endothelin-1 and defibrotide

Defibrotide is a polydeoxyribonucleotide extracted from mammalian organs (porcine) and prepared by controlled depolymerization, resulting in a single-stranded deoxyribonucleotide with a mean molecular weight of 15 to 30 kDa. Early studies of experimental pharmacology in different animal species (1981-1986) were focused on an antithrombotic effect in arteries, veins, and the microcirculation, attributed to a dose-dependent activation of fibrinolysis. More recently, a number of new data have raised interest in an "anti-ischemic" action of the substance, as suggested by its evident protective effect in different models of tissue and organ ischemia. Protection from myocardial ischemia was demonstrated in different experimental models, and several ischemic features, such as heart muscle contracture, loss of high-energy substrates, decline in beta-adrenergic receptor sensitivity, and drop in infarct-related blood flow, were successfully prevented. Similar protective effects were observed during liver and kidney ischemia and in different types of experimental shock. The mechanisms involved in the anti-ischemic properties of defibrotide have been investigated in studies of experimental and human pharmacology. The substance has been shown to modulate arachidonic acid metabolism by enhancing the production and release of prostacyclin and prostaglandin E2 from tissues and whole blood, and inhibiting leukotriene B4 generation in leukocytes. Furthermore, an effect of defibrotide on activation of polymorphonuclear leukocytes and their incorporation into thrombi was described. Favorable effects on blood rheology were also reported. In summary, defibrotide deserves attention for therapeutic trials in clinical conditions characterized by organ or tissue ischemia.

Topics: Animals; Antifibrinolytic Agents; Endothelin-1; Epoprostenol; Humans; Ischemia; Polydeoxyribonucleotides; Vasoconstriction

Microvascular alterations, impairment of coagulation, ischemia and diffuse endothelial damage are related to the progression of diabetic retinopathy. Defibrotide has been demonstrated to produce profibrinolytic, cytoprotective and vasofacilatory activities. The aim of the present study was to evaluate the therapeutic effect of Defibrotide in the treatment of nonproliferative diabetic retinopathy.. Two randomized age- and sex-matched groups (cases and controls) of 35 NIDDM patients presenting non-proliferative diabetic retinopathy were included in this study: cases were treated with Defibrotide (800-1600 mg daily) for two years.. All tested parameters (ETDRS visual acuity; computerized perimetry; retinography; fluorescein angiography), improved significantly (p<0.001) in Defibrotide-treated patients compared to controls. In our opinion, Defibrotide's manifold effects on vascular endothelia may account for this improvement by stimulation of tPA, PGI2, PGE2, thrombomodulin and modulation of endothelin-1 release.. Our preliminary data seem to suggest that Defibrotide could be proposed for medical treatment of nonproliferative diabetic retinopathy.

Topics: Aged; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Dinoprostone; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; Fibrinolytic Agents; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Humans; Male; Middle Aged; Pilot Projects; Polydeoxyribonucleotides; Retina; Thrombomodulin; Tissue Plasminogen Activator; Treatment Outcome; Visual Field Tests

In a previous paper we gave evidence that chronic oral defibrotide antagonizes the noxious effect of developing atherosclerosis in the cardiovascular system. In the present paper we give evidence that defibrotide is still capable of exerting beneficial effects on cardiovascular function once atherosclerosis is established. In fact, there was statistically significant amelioration by defibrotide infusion in the following, all of which were hampered by established atherosclerosis: in rabbit aorta relaxation to acetylcholine, prostaglandin E2, and 6-keto-prostaglandin F1alpha generation from rabbit aortas, rabbit heart left ventricular end-diastolic pressure, coronary perfusion pressure, and left ventricular developed pressure, vasopressor activity of acetylcholine and endothelin-1 on coronary perfusion pressure, and 6-keto-prostaglandin F1alpha generation from the rabbit heart. Since prostacyclin takes part in NO generation, is cellular protective, and inhibits 5-lipoxygenase product synthesis, its increase, caused by defibrotide, could explain defibrotide cardioprotective activity. Prostacyclin activity could be backed by prostaglandin E2, another cardioprotective prostaglandin.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Animals; Aorta; Arteriosclerosis; Blood Pressure; Body Weight; Cardiovascular Physiological Phenomena; Cholesterol, Dietary; Dinoprostone; Endothelin-1; Fibrinolytic Agents; Heart; In Vitro Techniques; Lipids; Male; Muscle Contraction; Muscle, Smooth, Vascular; Organ Size; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Rabbits; Reperfusion; Ventricular Function, Left

Defibrotide is a polydeoxyribonucleotide derived agent with a weight average of 15 to 18 kDa. By virtue of its chemical nature, this polyelectrolyte agent exerts multiple pharmacologic actions at various plasmatic and cellular sites. In recent studies, this agent has been demonstrated to exhibit cardioprotective and vasomodulatory actions. To test the effect of defibrotide on the vascular smooth muscle contractile responses, its effects were evaluated on contractile response induced by agonists in canine femoral and pulmonary arterial smooth muscle preparation. These arterial preparations were harvested from anesthetized and anticoagulated (Heparinized 3-5 U/ml) dogs. Defibrotide was administered to dogs at 10 mg/kg, i.v. and segments of canine arteries were harvested at 30 minutes after the administration of this agent. The control and defibrotide treated canine arterial ring preparations were tested against serotonin, endothelin-I, serum and control platelet rich plasma(PRP) with arachidonic acid(AA). The contractile response of arterial rings obtained for treated groups were measured using serotonin, endothelin-I, serum and PRP/AA as agonists. The contractile action of serotonin, endothelin-I, serum and PRP/AA were inhibited by pretreatment of the animal with defibrotide. The arterial ring isolated from dogs treated with defibrotide exhibited a weaker contraction. These studies support the hypothesis that defibrotide modulates endothelial function and the response to the contractile actions of various agonists may be related to this effect.

Topics: Animals; Blood; Dogs; Dose-Response Relationship, Drug; Endothelin-1; Femoral Artery; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Polydeoxyribonucleotides; Pulmonary Artery; Serotonin; Thromboxanes