New (re)purpose for an old drug: purinergic modulation may extinguish the COVID-19 thromboinflammatory firestorm.
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ABSTRACT:
SUBMITTER: Kanthi Y
PROVIDER: S-EPMC7453890 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
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New (re)purpose for an old drug: purinergic modulation may extinguish the COVID-19 thromboinflammatory firestorm.
Kanthi Yogendra Y Knight Jason S JS Zuo Yu Y Pinsky David J DJ
JCI insight 20200723 14
Purinergic signaling is discussed as a potential therapeutic target to reduced COVID-19 severity. ...[more]
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Project description:Purpose of Review:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, is a pandemic causing havoc globally. Currently, there are no Food and Drug Administration (FDA)-approved drugs to treat COVID-19. In the absence of effective treatment, off-label drug use, in lieu of evidence from published randomized, double-blind, placebo-controlled clinical trials, is common in COVID-19. Although it is vital to treat affected patients with antiviral drugs, there is a knowledge gap regarding the use of anti-inflammatory drugs in these patients. Recent Findings:Colchicine trials to combat inflammation in COVID-19 patients have not received much attention. We await the results of ongoing colchicine randomized controlled trials in COVID-19, evaluating colchicine's efficacy in treating COVID-19. Summary:This review gives a spotlight on colchicine's anti-inflammatory and antiviral properties and why colchicine may help fight COVID-19. This review summarizes colchicine's mechanism of action via the tubulin-colchicine complex. Furthermore, it discussed how colchicine interferes with several inflammatory pathways, including inhibition of neutrophil chemotaxis, adhesion, and mobilization; disruption of superoxide production, inflammasome inhibition, and tumor necrosis factor reduction; and its possible antiviral properties. In addition, colchicine dosing and pharmacokinetics, as well as drug interactions and how they relate to ongoing, colchicine in COVID-19 clinical trials, are examined.
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Project description:ObjectiveTo evaluate differences in thromboinflammatory biomarkers between patients with severe coronavirus disease 2019 (COVID-19) infection/death and mild infection.Patients and methodsMEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, EBSCO, Web of Science, and CINAHL databases were searched for studies comparing thromboinflammatory biomarkers in COVID-19 among patients with severe COVID-19 disease or death (severe/nonsurvivors) and those with nonsevere disease or survivors (nonsevere/survivors) from January 1, 2020, through July 11, 2020. Inclusion criteria were (1) hospitalized patients 18 years or older comparing severe/nonsurvivors vs nonsevere/survivors and (2) biomarkers of inflammation and/or thrombosis. A random-effects model was used to estimate the weighted mean difference (WMD) between the 2 groups of COVID-19 severity.ResultsWe included 75 studies with 17,052 patients. The severe/nonsurvivor group was older, had a greater proportion of men, and had a higher prevalence of hypertension, diabetes, cardiac or cerebrovascular disease, chronic kidney disease, malignancy, and chronic obstructive pulmonary disease. Thromboinflammatory biomarkers were significantly higher in patients with severe disease, including D-dimer (WMD, 0.60; 95% CI, 0.49 to 0.71; I 2 =83.85%), fibrinogen (WMD, 0.42; 95% CI, 0.18 to 0.67; I 2 =61.88%; P<.001), C-reactive protein (CRP) (WMD, 35.74; 95% CI, 30.16 to 41.31; I 2 =85.27%), high-sensitivity CRP (WMD, 62.68; 95% CI, 45.27 to 80.09; I 2 =0%), interleukin 6 (WMD, 22.81; 95% CI, 17.90 to 27.72; I 2 =90.42%), and ferritin (WMD, 506.15; 95% CI, 356.24 to 656.06; I 2 =52.02%). Moderate to significant heterogeneity was observed for all parameters (I 2 > 25%). Subanalysis based on disease severity, mortality, and geographic region of the studies revealed similar inferences.ConclusionThromboinflammatory biomarkers (D-dimer, fibrinogen, CRP, high-sensitivity CRP, ferritin, and interleukin 6) and marker of end-organ damage (high-sensitivity troponin I) are associated with increased severity and mortality in COVID-19 infection.
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Project description:BackgroundThe peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19.MethodsIn this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50?IU anti-Xa/kg twice daily-or 75?IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement.DiscussionIn this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome.Trial registrationThe EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.
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