Effect of defibrotide on platelet function.

Defibrotide, a polydeoxyribonucleotide, has been found to modulate endothelial cell function, causing an increase in tissue plasminogen activator (t-PA) levels, a decrease in plasminogen activator inhibitor (PAI) levels, and an increase in prostaglandin I2 (PGI2) formation in humans. Defibrotide has no direct anticoagulant effect but has a synergistic action with heparin. A strong antithrombotic effect has been observed in animal models. Thus, defibrotide has a beneficial effect in cases of deep venous thrombosis (DVT), peripheral obliterative vascular disorder (POVD), stroke, vasculitis, and thromboembolism. Defibrotide also inhibits platelet function and activation. A significant decrease in platelet aggregate formation on the suture line in microarterial anastomosis in rats is one way defibrotide can inhibit platelet function and activation. In humans, a slight prolongation' of the lag period in collagen-induced aggregation has been observed. In addition, a slight decrease in the maximum amplitude of the secondary wave of ADP and adrenalin-induced aggregations was also found. Platelet adhesion is diminished, the platelet differential count on formvar membrane is altered, and platelet aggregate formation is significantly inhibited. With an increase in platelet cyclic AMP (cAMP) content and a decrease in malonyl dialdehyde (MDA) and thromboxane B2 (TXB2) formation, the levels of platelet secretion products such as PF-4 and beta-thromboglobulin (beta-TG) in plasma decreased progressively. It was also demonstrated that the 14C-glucose transport defect of the platelet membrane of atherosclerotic patients was partially corrected with defibrotide treatment.

The pharmacology and clinical pharmacology of defibrotide: a new profibrinolytic, antithrombotic and anti-platelet substance.

Defibrotide, a deoxypolyribonuclide, has been found to modulate endothelial cell function causing increase in t-PA and decrease in PAI levels and also increase in PGI2 production. In addition, it increases platelet c-AMP levels and decreases MDA and TXB2 formation in human. Defibrotide inhibits platelet aggregate formation in vitro experiments as well as end-to-end anostomosis in rats. So, defibrotide inhibits the activation of platelets. Besides an increase of protein C and S levels a synergic action of heparin was observed in animal experiments. A strong antithrombotic effect has been observed in animal models. The drug has a beneficial effect in the cases of DVT, POVD, stroke and thromboembolism. Through its action we may say that the drug acts in a novel fashion in contrast to the other drugs used in this area. Defibrotide is a single-stranded polydeoxyribonucleotide obtained from deoxyribonucleic acid of mammalian lungs by controlled depolimerization. Since 1981 in our laboratory and in the clinical department we have been investigating a newly developed agent defibrotide in vitro experiments, animal experiments, and also its clinical pharmacology and clinical application. Some of our findings are already published and compared with literature (40, 43, 46). Because of the limited space we are not going to review the literature in detail but we are going to summarize our observations on this compound in the following order. I--in vitro experiments, II--Animal experiments, III--clinical pharmacology in human.

Clinical pharmacology and mode of action of a new antithrombotic compound: Defibrotide.

Defibrotide is a derivative of polydeoxyribonucleotide extracted from bovine lung. Defibrotide has been found to modulate endothelial cell function causing increase in t-PA production and release with correction the defect in Cuff test in vascular disorders. Defibrotide causes a significant elevation in the PGI2 formation. In addition increase of platelet c-AMP levels with a decrease of MDA and TXA2 formation has been shown in human subjects. Defibrotide causes an inhibition of platelet activation were demonstrated with surface activation method as well ultrastructurally. Besides, an increase of protein C and FV were observed, a synergic action with heparin was observed. A strong antithrombotic effect has been shown in animal models and unlike most antithrombotic drugs defibrotide did not cause any effect of clotting tests in animals and human subjects. All findings support our earlier suggestion that defibrotide mainly acts via the modulation of endothelial cell function and acts as a novel fashion in contrast to the other drugs used in this area.

In vivo effects of defibrotide on platelet c-AMP and blood prostanoid levels.

Patients were treated with defibrotide (3 X 200 mg/day) for 7 days. Plasma PGI2 and TXB2 levels were measured by RIA using EDTA-aspisol as anticoagulant and cyclooxygenase inhibitor. Isolated platelet c-AMP levels were also determined by RIA, using EDTA-dipyridamole as anticoagulant and phosphodiesterase inhibitor. Blood PGI2 levels were found to increase significantly upon treatment while the increase in TXB2 levels was not significant. Blood PGI2/TXB2 ratio increased 51%, 30 min after intravenous injection and it remained 28% higher during therapy than the predrug blood level. Significantly higher platelet c-AMP levels were also obtained after the injection of drug (0.02 less than p less than 0.05).

Alteration of prostanoids in atherosclerosis.

We have briefly summarized only the data obtained in our own laboratory without including an extensive literature review. We have evaluated the changes in platelet membrane phospholipids and prostanoid formation in platelets. In atherosclerosis platelets show an activated prostanoid formation, whereas the plasma PGI2 levels are decreased.