Defibrotide as a possible anti-ischemic drug.
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.
Coccheri
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Division of Vascular Medicine, University Hospital St. Orsola, Bologna, Italy.
Nazzari
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D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors; D011464:Epoprostenol / Q000096:biosynthesis; D006801:Humans; D007511:Ischemia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D011089:Polydeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D014661:Vasoconstriction / Q000187:drug effects
D000933:Antifibrinolytic Agents; D019332:Endothelin-1; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D011464:Epoprostenol