Karlsson Jan Olof G, Jynge Per, Ignarro Louis J
Division of Drug Research/Pharmacology, Linköping University, SE-581 83 Linköping, Sweden.
Innlandet Trust Hospital, Gjøvik Hospital, NO-2819 Gjøvik, Norway.
Antioxidants (Basel). 2020 Oct 10;9(10):971. doi: 10.3390/antiox9100971.
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 (O), 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 O-driven destruction of NO by neutralizing inflammatory O. 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.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的特征是动脉内皮大量炎症，伴有血管收缩和广泛的肺微血栓形成。因此，由于炎症超氧化物（O）对一氧化氮（NO）的破坏，肺内NO浓度停止，导致血小板不受控制地聚集和大量血栓形成，从而导致患者死亡。通过吸入（INO）引入NO可能会弥补内皮源性NO的损失。SARS-CoV-2患者INO临床试验的初步结果显示心肺功能迅速且持续改善，炎症减轻。一项正在进行的III期研究有望证实该方法的疗效。因此，INO可能会成为SARS-CoV-2患者的一线治疗方法。然而，由于脱氧血红蛋白会迅速将NO失活为硝酸盐，肺部给予NO无法保护远处器官。另一种与INO相关的药理学方法是通过中和炎症性O来抑制O驱动的NO破坏，从而保护SARS-CoV-2患者不发展为危及生命的疾病。利用模拟锰超氧化物歧化酶（MnSOD）作用的低分子量化合物。所谓卟啉型（如AEOL 10150）、salen型（如EUK-8）和环状多胺型（如M40419——现称为GC4419和avasopasem锰）的MnSOD模拟物在慢性阻塞性肺疾病临床前模型中均已显示对肺上皮细胞的炎症反应有积极影响。二吡啶氧基乙二胺锰（MnPLED）型的锰福地匹三钠（二吡啶氧基二磷酸锰-MnDPDP），一种具有MnSOD模拟活性的磁共振成像（MRI）造影剂，在临床前和临床环境中的各种炎症形式中均显示出有前景的结果。与INO相比静脉注射锰福地匹三钠能够到达远处器官，因此可能成为INO的重要补充。从作者的观点来看，在有发展为危及生命的SARS-CoV-2风险的COVID-19患者中测试锰福地匹三钠似乎是合理的。在提交本手稿五天后，Galera制药公司宣布在一项针对COVID-19的GC4419随机、双盲II期临床试验中对第一名患者给药。该研究于2020年9月18日首次发布在ClinicalTrials.gov（标识符：NCT04555096）上。
