating a shift in the equilibrium water exchange between intra- and extracellular compartments from the fast-exchange limit to the slow-exchange regime. Using a two-site water exchange analysis, the lifetime of intracellular water, T(ic), was found to be 475 ms, with a fraction, p(ic), of 0.71.

Manganese-calcium interactions with contrast media for cardiac magnetic resonance imaging: a study of manganese chloride supplemented with calcium gluconate in isolated Guinea pig hearts.

OBJECTIVES: Manganese ions (Mn) enter cardiomyocytes via calcium (Ca) channels and enhance relaxation intracellularly. To prevent negative inotropy, new Mn-releasing contrast agents have been supplemented with high Ca. The study aim was to investigate how this affects cardiac function and magnetic resonance efficacy. MATERIALS AND METHODS: MnCl2 based contrast agents, manganese and manganese-calcium (Ca:Mn 10:1), were infused during 4 repeated washin-washout sequences in perfused guinea pig hearts. [Mn] were 10, 50, 100 and 500 microM. RESULTS: During washin, manganese depressed left ventricular developed pressure (LVDP) by 4, 9, 17, and 53% whereas manganese-calcium increased LVDP by 13, 18, 25, and 56%. After experiments, tissue Mn contents (nmol/g dry wt) were control <40, manganese 3720, and manganese-calcium 1620. T1 was reduced by 85-92% in Mn-enriched hearts. CONCLUSIONS: High Ca supplements to Mn-releasing contrast agents may be counterproductive by inducing a strong positive inotropic response and by reducing the magnetic resonance efficacy.