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The effect of defibrotide on thromboembolism in the pulmonary vasculature of mice and rabbits and in the cerebral vasculature of rabbits
Author(s) -
Paul W.,
Gresele P.,
Momi S.,
Bianchi G.,
Page C.P.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb14002.x
Subject(s) - defibrotide , thrombin , platelet , bolus (digestion) , medicine , pharmacology , nitric oxide synthase , endocrinology , nitric oxide , anesthesia , chemistry , transplantation , hematopoietic stem cell transplantation
1 Administration of bovine thrombin (100 u kg −1 ) into the carotid artery of rabbits induces a sustained accumulation of 111 Indium‐labelled platelets within the cranial vasculature over the subsequent 3 h. 2 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. 3 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. 4 Intravenous administration of the nitric oxide (NO)‐synthase inhibitor N G ‐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.). 5 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. 6 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.). 7 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. 8 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.