Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies

BACKGROUND: Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppre...

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Autores principales: Rabin, Joseph, Zhao, Yunge, Mostafa, Ezzat, Al-Suqi, Manal, Fleischmann, Emily, Conaway, Mark R., Mann, Barbara J., Chhabra, Preeti, Brayman, Kenneth L., Krupnick, Alexander, Linden, Joel, Lau, Christine L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10420352/
https://www.ncbi.nlm.nih.gov/pubmed/37566593
http://dx.doi.org/10.1371/journal.pone.0288920
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author Rabin, Joseph
Zhao, Yunge
Mostafa, Ezzat
Al-Suqi, Manal
Fleischmann, Emily
Conaway, Mark R.
Mann, Barbara J.
Chhabra, Preeti
Brayman, Kenneth L.
Krupnick, Alexander
Linden, Joel
Lau, Christine L.
author_facet Rabin, Joseph
Zhao, Yunge
Mostafa, Ezzat
Al-Suqi, Manal
Fleischmann, Emily
Conaway, Mark R.
Mann, Barbara J.
Chhabra, Preeti
Brayman, Kenneth L.
Krupnick, Alexander
Linden, Joel
Lau, Christine L.
author_sort Rabin, Joseph
collection PubMed
description BACKGROUND: Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppressing the activation of invariant natural killer T (iNKT) cells. The anti-inflammatory effects of RA are magnified in injured tissues due to induction in immune cells of A2ARs and ecto-enzymes CD39 and CD73 that convert ATP to adenosine in the extracellular space. Here we describe the results of a five patient study designed to evaluate RA safety and to seek evidence of reduced cytokine storm in hospitalized COVID-19 patients. METHODS AND FINDINGS: Five COVID-19 patients requiring supplemental oxygen but not intubation (WHO stages 4–5) were infused IV with a loading RA dose of 5 μg/kg/h for 0.5 h followed by a maintenance dose of 1.44 μg/kg/h for 6 hours, Vital signs and arterial oxygen saturation were recorded, and blood samples were collected before, during and after RA infusion for analysis of CRP, D-dimer, circulating iNKT cell activation state and plasma levels of 13 proinflammatory cytokines. RA was devoid of serious side effects, and within 24 hours from the start of infusion was associated with increased oxygen saturation (93.8 ± 0.58 vs 96.6 ± 1.08%, P<0.05), decreased D-dimer (754 ± 17 vs 518 ± 98 ng/ml, P<0.05), and a trend toward decreased CRP (3.80 ± 1.40 vs 1.98 ± 0.74 mg/dL, P = 0.075). Circulating iNKT cells, but not conventional T cells, were highly activated in COVID-19 patients (65% vs 5% CD69+). RA infusion for 30 minutes reduced iNKT cell activation by 50% (P<0.01). RA infusion for 30 minutes did not influence plasma cytokines, but infusion for 4.5 or 24 hours reduced levels of 11 of 13 proinflammatory cytokines. In separate mouse studies, subcutaneous RA infusion from Alzet minipumps at 1.44 μg/kg/h increased 10-day survival of SARS-CoV-2-infected K18-hACE2 mice from 10 to 40% (P<0.001). CONCLUSIONS: Infused RA is safe and produces rapid anti-inflammatory effects mediated by A2A adenosine receptors on iNKT cells and possibly in part by A2ARs on other immune cells and platelets. We speculate that iNKT cells are activated by release of injury-induced glycolipid antigens and/or alarmins such as IL-33 derived from virally infected type II epithelial cells which in turn activate iNKT cells and secondarily other immune cells. Adenosine released from hypoxic tissues, or RA infused as an anti-inflammatory agent decrease proinflammatory cytokines and may be useful for treating cytokine storm in patients with Covid-19 or other inflammatory lung diseases or trauma.
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spelling pubmed-104203522023-08-12 Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies Rabin, Joseph Zhao, Yunge Mostafa, Ezzat Al-Suqi, Manal Fleischmann, Emily Conaway, Mark R. Mann, Barbara J. Chhabra, Preeti Brayman, Kenneth L. Krupnick, Alexander Linden, Joel Lau, Christine L. PLoS One Research Article BACKGROUND: Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppressing the activation of invariant natural killer T (iNKT) cells. The anti-inflammatory effects of RA are magnified in injured tissues due to induction in immune cells of A2ARs and ecto-enzymes CD39 and CD73 that convert ATP to adenosine in the extracellular space. Here we describe the results of a five patient study designed to evaluate RA safety and to seek evidence of reduced cytokine storm in hospitalized COVID-19 patients. METHODS AND FINDINGS: Five COVID-19 patients requiring supplemental oxygen but not intubation (WHO stages 4–5) were infused IV with a loading RA dose of 5 μg/kg/h for 0.5 h followed by a maintenance dose of 1.44 μg/kg/h for 6 hours, Vital signs and arterial oxygen saturation were recorded, and blood samples were collected before, during and after RA infusion for analysis of CRP, D-dimer, circulating iNKT cell activation state and plasma levels of 13 proinflammatory cytokines. RA was devoid of serious side effects, and within 24 hours from the start of infusion was associated with increased oxygen saturation (93.8 ± 0.58 vs 96.6 ± 1.08%, P<0.05), decreased D-dimer (754 ± 17 vs 518 ± 98 ng/ml, P<0.05), and a trend toward decreased CRP (3.80 ± 1.40 vs 1.98 ± 0.74 mg/dL, P = 0.075). Circulating iNKT cells, but not conventional T cells, were highly activated in COVID-19 patients (65% vs 5% CD69+). RA infusion for 30 minutes reduced iNKT cell activation by 50% (P<0.01). RA infusion for 30 minutes did not influence plasma cytokines, but infusion for 4.5 or 24 hours reduced levels of 11 of 13 proinflammatory cytokines. In separate mouse studies, subcutaneous RA infusion from Alzet minipumps at 1.44 μg/kg/h increased 10-day survival of SARS-CoV-2-infected K18-hACE2 mice from 10 to 40% (P<0.001). CONCLUSIONS: Infused RA is safe and produces rapid anti-inflammatory effects mediated by A2A adenosine receptors on iNKT cells and possibly in part by A2ARs on other immune cells and platelets. We speculate that iNKT cells are activated by release of injury-induced glycolipid antigens and/or alarmins such as IL-33 derived from virally infected type II epithelial cells which in turn activate iNKT cells and secondarily other immune cells. Adenosine released from hypoxic tissues, or RA infused as an anti-inflammatory agent decrease proinflammatory cytokines and may be useful for treating cytokine storm in patients with Covid-19 or other inflammatory lung diseases or trauma. Public Library of Science 2023-08-11 /pmc/articles/PMC10420352/ /pubmed/37566593 http://dx.doi.org/10.1371/journal.pone.0288920 Text en © 2023 Rabin et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Rabin, Joseph
Zhao, Yunge
Mostafa, Ezzat
Al-Suqi, Manal
Fleischmann, Emily
Conaway, Mark R.
Mann, Barbara J.
Chhabra, Preeti
Brayman, Kenneth L.
Krupnick, Alexander
Linden, Joel
Lau, Christine L.
Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies
title Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies
title_full Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies
title_fullStr Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies
title_full_unstemmed Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies
title_short Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies
title_sort regadenoson for the treatment of covid-19: a five case clinical series and mouse studies
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10420352/
https://www.ncbi.nlm.nih.gov/pubmed/37566593
http://dx.doi.org/10.1371/journal.pone.0288920
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