A hitchhiker's guide through the COVID-19 galaxy

Felsenstein, Susanna; Reiff, Andreas

doi:10.1016/j.clim.2021.108849

Cited by 3 publications

(3 citation statements)

References 466 publications

(411 reference statements)

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“…As mentioned in Felsenstein and Reiff, 2021 , the inflammatory process changes pathophysiologically as COVID-19 progresses. Therefore, it is important to predict disease progression of COVID-19 through appropriate biomarkers or inflammatory markers; these markers should be considered in patient risk stratification and drug efficacy assessment with respect to disease progression.…”

Section: Discussionmentioning

confidence: 94%

“…On the other hand, biomarkers for the formation of neutrophil extracellular traps (i.e., NETosis) associated with the bacterial and viral defense system of neutrophils are significantly elevated in hospitalized patient requiring non-invasive ventilation or high-flow oxygen (e.g., WHO stage 5). Also, secondary fungal infections (e.g., mucormycosis, aspergillus) should be carefully monitored during follow-up visits in long-term treated patients or who received long half-life anti-inflammatory agents, and safety monitoring plan for secondary infections should be provided during the clinical trial of anti-inflammatory agents ( Felsenstein and Reiff, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

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Key Considerations for Phase 2 or 3 Clinical Study Design of Anti-Inflammatory Agent for COVID-19 Treatment

Park

Cho

et al. 2022

Front. Pharmacol.

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Purpose: Current understanding of COVID-19 disease progression suggests a major role for the “cytokine storm” as an important contributor to COVID-19 mortality. To prevent an exaggerated immune response and improve COVID-19 patient endpoints, anti-inflammatory therapeutics have been proposed as clinically useful in severe patients with COVID-19. The purpose of this study was to propose a clinical trial design for the development of anti-inflammatory agents for the treatment of COVID-19, taking into account the physiological and immunological process of COVID-19 and the treatment mechanism of anti-inflammatory agents.Methods: We reviewed and analyzed the guidelines for the development of COVID-19 treatments and the treatment of COVID-19 by regulatory agencies and previously conducted clinical trials on anti-inflammatory drugs for COVID-19. Finally, after discussing with an advisory group, a synopsis was presented for an example protocol for a COVID-19 anti-inflammatory agent phase 2 or 3 study that considers the drug mechanism and the disease progression of COVID-19.Results: A randomized, placebo-controlled, double-blind parallel-group design was suggested as a phase 2 or 3 trial design for developing an anti-inflammatory agent as a COVID-19 treatment. A key item of the example protocol specific to anti-inflammatory agents was the inclusion and exclusion criteria, taking into account the immunosuppressive effects of the drug, clinical time course of COVID-19 disease, and treatment guidelines for COVID-19. Time to recovery is the primary endpoint associated with clinical efficacy and is generally well accepted by many experts.Conclusion: Through this suggested phase 2 or 3 study design of an anti-inflammatory drug for COVID-19, we provide a basis for a study design that can be utilized in clinical development by pharmaceutical companies which are developing a potential anti-inflammatory agent for COVID-19.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Key Considerations for Phase 2 or 3 Clinical Study Design of Anti-Inflammatory Agent for COVID-19 Treatment

Park

Cho

et al. 2022

Front. Pharmacol.

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“…By comparison, RA administered as Lexiscan, a 400 μg bolus over 10 seconds for myocardial perfusion imaging results in a peak plasma level of about 15 ng/ml, and is associated with unpleasant side effects [32,33]. The 5 subjects enrolled in this study were all unvaccinated and classified as WHO stages 4-5 [34]. Based on their clinical need they were given supplemental oxygen by nasal canula (NC) including high flow NC, but none required intubation.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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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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Tetrandrine Treatment May Improve Clinical Outcome in Patients with COVID-19

et al. 2022

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Background and objectives: The COVID-19 pandemic continues worldwide, and there is no effective treatment to treat it. Chinese medicine is considered the recommended treatment for COVID-19 in China. This study aimed to examine the effectiveness of tetrandrine in treating COVID-19, which is originally derived from Chinese medicine. Materials and Methods: A total of 60 patients, categorized into three types (mild, moderate, severe), from Daye Hospital of Chinese Medicine with a diagnosis of COVID-19 were included in this study. Demographics, medical history, treatment, and results were collected. We defined two main groups according to the clinical outcome between improvement and recovery. All underlying factors including clinical outcomes were assessed in the total number of COVID-19 patients and moderate-type patients. Results: In a total of 60 patients, there were significant differences in the clinical outcome underlying treatment with antibiotics, tetrandrine, and arbidol (p < 0.05). When the comparison was limited to the moderate type, treatment with tetrandrine further increased recovery rate (p = 0.007). However, the difference disappeared, and no association was indicated between the clinical outcome and the treatment with and without antibiotic (p = 0.224) and arbidol (p = 0.318) in the moderate-type patients. In all-type and moderate-type patients, tetrandrine improved the rate of improvement in cough and fatigue on day 7 (p < 0.05). Conclusions: Tetrandrine may improve clinical outcome in COVID-19 patientsand could be a promising potential natural antiviral agent for the prevention and treatment of COVID-19.

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A hitchhiker's guide through the COVID-19 galaxy

Cited by 3 publications

References 466 publications

Key Considerations for Phase 2 or 3 Clinical Study Design of Anti-Inflammatory Agent for COVID-19 Treatment

Key Considerations for Phase 2 or 3 Clinical Study Design of Anti-Inflammatory Agent for COVID-19 Treatment

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

Tetrandrine Treatment May Improve Clinical Outcome in Patients with COVID-19

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