Rejuveinix Shows a Favorable Clinical Safety Profile in Human Subjects and Exhibits Potent Preclinical Protective Activity in the Lipopolysaccharide-Galactosamine Mouse Model of Acute Respiratory Distress Syndrome and Multi-Organ Failure

Fatih M Uckun, James Carlson, Cemal Orhan, Joy Powell, Natalie M Pizzimenti, Hendrik van Wyk, Ibrahim H Ozercan, Michael Volk, Kazim Sahin, Fatih M Uckun, James Carlson, Cemal Orhan, Joy Powell, Natalie M Pizzimenti, Hendrik van Wyk, Ibrahim H Ozercan, Michael Volk, Kazim Sahin

Abstract

Background: New treatment platforms that can prevent acute respiratory distress syndrome (ARDS) or reduce its mortality rate in high-risk coronavirus disease 2019 (COVID-19) patients, such as those with an underlying cancer, are urgently needed. Rejuveinix (RJX) is an intravenous formulation of anti-oxidants and anti-inflammatory agents. Its active ingredients include ascorbic acid, cyanocobalamin, thiamine hydrochloride, riboflavin 5' phosphate, niacinamide, pyridoxine hydrochloride, and calcium D-pantothenate. RJX is being developed as an anti-inflammatory and anti-oxidant treatment platform for patients with sepsis, including COVID-19 patients with viral sepsis and ARDS. Here, we report its clinical safety profile in a phase 1 clinical study (ClinicalTrials.gov Identifier: NCT03680105) and its potent protective activity in the lipopolysaccharide galactosamine (LPS-GalN) mouse model of ARDS. Methods: A phase 1, double-blind, placebo-controlled, randomized, two-part, ascending dose-escalation study was performed in participating 76 healthy volunteer human subjects in compliance with the ICH (E6) good clinical practice guidelines to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of RJX (Protocol No. RPI003; ClinicalTrials.gov Identifier: NCT03680105). The ability of RJX to prevent fatal shock, ARDS, and multi-organ failure was examined in the well-established LPS-GalN mouse model of sepsis and ARDS. Standard methods were employed for the statistical analysis of data in both studies. Findings: In the phase 1 clinical study, no participant developed serious adverse events (SAEs) or Grade 3-Grade 4 adverse events (AEs) or prematurely discontinued participation in the study. In the non-clinical study, RJX exhibited potent and dose-dependent protective activity, decreased the inflammatory cytokine responses (interleukin-6, tumor necrosis factor alpha, transforming growth factor beta), and improved survival in the LPS-GalN mouse model of sepsis and ARDS. Histopathological examinations showed that RJX attenuated the LPS-GalN induced acute lung injury (ALI) and pulmonary edema as well as liver damage. Conclusion: RJX showed a very favorable safety profile and tolerability in human subjects. It shows potential to favorably affect the clinical course of high-risk COVID-19 by preventing ARDS and its complications.

Keywords: COVID-19; acute lung injury; cancer; cytokine release syndrome; multi-organ dysfunction; pneumonia; sepsis.

Copyright © 2020 Uckun, Carlson, Orhan, Powell, Pizzimenti, van Wyk, Ozercan, Volk and Sahin.

Figures

FIGURE 1
FIGURE 1
Plasma Pharmacokinetic Parameters for Ascorbic Acid (Panel A); Cyanocobalamin (Panel B); Niacinamide (Panel C); Thiamine (Panel D) after Single Ascending Dose of IV Infusion of Rejuveinix in Healthy Adult and Elderly Volunteers. See text for discussion.
FIGURE 2
FIGURE 2
Dose-Dependent In Vivo Protective Activity of Prophylactic Rejuveinix (RJX) Treatments in the Lipopolysaccharide-Galactosamine (LPS-GalN) Model of acute respiratory distress syndrome (ARDS) and Multiorgan Failure. Groups of 10 BALB/C mice were treated with i.p injections of RJX (0.5, 1.05, 2.1, 4.2 ml/kg of 6‐fold diluted RJX, 0.5 ml/mouse) or vehicle (NS) 2 h before or 2 h post-injection of LPS-GalN. Except for untreated control mice (Control), each mouse received 0.5 ml of LPS-GalN (consisting of 100 ng of LPS plus 8 mg of D-galactosamine) i.p. The cumulative proportion of mice remaining alive (Survival, %) is shown as a function of time after the LPS-GalN challenge. Depicted are the Kaplan Meier survival curves (Panel A) and survival data with statistical analysis (Panels B,C) of the different treatment groups. The RJX dose levels (in ml/kg) are indicated in parentheses.
FIGURE 3
FIGURE 3
Rejuveinix (RJX) Prevents the Surge of Inflammatory Markers in the Blood Following Lipopolysaccharide-Galactosamine (LPS-GalN) Challenge in a Mouse Model of acute respiratory distress syndrome (ARDS) and Multi-organ Failure. Mice were treated with i.p injections of RJX (0.5, 1.05, 2.1, 4.2 ml/kg of 6‐fold diluted RJX, 0.5 ml/mouse) or normal saline (NS) 2 h before and 2 h post-injection of LPS-GalN. Except for untreated mice (Control), each mouse received 0.5 ml of LPS-GalN (consisting of 100 ng of LPS plus 8 mg of D-galactosamine) i.p. The RJX dose levels (in ml/kg) are indicated in parentheses. See text for discussion of results. The depicted lines represent the mean and standard deviation for the indicated inflammatory markers, namely serum IL‐6 (Panel A), TNF‐a (Panel B), and LDH levels (Panel C). ANOVA and Tukey’s post-hoc test were used for comparing the results among different treatment groups. Statistical significance between groups is shown by: ****p < 0.0001 compared as control group and, #p < 0.05; ##p < 0.01; ####p < 0.0001 compared as LPS/GaIN + NS group).
FIGURE 4
FIGURE 4
Rejuveinix (RJX) Prevents Pro-inflammatory Cytokine Response in the Lungs of Mice Challenged with Lipopolysaccharide-Galactosamine (LPS-GalN). Mice were treated with i.p injections of RJX (0.5, 1.05, 2.1, 4.2 ml/kg, 0.5 ml/mouse) or normal saline (NS) 2 h before and 2 h post-injection of LPS-GalN. Except for untreated mice (Control), each mouse received 0.5 ml of LPS-GalN (consisting of 100 ng of LPS plus 8 mg of d-galactosamine) i.p. The RJX dose levels (in ml/kg) are indicated in parentheses. See text for discussion of results. Depicted are the results of Western blot analyses of cytokine expression in the pooled lung tissue samples from mice in various treatment groups. Panel A: Lung IL‐1b levels; Panel B: Lung TNF‐a levels; Panel C: Lung IL‐6 levels; D: Lung TGF‐b levels; E: Immunoblot. Results are expressed as percent of control with the expression level in the lung tissue sample from untreated control mice taken as 100% for comparisons. The bar represents mean and standard deviation. Immunoblotting with an anti-actin antibody was used to ensure equal protein loading. (ANOVA and Tukey’s post-hoc test. Statistical significance between groups is shown by: ***p < 0.001; ****p < 0.0001 compared as control group and, #p < 0.05; ###p < 0.001; ####p < 0.0001 compared as LPS/GaIN + NS group).
FIGURE 5
FIGURE 5
Tissue-Level In Vivo Anti-Inflammatory and Anti-Oxidant Activity of Rejuveinix (RJX) in the Lipopolysaccharide-Galactosamine (LPS-GalN) Mouse Model of acute respiratory distress syndrome (ARDS) and Multi-organ Failure. Mice were treated with i.p injections of RJX (0.5, 1.05, 2.1, 4.2 ml/kg, 0.5 ml/mouse) or normal saline (NS) 2 h before and 2 h post-injection of LPS-GalN. Except for untreated mice (Control), each mouse received 0.5 ml of LPS-GalN (consisting of 100 ng of LPS plus 8 mg of D-galactosamine) i.p. The RJX dose levels (in ml/kg) are indicated in parentheses. See text for discussion of results. These assays were performed on the lungs of mice that died after the LPS-GalN challenge. The lungs of the mice were harvested at the time of death which occurred within 24 h for all mice. The depicted lines represent the mean and standard deviation for the indicated parameters. In (A), the score was graded according to a 5-point scale from 0 to 4 as follows: 0, l, 2, three and four represented no damage, mild damage, moderate damage, severe damage and very severe damage, respectively. Statistical significance between groups is shown by: ****p < 0.0001 compared as control group and, ##p < 0.01; ####p < 0.0001 compared as LPS/GaIN + NS group, Kruskal-Wallis test and Mann Whitney test. In (B–F), ANOVA and Tukey’s post-hoc test were used for comparing the results among different treatment groups. Statistical significance between groups is shown by: ****p < 0.0001 compared as control group and, #p < 0.05; ##p < 0.01; ####p < 0.0001 compared as LPS/GaIN + NS group).
FIGURE 6
FIGURE 6
Rejuveinix (RJX) Prevents Acute Lung Injury and Inflammation in the Lipopolysaccharide-Galactosamine (LPS-GalN) Mouse Model of acute respiratory distress syndrome (ARDS) and Multi-organ Failure. Mice were treated with i.p injections of RJX (0.5, 1.05, 2.1, 4.2 ml/kg, 0.5 ml/mouse) or normal saline (NS) 2 h before and 2 h post-injection of LPS-GalN. Except for untreated mice (Control), each mouse received 0.5 ml of LPS-GalN (consisting of 100 ng of LPS plus 8 mg of D-galactosamine) i.p. The RJX dose levels (in ml/kg) are indicated in parentheses. Yellow arrow: inflammatory cell infiltration; Blue arrow: Exudate; Orange arrow: hemorrhage; Green block: thickness of alveolar wall. Panel B: Blue arrow: Exudate (see B1 of Supplementary Figure S7 for an enlarged inset); Yellow arrow: inflammatory cell infiltration (see B2 of Supplementary Figure S7 for an enlarged inset); Green block: thickness of alveolar wall (see B3 of Supplementary Figure S7 for an enlarged inset). Orange arrow: hemorrhage (see B4 of Supplementary Figure S7 for an enlarged inset); H&E ×400.
FIGURE 7
FIGURE 7
Rejuveinix (RJX) Prevents Acute Liver Injury and Inflammation in the Lipopolysaccharide-Galactosamine (LPS-GalN) Mouse Model of acute respiratory distress syndrome (ARDS) and Multi-organ Failure. Mice were treated with i.p injections of RJX (0.5, 1.05, 2.1, 4.2 ml/kg, 0.5 ml/mouse) or normal saline 2 h before and 2 h post-injection of LPS-GalN. Except for untreated mice (Control), each mouse received 0.5 ml of LPS-GalN (consisting of 100 ng of LPS plus 8 mg of D-galactosamine) i.p. The RJX dose levels (in ml/kg) are indicated in parentheses. Panel A: Treatment‐naive control mouse; Panel B: Mouse challenged with LPS‐GalN and treated with vehicle (placebo) (i.e., NS); Panel C: Mouse challenged with LPS‐GalN and treated with 0.5 ml/kg 6‐fold diluted RJX; Panel D: Mouse challenged with LPS‐GalN and treated with 1.05 ml/kg 6‐fold diluted RJX; Panel E: Mouse challenged with LPS‐GalN and treated with 2.1 ml/kg 6‐fold diluted RJX; Panel D: Mouse challenged with LPS‐GalN and treated with 4.2 ml/kg 6‐fold diluted RJX; Panel B: White arrow (long): necrosis (see B1 of Supplementary Figure S11 for an enlarged inset); Black arrow: inflammatory cell infiltration (see B2 of Supplementary Figure S11 for an enlarged inset); White arrow (short): hemorrhage (see B3 of Supplementary Figure S11 for an enlarged inset). See text for a discussion of the findings. H&E ×400
FIGURE 8
FIGURE 8
In Vivo Protective Activity of Delayed-Onset Rejuveinix (RJX) Treatments in the Lipopolysaccharide-Galactosamine (LPS-GalN) Model of acute respiratory distress syndrome (ARDS) and Multiorgan Failure. Groups of 6 BALB/C mice were treated with i.p. injections of 6-fold diluted RJX (4.2 ml/kg, 0.5 ml/mouse) or vehicle [normal saline (NS)] 2 and 3 h post-injection of LPS-GalN. Each mouse received 0.5 ml of LPS-GalN (consisting of 100 ng of LPS plus 8 mg of Dgalactosamine) i.p. Percent (%) survival for each treatment group is shown as a function of time after the LPS-GalN challenge. Depicted are the survival curves for each group along with the median survival times and the log-rank p-value for the comparison of LPS-GalN + RJX group vs. the LPS/GaIN + NS group.

References

    1. Bi Q., Hong C., Meng J., Wu Z., Zhou P., Ye C., et al. (2020). Characterizing clinical progression of COVID-19 among patients in Shenzhen, China: an observational cohort study. medRxiv 10.1101/2020.04.22.20076190
    1. Budinger G. R. S., Chandel N. S., Donnelly H. K., Eisenbart J., Oberoi M., Jain M. (2005). Active transforming growth factor-β1 activates the procollagen I promoter in patients with acute lung injury. Intensive Care Med. 31, 121–128. 10.1007/s00134-004-2503-2
    1. Byerly S., Parreco J. P., Soe-Lin H., Parks J. J., Lee E. E., Shnaydman I., et al. (2020). Vitamin C and thiamine are associated with lower mortality in sepsis. J. Trauma Acute Care Surg. 89 (1), 111–117. 10.1097/TA.0000000000002613
    1. Cabala K., Earabino J., Pacult P., Uckun F. M. (2020). Rationale for A randomized, placebo-controlled, phase 2 study of Rejuveinix (RJX) in COVID-19 patients with acute lung injury and hypoxemic respiratory failure. Clin. Invest. 10 (2), 185–189.
    1. Carver C., Jones N. (2020). Are there risk factors and preventive interventions for acute respiratory distress syndrome (ARDS) in COVID-19. COVID-19 Evidence Service, Centre for Evidence-Based Medicine (CEBM) 2020 Jun 8; Edinburg. Available at: .
    1. Chen X., Zhao B., Qu Y., Chen Y., Xiong J., Feng Y., et al. (2020). Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin. Infect. Dis. ciaa449 10.1093/cid/ciaa449
    1. Dong Z., Yuan Y. (2018). Accelerated inflammation and oxidative stress induced by LPS in acute lung injury: inhibition by ST1926. Int. J. Mol. Med. 41 (6), 3405–3421. 10.3892/ijmm.2018.3574
    1. Fahy R. J., Lichtenberger F., McKeegan C. B., Nuovo G. J., Marsh C. B., Wewers M. D. (2003). The acute respiratory distress syndrome. Am. J. Respir. Cell Mol. Biol. 28 (4), 499–503. 10.1165/rcmb.2002-0092oc
    1. Fox R., Akmatbekov A., Harbert J., Li G., Brown Q., Vander Heide R. S., (2020). Pulmonary and cardiac pathology in COVID -19; the first autopsy series from New Orleans. medRxiv 10.1101/2020.04.06.210.1101/2020.04.06.20050575
    1. Frank J., Roux J., Kawakatsu H., Su G., Dagenais A., Berthiaume Y., et al. (2003). Transforming growth factor-β1 decreases expression of the epithelial sodium channel αENaC and alveolar epithelial vectorial sodium and fluid transport via an ERK1/2-dependent mechanism. J. Biol. Chem. 278 (45), 43939–43950. 10.1074/jbc.m304882200
    1. Frank J. A., Matthay M. A. (2014). TGF- and lung fluid balance in ARDS. Proc. Natl. Acad. Sci. U.S.A. 111, 885–886. 10.1073/pnas.1322478111
    1. Fujii T., Luethi N., Young P. J., Frei D. R., Eastwood G. M., French C. J., et al. (2020). Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock. JAMA 323 (5), 423–431. 10.1001/jama.2019.22176
    1. Gold J. A. W., Wong K. K., Szablewski C. M., Patel P. R., Rossow J., da Silva J., et al. (2020). Characteristics and clinical outcomes of adult patients hospitalized with COVID-19 - Georgia, March 2020. MMWR Morb. Mortal. Wkly. Rep. 69 (18), 545–550. 10.15585/mmwr.mm6918e1
    1. Hager D. N., Hooper M. H., Bernard G. R., Busse L. W., Ely E. W., Fowler A. A., et al. (2019). The vitamin C, thiamine and steroids in sepsis (VICTAS) protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial. Trials 20 (1), 197 10.1186/s13063-019-3254-2
    1. Harahsheh A. S., Dahdah N., Newburger J. W., Portman M. A., Piram M., Tulloh R., et al. (2020). Missed or delayed diagnosis of Kawasaki disease during the 2019 novel coronavirus disease (COVID-19) pandemic. J. Pediatr. 222, 261–262. 10.1016/j.jpeds.2020.04.052
    1. Hu X., Huang X. (2019). Alleviation of inflammatory response of pulmonary fibrosis in acute respiratory distress syndrome by puerarin via transforming growth factor (TGF-β1). Med. Sci. Mon. 25, 6523–6531. 10.12659/msm.915570
    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506. 10.1016/S0140-6736(20)30183-5
    1. Ighodaro O. M., Akinloye O. A. (2018). First line defence antioxidants-superoxide dismutase (SOD), catalase (cat) and glutathione peroxidase (gpx): their fundamental role in the entire antioxidant defence grid. Alexandria J. Med. 54 (4), 287–293. 10.1016/j.ajme.2017.09.001
    1. Iglesias J., Vassallo A. V., Patel V. V., Sullivan J. B., Cavanaugh J., Elbaga Y. (2020). Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis. Chest 158, 164–173. 10.1016/j.chest.2020.02.049
    1. Jones V. G., Mills M., Suarez D., Hogan C. A., Yeh D., Segal J. B., et al. (2020). COVID-19 and Kawasaki disease: novel virus and novel case. Hosp. Pediatr. 10, 537 10.1542/hpeds.2020-0123
    1. Josephs M. D., Bahjat F. R., Fukuzuka K., Ksontini R., Solorzano C. C., Edwards C. K., et al. (2000). Lipopolysaccharide and D-galactosamine-induced hepatic injury is mediated by TNF-alpha and not by Fas ligand. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278 (5), R1196–R1201. 10.1152/ajpregu.2000.278.5.R1196.
    1. Jenkins R. G., Su X., Su G., Scotton C. J., Camerer E., Laurent G. J., et al. (2006). Ligation of protease-activated receptor 1 enhances v 6 integrin-dependent TGF- activation and promotes acute lung injury. J. Clin. Invest. 116 (6), 1606–1614. 10.1172/jci27183
    1. Kuderer N. M., Choueiri T. K., Shah D. P., Shyr Y., Rubinstein S. M., Rivera D. R., et al. (2020). Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet 395 (10241), 1907–1918. 10.1016/S0140-6736(20)31187-9
    1. Lee A. M., Shimizu C., Oharaseki T., Takahashi K., Daniels L. B., Kahn A., et al. (2015). Role of TGF-β signaling in remodeling of noncoronary artery aneurysms in Kawasaki disease. Pediatr. Dev. Pathol. 18 (4), 310–317. 10.2350/14-12-1588-OA.1
    1. Lev P. R., Salim J. P., Marta R. F., Mela Osorio M. J., Goette N. P., Molinas F. C. (2007). Platelets possess functional TGF-β receptors and Smad2 protein. Platelets 18, 35–42. 10.1080/09537100600800743
    1. Li J. (2018). Evidence is stronger than you think: a meta-analysis of vitamin C use in patients with sepsis. Crit. Care 22 (1), 258 10.1186/s13054-018-2191-x
    1. Lian J., Jin X., Hao S., Zhang S., Zheng L., Jia H., et al. (2020). Analysis of epidemiological and clinical features of older patients with coronavirus disease 2019 (COVID-19) outside Wuhan. Clin. Infect. Dis. ciaa242 10.1093/cid/ciaa242
    1. McCrindle B. W., Rowley A. H., Newburger J. W., Burns J. C., Bolger A. F., Gewitz M., et al. (2017). Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American heart association. Circulation 135 (17), e927–e999. 10.1161/cir.0000000000000484
    1. Moskowitz A., Huang D. T., Hou P. C., Gong J., Doshi P. B., Grossestreuer A. V., et al. (2020). Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock. JAMA 324 (7), 642–650. 10.1001/jama.2020.11946.PMID:32809003ClinicalTrial
    1. Nair A., Jacob S. (2016). A simple practice Guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7 (2), 27–31. 10.4103/0976-0105.177703
    1. Nithiananthan S., Crawford A., Knock J. C., Lambert D. W., Whawell S. A. (2017). Physiological fluid flow moderates fibroblast responses to TGF-β1. J. Cell. Biochem. 118 (4), 878–890. 10.1002/jcb.25767
    1. Noormandi A., Khalili H., Mohammadi M., Abdollahi A. (2020). Effect of magnesium supplementation on lactate clearance in critically ill patients with severe sepsis: a randomized clinical trial. Eur. J. Clin. Pharmacol. 76 (2), 175–184. 10.1007/s00228-019-02788-w
    1. Obi J., Pastores S. M., Ramanathan L. V., Yang J., Halpern N. A. (2020). Treating sepsis with vitamin C, thiamine, and hydrocortisone: exploring the quest for the magic elixir. J. Crit. Care 57, 231–239. 10.1016/j.jcrc.2019.12.011
    1. Pan J., Peng M., Liao C., Hu X., Wang A., Li X. (2019). Relative efficacy and safety of early lactate clearance-guided therapy resuscitation in patients with sepsis: a meta-analysis. Medicine (Baltimore) 98 (8), e14453 10.1097/MD.0000000000014453
    1. Peters D. M., Vadasz I., Wujak L., Wygrecka M., Olschewski A., Becker C., et al. (2013). TGF- directs trafficking of the epithelial sodium channel ENaC which has implications for ion and fluid transport in acute lung injury. Proc. Natl. Acad. Sci. U.S.A. 111, E374–E383. 10.1073/pnas.1306798111
    1. Pittet J.-F., Griffiths M. J. D., Geiser T., Kaminski N., Dalton S. L., Huang X., et al. (2001). TGF-β is a critical mediator of acute lung injury. J. Clin. Invest. 107, 1537–1544. 10.1172/jci11963
    1. Putzu A., Daems A.-M., Lopez-Delgado J. C., Giordano V. F., Landoni G. (2019). The effect of vitamin C on clinical outcome in critically ill patients. Crit. Care Med. 47 (6), 774–783. 10.1097/CCM.0000000000003700
    1. Shan M. R., Zhou S. N., Fu C. N., Song J. W., Wang X. Q., Bai W. W., et al. (2020). Vitamin B6 inhibits macrophage activation to prevent lipopolysaccharide‐induced acute pneumonia in mice. J. Cell Mol. Med. 24 (5), 3139–3148. 10.1111/jcmm.14983
    1. Shimbori C., Bellaye P.-S., Xia J., Gauldie J., Ask K., Ramos C., et al. (2016). Fibroblast growth factor-1 attenuates TGF-β1-induced lung fibrosis. J. Pathol. 240 (2), 197–210. 10.1002/path.4768
    1. Shimizu C., Jain S., Davila S., Hibberd M. L., Lin K. O., Molkara D., et al. (2011). Transforming growth factor-β signaling pathway in patients with Kawasaki disease. Circ. Cardiovasc. Genet. 4 (1), 16–25. 10.1161/CIRCGENETICS.110.940858
    1. Stafford N., Arnold A., Jebakumar S., Manglam V., Sangwaiya A., Arnold J., (2020). Therapeutic strategies for COVID-19: new insights into the value of transforming growth factor beta (TGFβ) antagonists such as imatinib and other kinase inhibitors. BMJ 369 10.1136/bmj.m1610
    1. Uckun F. M. (2020a). Prognostic factors associated with high-risk for fatal ARDS in COVID-19 and potential role for precision medicines as part of COVID-19 supportive care algorithms. Ann. Pulm. Crit. Care Med. 3 (2), 1–4.
    1. Uckun F. M. (2020b) Reducing the fatality rate of COVID-19 by applying clinical insights from immuno-oncology and lung transplantation. Front. Pharmacol. 11, 796 10.3389/fphar.2020.00796
    1. Uckun F. M. (2020c). Treating severe COVID-19 in cancer patients. Cancer Res. Rev. 3, 1–2. 10.15761/CRR.1000198
    1. Uckun F. M., Ervin J., Sahin K., Powell J., Pizzimenti N., Earabino J., et al. (2020). Clinical impact potential of Rejuveinix (RJX) for prevention of fatal acute respiratory distress syndrome (ARDS) and multi-organ failure in covid-19 patients. Clin. Invest. 10 (2), 177–184.
    1. Uckun F. M., Tibbles H., Ozer Z., Qazi S., Vassilev A. (2008). Anti-inflammatory activity profile of JANEX-1 in preclinical animal models. Bioorg. Med. Chem. 16 (3), 1287–1298. 10.1016/j.bmc.2007.10.066
    1. Uckun F. M., Trieu V. (2020a). Medical-scientific rationale for a randomized, placebo-controlled, phase 2 study of trabedersen/OT-101 in COVID-19 patients with hypoxemic respiratory failure. Ann. Pulm. Crit. Care Med. 3 (1), 1–9.
    1. Uckun F. M., Trieu V. (2020b). Targeting TGF-b for treatment of COVID-19 associated Kawasaki disease in children. Clin. Res. Pediatr. 3 (1), 1–3.
    1. Van Wyk H., Van Wyk M., Krebs T., Lange P., Denomme B., Volk M. A. (2017). US Patent Application No. 9775798 2017; Composition and methods for the prevention and treatment of cardiovascular diseases - continuation of U.S. patent application Ser. No. 14/550,677 as a divisional of U.S. patent application Ser. No. 13/055,691, which issued as U.S. Pat. No. 9,101,537. Publication# 20170360696. Available at: (Accessed October 1, 2020).
    1. Wang T., Xia Y., Hao D. (2014). The significance of lactic acid in early diagnosis and goal-directed therapy of septic shock patients. Chin. Crit. Care Med. 26, 51–55.
    1. Willis B. C., Kim K.-J., Li X., Liebler J., Crandall E. D., Borok Z. (2003). Modulation of ion conductance and active transport by TGF-β1 in alveolar epithelial cell monolayers. Am. J. Physiol. Lung Cell Mol. Physiol. 285 (6), L1192–L1200. 10.1152/ajplung.00379.2002
    1. Woolum J. A., Abner E. L., Kelly A., Thompson Bastin M. L., Morris P. E., Flannery A. H. (2018). Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit. Care Med. 46 (11), 1747–1752. 10.1097/CCM.0000000000003311
    1. Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S., et al. (2020). Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med. 180, 934 10.1001/jamainternmed.2020.0994
    1. Xiong Y., Liu Y., Cao L., Wang D., Guo M., Jiang A., et al. (2020). Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerg. Microb. Infect. 9 (1), 761–770. 10.1080/22221751.2020.1747363
    1. Young B. E., Ong S. W. X., Kalimuddin S., Low J. G., Tan S. Y., Loh J., et al. (2020). Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 323, 1488 10.1001/jama.2020.3204
    1. Zheng Z., Peng F., Xu B., Zhao J., Liu H., Peng J., et al. (2020). Risk factors of critical and mortal COVID-19 cases: a systematic literature review and meta-analysis. J. Infect. 81 (2), e16–e25. 10.1016/j.jinf.2020.04.021
    1. Zhou F., Yu T., Du R., Fan G., Liu Z., Xiang J., et al. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062. 10.1016/s0140-6736(20)30566-3
    1. Zumla A., Hui D. S., Azhar E. I., Memish Z. A., Maeurer M. (2020). Reducing mortality from 2019-nCoV: host-directed therapies should be an option. Lancet 395 (10224), e35–e36. 10.1016/S0140-6736(20)30305-6

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