A novel insight into the mechanism of the antithrombotic action of defibrotide.
Defibrotide is a polydeoxyribonucleotide sodium salt with antithrombotic properties. These properties have been attributed to its profibrinolytic activity [increase of tissue plasminogen activator (t-PA) activity, concomitant decrease of that of plasminogen activator inhibitor (PAI)], but there could conceivably be other factor(s). To look for these, we studied Defibrotide in a thrombosis model (pulmonary thromboembolism in mice) in which free radicals play a pivotal role. Defibrotide was found to be active after both intravenous and oral administration. Defibrotide behaved in vitro like a scavenger of H2O2 but not of O2.- in cell-free systems. Defibrotide added in vitro to cellular systems decreased the stimulated release of beta-glucuronidase from polymorphonuclear cells (PMNs), the luminol chemiluminescence induced by oxygen species generated by stimulated PMNs and the generation of O2.- from stimulated macrophages. We think that the antithrombotic activity of Defibrotide is based on other factor(s) in addition to profibrinolytic activity, i.e., some scavenger activity and desensitization of cells involved in thrombus formation must also be taken into account.
Tettamanti
R
R
Crinos Biological Research Laboratories, Villa Guardia, Italy.
Bianchi
G
G
Vitte
P A
PA
Kato
G
G
Porta
R
R
Thiemermann
C
C
Pescador
R
R
Mantovani
M
M
D000818:Animals; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005966:Glucuronidase / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D011655:Pulmonary Embolism / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; D013481:Superoxides; C036901:defibrotide; D006861:Hydrogen Peroxide; D005966:Glucuronidase