defibrotide and Coronary-Disease

Defibrotide has been evaluated in patients with peripheral arterial disease (PAD) of the lower limbs, with coronary artery disease (CAD), and with Raynaud's phenomenon (RP). In PAD patients, defibrotide improved physical performance, restored deficient fibrinolysis, and affected rheology and blood flow. Further events-oriented trials are needed. For CAD patients, defibrotide could be applicable as an adjunct treatment following thrombolysis, instead of heparin. Defibrotide does not increase bleeding risk. There is a need to study other medications together with defibrotide for their synergistic effects. In patients with RP, defibrotide restored deficient fibrinolysis, but its true clinical potential needs to be assessed.

Topics: Antifibrinolytic Agents; Clinical Trials as Topic; Coronary Disease; Humans; Peripheral Vascular Diseases; Polydeoxyribonucleotides; Raynaud Disease; Vascular Diseases

Topics: Animals; Cats; Coronary Circulation; Coronary Disease; Fibrinolytic Agents; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Polydeoxyribonucleotides; Prostaglandins; Rabbits; Species Specificity; Swine; Ventricular Fibrillation

Defibrotide, a polydeoxyribonucleotide of mammalian origin, has been shown to reduce the blood level of the plasminogen activator inhibitor, and so to increase the activity of tissue plasminogen activator without any adverse effect. A randomized, double-blind, placebo-controlled study has been done in 22 patients, 14 with peripheral vascular disease, 6 with coronary heart disease and 2 with cerebrovascular disease. Patients were given defibrotide 400 mg b.d. or identical placebo for 30 days and the parameters of fibrinolysis were evaluated before and after the treatment. A significant increase in tissue plasminogen activator activity at rest and after venostasis was observed after defibrotide; tissue plasminogen activator antigen at rest and after venostasis was not affected by either treatment. Defibrotide significantly reduced plasminogen activator inhibitor activity and antigen at rest. Only one patient complained of gastric pain after placebo treatment. The study shows that defibrotide has profibrinolytic property and that it could be used to explore the role of plasminogen activator inhibitor in venous and arterial thrombosis.

Topics: Administration, Oral; Aged; Blood Coagulation Tests; Cerebrovascular Disorders; Coronary Disease; Double-Blind Method; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Plasminogen Inactivators; Polydeoxyribonucleotides; Tissue Plasminogen Activator

Topics: Blood Coagulation; Coronary Disease; Creatine Kinase; Drug Evaluation; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Myocardial Infarction; Pilot Projects; Polydeoxyribonucleotides

Defibrotide (D), a polydeoxyribonucleotide obtained from mammalian lungs, reduced the ischemic contracture due to low perfusion (0.2 ml/min) of the isovolumic left heart of the rabbit and abolished the irregularity of the rhythm of the heart, thereby restoring the cardiomechanical activity upon reperfusion (20 ml/min). D stimulated the release of PG-like material. Indomethacin infusion completely prevented both the antiischemic activity of D and its ability to increase the generation of prostaglandins in the rabbit heart. Measurement by atomic absorption spectroscopy of calcium content in ischemic heart tissue and its mitochondrial fraction indicated that the ischemic procedure significantly increased tissue calcium content in both. D, Prostacyclin (PGI2) and Nifedipine protected the heart from ischemic ventricular contracture and prevented accumulation of calcium in the heart. The effect of D on preventing Ca++ overload was completely abolished by indomethacin infusion. The results indicate that the beneficial effects of Defibrotide in experimental ischemia are primarily due to a release of Prostaglandin E2 (PGE2) and PGI2, which in turn may inhibit the detrimental effects of calcium overload in myocytes and mitochondria.

Topics: Animals; Calcium; Coronary Disease; Dinoprostone; Epoprostenol; Fibrinolytic Agents; Indomethacin; Male; Perfusion; Polydeoxyribonucleotides; Rabbits

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Disease; Epoprostenol; Fibrinolytic Agents; In Vitro Techniques; Myocardial Reperfusion Injury; Platelet Activating Factor; Polydeoxyribonucleotides; Rabbits

We studied the efficacy of defibrotide, a prostacyclin-stimulating agent, in preventing ischemia reperfusion injury in Wistar rat heart by using three experimental models: (1) hearts from donors were perfused with the drug (32 mg/kg/hr) during 15, 30, 45, and 60 min of cold ischemia following 5, 10, and 15 min of warm ischemia; (2) hearts from donors treated with the drug were cold-stored for 12 or 24 hr; and (3) procured hearts perfused with the drug were isografted, after 30 or 60 min of warm ischemia, in recipient rats treated daily with defibrotide. Hearts perfused with saline and/or vehicle of the drug were used as controls. At the end of established ischemia times, and after 30 min, and 2, 4, 7 and 14 days from transplantation, hearts were rapidly cooled in liquid nitrogen. ATP, ADP, AMP, cAMP contents, and NAD+/NADH ratios were evaluated in prepared tissue extracts. Cardiac ATP and ADP levels and NAD+/NADH ratios were significantly higher in defibrotide-treated organs than in controls. Isografted defibrotide-treated hearts were also significantly preserved, with respect to controls, from the loss of ATP levels until rejection occurred. Our results demonstrate the protective activity of the drug against the myocardial metabolic damage due to ischemia-reperfusion.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Cold Temperature; Coronary Disease; Fibrinolytic Agents; Heart; Heart Transplantation; Hot Temperature; Male; Myocardial Reperfusion Injury; Myocardium; Polydeoxyribonucleotides; Rats; Rats, Inbred Strains; Time Factors; Tissue and Organ Procurement; Transplantation, Heterotopic

Defibrotide is known to enhance prostacyclin (PGI2) release from the vascular endothelium. We investigated the vasoactive effects of defibrotide in isolated rat hearts perfused at constant flow subjected to ischaemia and reperfusion. Defibrotide at 10 or 100 micrograms/ml did not exert any direct vasoactive effect on normal rats hearts. However, ischaemia and reperfusion resulted in an impaired vasodilation to acetylcholine, an endothelium-dependent vasodilator. In contrast, the vasodilator response to the endothelium-independent dilator, nitroglycerin, was unaffected. Defibrotide, at 10 or 100 micrograms/ml, markedly restored the vasodilation to acetylcholine 10 nmol/l to 1 mumol/l (P less than 0.01) without influencing the vasodilator response to nitroglycerin (2 to 200 micrograms/l). Haemoglobin (150 nmol/l) inhibited the dilation to acetylcholine in response to defibrotide. However, no evidence of PGI2 release was observed with acetylcholine-induced vasodilation in the presence or absence of defibrotide. Additionally, 10-100 micrograms/ml of defibrotide did not significantly decrease superoxide radicals generated by a xanthine-xanthine oxidase synthetic system under conditions in which superoxide dismutase was effective. Thus, defibrotide appears to exert an endothelium-protective effect preserving endothelium-derived relaxing factor (EDRF) without directly scavenging free signals.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Acetylcholine; Animals; Coronary Disease; Coronary Vessels; Endothelium, Vascular; Epoprostenol; Fibrinolytic Agents; In Vitro Techniques; Male; Myocardial Reperfusion; Nitric Oxide; Nitroglycerin; Polydeoxyribonucleotides; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred Strains; Superoxide Dismutase; Superoxides

Topics: Animals; Blood Platelets; Cats; Coronary Disease; Epoprostenol; Fibrinolytic Agents; Polydeoxyribonucleotides; Swine; Swine, Miniature

Defibrotide, a polydeoxyribonucleotide obtained from mammalian lungs, has been demonstrated to exert profibrinolytic and antithrombotic activity through stimulation of vascular prostacyclin (PGI2) production. We studied the effect of defibrotide administration in protecting liver and heart from ischaemic and postischaemic reperfusion damage. Defibrotide was administered as an i.v. bolus (30 mg/kg) at the beginning of liver ischaemia and at the same dose continuously during 60 min of postischaemic reperfusion. ATP levels were significantly improved in livers of defibrotide-treated rats as compared to those obtained in livers of rats treated with vehicle of the drug. Intrahepatic cytoplasmic and mitochondrial NAD+/NADH ratios were higher in defibrotide-treated than in vehicle-treated animals. The hearts, isolated from rats according to the transplantation procedure, were subjected to different times of warm + cold ischaemia. During ischaemia, the hearts were perfused continuously with 60 mg/kg of defibrotide or vehicle of the drug. The loss of creatine phosphokinase and lactate dehydrogenase activities due to an increased ischaemia time was limited in defibrotide-perfused hearts. Intracardiac ATP and ADP levels were significantly higher in defibrotide-treated organs than in controls. Our results demonstrate the efficacy of defibrotide in protecting liver and heart from ischaemia.

Topics: Animals; Coronary Disease; Cytoplasm; Epoprostenol; Ischemia; Liver; Male; Mitochondria, Liver; Myocardium; Nucleotides; Polydeoxyribonucleotides; Rats; Rats, Inbred Strains; Reperfusion Injury

1. Defibrotide, a single-stranded polydeoxyribonucleotide obtained from bovine lungs, has significant anti-thrombotic, pro-fibrinolytic and prostacyclin-stimulating properties. 2. The present study was designed to evaluate the effects of defibrotide on infarct size and regional myocardial blood flow in a rabbit model of myocardial ischaemia and reperfusion. 3. Defibrotide (32 mg kg-1 bolus + 32 mg kg-1 h-1, i.v.) either with or without co-administration of indomethacin (5 mg kg-1 x 2, i.v.) was administered 5 min after occlusion of the left anterior-lateral coronary artery and continued during the 60 min occlusion and subsequent 3 h reperfusion periods. 4. Defibrotide significantly attenuated the ischaemia-induced ST-segment elevation and abolished the reperfusion-related changes (R-wave reduction and Q-wave development) in the electrocardiogram. In addition, defibrotide significantly improved myocardial blood flow in normal and in ischaemic, but not in infarcted sections of the heart. The improvement in blood flow in normal perfused myocardium, but not in the ischaemic area was prevented by indomethacin. 5. Although the area at risk was similar in all animal groups studied, defibrotide treatment resulted in a 51% reduction of infarct size. Indomethacin treatment abolished the reduction of infarct size seen with defibrotide alone. 6. The data demonstrate a considerable cardioprotective effect of defibrotide in the reperfused ischaemic rabbit myocardium. This effect may be related, at least in part, to a stimulation of endogenous prostaglandin formation. Other possible mechanisms are discussed.

Topics: Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Electrocardiography; Heart Rate; Hemodynamics; Indomethacin; Male; Microspheres; Myocardial Infarction; Polydeoxyribonucleotides; Rabbits; Reperfusion Injury

The following study was designed to investigate the therapeutic value of defibrotide (32 mg/kg bolus + 32 mg/kg x h i.v.) in a cat model of acute myocardial ischaemia (MI) and reperfusion and to elucidate its possible mechanism(s) of action. Infusion of defibrotide (DEF), starting 30 min after the onset of ischaemia, had no effect on any of the hemodynamic parameters measured. In comparison with vehicle-treated animals, DEF largely attenuated the MI-associated ST-segment elevation and completely prevented the development of a pathological Pardee-Q-wave upon reperfusion. Furthermore, DEF largely antagonized the loss of creatine phosphokinase from the ischaemic reperfused myocardium. DEF significantly reduced the MI-induced thrombocytopenia and inhibited the collagen-induced platelet ATP-secretion ex vivo. Interestingly, DEF-treatment did not modify the MI-induced leucocytosis or the release of reactive oxygen radicals from activated neutrophils. These findings indicate that stimulation of endogenous prostacyclin formation by DEF reduces myocardial reperfusion injury independently of any direct effects of the compound on neutrophil activation.

Topics: Animals; Blood Pressure; Cats; Coronary Disease; Fibrinolytic Agents; Heart; Heart Rate; Leukocyte Count; Myocardial Reperfusion Injury; Polydeoxyribonucleotides; Reference Values

Defibrotide, a polydeoxyribonucleotide obtained from mammalian lungs, reduced in a dose-dependent fashion the ischemic contracture due to low perfusion (0.2 ml/min) of isovolumic left heart of rabbit and abolished the irregular rhythm of the heart, thereby restoring the cardiomechanical activity upon reperfusion (20 ml/min). Defibrotide stimulated the release of PG-like material from the heart in a dose-dependent manner without modifying the basal contractility. Both PGE2 and PGI2 (10 ng/ml) have an antiischemic activity on this preparation as shown by the partial reduction of the ischemic contracture and by the improvement of heart contractility upon reperfusion. Indomethacin infusion (1 microgram/ml) completely removed both the antiischemic activity of Defibrotide (400 micrograms/ml) and its ability to increase the generation of prostaglandins in the rabbit heart. These results suggest that Defibrotide has a beneficial influence on ischemic rabbit heart through an increase in prostaglandin synthesis. However other mechanisms not necessarily related to prostaglandin generation, such as a direct effect on membrane function deactivation and mitochondrial Ca2+ overload, should be considered in explaining the antiischemic activity of Defibrotide in the rabbit heart.

Topics: Animals; Coronary Disease; Dinoprostone; Epoprostenol; Fibrinolytic Agents; In Vitro Techniques; Indomethacin; Male; Myocardial Contraction; Platelet Aggregation; Polydeoxyribonucleotides; Prostaglandins E; Rabbits

Defibrotide (D) is a natural polydeoxyribonucleotide from mammalian lungs with profibrinolytic and antithrombotic activities. D also has PGI2-stimulating and tissue plasminogen activator (TPA)-releasing activities, but has no anticoagulant properties. The protective effects of D were demonstrated very recently in a model for non-lethal ischemia in the cat. In the experiments reported here Defibrotide was tested in a model for acute myocardial ischemia leading to ventricular fibrillation (VF) and death of the cat. Occlusion of the coronary artery (LAD) at its origin induced VF and death in 17 of 20 control cats. When cats were treated with D (32 mg Kg-1, bolus i.v., + 32 mg Kg-1 h-1, i.v., after LAD occlusion) 19 of 20 animals survived until the end of experiments. D also prevented changes in plasma and myocardial CPK, hemodynamics and ECG. D was compared with a variety of pharmacological agents which are used clinically for specific cardiovascular diseases. The ability of D to promote considerable generation of PGI2 from vascular walls plus its ability to prevent the decreases in CPK-activity and ATP in the myocardial tissue may have roles in its beneficial effects against ischemic heart in the cat. However, the mechanism/s of the substantial protective effect of D against cardiac death has still to be clarified.

Topics: Animals; Cats; Coronary Disease; Creatine Kinase; Epoprostenol; Heart Ventricles; Hemodynamics; Male; Nitroglycerin; Polydeoxyribonucleotides; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Ventricular Fibrillation

We evaluated the effects of defibrotide (D), a natural profibrinolytic and antithrombotic agent with endogenous PGI2-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 elucidated.

Topics: Adenosine Triphosphate; Animals; Atenolol; Cats; Coronary Disease; Creatine Kinase; Epoprostenol; Fibrinolytic Agents; Hemodynamics; Lactates; Male; Myocardium; Polydeoxyribonucleotides

We investigated the effects of Defibrotide (D), a natural polydeoxyribonucleotide, on acute myocardial ischemia (AMI) in anesthetized cats. A permanent ligature was placed around the left anterior descending coronary artery (LAD) 12-14 mm from its origin. Ventricular fibrillation and death were exceptional and when they occurred the cats were not included in the evaluation. Pretreatment of cats with D, 32 mg Kg-1 h-1, i.v. infusion, maintained throughout the 5 h occlusion period, reduced AMI-ST segment increases and increased the diminished pressure-rate index (PRI). AMI-induced changes in lactate, ATP and CPK in ischemic tissue were prevented by D. PGI2 gave the same results as D. Atenolol prevented the loss of myocardial CPK, but had no favourable effects on lactate and ATP in ischemic tissue. The beneficial effects of D in AMI reported here could be partly attributed to its ability to enhance PGI2 release from vascular walls; D might also relieve ischemia by improvement of local tissue oxygenation, energy supplies and platelet function by its ability to deaggregate platelet clumps.

Topics: Acute Disease; Adenosine Triphosphate; Animals; Atenolol; Cats; Coronary Disease; Creatine Kinase; Electrocardiography; Epoprostenol; Fibrinolytic Agents; Hemodynamics; Lactates; Male; Myocardium; Polydeoxyribonucleotides

Defibrotide, a partially depolymerized polydeoxyribonucleotide obtained from mammalian lungs, was found to stimulate prostacyclin (PGI2) production and to possess significant antithrombotic and fibrinolytic activities. The present study was designed to evaluate the actions of defibrotide on feline myocardial ischemia, produced by 3 hours of occlusion of the left anterior descending coronary artery (LAD) and followed by 2 hours of reperfusion. Intravenous administration of defibrotide (32 mg/kg/hour subsequent to a 32 mg/kg bolus injection), beginning 30 minutes after LAD occlusion, resulted in a 60% reduction in loss of CK specific activity from ischemic myocardium at 5 hours, while the nonischemic myocardium remained unaffected. Defibrotide largely antagonized the increase in ST segment during LAD occlusion and prevented the appearance of a Q wave during early reperfusion, which was found in all vehicle-treated cats. Although 2 of 8 vehicle-treated cats died from ventricular fibrillation and another had severe ventricular tachyarrhythmia, none of the defibrotide-treated cats had similar severe changes in the electrocardiogram and all 7 cats survived the 5-hour observation period. Defibrotide had no direct action on general hemodynamic functions. In a separate set of experiments, defibrotide (0.1 mg/ml) produced an 8- to 10-fold stimulation of PGI2 release. The data suggest a remarkable protective potential of defibrotide on reperfusion damage of the ischemic myocardium, which may be associated with a PGI2-related mechanism.

Topics: Adenosine Triphosphate; Animals; Blood Platelets; Cats; Coronary Disease; Creatine Kinase; Electrocardiography; Epoprostenol; Female; Fibrinolytic Agents; Heart; Hemodynamics; Male; Myocardium; Platelet Aggregation; Polydeoxyribonucleotides