Thrombolytic activity of defibrotide: A morphometric evaluation in experimental venous thrombosis

Fumagalli, Guido Francesco; Sala, Carlo; Angelaccio, Erenia; Lombardo, Nunzio; Clementi, Francesco

doi:10.1016/s1043-6618(89)80007-6

Cited by 11 publications

(10 citation statements)

References 10 publications

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“…Interestingly, the aggregation of platelets within the pulmonary (but not the cerebral) circulation could be increased by pretreating animals with N0-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO)-synthase (May et al, 1991), suggesting that the control of the interaction of blood elements with the vessel wall may vary in different vascular beds. While established fibrinolytic agents such as urokinase, eminase or recombinant tissue-plasminogen activator (rt-PA) could effectively reverse thrombin-induced embolisation within the cerebral vasculature, defibrotide only weakly affected this response (May et al, 1992), an observation which conflicted with previously reported data showing that defibrotide was able to reduce the size of pre-formed thrombi (Fumagalli et al, 1989). The reason for this discrepancy is not clear and remains to be explained.…”

Section: Introducdonmentioning

confidence: 78%

The effect of defibrotide on thromboembolism in the pulmonary vasculature of mice and rabbits and in the cerebral vasculature of rabbits

Paul

Gresele

Momi

et al. 1993

British J Pharmacology

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Administration of bovine thrombin (100 u kg−1) into the carotid artery of rabbits induces a sustained accumulation of 111Indium‐labelled platelets within the cranial vasculature over the subsequent 3 h. Intracarotid (i.c.) administration of defibrotide (64 mg kg−1 bolus plus 64 mg kg−1 h−1 for 1 h) prior to i.c. thrombin (100 u kg−1) significantly reduces the ability of thrombin to induce cranial thromboembolism in rabbits. Intravenous (i.v.) administration of thrombin (20 u kg−1) in rabbits induces a reversible accumulation of radiolabelled platelets into the thoracic circulation which is significantly reduced by i.v. administration of defibrotide (64 mg kg−1 bolus plus 64 mg kg−1 h−1 for 1 h) prior to i.v. thrombin. In contrast, platelet accumulation in response to adenosine diphosphate (ADP; 20 μg kg−1, i.v.) or platelet activating factor (PAF; 50 ng kg−1, i.v.) is not significantly affected by this treatment. Intravenous administration of the nitric oxide (NO)‐synthase inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME; 10 mg kg−1) potentiates platelet accumulation induced by low dose thrombin (10 u kg−1, i.v.) within the pulmonary vasculature of rabbits. The potentiated response is significantly abrogated following pretreatment with defibrotide (64 mg kg−1 bolus plus 64 mg kg−1 h−1 for 1 h, i.v.). Intravenous injection of human thrombin (1250 u kg−1) to mice induces death within the majority of animals which is significantly reduced by pretreatment with defibrotide (150–175 mg kg−1, i.v.). In contrast, death induced by i.v. collagen (1.25 mg kg−1) plus adrenaline (75 μg kg−1) is not significantly affected by defibrotide pretreatment. The inhibitory effect of defibrotide in mice is abolished following concomitant treatment with the inhibitor of fribrinolysis, tranexamic acid (100 mg kg−1, i.v.), but is unaffected following treatment with the cyclo‐oxygenase inhibitor, aspirin (300 mg kg−1, i.p.). The protective effect of defibrotide against thrombin‐induced thromboembolism in the mouse is potentiated by recombinant tissue‐plasminogen activator (rt‐PA; 1 mg kg−1, i.v.) or unfractionated heparin (10 u kg−1, i.v.) administration. The results suggest that defibrotide may possess antithrombotic activity on thrombin‐induced thromboembolism which, at least in the mouse, may be partially mediated via induction of the fibrinolytic pathway.

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Section: Introducdonmentioning

confidence: 78%

The effect of defibrotide on thromboembolism in the pulmonary vasculature of mice and rabbits and in the cerebral vasculature of rabbits

Paul

Gresele

Momi

et al. 1993

British J Pharmacology

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“…In the first 100 days after transplantation, [3][4][5]. The inflammatory stress induced by a conditioning regimen via interleukin (IL)-1 and tumor necrosis factor alpha (TNFa) cytokines plays a major role in this process [6].…”

Section: Discussionmentioning

confidence: 99%

Does Defibrotide Induce a Delay to Polymorphonuclear Neutrophil Engraftment After Hematopoietic Stem Cell Transplantation? Observation in a Pediatric Population

et al. 2015

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“…DFT has antithrombotic-thrombolytic activity in several different experimental models (28,29,30,34,41,53,57,62,64,78). DFT increases thrombomodulin (TM) (82), protein C (4), t-PA (42,44,45), Tissue Factor Pathway Inhibitor (TFPI) (52), PGI 2 (8,9,35,48), PGI 2 receptors on the surface of platelets and their affinity for PGI 2 (49), production of NO (50) and NOS activity, and NOS protein (36).…”

Section: Change In Phenotype From Antithrombotic To Prothromboticmentioning

confidence: 99%

Defibrotide and Endothelial Cell Activation

Pescador¹,

Porta²,

Ferro³

2000

Cardiovascular Drug Reviews

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Defibrotide has several activities [profibrinolytic, antithrombotic-thrombolytic, antiischemic (heart, liver, kidney, skin, brain), antishock, antiatherosclerotic, and antirejection]. This host of activities has puzzled several people accustomed to the concept: one drug -one activity. But, if you see defibrotide as an antiendothelial cell activation drug, each piece of the puzzle will neatly fit into its right place and the host of activities becomes an array of activities. In fact the polyhedric inflammatory process is the common background of seemingly different illnesses, both acute and chronic. So the old concept of one drug-one activity proves true; one drug: defibrotide -one activity; antiendothelial cell activation activity.

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Thrombolytic activity of defibrotide: A morphometric evaluation in experimental venous thrombosis

Cited by 11 publications

References 10 publications

The effect of defibrotide on thromboembolism in the pulmonary vasculature of mice and rabbits and in the cerebral vasculature of rabbits

The effect of defibrotide on thromboembolism in the pulmonary vasculature of mice and rabbits and in the cerebral vasculature of rabbits

Does Defibrotide Induce a Delay to Polymorphonuclear Neutrophil Engraftment After Hematopoietic Stem Cell Transplantation? Observation in a Pediatric Population

Defibrotide and Endothelial Cell Activation

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