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1.
Arch Med Res ; 51(7): 631-635, 2020 10.
Article in English | MEDLINE | ID: covidwho-1023470

ABSTRACT

The novel coronavirus 2019-nCoV (SARS-CoV-2) infection that emerged in China in December 2019 has rapidly spread to become a global pandemic. This article summarizes the potential benefits of erythropoietin (EPO) in alleviating SARS-CoV-2 pathogenesis which is now called COVID-19. As with other coronavirus infection, the lethality of COVID-19 is associated with respiratory dysfunction due to overexpression of proinflammatory cytokines induced by the host immune responses. The resulting cytokine storm leads to the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Erythropoietin, well known for its role in the regulation of erythropoiesis, may have protective effects against ALI/ARDS induced by viral and other pathogens. EPO exerts antiapoptotic and cytoprotective properties under various pathological conditions. With a high safety profile, EPO promotes the production of endothelial progenitor cells and reduce inflammatory processes through inhibition of the nuclear factor-κB (NF-κB) and JAK-STAT3 signaling pathways. Thus, it may be considered as a safe drug candidate for COVID-19 patients if given at the early stage of the disease. The potential effects of erythropoietin on different aspects of ALI/ARDS associated with SARS-CoV-2 infection are reviewed.


Subject(s)
Acute Lung Injury , Anti-Inflammatory Agents/therapeutic use , Erythropoietin/therapeutic use , Acute Lung Injury/drug therapy , Acute Lung Injury/virology , /drug therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Humans , /virology
2.
Front Immunol ; 11: 598444, 2020.
Article in English | MEDLINE | ID: covidwho-1013338

ABSTRACT

Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.


Subject(s)
/drug therapy , Cytokine Release Syndrome/drug therapy , NF-kappa B/antagonists & inhibitors , Proteasome Inhibitors/pharmacology , /drug effects , Animals , /pathology , Cytokine Release Syndrome/pathology , Cytokines/blood , Disease Models, Animal , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H5N1 Subtype/drug effects , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/drug therapy , /immunology
3.
Recent Pat Antiinfect Drug Discov ; 15(2): 104-112, 2020.
Article in English | MEDLINE | ID: covidwho-1013263

ABSTRACT

To date, severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) has infected millions of individuals worldwide. This virus causes coronavirus disease 2019 (COVID-19) and has led to numerous deaths worldwide. A large percentage of infected patients present asymptomatically, augmenting the spread of the virus. Symptomatic COVID-19 commonly causes mild to severe respiratory disease and fever, but some individuals experience serious complications resulting in death. Immune compromised, high risk, and elderly individuals are at an increased risk of more severe consequences of the illness such as respiratory failure, organ dysfunction, and shock. Cytokine storm (also known as cytokine release syndrome (CRS)), a systemic inflammatory response that can be triggered by an infection, has been associated with the symptom progression of COVID-19. This review evaluates several published studies that have implemented tocilizumab (TCZ), an IL-6 receptor antibody (US20120253016A1), in COVID-19 treatment. Outcomes and biomarkers of patients treated with TCZ are compared to patients treated with standard of care regimens. Interleukin-6 (IL-6), a prominent inflammatory cytokine involved in CRS in various inflammatory conditions, may have a vital role in the underlying mechanism involved in debilitating SARS-CoV-2 infections and could serve as a viable treatment target. Studies suggest that TCZ may aid in the recovery of patients with COVID-19 and reduce mortality.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Cytokine Release Syndrome/drug therapy , Receptors, Interleukin-6/antagonists & inhibitors , Animals , Antibodies, Monoclonal, Humanized/pharmacology , /metabolism , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/metabolism , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Receptors, Interleukin-6/metabolism , Treatment Outcome
4.
Eur Cytokine Netw ; 31(3): 81-93, 2020 Sep 01.
Article in English | MEDLINE | ID: covidwho-999892

ABSTRACT

Coronavirus disease (COVID-19) reached pandemic proportions at the beginning of 2020 and continues to be a worldwide concern. End organ damage and acute respiratory distress syndrome are the leading causes of death in severely or critically ill patients. The elevated cytokine levels in severe patients in comparison with mildly affected patients suggest that cytokine release syndrome (CRS) occurs in the severe form of the disease. In this paper, the significant role of pro-inflammatory cytokines, including IL-1, IL-6, and TNF-alpha, and their mechanism of action in the CRS cascade is explained. Potential therapeutic approaches involving anti-IL-6 and anti-TNF-alpha antibodies to fight COVID-19 and reduce mortality rate in severe cases are also discussed.


Subject(s)
Antibodies/therapeutic use , Cytokine Release Syndrome , Interleukin-6/antagonists & inhibitors , Pandemics , Tumor Necrosis Factor-alpha/antagonists & inhibitors , /blood , /drug therapy , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/mortality , Humans , Interleukin-6/blood , Tumor Necrosis Factor-alpha/blood
6.
Front Endocrinol (Lausanne) ; 11: 569241, 2020.
Article in English | MEDLINE | ID: covidwho-995769

ABSTRACT

The clinical hallmarks of infections caused by critical respiratory viruses consist of pneumonia, which can progress to acute lung injury (ALI), and systemic manifestations including hypercoagulopathy, vascular dysfunction, and endotheliitis. The disease outcome largely depends on the immune response produced by the host. The bio-molecular mechanisms underlying certain dire consequences of the infection partly arise from an aberrant production of inflammatory molecules, an event denoted as "cytokine storm". Therefore, in addition to antiviral therapies, molecules able to prevent the injury caused by cytokine excess are under investigation. In this perspective, taking advantage of melanocortin peptides and their receptors, components of an endogenous modulatory system that exerts marked anti-inflammatory and immunomodulatory influences, could be an effective therapeutic strategy to control disease evolution. Exploiting the melanocortin system using natural or synthetic ligands can form a realistic basis to counteract certain deleterious effects of respiratory virus infections. The central and peripheral protective actions exerted following melanocortin receptor activation could allow dampening the harmful events that trigger the cytokine storm and endothelial dysfunction while sustaining the beneficial signals required to elicit repair mechanisms. The long standing evidence for melanocortin safety encourages this approach.


Subject(s)
/drug therapy , Receptors, Melanocortin/agonists , Respiratory Tract Infections/drug therapy , Acute Lung Injury/drug therapy , Animals , Anti-Inflammatory Agents/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokines/metabolism , Humans , Melanocyte-Stimulating Hormones/metabolism , Respiratory Tract Infections/etiology , Respiratory Tract Infections/metabolism
7.
Eur Rev Med Pharmacol Sci ; 24(23): 12527-12535, 2020 12.
Article in English | MEDLINE | ID: covidwho-995013

ABSTRACT

Since December 2019, an outbreak of a new coronavirus, COVID-19, infection has been taking place. At present, COVID-19 has spread to most countries worldwide. The latest evidence suggests that cytokine storm syndrome (CSS) is an important cause of the transition from mild to critical pneumonia and critically ill patients' death. The sudden exacerbation of COVID-19 may be related to a cytokine storm. Therefore, early identification and active treatment of CSS may play very important roles in improving the patients' prognosis, and these tasks are given attention in the current treatment of new Coronavirus pneumonia. However, there is still no specific medicine for this purpose. This article reviews cytokine storms and conducts an exploratory review of pharmacotherapy for cytokine storms to provide a reference for clinical treatment.


Subject(s)
/immunology , Cytokine Release Syndrome/immunology , Myocarditis/immunology , /metabolism , Antibodies, Monoclonal, Humanized/therapeutic use , Antioxidants/therapeutic use , Apoptosis , Atrial Natriuretic Factor/therapeutic use , Azetidines/therapeutic use , Benzyl Compounds/therapeutic use , Cytokine Release Syndrome/drug therapy , Enzyme Inhibitors/therapeutic use , Glucocorticoids/therapeutic use , Glycoproteins/therapeutic use , Humans , Hypoxia/metabolism , Hypoxia/therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Myocardial Ischemia/metabolism , Myocarditis/metabolism , Myocarditis/therapy , Myocytes, Cardiac/metabolism , Oxidative Stress , Oxygen Inhalation Therapy , Respiration, Artificial , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Trypsin Inhibitors/therapeutic use , Tumor Necrosis Factor Inhibitors/therapeutic use , alpha-Methyltyrosine/therapeutic use
8.
Clin Rheumatol ; 39(7): 2077-2084, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-980874

ABSTRACT

The novel coronavirus (Sars-CoV-2) pandemic has spread rapidly, from December to the end of March, to 185 countries, and there have been over 3,000,000 cases identified and over 200,000 deaths. For a proportion of hospitalized patients, death can occur within a few days, mainly for adult respiratory distress syndrome or multi-organ dysfunction syndrome. In these patients, clinical signs and symptoms, as well as laboratory abnormalities, suggest a cytokine storm syndrome in response to the viral infection. No current targeted treatment is yet available for COVID-19, an unknown disease up to 2 months ago, which challenges doctors and researchers to find new drugs or reallocate other treatments for these patients. Since the beginning of the COVID-19 outbreak, a growing body of information on diagnostic and therapeutic strategies has emerged, mainly based on preliminary experience on retrospective studies or small case series. Antivirals, antimalarials, corticosteroids, biotechnological and small molecules, convalescent plasma and anticoagulants are among the drugs proposed for the treatment or in tested for COVID-19. Given the complexity of this new condition, a multidisciplinary management seems to be the best approach. Sharing and integrating knowledge between specialists, to evaluate the correct timing and setting of every treatment, could greatly benefit our patients. We reviewed the literature, combining it with our experiences and our specialist knowledge, to propose a management algorithm, correlating the clinical features with laboratory and imaging findings to establish the right timing for each treatment.Key Points• Critically ill COVID-19 patients show signs of cytokine storm syndrome.• No current targeted therapy is available, but a lot of drugs are in tested.• A multidisciplinary approach is crucial to manage COVID-19.• Choosing the correct timing of treatment is of pivotal importance to avoid the most severe complications.


Subject(s)
Antiviral Agents , Clinical Laboratory Techniques/methods , Coronavirus Infections , Cytokine Release Syndrome , Pandemics , Patient Care Team/organization & administration , Pneumonia, Viral , Algorithms , Antiviral Agents/immunology , Antiviral Agents/pharmacology , Betacoronavirus/isolation & purification , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Critical Pathways , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Humans , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/therapy
9.
Virus Res ; 292: 198246, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-974719

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Carbamates/pharmacology , Carbazoles/pharmacology , Cytokines/antagonists & inhibitors , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Virus Replication/drug effects , Animals , Chlorocebus aethiops , Cytokine Release Syndrome/drug therapy , Cytokines/immunology , HeLa Cells , Humans , Inflammation/drug therapy , Inflammation/virology , Vero Cells
10.
Molecules ; 25(24)2020 Dec 12.
Article in English | MEDLINE | ID: covidwho-972696

ABSTRACT

SARS-CoV-2 first emerged in China during late 2019 and rapidly spread all over the world. Alterations in the inflammatory cytokines pathway represent a strong signature during SARS-COV-2 infection and correlate with poor prognosis and severity of the illness. The hyper-activation of the immune system results in an acute severe systemic inflammatory response named cytokine release syndrome (CRS). No effective prophylactic or post-exposure treatments are available, although some anti-inflammatory compounds are currently in clinical trials. Studies of plant extracts and natural compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation. The aim of this manuscript is to review the published background on the possible effectiveness of polyphenols to fight SARS-COV-2 infection, contributing to the reduction of inflammation. Here, some of the anti-inflammatory therapies are discussed and although great progress has been made though this year, there is no proven cytokine blocking agents for COVID currently used in clinical practice. In this regard, bioactive phytochemicals such as polyphenols may become promising tools to be used as adjuvants in the treatment of SARS-CoV-2 infection. Such nutrients, with anti-inflammatory and antioxidant properties, associated to classical anti-inflammatory drugs, could help in reducing the inflammation in patients with COVID-19.


Subject(s)
/drug therapy , Cytokine Release Syndrome/drug therapy , Pandemics , Phytochemicals/therapeutic use , Polyphenols/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Antiviral Agents/therapeutic use , China/epidemiology , Cytokine Release Syndrome/epidemiology , Humans , Inflammation/drug therapy , Inflammation/epidemiology , Polyphenols/chemistry
11.
Mol Cell Endocrinol ; 520: 111095, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-966632

ABSTRACT

The literature has reported a higher prevalence of negative clinical outcomes due to Coronavirus disease 19 (COVID-19) in obese individuals. This can be explained by the cytokine storm, result from the cytokine production from both obesity and viral infection. Gamma-oryzanol (γOz) is a compound with anti-inflammatory and antioxidant activities. However, little is known about the γOz action as a possible agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). The aim of this study was to test the hypothesis that γOz attenuates the cytokine storm by stimulating PPAR-γ in the adipose tissue. METHODS: Male Wistar rats were randomly divided into three experimental groups and fed ad libitum for 30 weeks with control diet (C, n = 6), high sugar-fat diet (HSF, n = 6) or high sugar-fat diet + Î³Oz (HSF + Î³Oz, n = 6). HSF groups also received water + sucrose (25%). The γOz dose was 0.5% in the chow. Evaluation in animals included caloric intake, body weight, adiposity index, plasma triglycerides, and HOMA-IR. In adipose tissue was evaluated: PPAR-γ gene and protein expression, inflammatory and oxidative stress parameters, and histological analysis. RESULTS: Adipose tissue dysfunction was observed in HSF group, which presented remarkable PPAR-γ underexpression and increased levels of cytokines, other inflammatory markers and oxidative stress. The γOz treatment prevented adipose tissue dysfunction and promoted PPAR-γ overexpression. CONCLUSION: Natural compounds as γOz can be considered a coadjutant therapy to prevent the cytokine storm in COVID-19 patients with obesity conditions.


Subject(s)
Adipose Tissue/metabolism , Cytokine Release Syndrome/drug therapy , Oxidative Stress/drug effects , PPAR gamma/metabolism , Phenylpropionates/pharmacology , /metabolism , Adipose Tissue/pathology , Adipose Tissue/virology , Animals , /pathology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Inflammation/virology , Male , Random Allocation , Rats , Rats, Wistar
13.
BMJ Open ; 10(11): e039951, 2020 11 14.
Article in English | MEDLINE | ID: covidwho-944946

ABSTRACT

INTRODUCTION: About 25% of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) associated with a high release of pro-inflammatory cytokines such as interleukin-6 (IL-6). The aim of the SARICOR study is to demonstrate that early administration of sarilumab (an IL-6 receptor inhibitor) in hospitalised patients with COVID-19, pulmonary infiltrates and a high IL-6 or D-dimer serum level could reduce the progression of ARDS requiring high-flow nasal oxygen or mechanical ventilation (non-invasive or invasive). METHODS AND ANALYSIS: Phase II, open-label, randomised, multicentre, controlled clinical trial to study the efficacy and safety of the administration of two doses of sarilumab (200 and 400 mg) plus best available therapy (BAT) in hospitalised adults with COVID-19 presenting cytokine release syndrome. This strategy will be compared with a BAT control group. The efficacy and safety will be monitored up to 28 days postadministration. A total of 120 patients will be recruited (40 patients in each arm). ETHICS AND DISSEMINATION: The clinical trial has been approved by the Research Ethics Committee of the coordinating centre and authorised by the Spanish Agency of Medicines and Medical Products. If the hypothesis is verified, the dissemination of the results could change clinical practice by increasing early administration of sarilumab in adult patients with COVID-19 presenting cytokine release syndrome, thus reducing intensive care unit admissions. TRIAL REGISTRATION NUMBER: NCT04357860.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome, Adult/drug therapy , Adolescent , Adult , Aged , Betacoronavirus , Clinical Trials, Phase II as Topic , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Interleukin-6/immunology , Male , Middle Aged , Multicenter Studies as Topic , Pandemics , Pneumonia, Viral/immunology , Randomized Controlled Trials as Topic , Respiration, Artificial , Respiratory Distress Syndrome, Adult/immunology , Young Adult
14.
Trials ; 21(1): 934, 2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-934298

ABSTRACT

OBJECTIVES: Zilucoplan (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms that lead to improvement in lung oxygenation parameters. The purpose of this study is to investigate the efficacy and safety of Zilucoplan in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. TRIAL DESIGN: This is a phase 2 academic, prospective, 2:1 randomized, open-label, multi-center interventional study. PARTICIPANTS: Adult patients (≥18y old) will be recruited at specialized COVID-19 units and ICUs at 9 Belgian hospitals. The main eligibility criteria are as follows: 1) Inclusion criteria: a. Recent (≥6 days and ≤16 days) SARS-CoV-2 infection. b. Chest CT scan showing bilateral infiltrates within the last 2 days prior to randomisation. c. Acute hypoxia (defined as PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen). d. Signs of cytokine release syndrome characterized by either high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those. 2) Exclusion criteria: e. Mechanical ventilation for more than 24 hours prior to randomisation. f. Active bacterial or fungal infection. g. History of meningococcal disease (due to the known high predisposition to invasive, often recurrent meningococcal infections of individuals deficient in components of the alternative and terminal complement pathways). INTERVENTION AND COMPARATOR: Patients in the experimental arm will receive daily 32,4 mg Zilucoplan subcutaneously and a daily IV infusion of 2g of the antibiotic ceftriaxone for 14 days (or until hospital discharge, whichever comes first) in addition to standard of care. These patients will receive additional prophylactic antibiotics until 14 days after the last Zilucoplan dose: hospitalized patients will receive a daily IV infusion of 2g of ceftriaxone, discharged patients will switch to daily 500 mg of oral ciprofloxacin. The control group will receive standard of care and a daily IV infusion of 2g of ceftriaxone for 1 week (or until hospital discharge, whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. MAIN OUTCOMES: The primary endpoint is the improvement of oxygenation as measured by mean and/or median change from pre-treatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) in PaO2/FiO2 ratio, P(A-a)O2 gradient and a/A PO2 ratio. (PAO2= Partial alveolar pressure of oxygen, PaO2=partial arterial pressure of oxygen, FiO2=Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 2:1 ratio (Zilucoplan: control). Randomization will be done using an Interactive Web Response System (REDCap). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 81 patients will be enrolled: 54 patients will be randomized to the experimental arm and 27 patients to the control arm. TRIAL STATUS: ZILU-COV protocol Version 4.0 (June 10 2020). Participant recruitment started on June 23 2020 and is ongoing. Given the uncertainty of the pandemic, it is difficult to predict the anticipated end date. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on May 11th, 2020 (ClinicalTrials.gov Identifier: NCT04382755 ) and on EudraCT (Identifier: 2020-002130-33 ). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Complement C5/antagonists & inhibitors , Coronavirus Infections/complications , Hypoxia/drug therapy , Pneumonia, Viral/complications , Respiratory Insufficiency/drug therapy , Acute Disease , Adult , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Belgium/epidemiology , Betacoronavirus/isolation & purification , Case-Control Studies , Ceftriaxone/administration & dosage , Ceftriaxone/therapeutic use , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/drug therapy , Drug Therapy, Combination , Humans , Infusions, Intravenous , Injections, Subcutaneous , Oxygen/blood , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Prospective Studies , Safety , Treatment Outcome
15.
Carbohydr Polym ; 254: 117232, 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-932797

ABSTRACT

The pandemic coronavirus disease 2019 (COVID-19), caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading globally. Clinical observations found that systemic symptoms caused by SARS-CoV-2 infection are attenuated when using the anticoagulant agent heparin, indicating that heparin may play other roles in managing COVID-19, in addition to prevention of pulmonary thrombosis. Several biochemical studies show strong binding of heparin and heparin-like molecules to the Spike protein, which resulted in inhibition of viral infection to cells. The clinical observations and in vitro studies argue for a potential multiple-targeting effects of heparin. However, adverse effects of heparin administration and some of the challenges using heparin therapy for SARS-CoV-2 infection need to be considered. This review discusses the pharmacological mechanisms of heparin regarding its anticoagulant, anti-inflammatory and direct antiviral activities, providing current evidence concerning the effectiveness and safety of heparin therapy for this major public health emergency.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , Heparin/therapeutic use , /drug effects , Animals , Cytokine Release Syndrome/drug therapy , Humans , Pandemics
16.
Theranostics ; 11(1): 316-329, 2021.
Article in English | MEDLINE | ID: covidwho-922935

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Cytokine Release Syndrome/immunology , Cytokines/metabolism , Immunosuppressive Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines/pharmacology , Azetidines/therapeutic use , /immunology , Clinical Trials as Topic , Cytokine Release Syndrome/drug therapy , Cytokines/antagonists & inhibitors , Cytokines/immunology , Humans , Immunosuppressive Agents/pharmacology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Purines/pharmacology , Purines/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , STAT Transcription Factors/antagonists & inhibitors , STAT Transcription Factors/metabolism , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/immunology , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Treatment Outcome
17.
Pharmacol Rep ; 72(6): 1529-1537, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-915270

ABSTRACT

BACKGROUND: This study was aimed to assess the efficacy and safety of tocilizumab (TCZ) and to investigate the factors related to the progress and mortality of patients with a secondary cytokine release syndrome caused by SARS-CoV-2. METHODS: A retrospective descriptive observational study of hospitalised patients with a positive polymerase chain reaction (PCR) result for SARS-CoV-2 and whose clinical evolution required the administration of one or more doses of TCZ was conducted. Demographic variables, clinical evolution, radiologic progress and analytical parameters were analysed on days 1, 3 and 5 after administration the first dose of TCZ. RESULTS: A total of 75 patients with a clinical history of Accurate Respiratory Distress Syndrome (ARDS) were analysed, among whom, 19 had mild ARDS (25.3%), 37 moderate ARDS (49.4%) and 19 severe ARDS (25.3%). Lymphocytopenia and high levels of PCR, D-Dimer and IL-6 were observed in almost all the patients (91.8%). Treatment with TCZ was associated with a reduction of lymphocytopenia, C-reactive protein (CRP) levels, severe ARDS cases and fever. Although a better evolution of PaO2/FiO2 was observed in patients who received two or more doses of TCZ (38/75), there was an increase in their mortality (47.4%) and ICU admission (86.8%). The 30-day mortality rate was 30.7% (20.5-42.4% CI) being hypertension, high initial D-dimer levels and ICU admission the only predictive factors found. CONCLUSION: Based on our results, treatment with TCZ was associated with a fever, swelling and ventilator support improvement. However, there is no evidence that the administration of two or more doses of TCZ was related to a mortality decrease.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Cytokine Release Syndrome/drug therapy , Intensive Care Units/statistics & numerical data , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , /mortality , Cytokine Release Syndrome/mortality , Female , Humans , Male , Middle Aged , Polymerase Chain Reaction , Respiration, Artificial/statistics & numerical data , Retrospective Studies , Severity of Illness Index , Treatment Outcome , Young Adult
18.
Biomedica ; 40(Supl. 2): 80-95, 2020 10 30.
Article in English, Spanish | MEDLINE | ID: covidwho-914749

ABSTRACT

Introduction: Recently, researchers from China and France reported on the effectiveness of chloroquine and hydroxychloroquine for the inhibition of SARS-CoV-2 viral replication in vitro. Timely dissemination of scientific information is key in times of pandemic. A systematic review of the effect and safety of these drugs on COVID-19 is urgently needed. Objective: To map published studies until March 25, 2020, on the use of chloroquine and its derivates in patients with COVID-19. Materials and methods: We searched on PubMed, Embase, Lilacs, and 15 registries from the World Health Organization's International Clinical Trials Registry Platform for theoretical and empirical research in English, Spanish, Italian, French, or Portuguese until March 25, 2020, and made a narrative synthesis of the results. Results: We included 19 records and 24 trial registries (n=43) including 18,059 patients. China registered 66% (16/24) of the trials. Nine trials evaluate chloroquine exclusively and eight hydroxychloroquine. The records are comments (n=9), in vitro studies (n=3), narrative reviews (n=2), clinical guidelines (n=2), as well as a systematic review, an expert consensus, and a clinical trial. Conclusions: One small (n=26), non-randomized, and flawed clinical trial supports hydroxychloroquine use in patients with COVID-19. There is an urgent need for more clinical trial results to determine the effect and safety of chloroquine and hydroxychloroquine on COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Betacoronavirus/physiology , Chloroquine/adverse effects , Chloroquine/pharmacology , Clinical Trials as Topic , Compassionate Use Trials , Cytokine Release Syndrome/drug therapy , Drug Repositioning , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/pharmacology , Multicenter Studies as Topic , Pandemics , Randomized Controlled Trials as Topic , Registries , Treatment Outcome , Virus Replication/drug effects
19.
Front Immunol ; 11: 573179, 2020.
Article in English | MEDLINE | ID: covidwho-909162

ABSTRACT

The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has generated a significant repercussion on the administration of adoptive cell therapies, including chimeric antigen receptor (CAR) T-cells. The closing of borders, the reduction of people transit and the confinement of the population has affected the supply chains of these life-saving medical products. The aim of this mini-review is to focus on how the COVID-19 pandemic has affected CAR T-cell therapy and taking into consideration the differences between the large-scale centralized productions for the pharmaceutical industry versus product manufacturing in the academic/hospital environment. We also review different aspects of CAR T-cell therapy and our managerial experience of patient selection, resource prioritization and some practical aspects to consider for safe administration. Although hospitals have been forced to change their usual workflows to cope with the saturation of health services by hospitalized patients, we recommend centers to continue offering this potentially curative treatment for patients with relapsed/refractory hematologic malignancies. Consequently, we propose appropriate selection criteria, early intervention to attenuate neurotoxicity or cytokine release syndrome with tocilizumab and prophylactic/preventive strategies to prevent infection. These considerations may apply to other emerging adoptive cell treatments and the corresponding manufacturing processes.


Subject(s)
/epidemiology , Immunotherapy, Adoptive/methods , Point-of-Care Systems , Antibodies, Monoclonal, Humanized/therapeutic use , Antigens, CD19/immunology , Cytokine Release Syndrome/drug therapy , Health Services Accessibility , Health Workforce , Hematologic Neoplasms/therapy , Humans , Patient Selection , Triage
20.
Int J Infect Dis ; 101: 59-64, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-905663

ABSTRACT

BACKGROUND: The release of pro-inflammatory cytokines, resulting in cytokine storm syndrome, contributes to the morbidity and mortality associated with COVID-19 disease. This study aimed to compare the effects of intravenous (IV) and subcutaneous (SC) tocilizumab, an IL-6 receptor antagonist, on respiratory parameters and clinical outcome in patients with COVID 19. METHODS: We performed a retrospective cohort study of hospitalized patients with COVID-19 treated with either IV or SC tocilizumab from March 26, 2020, to May 18, 2020. Respiratory parameters seven days after receiving tocilizumab therapy were compared to baseline measurements. All patients were assessed until discharged from the hospital. RESULTS: Tocilizumab was administered to 125 patients: 65 received IV, and 60 received SC therapy. At day seven, 52% of the IV group patients demonstrated improvement in respiratory parameters, compared to 28% in the SC group (P = 0.01). Mortality rates at days seven and 28 were 15% and 37%, respectively, in the IV group and 17% and 50%, respectively, in the SC group (PNS). The in-hospital mortality rate was 38% for the IV group versus 57% for the SC group (P = 0.04). More than 90% of patients in each group received corticosteroids; however, significantly more patients received convalescent plasma in the IV group. CONCLUSIONS: At the doses used in this study, IV tocilizumab is preferred over SC therapy to treat cytokine storm syndrome due to COVID-19.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , /drug therapy , Administration, Intravenous , Adult , Aged , Cytokine Release Syndrome/drug therapy , Female , Hospital Mortality , Humans , Injections, Subcutaneous , Male , Middle Aged , Retrospective Studies
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