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1.
Bone Marrow Transplant ; 56(12): 2889-2896, 2021 12.
Статья в английский | MEDLINE | ID: covidwho-1956396

Реферат

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), a potentially life-threatening complication of hematopoietic cell transplantation (HCT), results from prolonged sinusoidal endothelial cell activation and profound endothelial cell damage, with sequelae. Defibrotide, the only drug approved in the United States and Europe for treating VOD/SOS post-HCT, has European Commission orphan drug designation for preventing graft-versus-host disease (GvHD), associated with endothelial dysfunction. This endothelial cell protector and stabilizing agent restores thrombo-fibrinolytic balance and preserves endothelial homeostasis through antithrombotic, fibrinolytic, anti-inflammatory, anti-oxidative, and anti-adhesive activity. Defibrotide also preserves endothelial cell structure by inhibiting heparanase activity. Evidence suggests that downregulating p38 mitogen-activated protein kinase (MAPK) and histone deacetylases (HDACs) is key to defibrotide's endothelial protective effects; phosphatidylinositol 3-kinase/Akt (PI3K/AKT) potentially links defibrotide interaction with the endothelial cell membrane and downstream effects. Despite defibrotide's being most extensively studied in VOD/SOS, emerging preclinical and clinical data support defibrotide for treating or preventing other conditions driven by endothelial cell activation, dysfunction, and/or damage, such as GvHD, transplant-associated thrombotic microangiopathy, or chimeric antigen receptor T-cell (CAR-T) therapy-associated neurotoxicity, underpinned by cytokine release syndrome and endotheliitis. Further preclinical and clinical studies will explore defibrotide's potential utility in a broader range of disorders resulting from endothelial cell activation and dysfunction.


Тема - темы
Hematopoietic Stem Cell Transplantation , Hepatic Veno-Occlusive Disease , Hematopoietic Stem Cell Transplantation/adverse effects , Hepatic Veno-Occlusive Disease/drug therapy , Hepatic Veno-Occlusive Disease/etiology , Hepatic Veno-Occlusive Disease/prevention & control , Humans , Phosphatidylinositol 3-Kinases/therapeutic use , Polydeoxyribonucleotides/pharmacology , Polydeoxyribonucleotides/therapeutic use
2.
JCI Insight ; 6(17)2021 09 08.
Статья в английский | MEDLINE | ID: covidwho-1413722

Реферат

Neutrophil-mediated activation and injury of the endothelium play roles in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap-derived [NET-derived] histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the US Food and Drug Administration-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.


Тема - темы
Fibrinolytic Agents/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Polydeoxyribonucleotides/pharmacology , Thrombosis/drug therapy , Animals , Extracellular Traps/drug effects , Extracellular Traps/metabolism , Fibrinolytic Agents/therapeutic use , Histones/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Polydeoxyribonucleotides/therapeutic use , Pyroptosis
3.
Expert Opin Ther Targets ; 25(6): 423-433, 2021 06.
Статья в английский | MEDLINE | ID: covidwho-1281815

Реферат

INTRODUCTION: Defibrotide (DF) is a polyribonucleotide with antithrombotic, pro-fibrinolytic, and anti-inflammatory effects on endothelium. These effects and the established safety of DF present DF as a strong candidate to treat viral and post-infectious syndromes involving endothelial dysfunction. AREAS COVERED: We discuss DF and other therapeutic agents that have the potential to target endothelial components of pathogenesis in viral and post-infectious syndromes. We introduce defibrotide (DF), describe its mechanisms of action, and explore its established pleiotropic effects on the endothelium. We describe the established pathophysiology of Coronavirus Disease 2019 (COVID-19) and highlight the processes specific to COVID-19 potentially modulated by DF. We also present influenza A and viral hemorrhagic fevers, especially those caused by hantavirus, Ebola virus, and dengue virus, as viral syndromes in which DF might serve therapeutic benefit. Finally, we offer our opinion on novel treatment strategies targeting endothelial dysfunction in viral infections and their severe manifestations. EXPERT OPINION: Given the critical role of endothelial dysfunction in numerous infectious syndromes, in particular COVID-19, therapeutic pharmacology for these conditions should increasingly prioritize endothelial stabilization. Several agents with endothelial protective properties should be further studied as treatments for severe viral infections and vasculitides, especially where other therapeutic modalities have failed.


Тема - темы
COVID-19/complications , Endothelium, Vascular/drug effects , Polydeoxyribonucleotides/pharmacology , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/etiology , COVID-19/physiopathology , COVID-19/virology , Endothelium, Vascular/physiopathology , Humans , Polydeoxyribonucleotides/therapeutic use , SARS-CoV-2/isolation & purification
4.
Br J Haematol ; 193(1): 43-51, 2021 04.
Статья в английский | MEDLINE | ID: covidwho-1066629
6.
J Pediatric Infect Dis Soc ; 9(5): 622-625, 2020 Nov 10.
Статья в английский | MEDLINE | ID: covidwho-919277

Реферат

The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, we treated 2 patients with defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved during treatment. Moreover, coagulation parameters indicating hypofibrinolysis and complement activation normalized. The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, 2 patients received defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved and hypofibrinolysis/complement activation normalized during treatment.


Тема - темы
Coronavirus Infections/complications , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/complications , Polydeoxyribonucleotides/therapeutic use , Systemic Inflammatory Response Syndrome/drug therapy , Abdominal Pain/etiology , Adolescent , Betacoronavirus , Blood Coagulation Factors/analysis , COVID-19 , Child , Coronavirus Infections/diagnosis , Female , Fever/etiology , Humans , Pandemics , Pneumonia, Viral/diagnosis , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology
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