Non-Randomized Trial of Dornase Alfa for Acute Respiratory Distress Syndrome Secondary to Covid-19.

Background: The most severe cases of Coronavirus-Disease-2019 (COVID-19) develop into Acute Respiratory Distress Syndrome (ARDS). It has been proposed that oxygenation may be inhibited by extracellular deoxyribonucleic acid (DNA) in the form of neutrophil extracellular traps (NETs). Dornase alfa (Pulmozyme, Genentech) is recombinant human deoxyribonuclease I that acts as a mucolytic by cleaving and degrading extracellular DNA. We performed a pilot study to evaluate the effects of dornase alfa in patients with ARDS secondary to COVID-19. Methods: We performed a pilot, non-randomized, case-controlled clinical trial of inhaled dornase for patients who developed ARDS secondary to COVID-19 pneumonia. Results: Improvement in arterial oxygen saturation to inhaled fraction of oxygen ratio (PaO2/FiO2) was noted in the treatment group compared to control at day 2 (95% CI, 2.96 to 95.66, P-value = 0.038), as well as in static lung compliance at days 3 through 5 (95% CI, 4.8 to 19.1 mL/cmH2O, 2.7 to 16.5 mL/cmH2O, and 5.3 to 19.2 mL/cmH2O, respectively). These effects were not sustained at 14 days. A reduction in bronchoalveolar lavage fluid (BALF) myeloperoxidase-DNA (DNA : MPO) complexes (95% CI, -14.7 to -1.32, P-value = 0.01) was observed after therapy with dornase alfa. Conclusion: Treatment with dornase alfa was associated with improved oxygenation and decreased DNA : MPO complexes in BALF. The positive effects, however, were limited to the time of drug delivery. These data suggest that degradation of extracellular DNA associated with NETs or other structures by inhaled dornase alfa can be beneficial. We propose a more extensive clinical trial is warranted. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT04402970.

Crocetin and related oxygen diffusion-enhancing compounds: Review of chemical synthesis, pharmacology, clinical development, and novel therapeutic applications.

The current pandemic forced us to introspect and revisit our armamentarium of medicinal agents which could be life-saving in emergency situations. Oxygen diffusion-enhancing compounds represent one such class of potential therapeutic agents, particularly in ischemic conditions. As rewarding as the name suggests, these agents, represented by the most advanced and first-in-class molecule, trans-sodium crocetinate (TSC), are the subject of intense clinical investigation, including Phase 1b/2b clinical trials for COVID-19. Being a successor of a natural product, crocetin, TSC is being investigated for various cancers as a radiosensitizer owing to its oxygen diffusion enhancement capability. The unique properties of TSC make it a promising therapeutic agent for various ailments such as hemorrhagic shock, stroke, heart attack, among others. The present review outlines various (bio)synthetic strategies, pharmacological aspects, clinical overview and potential therapeutic benefits of crocetin and related compounds including TSC. The recent literature focusing on the delivery aspects of these compounds is covered as well to paint the complete picture to the curious reader. Given the potential TSC holds as a first-in-class agent, small- and/or macromolecular therapeutics based on the core concept of improved oxygen diffusion from blood to the surrounding tissues where it is needed the most, will be developed in future and satisfy the unmet medical need for many diseases and disorders.

COVID-19 and Acute Respiratory Distress Syndrome. Impact of corticosteroid treatment and predictors of poor outcome.

OBJECTIVE: To assess the impact of corticosteroids on inflammatory and respiratory parameters of patients with COVID-19 and acute respiratory distress syndrome (ARDS). METHODS: Longitudinal, retrospective, observational study conducted in an ICU of a second level hospital. Adult patients with COVID-19 were included. Baseline characteristics, data on SARS-CoV-2 infection, treatment received, evolution of respiratory and inflammatory parameters, and ICU and hospital stay and mortality were analyzed. RESULTS: A total of 27 patients were included, 63% men, median age: 68.4 (51.8, 72.2) years. All patients met ARDS criteria and received MV and corticosteroids. After corticosteroids treatment we observed a reduction in the O2 A-a gradient [day 0: 322 (249, 425); day 3: 169 (129.5, 239.5) p<0.001; day 5: 144 (127.5, 228.0) p<0.001; day 7: 192 (120, 261) p=0.002] and an increase in the pO2/FiO2 ratio on days 3 and 5, but not on day 7 [day 0: 129 (100, 168); day 3: 193 (140, 236) p=0.002; day 5: 183 (141, 255) p=0.004; day 7: 170 (116, 251) p=0.057]. CRP also decreased on days 3 and 5 and increased again on day 7 [day 0: 16 (8.6, 24); day 3: 3.4 (1.7, 10.2) p<0.001; day 5: 4.1 (1.4, 10.2) p<0.001; day 7: 13.5 (6.8, 17.3) p=0.063]. Persistence of moderate ARDS on day 7 was related to a greater risk of poor outcome (OR 6.417 [1.091-37.735], p=0.040). CONCLUSIONS: Corticosteroids appears to reduce the inflammation and temporarily improve the oxygenation in COVID-19 and ARDS patients. Persistence of ARDS after 7 days treatment is a predictor of poor outcome.

Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis.

It has been reported that frequent occurrence of COVID-19 infection in these patients is associated with low cytosolic pH. During virus infection, serum lactate dehydrogenase (LDH) level excessively rises. LDH is a cytosolic enzyme and the serum level increases as the cell break down. When anaerobic conditions develop, lactate formation increases from pyruvate. Cell pH is regulated by very complex mechanisms. When lactate increases in the extracellular area, this symporter carries lactate and H+ ion into the cell, and the intracellular pH quickly becomes acidic. Paradoxically, Na+/H+ exchanger activation takes place. While H+ ion is thrown out of the cell, Na+ and Ca+2 enter the cell. When Na+ and Ca+2 increase in the cell, the cells swell and die. Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor. Dapagliflozin has been reported to reduce lactate levels by various mechanisms. Also, it reduces oxygen consumption in tissues and causes the use of glucose in the aerobic pathway, thereby reducing lactate production. A lactate decrease in the environment reduces the activation of lactate/H+ symporter. Thus, the H ion pumping into the cell by this symporter is reduced and the cytosolic pH is maintained. Dapagliflozin also directly inhibits NHE. Thus, Na+ and Ca+2 flow to the cell are inhibited. Dapagliflozin provides the continuation of the structure and functions of the cells. Dapagliflozin can prevent the severe course of COVID-19 infection by preventing the lowering of cytosolic pH and reducing the viral load.