Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies
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 ac...
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| Veröffentlicht in: | PloS one 2023-08, Vol.18 (8), p.e0288920-e0288920 |
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| creator | 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 |
| description | 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.
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 |
| doi_str_mv | 10.1371/journal.pone.0288920 |
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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).
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0288920</identifier><identifier>PMID: 37566593</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine ; Anemia ; Anti-inflammatory agents ; Antigens ; Biology and Life Sciences ; Blood pressure ; Cardiovascular disease ; CD69 antigen ; CD73 antigen ; Cell activation ; COVID-19 ; Cytokine storm ; Cytokines ; Dimers ; Drug dosages ; Enzymes ; Epithelial cells ; Epithelium ; Evaluation ; Heart rate ; Hospitalization ; Hypoxia ; Immune system ; Infection ; Inflammation ; Injury prevention ; Ischemia ; Kinases ; Lung diseases ; Lung transplantation ; Lymphocytes ; Lymphocytes T ; Medicine and Health Sciences ; Mortality ; Natural killer cells ; Oxygen ; Oxygen content ; Oxygen saturation ; Patients ; Physical Sciences ; Plasma ; Plasma levels ; Platelets ; Receptors ; Risk factors ; Sea level ; Severe acute respiratory syndrome coronavirus 2 ; Sickle cell disease ; Side effects ; Tissues ; Transplantation ; United States</subject><ispartof>PloS one, 2023-08, Vol.18 (8), p.e0288920-e0288920</ispartof><rights>Copyright: © 2023 Rabin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2023 Public Library of Science</rights><rights>2023 Rabin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 Rabin et al 2023 Rabin et al</rights><rights>2023 Rabin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c627t-c39b447372f9f45603bb03af8b9af09a32ea76e5f25b2bec38222d84db21d4b83</citedby><cites>FETCH-LOGICAL-c627t-c39b447372f9f45603bb03af8b9af09a32ea76e5f25b2bec38222d84db21d4b83</cites><orcidid>0000-0002-0459-2336 ; 0000-0002-2229-3479 ; 0000-0002-9921-0598</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10420352/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10420352/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37566593$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Chenette, Emily</contributor><creatorcontrib>Rabin, Joseph</creatorcontrib><creatorcontrib>Zhao, Yunge</creatorcontrib><creatorcontrib>Mostafa, Ezzat</creatorcontrib><creatorcontrib>Al-Suqi, Manal</creatorcontrib><creatorcontrib>Fleischmann, Emily</creatorcontrib><creatorcontrib>Conaway, Mark R</creatorcontrib><creatorcontrib>Mann, Barbara J</creatorcontrib><creatorcontrib>Chhabra, Preeti</creatorcontrib><creatorcontrib>Brayman, Kenneth L</creatorcontrib><creatorcontrib>Krupnick, Alexander</creatorcontrib><creatorcontrib>Linden, Joel</creatorcontrib><creatorcontrib>Lau, Christine L</creatorcontrib><title>Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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).
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.</description><subject>Adenosine</subject><subject>Anemia</subject><subject>Anti-inflammatory agents</subject><subject>Antigens</subject><subject>Biology and Life Sciences</subject><subject>Blood pressure</subject><subject>Cardiovascular disease</subject><subject>CD69 antigen</subject><subject>CD73 antigen</subject><subject>Cell activation</subject><subject>COVID-19</subject><subject>Cytokine storm</subject><subject>Cytokines</subject><subject>Dimers</subject><subject>Drug dosages</subject><subject>Enzymes</subject><subject>Epithelial cells</subject><subject>Epithelium</subject><subject>Evaluation</subject><subject>Heart rate</subject><subject>Hospitalization</subject><subject>Hypoxia</subject><subject>Immune 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for the treatment of COVID-19: A five case clinical series and mouse studies</title><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></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c627t-c39b447372f9f45603bb03af8b9af09a32ea76e5f25b2bec38222d84db21d4b83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Adenosine</topic><topic>Anemia</topic><topic>Anti-inflammatory agents</topic><topic>Antigens</topic><topic>Biology and Life Sciences</topic><topic>Blood pressure</topic><topic>Cardiovascular disease</topic><topic>CD69 antigen</topic><topic>CD73 antigen</topic><topic>Cell activation</topic><topic>COVID-19</topic><topic>Cytokine storm</topic><topic>Cytokines</topic><topic>Dimers</topic><topic>Drug 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One</addtitle><date>2023-08-11</date><risdate>2023</risdate><volume>18</volume><issue>8</issue><spage>e0288920</spage><epage>e0288920</epage><pages>e0288920-e0288920</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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).
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>37566593</pmid><doi>10.1371/journal.pone.0288920</doi><tpages>e0288920</tpages><orcidid>https://orcid.org/0000-0002-0459-2336</orcidid><orcidid>https://orcid.org/0000-0002-2229-3479</orcidid><orcidid>https://orcid.org/0000-0002-9921-0598</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2023-08, Vol.18 (8), p.e0288920-e0288920 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2849307190 |
| source | DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenosine Anemia Anti-inflammatory agents Antigens Biology and Life Sciences Blood pressure Cardiovascular disease CD69 antigen CD73 antigen Cell activation COVID-19 Cytokine storm Cytokines Dimers Drug dosages Enzymes Epithelial cells Epithelium Evaluation Heart rate Hospitalization Hypoxia Immune system Infection Inflammation Injury prevention Ischemia Kinases Lung diseases Lung transplantation Lymphocytes Lymphocytes T Medicine and Health Sciences Mortality Natural killer cells Oxygen Oxygen content Oxygen saturation Patients Physical Sciences Plasma Plasma levels Platelets Receptors Risk factors Sea level Severe acute respiratory syndrome coronavirus 2 Sickle cell disease Side effects Tissues Transplantation United States |
| title | Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies |
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