ABSTRACT
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.
Subject(s)
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 , Post-Acute COVID-19 SyndromeABSTRACT
Compelling evidence ties heparanase, an endoglycosidase that cleaves heparan sulfate side (HS) chains of proteoglycans, with all steps of tumor development, including tumor initiation, angiogenesis, growth, metastasis, and chemoresistance. Moreover, heparanase levels correlate with shorter postoperative survival of cancer patients, encouraging the development of heparanase inhibitors as anti-cancer drugs. Heparanase-inhibiting heparin/heparan sulfate-mimicking compounds and neutralizing antibodies are highly effective in animal models of cancer progression, yet none of the compounds reached the stage of approval for clinical use. The present study focused on newly synthesized triazolo-thiadiazoles, of which compound 4-iodo-2-(3-(p-tolyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenol (4-MMI) was identified as a potent inhibitor of heparanase enzymatic activity, cell invasion, experimental metastasis, and tumor growth in mouse models. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with small molecules that inhibit heparanase enzymatic activity. This result encourages the optimization of 4-MMI for preclinical and clinical studies primarily in cancer but also other indications (i.e., colitis, pancreatitis, diabetic nephropathy, tissue fibrosis) involving heparanase, including viral infection and COVID-19.
Subject(s)
COVID-19/complications , Endothelial Cells/virology , Endothelium, Vascular/virology , Pandemics , SARS-CoV-2/pathogenicity , Vasculitis/etiology , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/physiopathology , Anticoagulants/therapeutic use , Apoptosis , Bone Marrow Transplantation/adverse effects , COVID-19/epidemiology , Endothelial Cells/pathology , Glucuronidase/antagonists & inhibitors , Graft vs Host Disease/etiology , Graft vs Host Disease/physiopathology , Heparin/therapeutic use , Hepatic Veno-Occlusive Disease/etiology , Hepatic Veno-Occlusive Disease/physiopathology , Humans , Idiopathic Interstitial Pneumonias/etiology , Idiopathic Interstitial Pneumonias/physiopathology , Interleukin-6/physiology , Multiple Organ Failure/etiology , Multiple Organ Failure/physiopathology , Organ Specificity , Polydeoxyribonucleotides/therapeutic use , SARS-CoV-2/isolation & purification , Stem Cell Transplantation/adverse effects , Thrombophilia/drug therapy , Thrombophilia/etiology , Thrombotic Microangiopathies/etiology , Thrombotic Microangiopathies/physiopathology , Vasculitis/drug therapy , Vasculitis/virology , Viral TropismABSTRACT
On March 11, 2020, the World Health Organization declared its assessment of coronavirus disease 2019 (COVID-19) as a global pandemic. However, specific anti-severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) drugs are still under development, and patients are managed by multiple complementary treatments. We performed a retrospective analysis to compare and evaluate the effect of low molecular weight heparin (LMWH) treatment on disease progression. For this purpose, the clinical records and laboratory indicators were extracted from electronic medical records of 42 patients with COVID-19 (21 of whom were treated with LMWH, and 21 without LMWH) hospitalized (Union Hospital of Huazhong University of Science and Technology) from February 1 to March 15, 2020. Changes in the percentage of lymphocytes before and after LMWH treatment were significantly different from those in the control group (P = 0.011). Likewise, changes in the levels of D-dimer and fibrinogen degradation products in the LMWH group before and after treatment were significantly different from those in the control group (P = 0.035). Remarkably, IL-6 levels were significantly reduced after LMWH treatment (P = 0.006), indicating that, besides other beneficial properties, LMWH may exert an anti-inflammatory effect and attenuate in part the "cytokine storm" induced by the virus. Our results support the use of LMWH as a potential therapeutic drug for the treatment of COVID-19, paving the way for a subsequent well-controlled clinical study.