Defibrotide: potential for treating endothelial dysfunction related to viral and post-infectious syndromes, 2021, Richardson et al

[SNT Gatchaman]

Defibrotide: potential for treating endothelial dysfunction related to viral and post-infectious syndromes
Edward Richardson, David García-Bernal, Eleonora Calabretta, Rubén Jara, Marta Palomo, Rebecca M Baron, Gregory Yanik, Jawed Fareed, Israel Vlodavsky, Massimo Iacobelli, Maribel Díaz-Ricart, Paul G Richardson, Carmelo Carlo-Stella, Jose M Moraleda

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.

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[SNT Gatchaman]

See also —

• The importance of endothelial protection: the emerging role of defibrotide in reversing endothelial injury and its sequelae (2021)
• Defibrotide (2016)

 

[SNT Gatchaman]

Sounds potentially useful for the immunothrombotic dysregulation being suggested as part of the long COVID phenotype —

DF has pleiotropic properties, including anti-thrombotic, pro-fibrinolytic, anti-inflammatory, and protective effects on vascular endothelia

With inhibition of macropinocytosis, however, the effects of DF on intracellular signaling are preserved, suggesting that DF can exert effects on the endothelial cell from the cell surface. This interaction impacts multiple-signaling cascades within ECs, including reductions of both the p38/MAPK pathway and the PI3K/Akt pathway.

Treatment with DF normalized the overexpression of HDAC1 in a dose-dependent manner in human umbilical cord vein endothelial cells exposed to sera of patients with chronic kidney disease, a condition associated with endothelial dysfunction [...] defibrotide inhibited the expression of ROS, ICAM-1, vWF, and Toll-like receptor 4 to levels consistent with normal endothelial function

decreases the expression of endothelial cell adhesion molecules critical to leukocyte transmigration and platelet activation, such as P-selectin, E-selectin, VCAM-1, and ICAM-1

DF directly increases cyclic adenosine monophosphate production in platelets

increases the expression of thrombomodulin, tissue plasminogen activator (t-PA), tissue factor pathway inhibitor, prostaglandin E2, prostaglandin I2, and protein C plasmin activity

simultaneously decreasing thromboxane A2, leukotriene B4, von Willebrand factor (VWF), plasminogen activator inhibitor-1 (PAI-1), platelet activating factor, and thrombin

decreases leukocyte and platelet aggregates in thrombi and attenuates the complement activation

 

[SNT Gatchaman]

Note that when used to rescue hepatic sinusoidal obstruction syndrome / veno-occlusive disease, 2-hour infusions every six hours, for up to 21 days are required. I do not know if there could even be a vague prospect of a low dose IV or alternative parenteral regimen. And of course no-one knows if reversing the hypercoagulable state and endothelial dysfunction would be sufficiently upstream to arrest the disease. It might just start up again under the influence of viral remnants, reactivation etc.

 

[Jonathan Edwards]

I find it hard to take this seriously. Why would a piece like this have 14 authors scattered across the globe if they were not all chums of the people at the biotech startup in Milan (Techitra)?

When you see people justifying a drug using words like 'dysfunction' and then giving 173 different possibly relevant pathways it is time to be sceptical. Effective drugs are justified by hard data relating to a single mechanism on the whole.

The existence of a journal called expert opinion in therapeutic targets is a bit of joke anyway.

 

[SNT Gatchaman]

See also in vitro study in acute covid and thrombotic microangiopathies: Defibrotide mitigates endothelial cell injury induced by plasmas from patients with COVID-19 and related vasculopathies (2023, Thrombosis Research)