ISSN:1424-8832    

DOI:10.1159/000215330

出版商:S. Karger AG    

年代:1986

数据来源: Karger

摘要:

Defibrotide (D) is a polydeoxyribonucleotide of mammalian origin that has no anticoagulant activity or hemodynamic effects but has considerable profibrinolytic and antithrombotic activities under several experimental conditions. In this paper the dynamics of D’s antithrombotic effects after oral administration and D’s thrombolystic activity after intravemous infusion on venous collagen-induced thrombosis in the rabbit are reported. D administered orally (12.5, 25 or 50 mg kg-1), from 0 to 360 min before thrombus induction, was able to impede thrombus formation in the first 2 h of growth. There is a linear correlation between the dose of D and peak activity and a correlation, described by a power function, between the dose and the area under the experimental inhibition curve. D infused intravenously (20, 31.7 or 50 mg kg-1 h-1 × 6 h) into rabbits with 24-hour-old thrombi, had significant and impressive dose-related thrombolytic activity. There is a direct relationship between the thrombolytic effect and plasma levels. In this experimental model, urokinase infused intravenously (750, 1,500 or 3,000 IU kg–1 h–1) had the same thrombolytic activity as D; heparin (76 IU kg–1 h–1) was completely ineffective and PGI2 showed a modest activity at 60 nmol kg–1 h–1. The antithrombotic and thrombolytic activities of D may be partly due to its ability to promote release of plasminogen activator factor and of prostacyclin from

ISSN:1424-8832    

DOI:10.1159/000215331

出版商:S. Karger AG    

年代:1986

数据来源: Karger

摘要:

The use of the Baumgartner perfusion system allows the morphometric quantification of platelets interacting with vessel wall, however it presents the basic difficulties of morphometrical measurements. In order to facilitate the procedure of evaluation we developed a semiautomated method to avoid the complexity of the classical evaluation. Our system consists on an optical picture analysis system connected with a specially developed computer program which allows fast quantification. Simultaneously to the outlining of interacting platelets the computer program recognizes, corrects, selects and stores the information, in order to perform the final calculations as previously established. This system has been demonstrated to be as effective as the classical morphometric evaluation in the measure of platelets interacting with subendothelium. Potential sources of error such as subjectivity of the observers in selecting the class of interacting platelets are avoided. The use of this combined method opens the possibility to adapt the Baumgartner perfusion system to clinical routine and to the screening of drugs that modify platelet adherence.

ISSN:1424-8832    

DOI:10.1159/000215263

出版商:S. Karger AG    

年代:1986

数据来源: Karger

摘要:

Thrombi were electrically induced in dogs. The alterations of the vessel wall were studied in samples obtained on the 8th day from control and treated animals. Changes in coagulation parameters were monitored daily. Animals were treated with 600 mg defibrotide (Crinos) daily for a week, starting 24 h after the induction of thrombi. In the control dogs there was thickening of intima with endothelial hyperplasia and smooth muscle proliferation. The treated animals did not show any morphological or ultrastructural alterations (SEM). This observation encourages us to examine the role of fibrinolytic and endothelial supportive therapy for prevention of development of vascular changes.

ISSN:1424-8832    

DOI:10.1159/000215332

出版商:S. Karger AG    

年代:1986

数据来源: Karger

摘要:

Defibrotide is a polydeoxyribonucleotide of mammalian origin which possesses profibrinolytic effect and PGI2-releasing capacity. Because of these properties, defibrotide has antithrombotic effects which are demonstrated in various experimental models of venous and arterial thrombosis.The present study indicates that defibrotide clearly protects against myocardial damage in the rabbit 3 days after total coronary artery occlusion. Furthermore, defibrotide prevents the decline of β-adrenergic receptor function, a phenomenon related to excessive circulating catecholamines that occurs during the myocardial infarct. Defibrotide prevents the dramatic fall of creatine phosphokinase activity in the ischemic ventricle: metabolic changes which reflect changes in the cells affected by prolonged ischemia. Assumptions about the mode of action of defibrotide are given particularly in consideration of the interaction between the fibrinolytic activity and the PGI2-releasing capacity of this substance

ISSN:1424-8832    

DOI:10.1159/000215334

出版商:S. Karger AG    

年代:1986

数据来源: Karger

摘要:

Desamino-D-arginine vasopressin (DDAVP) is known to stimulate factor VIII (FVIII) and plasminogen activator release from endothelial cells, and has been shown to stimulate prostacyclin (PGI2) production in normal and haemophilic subjects. In von Willebrand’s disease (vWd) some patients have a dissociate response with regard to FVIII and plasminogen activator. The aim of our study was to compare the PGI2, FVIII and plasminogen activator response to DDAVP infusion in vWd with the response to DDAVP in normal and haemophilic subjects. PGI2 metabolites thromboxane B2 (TxB2), factor VIII coagulant activity, factor VIII-related antigen and plasminogen activator were measured before and after DDAVP infusion. There was a significant increase in PGI2 metabolites, factor VIII-related antigen and plasminogen activator in all groups following DDAVP, but no effect on TxB2 was found, and there was no evidence of any dissociate response to DDAVP in any of the groups. Basal levels of PGI2 metabolites, however, were significantly lower in vWd as compared to normal and haemophilic subjects. Post-DDAVP levels of PGI2 metabolites were also significantly lower in vWd as compared with normal subjects. This may be due to a reduced stimulus to PGI2 production in vWd secondary to defective platelet adhesio

ISSN:1424-8832    

DOI:10.1159/000215264

出版商:S. Karger AG    

年代:1986

数据来源: Karger

摘要:

We evaluated the effects of defibrotide (D), a natural profibrinolytic and anti-thrombotic agent with endogenous PGl2-stimulating properties, on acute lethal and nonlethal myocardial ischemia (L-AMI and NL-AMI) in the cat. The coronary artery was occluded at 12–14 mm from its origin. In L-AMI, 12 of 15 control cats developed ventricular fibrillation and died; D (32 mg kg-1, bolus intravenously plus infusion) provided total protection against death and showed protective effects on plasma and myocardial creatine phosphokinase (CPK), hemodynamics and ECG. In NL-AMI, pretreatment of cats with D at the same dosage (intravenous infusion) reduced AMI-ST segment increases and AMI changes in hemodynamics. AMI-induced changes in lactate adenosine triphosphate and CPK in ischemic tissues were prevented by D. The beneficial effects of D in NL-AMI could be partly attributed to its stimulatory effect on vascular PGI2 release; the mechanism of the impressive protection by D observed in L-AMI has still to be elucidate

ISSN:1424-8832    

DOI:10.1159/000215335

出版商:S. Karger AG    

年代:1986

数据来源: Karger

摘要:

ZK 36374 (Iloprost), a stable prostacyclin analogue, was administered to 6 healthy volunteers for 2-hour periods, with dose rates increasing from 0.5 to 2 ng/kg/min within that time. At these doses, which did not give troublesome side effects clinically, there was significant inhibition of ex vivo platelet aggregation responses to ADP and collagen. There was some rebound platelet hyperaggregability in all subjects, occurring between 1 and 2 h after termination of the infusion; this was of minor degree and was not associated with any clinical problems.

ISSN:1424-8832    

DOI:10.1159/000215265

出版商:S. Karger AG    

年代:1986

数据来源: Karger

摘要:

A pharmacokinetic study of defibrotide, an antithrombotic polydeoxyribonucleotide extract, was performed in 5 healthy volunteers after rapid intravenous injection at three different doses: 0.5, 4 and 16 mg/kg. Defibrotide was given to 2 additional healthy volunteers by slow perfusion of 600 mg over 6 h, after a 200-mg intravenous bolus injection. The blood levels of defibrotide were determined by a method supplied by Crinos (detection of 6-desoxyribose). A one-compartment model was used to describe the kinetics of the drug in plasma. All the most important pharmacokinetic parameters (i.e. elimination constant, half-life, AUC and volume of distribution) were dose dependent. The half-lives were 9.8 min at 0.5 mg/kg, 14.2 min at 4 mg/kg and 21.1 min at 16 mg/kg. The dose-response curves for elimination indicated saturation. During slow infusion following the bolus injection a steady state was reached at 90–120 min, with a blood level of 10–15 μ

ISSN:1424-8832    

DOI:10.1159/000215336

出版商:S. Karger AG    

年代:1986

数据来源: Karger

摘要:

Platelets from 6 out of 10 patients with myeloproliferative disorders showed only a single reversible wave of aggregation when challenged with platelet activating factor (PAF). Preexposure to subthreshold concentrations of adrenaline resulted in a full irreversible response to PAF. Aspirin, however, removed this synergism. In the remaining 4 patients, PAF induced a full response but aspirin abolished the synergism with adrenaline in 2 of them. In platelets from all controls aspirin failed to abolish the synergism between PAF and adrenaline. It is suggested that patients with myeloproliferative disorders lack – to varying degrees -an aspirin-independent mechanism which amplifies the primary response to PAF. Such a mechanism could involve the products of arachidonic acid metabolism catalyzed by lipoxygenas

ISSN:1424-8832    

DOI:10.1159/000215266

出版商:S. Karger AG    

年代:1986

数据来源: Karger