Evaluation of the potential of Rejuveinix plus dexamethasone against sepsis.

Aim: Our main objectives were to compare the effects of Rejuveinix (RJX), dexamethasone (DEX) and their combination on the severity of sepsis and survival outcome in an animal model of fatal sepsis. Methods: We used the LPS plus D-galactosamine mouse model of sepsis to compare the anti-inflammatory activities of RJX, dexamethasone and a combination of RJX plus DEX. Additionally, we examined the clinical feasibility and tolerability of combining RJX with DEX in COVID-19 patients in a clinical phase I study. Data were analyzed using standard methods. Results & conclusion: RJX exhibited potent anti-inflammatory activity in the murine sepsis model. The combination of RJX plus DEX was more effective than either agent alone, decreased the inflammatory cytokine responses and associated organ damage, and improved the survival outcome in mice. In the phase I clinical study, RJX plus DEX was well tolerated by COVID-19 patients.

Palliative Care Always: Hepatology-Virtual Primary Palliative Care Training for Hepatologists.

Palliative care (PC) benefits patients with serious illness including end-stage liver disease (ESLD). As part of a cluster randomized trial, hepatologists were trained to deliver primary palliative care to patients with ESLD using an online course, Palliative Care Always: Hepatology (PCA:Hep). Here we present a multimethod formative evaluation (feasibility, knowledge acquisition, self-efficacy, and practice patterns) of PCA:Hep. Feasibility was measured by completion of coursework and achieving a course grade of >80%. Knowledge acquisition was measured through assessments before and throughout the course. Pre/post-course surveys were conducted to determine self-efficacy and practice patterns. The hepatologists (n = 39) enrolled in a 12-week online course and spent 1-3 hours on the course weekly. The course was determined to be feasible as 97% successfully completed the course and 100% passed. The course was acceptable to participants; 91.7 % reported a positive course experience and satisfaction with knowledge gained (91.6%). The pre/post knowledge assessment showed an improvement of 6.0% (pre 85.9% to post 91.9%, 95% CI [2.8, 9.2], P = 0.001). Self-efficacy increased significantly (P < 0.001) in psychological symptom management, hospice, and psychosocial support. A year after training, over 80% of the hepatologists reported integrating a variety of PC skills into routine patient care. Conclusion: PCA:Hep is feasible, acceptable, and improves learner knowledge and confidence in palliative care skills. This is a viable method to teach primary PC skills to specialists caring for patients with ESLD.

Acute Liver Injury in Patients Hospitalized with COVID-19.

INTRODUCTION: The prevalence and significance of acute liver injury in patients with COVID-19 are poorly characterized. METHODS: Patients with confirmed COVID-19 who were hospitalized in geographically diverse medical centers in North America were included. Demographics, symptoms, laboratory data results, and outcomes were recorded. Linear and logistic regression identified factors associated with liver injury, in-hospital mortality, and length of stay (LOS). RESULTS: Among 1555 patients in the cohort, most (74%) had an elevated alanine aminotransferase (ALT) during hospitalization, which was very severe (> 20 × upper limit of normal [ULN]) in 3%. Severe acute liver injury (ALI) was uncommon, occurring in 0.1% on admission and 2% during hospitalization. No patient developed acute liver failure (ALF). Higher ALT was associated with leukocytosis (per mL3) (ß 10.0, 95% confidence interval (CI) 6.7-12.6, p < 0.001) and vasopressors use (ß 80.2, 95%CI 21.5-138.8, p = 0.007). In-hospital mortality was associated with ALT > 20 × ULN (unadjusted OR 6.0, 95%CI 3.1-11.5, p < 0.001), ALP > 3 × ULN (unadjusted OR 4.4, 95%CI 2.5-7.7, p < 0.001), and severe ALI (unadjusted OR 6.8, 95%CI 3.0-15.3, p < 0.001) but lost significance after adjusting for covariates related to severe COVID-19 and hemodynamic instability. Elevated ALP and ALT were associated with longer LOS, admission to intensive care, mechanical ventilation, vasopressor use, and extracorporeal membrane oxygenation use (p < 0.001). CONCLUSIONS: Transaminase elevation is common in hospitalized patients with COVID-19. Severe ALI is rare, and ALF may not be a complication of COVID-19. Extreme elevations in liver enzymes appear to be associated with mortality and longer LOS due to more severe systemic disease rather than SARS-CoV-2-related hepatitis.

Non-clinical safety profile and pharmacodynamics of two formulations of the anti-sepsis drug candidate Rejuveinix (RJX).

Here, we demonstrate that the two distinct formulations of our anti-sepsis drug candidate Rejuveinix (RJX), have a very favorable safety profile in Wistar Albino rats at dose levels comparable to the projected clinical dose levels. 14-day treatment with RJX-P (RJX PPP.18.1051) or RJX-B (RJX-B200702-CLN) similarly elevated the day 15 tissue levels of the antioxidant enzyme superoxide dismutase (SOD) as well as ascorbic acid in both the lungs and liver in a dose-dependent fashion. The activity of SOD and ascorbic acid levels were significantly higher in tissues of RJX-P or RJX-B treated rats than vehicle-treated control rats (p < 0.0001). There was no statistically significant difference between tissue SOD activity or ascorbic acid levels of rats treated with RJX-P vs. rats treated with RJX-B (p > 0.05). The observed elevations of the SOD and ascorbic acid levels were transient and were no longer detectable on day 28 following a 14-day recovery period. These results demonstrate that RJX-P and RJX-B are bioequivalent relative to their pharmacodynamic effects on tissue SOD and ascorbic acid levels. Furthermore, both formulations showed profound protective activity in a mouse model of sepsis. In agreement with the PD evaluations in rats and their proposed mechanism of action, both RJX-P and RJX-B exhibited near-identical potent and dose-dependent anti-oxidant and anti-inflammatory activity in the LPS-GalN model of ARDS and multi-organ failure in mice.

Liver Transplantation for T2 Hepatocellular Carcinoma during the COVID-19 Pandemic: A Novel Model Balancing Individual Benefit against Healthcare Resources.

The COVID-19 pandemic caused temporary drops in the supply of organs for transplantation, leading to renewed debate about whether T2 hepatocellular carcinoma (HCC) patients should receive priority during these times. The aim of this study was to provide a quantitative model to aid decision-making in liver transplantation for T2 HCC. We proposed a novel ethical framework where the individual transplant benefit for a T2 HCC patient should outweigh the harm to others on the waiting list, determining a "net benefit", to define appropriate organ allocation. This ethical framework was then translated into a quantitative Markov model including Italian averages for waiting list characteristics, donor resources, mortality, and transplant rates obtained from a national prospective database (n = 8567 patients). The net benefit of transplantation in a T2 HCC patient in a usual situation varied from 0 life months with a model for end-stage liver disease (MELD) score of 15, to 34 life months with a MELD score of 40, while it progressively decreased with acute organ shortage during a pandemic (i.e., with a 50% decrease in organs, the net benefit varied from 0 life months with MELD 30, to 12 life months with MELD 40). Our study supports the continuation of transplantation for T2 HCC patients during crises such as COVID-19; however, the focus needs to be on those T2 HCC patients with the highest net survival benefit.

Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019.

BACKGROUND & AIMS: The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19. METHODS: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. RESULTS: A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76-1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80-2.12) were not associated independently with mechanical ventilation or death. CONCLUSIONS: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.

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.

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.