defibrotide and Vascular-Diseases

Defibrotide is a deoxyribonucleic acid derivative that has been developed for the treatment of different vascular disorders.. The authors reviewed the literature to give due representation to the spectrum of pharmacological properties and clinical application of this drug, evaluating consolidate and innovative application.. The authors used PubMed from November 1982 to December 2007 and meeting abstracts (form American Society of Hematology Annual Meeting) with updated data as the sources for this review and selecting the most relevant papers when two or more articles covered the same point of interest.. Defibrotide has been used effectively in the treatment of endothelial complications of allogeneic stem cell transplantation and recent preclinical evidences suggest an antiangiogenic effect and an anticancer activity. Further in vivo and in vitro investigations are needed.

Topics: Endothelium, Vascular; Fibrinolytic Agents; Humans; Polydeoxyribonucleotides; Vascular Diseases

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

Defibrotide is a deoxyribonucleic acid derivative extracted from mammalian organs, which has been developed for the treatment of a number of vascular disorders. It appears to increase fibrinolysis and may possess antithrombotic, antiatherosclerotic and anti-ischaemic actions, probably due to its ability to selectively increase prostaglandin I2 and E2 levels and to increase tissue plasminogen activator and decrease plasminogen activator inhibitor function. Defibrotide is available as an intravenous and intramuscular preparation, and also as an oral formulation for long term use. Trials performed to date have provided initial evidence that defibrotide is effective in the treatment of peripheral obliterative arterial disease and acute thrombophlebitis, while preliminary data suggest possible use in preventing fibrin deposition in the circuitry of renal haemodialysis equipment. Efficacy in preventing deep vein thrombosis after surgery has been demonstrated but defibrotide does not appear to offer any therapeutic advantage over heparin. Further clinical experience is required in other disorders, including acute myocardial infarction, Raynaud's phenomenon, renal thrombotic microangiopathy and renal transplant rejection, before adequate assessment of efficacy in these areas can be made. Defibrotide is well tolerated, as assessed in trials of up to 6 months duration, with a low global incidence of adverse events (< 1 to 9%). Mild allergic reactions and gastrointestinal disturbances have occasionally been described, and a hypotensive effect has also infrequently been observed. Thus, available data suggest that defibrotide is a well tolerated agent with little or no anticoagulant activity, which is conveniently available in both parenteral and oral formulations. Initial data indicate that the drug may be a useful alternative in the treatment of peripheral obliterative arterial disease and thrombophlebitis, while its therapeutic potential in other vascular disorders and efficacy relative to established agents remains to be fully determined.

Topics: Animals; Arachidonic Acid; Fibrinolytic Agents; Hemostasis; Humans; Myocardial Infarction; Polydeoxyribonucleotides; Thrombosis; Vascular Diseases

In the present study the effect of defibrotide, an antithrombotic and profibrinolytic agent, was investigated in patients with chronic venous insufficiency (CVI) due to deep vein obstruction and/or reflux (chronic deep vein insufficiency, CDVI).. The study was a multicenter, randomized, double blind placebo controlled trial in which only patients with CDVI confirmed by ultrasound were enrolled. All patients were treated with adequate elastic compression and randomized to receive either oral defibrotide (800 mg/die) or matching placebo for 1 year. Patients with active or previous leg ulcer were excluded.. A total of 288 patients were randomized and 159 completed the study. At baseline ultrasound investigation, obstructive changes were found in 2/3 of all patients thus ascertaining a post-thrombotic syndrome (PTS). The primary endpoint, ankle circumference, was significantly reduced under defibrotide from day 120 throughout 360. Scores for pain and edema were improved. The number of episodes of superficial thrombophlebitis and deep vein thrombosis was significantly lower under defibrotide (n=2) than under placebo (n=10). The majority of these events occurred in the subset of patients with documented PTS.. Treatment with defibrotide in addition to elastic compression in patients with objectively assessed CDVI, mostly due to PTS, resulted in clinical benefits and prevented thrombotic complications harmful to the limb conditions.

Topics: Aged; Ankle; Bandages; Chronic Disease; Double-Blind Method; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Polydeoxyribonucleotides; Ultrasonography, Doppler; Vascular Diseases; Venous Thrombosis

COVID-19 progression is characterized by systemic small vessel arterial and venous thrombosis. Microvascular endothelial cell (MVEC) activation and injury, platelet activation, and histopathologic features characteristic of acute COVID-19 also describe certain thrombotic microangiopathies, including atypical hemolytic-uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP), and hematopoietic stem cell transplant (HSCT)-associated veno-occlusive disease (VOD). We explored the effect of clinically relevant doses of defibrotide, approved for HSCT-associated VOD, on MVEC activation/injury.. Human dermal MVEC were exposed to plasmas from patients with acute TMAs or acute COVID-19 in the presence and absence of defibrotide (5μg/ml) and caspase 8, a marker of EC activation and apoptosis, was assessed. RNAseq was used to explore potential mechanisms of defibrotide activity.. Defibrotide suppressed TMA plasma-induced caspase 8 activation in MVEC (mean 60.2 % inhibition for COVID-19; p = 0.0008). RNAseq identified six major cellular pathways associated with defibrotide's alteration of COVID-19-associated MVEC changes: TNF-α signaling; IL-17 signaling; extracellular matrix (ECM)-EC receptor and platelet receptor interactions; ECM formation; endothelin activity; and fibrosis. Communications across these pathways were revealed by STRING analyses. Forty transcripts showing the greatest changes induced by defibrotide in COVID-19 plasma/MVEC cultures included: claudin 14 and F11R (JAM), important in maintaining EC tight junctions; SOCS3 and TNFRSF18, involved in suppression of inflammation; RAMP3 and transgelin, which promote angiogenesis; and RGS5, which regulates caspase activation and apoptosis.. Our data, in the context of a recent clinical trial in severe COVID-19, suggest benefits to further exploration of defibrotide and these pathways in COVID-19 and related endotheliopathies.

Topics: Anticoagulants; Caspase 8; COVID-19; Endothelial Cells; Hematopoietic Stem Cell Transplantation; Humans; Vascular Diseases

Topics: Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Polydeoxyribonucleotides; Vascular Diseases

Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplant (HSCT), with high mortality in severe cases and until recently very limited therapeutic options consisting largely of supportive care. Defibrotide was recently approved in the United States for the treatment of severe VOD in patients with renal or pulmonary dysfunction after HSCT. Our group previously published on the use of high-dose methylprednisolone (500 mg/m

Topics: Adolescent; Child; Child, Preschool; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Methylprednisolone; Multiple Organ Failure; Polydeoxyribonucleotides; Retrospective Studies; Treatment Outcome; Vascular Diseases

Topics: Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Male; Mastocytosis, Systemic; Middle Aged; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Pulmonary Veno-Occlusive Disease; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vascular Diseases

Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin level > 2.0 mg/dL by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any noninfectious pulmonary abnormality. Patients with severe VOD were divided into 2 groups for analysis: those treated with defibrotide (n = 41) and those not treated with defibrotide (n = 55). Patients in the nondefibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival rate at day +100 was 39% (95% CI, 24.8% to 54.3%) in patients receiving defibrotide and 30.9% (95% CI, 19.5% to 43.6%) in those not receiving defibrotide. Resolution rate of VOD at day +100 was 51% in the defibrotide group and 29% in the nondefibrotide group (difference, 22.1%; 95% CI, 2.6% to 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Databases, Factual; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Infant; Male; Middle Aged; Multiple Organ Failure; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Retrospective Studies; Treatment Outcome; Vascular Diseases; Young Adult

Topics: Adult; Aged; Diagnosis, Differential; Disease-Free Survival; Female; Fibrinolytic Agents; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Liver Diseases; Male; Middle Aged; Polydeoxyribonucleotides; Time Factors; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Vascular Diseases

Fludarabine is a nonmyeloablative immunosuppressant increasingly used as a component of alternative reduced-intensity conditioning regimens prior to allogeneic stem cell transplantation (SCT). However, we have previously shown that 2-fluoroadenine 9-beta-D-arabinofuranoside (F-Ara) as the active metabolized form of fludarabine induces damage, activation and allogenicity in human microvascular endothelial cells (HMEC). We had also identified the pharmaceutic compound Defibrotide (DF), originally used in the treatment of veno-occlusive disease and thrombotic microangiopathy, as being protective against F-Ara-induced dysfunction of HMEC, importantly, without affecting the antileukemic effect of F-Ara. In the present report, we show that a recently developed derivative of DF, Oligotide, similarly downregulates F-Ara-induced activation and damage of HMEC as well as their antigenicity for allogeneic CD8+ T cells. In addition, Oligotide could also block F-Ara-mediated transendothelial migration of peripheral blood cells across the HMEC barrier. Taken together, these observations argue for a potential clinical use of both DF and Oligotide in pre transplant conditioning.

Topics: Antineoplastic Agents; Cell Line; Cell Movement; Endothelial Cells; Endothelium, Vascular; Oligodeoxyribonucleotides; Polydeoxyribonucleotides; Transplantation Conditioning; Vascular Diseases; Vidarabine

The aim of our study was to evaluate the incidence of venous toxicity induced by vinorelbine administration in patients who received a preventive therapy with defibrotide.. From July 1996 to July 2002 we treated 203 patients with vinorelbine, 51 with vinorelbine alone and 152 with vinorelbine in combination with other drugs via peripheral vein infusion. Of the 203 patients, 123 were male and 80 female with a median age of 67 years (range 18 to 82 years), and 118 were chemotherapy-naive. Defibrotide was delivered i.v. at a dose of 400 mg in 250 ml normal saline. After infusion of 125 ml over about 15 min, vinorelbine mixed with 10 ml normal saline was delivered as quick brief repeated pulses over 5 min through the plastic tube, followed by infusion of the remaining defibrotide. The specific Rittenberg scale was used to assess venous irritation episodes.. Among a total of 1336 vinorelbine infusions, with a median of five infusions per patient, the incidence of venous irritation episodes graded according to Rittenberg scale was 1.1% (15), of which 0.6% (8) were grade 2 and 0.5% (7) grade 1. Globally, 15 patients (7.3%) developed venous toxicity after a median of 3 infusions (range 1-14), but no patient had more than one event.. Our findings support the use of defibrotide as an effective, safe and low-cost means for preventing vinorelbine-related venous damage.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Severity of Illness Index; Vascular Diseases; Veins; Vinblastine; Vinorelbine

Defibrotide (DEF) is a polydeoxyribonucleotide agent provided with profibrinolytic and antithrombotic properties. Moreover, an antiischemic, cardioprotective effect of the drug has recently been demonstrated in experimental animals. Increasing evidence exists of the important role played by neutrophils in the development of tissue damage during chronic and acute ischemia and in the early phases of reperfusion. In order to evaluate whether the overall cytoprotective effect of DEF could be based, at least in part, on a neutrophil-involving mechanism, the authors studied the in vitro effects of the drug on human neutrophil activation triggered by several specific stimuli. The drug dose-dependently (10-100 microM) inhibited enzyme release, superoxide anion generation, and chemiluminescence induced in neutrophils by the chemoattractant oligopeptide fMLP and by the divalent cation ionophores A23187 and ionomycin. The increase of extracellular calcium concentration from 0.5 to 2.0 mM antagonized the inhibitory effect of DEF. The use of the fluorescent probe Fura 2/AM led them to show that DEF is able to reduce the cytosolic free calcium increase following specific stimulation by affecting extracellular calcium entrance. Such a behavior resembles that of calcium-antagonistic drugs, thus suggesting that DEF works, at least in part, similarly to calcium entry blockers. Such an activity on cell calcium translocation could represent the underlying molecular mechanism of cytoprotection. Finally, the inhibitory action on neutrophil functions may play a role in tissue protection during ischemic injury.

Topics: Calcium; Dose-Response Relationship, Drug; Fibrinolytic Agents; Free Radicals; Humans; Luminescent Measurements; Muramidase; Neutrophils; Polydeoxyribonucleotides; Superoxides; Vascular Diseases

Topics: Animals; Endothelium, Vascular; Fibrinolytic Agents; Humans; Polydeoxyribonucleotides; Thrombosis; Vascular Diseases