The angiotensin type 2 receptor agonist C21 restores respiratory function in COVID19 - a double-blind, randomized, placebo-controlled Phase 2 trial

Tornling, Göran; Batta, Rohit; Porter, Joanna C.; Bengtsson, Thomas; Parmar, Kartikeya; Kashiva, Reema; Cohrt, Anne Kartine; Westergaard, Kate; Hallberg, Anders; Dalsgaard, C.‐J.; Raud, J.

doi:10.1101/2021.01.26.21250511

Cited by 9 publications

(6 citation statements)

References 29 publications

(37 reference statements)

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“…Restoring RAS balance could be achieved through many means, including injections of soluble human recombinant ACE2 [ 19 ], AT2R activators [ 68 ], AT1R blockers (ARBs) [ 65 ] or angiotensin converting enzyme inhibitors (ACEIs) [ 67 ]. Accordingly, an agonist of AT2R improves respiratory functions and reduces mortality in COVID-19 patients [ 74 ]. Similarly, it has been recently shown that the treatment with ACEIs or ARBs during COVID-19 hospitalization reduces mortality [ 75 , 76 ].…”

Section: Methodsmentioning

confidence: 99%

A comparison between virus- versus patients-centred therapeutic attempts to reduce COVID-19 mortality

Camelo

Latil

Agus³

et al. 2021

Emerging Microbes & Infections

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Since December 2019, coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has changed our lives. Elderly and those with comorbidities represent the vast majority of patients hospitalized with severe COVID-19 symptoms, including acute respiratory disease syndrome and cardiac dysfunction. Despite a huge effort of the scientific community, improved treatment modalities limiting the severity and mortality of hospitalized COVID-19 patients are still required. Here, we compare the effectiveness of virus- and patients-centred strategies to reduce COVID-19 mortality. We also discuss the therapeutic options that might further reduce death rates associated with the disease in the future. Unexpectedly, extensive review of the literature suggests that SARS-CoV-2 viral load seems to be associated neither with the severity of symptoms nor with mortality of hospitalized patients with COVID-19. This may explain why, so far, virus-centred strategies using antivirals aiming to inhibit the viral replicative machinery have failed to reduce COVID-19 mortality in patients with respiratory failure. By contrast, anti-inflammatory treatments without antiviral capacities but centred on patients, such as dexamethasone or Tocilizumab ® , reduce COVID-19 mortality. Finally, since the spike protein of SARS-CoV-2 binds to angiotensin converting enzyme 2 and inhibits its function, we explore the different treatment options focussing on rebalancing the renin-angiotensin system. This new therapeutic strategy could hopefully further reduce the severity of respiratory failure and limit COVID-19 mortality in elderly patients.

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Section: Methodsmentioning

confidence: 99%

A comparison between virus- versus patients-centred therapeutic attempts to reduce COVID-19 mortality

Camelo

Latil

Agus³

et al. 2021

Emerging Microbes & Infections

View full text Add to dashboard Cite

show abstract

“…Instead of increasing ACE2, selective AT1R antagonism by ARBs has been hypothesized to aid in ameliorating lung pathology in COVID-19 through rebalancing Ang II/angiotensin (1-7) ratio and indirectly promoting Ang II-induced activation of AT2R with antagonistic effect against Ang II activation of AT1R [34,40]. A recent small randomized clinical trial showed that C21, an agonist of AT2R, could improve mortality rate and respiratory function significantly in hospitalized patients with COVID-19 [41]. However, the use of ARBs was constrained in the early phase of the pandemic due to concerns over their possible role in increasing viral load due to ACE2upregulating effect of these drugs [42,43].…”

Section: Introductionmentioning

confidence: 99%

Losartan Inhibits SARS-CoV-2 Replication in Vitro

et al. 2021

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Purpose: SARS-CoV-2 infection is associated with substantial mortality and high morbidity. This study tested the effect of angiotensin II type I receptor blocker, losartan, on SARS-CoV-2 replication and inhibition of the papain-like protease of the virus. Methods: The dose-dependent inhibitory effect of losartan, in concentrations from 1μM to 100μM as determined by quantitative cell analysis combining fluorescence microscopy, image processing, and cellular measurements (Cellomics analysis) on SARS-CoV-2 replication was investigated in Vero E6 cells. The impact of losartan on deubiquitination and deISGylation of SARS-CoV-2 papain-like protease (PLpro) were also evaluated. Results: Losartan reduced PLpro cleavage of tetraUbiquitin to diUbiquitin. It was less effective in inhibiting PLpro’s cleavage of ISG15-AMC than Ubiquitin-AMC. To determine if losartan inhibited SARS-CoV-2 replication, losartan treatment of SARS-CoV-2 infected Vero E6 was examined. Losartan treatment one hour prior to SARS-CoV-2 infection reduced levels of SARS-CoV-2 nuclear protein, an indicator of virus replication, by 80% and treatment one-hour post-infection decreased viral replication by 70%. Conclusion: Losartan was not an effective inhibitor of deubiquitinase or deISGylase activity of the PLpro but affected the SARS-CoV-2 replication of Vero E6 cells in vitro. As losartan has a favorable safety profile and is currently available it has features necessary for efficacious drug repurposing and treatment of COVID-19.

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“…After abstract screening and full-text reading, 152 RCTs were included in the analysis. All 152 RCTs were posted on the medRxiv server …”

Section: Resultsmentioning

confidence: 99%

Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles

et al. 2023

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ImportanceRandomized clinical trials (RCTs) on COVID-19 are increasingly being posted as preprints before publication in a scientific, peer-reviewed journal.ObjectiveTo assess time to journal publication for COVID-19 RCT preprints and to compare differences between pairs of preprints and corresponding journal articles.Evidence ReviewThis systematic review used a meta-epidemiologic approach to conduct a literature search using the World Health Organization COVID-19 database and Embase to identify preprints published between January 1 and December 31, 2021. This review included RCTs with human participants and research questions regarding the treatment or prevention of COVID-19. For each preprint, a literature search was done to locate the corresponding journal article. Two independent reviewers read the full text, extracted data, and assessed risk of bias using the Cochrane Risk of Bias 2 tool. Time to publication was analyzed using a Cox proportional hazards regression model. Differences between preprint and journal article pairs in terms of outcomes, analyses, results, or conclusions were described. Statistical analysis was performed on October 17, 2022.FindingsThis study included 152 preprints. As of October 1, 2022, 119 of 152 preprints (78.3%) had been published in journals. The median time to publication was 186 days (range, 17-407 days). In a multivariable model, larger sample size and low risk of bias were associated with journal publication. With a sample size of less than 200 as the reference, sample sizes of 201 to 1000 and greater than 1000 had hazard ratios (HRs) of 1.23 (95% CI, 0.80-1.91) and 2.19 (95% CI, 1.36-3.53) for publication, respectively. With high risk of bias as the reference, medium-risk articles with some concerns for bias had an HR of 1.77 (95% CI, 1.02-3.09); those with a low risk of bias had an HR of 3.01 (95% CI, 1.71-5.30). Of the 119 published preprints, there were differences in terms of outcomes, analyses, results, or conclusions in 65 studies (54.6%). The main conclusion in the preprint contradicted the conclusion in the journal article for 2 studies (1.7%).Conclusions and RelevanceThese findings suggest that there is a substantial time lag from preprint posting to journal publication. Preprints with smaller sample sizes and high risk of bias were less likely to be published. Finally, although differences in terms of outcomes, analyses, results, or conclusions were observed for preprint and journal article pairs in most studies, the main conclusion remained consistent for the majority of studies.

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The angiotensin type 2 receptor agonist C21 restores respiratory function in COVID19 - a double-blind, randomized, placebo-controlled Phase 2 trial

Cited by 9 publications

References 29 publications

A comparison between virus- versus patients-centred therapeutic attempts to reduce COVID-19 mortality

A comparison between virus- versus patients-centred therapeutic attempts to reduce COVID-19 mortality

Losartan Inhibits SARS-CoV-2 Replication in Vitro

Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles

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