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PubMed1986

Defibrotide is antithrombotic and thrombolytic against rabbit venous thrombosis.

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 X 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 vascular tissue.

Animals↗

PubMed1986

Beneficial effects of defibrotide against myocardial ischemia and decline of beta-adrenoceptor function in the rabbit.

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 beta-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.

Animals↗

PubMed1986

Pharmacokinetics of defibrotide in healthy volunteers.

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 micrograms/ml.

Adult↗

PubMed1986

Thymine and guanine base specificity of human myeloma proteins with anti-DNA activity.

To further our understanding of the molecular basis of DNA-autoantibody interactions, we have characterized the specificities of three IgG human myeloma proteins that bind DNA. We measured their binding to synthetic single- and double-stranded homopolynucleotides, random and alternating copolymers, oligonucleotides, and nucleotides or nucleosides conjugated to non-nucleic acid carriers. All three antibodies bound single-stranded nucleic acids, including both polyribonucleotides and polydeoxyribonucleotides. They varied in relative affinities for polynucleotides of varying base composition. Polymers containing the purines guanine or hypoxanthine and/or the pyrimidine thymine were most reactive with all three proteins. A myeloma protein that reacted with poly(G), poly(I), or poly(dT) also bound to the corresponding nucleosides or nucleotides conjugated to bovine serum albumin. None of the antibodies reacted with base-paired double-helical polynucleotides (double-stranded RNA, RNA-DNA hybrid or double-stranded DNA). The results indicate that base specificity is prominent in their reactions and that the accessible epitopes in single-stranded polynucleotides become masked upon base pairing in double-stranded helices. These findings suggest a model in which positions N1 and O6 of guanine and hypoxanthine and N3 and O4 of thymine interact with amino acids of the antibody-combining site.

Autoantibodies↗

PubMed1991

Defibrotide inhibits Ca2+ dependent neutrophil activation: implications for its pharmacological activity in vascular disorders.

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.

Calcium↗

PubMed2001

Tissue factor pathway inhibitor release induced by defibrotide and heparins.

We evaluated the release of tissue factor pathway inhibitor (TFPI) induced by defibrotide (DF), a single-stranded, negatively charged polydeoxyribonucleotide extracted from mammalian organ. Ten normal volunteers were injected with an intravenous bolus of 400 mg DF and 2,000 IU unfractionated heparin (UFH). In addition, three volunteers were also injected with an intravenous bolus of 2,000 anti-Xa U of two low-molecular-weight heparins (LMWHs), enoxaparin and nadroparin. UFH caused a 4-fold increase in plasma TFPI at 5 minutes, with a decrease that was parallel to the heparin level measured by the anti-Xa assay. However, at 80 minutes, although the plasma anti-Xa activity of UFH was almost undetectable, the level of TFPI remained 2-fold baseline. DF induced an increase of TFPI that was 2-fold higher than the baseline level, with a steady state achieved between 5 and 20 minutes. At 40 minutes, the TFPI levels returned to basal level. This pattern was not coincident with the clearance of DF and at 40 minutes, the concentration of DF was still one third of the levels at 5 minutes (25.4 +/- 4.04 microg/mL). Both of the LMWHs induced a similar TFPI peak level at 5 minutes (1.5-fold increase) and at 40 minutes the TFPI levels returned to the initial levels. At 5 minutes, both LMWHs showed a higher plasma anti-Xa activity than UFH, which was detectable even at 80 minutes. The current study demonstrated that one of the mechanisms of the antithrombotic activity of DF is mediated via TFPI. Furthermore, the release of TFPI by heparin is mediated by non-antithrombin III binding fragments. Thus, polyanionic electrolytes are capable of releasing TFPI irrespective of their antithrombin III effect.

Adult↗

PubMed2002

Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome.

Veno-occlusive disease (VOD) is the most common regimen-related toxicity accompanying stem cell transplantation (SCT). Severe VOD complicated by multisystem organ failure (MOF) remains almost uniformly fatal. Preliminary experience with defibrotide (DF), a single-stranded polydeoxyribonucleotide with fibrinolytic, antithrombotic, and anti-ischemic properties, in the treatment for severe VOD has suggested safety and activity. Eighty-eight patients who developed severe VOD after SCT were treated with DF under a defined treatment plan. At diagnosis, median bilirubin was 76.95 microM (4.5 mg/dL), median weight gain was 7%, ascites was present in 84%, and abnormal hepatic portal venous flow was present in 35%. At DF initiation, median bilirubin had increased to 215.46 microM (12.6 mg/dL), and MOF was present in 97%. DF was administered intravenously in doses ranging from 5 to 60 mg/kg per day for a median of 15 days. No severe hemorrhage or other serious toxicity related to DF was reported. Complete resolution of VOD was seen in 36%, with 35% survival at day +100. Predictors of survival included younger age, autologous SCT, and abnormal portal flow, whereas busulfan-based conditioning and encephalopathy predicted worse outcome. Decreases in mean creatinine and plasminogen activator inhibitor 1(PAI-1) levels during DF therapy predicted better survival. The complete response rate, survival to day +100, and absence of significant DF-associated toxicity in this largest patient cohort reported to date confirm the results of earlier studies. Certain features associated with successful outcome may correlate with DF-related treatment effects, and prospective evaluation of DF therapy for severe VOD should allow better definition of predictors of response or failure.

Adolescent↗

PubMed1984

Effect of the strandedness of cofactor DNA on the activities of DNA-dependent ATPases B and C3 from FM3A cells.

The requirements of cofactor DNA for DNA-dependent ATPases B and C3 were analyzed in detail. ATPase B and C3 required the presence of a polynucleotide for their activities. Among the DNAs tested, ATPase B showed a preference for poly(dT) as its cofactor. The other deoxyhomopolymers, except poly(dG) and heat-denatured DNA also were effective. The alternating polydeoxyribonucleotide, poly[d(A-T)] had an efficiency 23% that of heat-denatured DNA. Unlike ATPase B, ATPase C3 showed almost no activity with deoxyhomopolymers. The most effective cofactor for ATPase C3 so far tested is poly[d(A-T)]. Relatively high activity was obtained with heat-denatured DNA. The high activity of ATPase B with poly(dT) was reduced by the addition of poly(dA). The addition of noncomplementary homopolymers did not affect enzyme activity. ATPase C3 activity in the presence of 10 microM poly(dT) increased gradually with concentrations of poly(dA) up to 20 microM, after which it decreased. Almost no increase in activity was observed when noncomplementary homopolymers were added. The relatively high activity of ATPase C3 with heat-denatured DNA was suggested by its high sensitivity to ethidium bromide to be due to the double-stranded region in the heat-denatured DNA formed by self-annealing.

Adenosine Triphosphatases↗

PubMed1986

Antibodies to DNA.

Antibodies that recognize specific conformational variations of DNA structure provide sensitive reagents for testing the extent to which such conformational heterogeneity occurs in nature. A most dramatic recent example has been the development and application of antibodies to left-handed Z-DNA. They provided the first identification of Z-DNA in fixed nuclei and chromosomes, and of DNA sequences that form Z-DNA under the influence of supercoiling. Antibodies have also been induced by chemically modified DNA and by synthetic polydeoxyribonucleotides that differ from the average B-DNA structure. These antibodies recognize only the features that differ from native DNA. In most experiments, native DNA itself is not immunogenic. Antibodies that do react with native DNA occur in sera of patients with autoimmune disease, but even monoclonal anti-DNA autoantibodies usually react with other polynucleotides as well. Anti-DNA antibodies, especially those of monoclonal origin, provide a model for the study of protein-nucleic acid recognition.

Animals↗

PubMedDate not supplied

[Relationship between the structural state of chromatin and the biosynthesis of rapidly labeling nuclear RNA in the thymuses of rats subjected to total x-irradiation].

Accumulation of polydeoxyribonucleotides (PDN) was studied in thymus of rats, subjected to total body X-ray irradiation at doses 400 and 800 rad. The content of PDN correlated with the time of treatment; its low-polymer components prevailed after irradiation with 800 rad. Protein/DNA ratio was decreased in DNP within 30 min after the irradiation and it returned to the initial level within 4 hrs. Capacity of DNP to make a complex with actinomycin D was inhibited within 30 min; however it exceeded the control level within 4 hrs after irradiation. Biosynthesis of nuclear RNA, estimated by incorporation of 14C-uridine, was distinctly decreased within the whole experimental period.

Animals↗

PubMedDate not supplied

[Effect of intercalators on the properties of liquid-crystalline dispersions of nucleic acid-chitosan complex].

Molecules of deoxyribonucleic acid and synthetic polydeoxyribonucleotides (NA) in the particles of liquid-crystalline dispersions resulting from interaction with chitosan are accessible to interaction with intercalators. The intercalation is accompanied by alteration in the direction of spatial twist of cholesterics of NA-chitosan complexes. This effect is absent in the case of "classical" cholesterics produced from NA molecules via phase exclusion, i.e., the cholesteric structure of NA-chitosan complex is very "labile" as distinct from "classical" cholesteric NA.

Chitin↗

PubMed2002

Defibrotide in combination with granulocyte colony-stimulating factor significantly enhances the mobilization of primitive and committed peripheral blood progenitor cells in mice.

Defibrotide is a polydeoxyribonucleotide, which significantly reduces the expression of adhesion molecules on endothelial cells. We investigated the activity of Defibrotide alone or in combination with recombinant human granulocyte colony-stimulating factor (rhG-CSF) to mobilize peripheral blood progenitor cells (PBPCs) in BALB/c mice. A 5-day treatment with Defibrotide alone (1-15 mg/mouse/day) had no effect on WBC counts, frequencies and absolute numbers of total circulating colony-forming cells (CFCs), i.e., granulocyte-macrophage colony-forming units, erythroid burst-forming units, and multilineage colony-forming units. As compared with mock-injected mice, administration of rhG-CSF alone (5 micro g/mouse/day) for 5 days significantly (P < or = 0.0001) increased WBC counts, CFC frequencies, and CFC absolute numbers by 2-, 13-, and 27-fold, respectively. As compared with control mice, the combined administration of Defibrotide (15 mg/mouse/day) and rhG-CSF significantly (P < or = 0.0001) increased WBC counts, frequencies and absolute numbers of CFCs by 4-, 38-, and 119-fold, respectively. As compared with rhG-CSF alone, administration of Defibrotide plus rhG-CSF resulted in a significant increase (P < or = 0.001) of the frequency of circulating long-term culture-initiating cells. In addition, transplantation of 2 x 10(5) rhG-CSF- or Defibrotide/rhG-CSF-mobilized mononuclear cells rescued 43% and 71% of recipient mice, respectively. Experiments of CFC homing performed in lethally irradiated or nonirradiated recipients showed that marrow homing of transplanted PBPCs was reduced by 3-fold in Defibrotide-treated animals as compared with mock-injected mice (P < or = 0.001), suggesting that the mobilizing effect of Defibrotide might be because of an effect on PBPC trafficking. In conclusion, our data demonstrate that Defibrotide synergizes with rhG-CSF and significantly increases the mobilization of a broad spectrum of PBPCs, including primitive and committed progenitor cells. These data might have relevant implications for autologous and allogeneic anticancer therapy in humans.

Animals↗

PubMed1992

Defibrotide inhibits platelet activation by cathepsin G released from stimulated polymorphonuclear leukocytes.

Defibrotide is a polydeoxyribonucleotide with antithrombotic effects in experimental animal models. Most of the actions of this drug have been observed in in vivo test models but no effects have been reported in in vitro systems. In this paper we demonstrate that defibrotide interferes with polymorphonuclear leukocyte-induced human platelet activation in vitro. This effect was not related to any direct interaction with polymorphonuclear leukocytes or platelets, but was due to the inhibition of cathepsin G, the main biochemical mediator of this cell-cell cooperation. Since cathepsin G not only induces platelet activation but also affects some endothelial cell functions, the anticathepsin G activity of defibrotide could help to explain the antithrombotic effect of this drug.

Catalysis↗

PubMed2005

Successful treatment with defibrotide for sinusoidal obstruction syndrome after hematopoietic stem cell transplantation.

Sinusoidal obstruction syndrome (SOS) (formerly known as hepatic veno-occlusive disease (VOD)) is a life-threatening complication subsequent to hematopoietic stem cell transplantation. However, no completely satisfactory strategies for the treatment of SOS have been established yet. Defibrotide is a single-stranded polydeoxyribonucleotide with anti-thrombotic, anti-ischemic, anti-inflammatory and thrombolytic properties, but without systemic anticoagulant effects, and some encouraging results have been reported in western countries. We treated four patients with defibrotide for SOS, since there seemed to be no possibility to cure the patients with conventionally available treatments in Japan. All patients showed evidence of multiple organ failure at the start of the treatment. Defibrotide was administered intravenously in normal saline in four divided doses for 14 to 27 days. Three patients (75%) responded to the therapy, while one died of SOS and cytomegalovirus infection despite intensive therapy. None of the patients suffered from significant adverse effects such as severe hemorrhage. This is the first report dealing with the treatment with defibrotide of Japanese patients with SOS. Because defibrotide is considered to be promising for the treatment of SOS, it is important to start a phase II study as soon as possible.

Adult↗

PubMed1991

Are increased ATP blood levels responsible for PGI2 release from endothelium?

Defibrotide, a polydeoxyribonucleotide with profibrinolytic and antithrombotic properties obtained from mammalian lungs was shown capable of favoring the release of prostacyclin from endothelial cells. We previously evidenced that the use of defibrotide i.p. (32 mg/kg for 30 min) or orally (50 mg/kg for 1 h) induced a significant increase in 2,3-diphosphoglycerate (2,3-DPG) content of blood cells in rats. We tested the in-vivo capacity of defibrotide to modify over 90 min the blood content of ATP, cAMP and 2,3-DPG. Male Wistar rats were anaesthetized with pentobarbital (20 mg/kg) i.p.; the left carotid artery was cannulated with a polyethylene tube, from which 0.4 ml of blood was drawn at 0, 5, 10, 15, 20, 30, 40, 50, 60 and 90 min. At 0 min, defibrotide was administered i.p. or i.v. (through the femoral vein) at the dose of 1 ml containing 80 mg of drug or orally at the dose of 1 ml containing 160 mg of drug. The control rats employed received either the vehicle of the drug or physiologic saline. Our results demonstrated a significant drug-related increase with time (maximal levels were revealed about 20 min after i.v., i.p., or oral defibrotide treatment) of blood ATP content and a significant decrease in cAMP content as compared with the controls. Our data confirm the relation between increased drug-induced prostacyclin production and that of ATP of in blood.

2,3-Diphosphoglycerate↗

PubMed1991

Effects of defibrotide on prostacyclin release from isolated rabbit kidneys and protection from post-ischemic acute renal failure in vivo.

We evaluated whether defibrotide, a single-stranded polydeoxyribonucleotide that enhances prostacyclin (PGI2) release from various isolated organs, could also release PGI2 from the rabbit kidney and prove effective against renal ischemic injury. Isolated perfused kidneys responded to defibrotide (100, 250 and 500 micrograms ml-1 min-1) with a dose-dependent release of immunoreactive 6-keto-PGF1 alpha (4-fold increase at highest dose), which was prevented by indomethacin pre-treatment. In vivo, venous blood withdrawn from heparinized rabbits (and representative of renal outflow) was conveyed over a collagen matrix, onto which platelets adhered and aggregated. Recording the weight increase of the matrix was used as a bioassay to follow the time-course of released PGI2. We observed that renal outflowing blood from defibrotide treated animals (50 mgKg-1 i.v.) displayed lower (P less than 0.05 versus controls) platelet activation, consistent with enhanced PGI2 release from the kidneys. Furthermore, the duration of this effect was longer lasting than that predicted from the known plasma half-life of the drug. After transient (30 min) occlusion of the renal arteries, glomerular filtration rate (GFR) dropped by about 50% (P less than 0.01) during the first reperfusion hour in control animals, with only mild recovery having occurred 4 h later. Defibrotide (16 mgKg-1 bolus + 16 mgKg-1h-1, i.v.) could not antagonize the initial impairment (40% GFR reduction), but allowed full recovery at the end of the observation period (P less than 0.05 vs controls). Indomethacin, instead, caused a dramatic reduction of GFR (70%) during early reperfusion, with no subsequent recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗

PubMed1991

A double-blind, multicenter, placebo-controlled, dose comparison study of orally administered defibrotide: preliminary results in patients with peripheral arterial disease.

Defibrotide is a polydeoxyribonucleotide drug known to modulate the endothelial cell release of t-PA, PAI, and PGI-2 and to improve blood flow and perfusion. A double-blind, multicenter, placebo-controlled, dose comparison study was carried out to test the long-term efficacy and safety of defibrotide in patients with PAD (Leriche stage 2). Informed patients suffering from PAD were enrolled, and after a 15-day washout period were randomly allocated in a double-blind fashion to one of the three following treatments: defibrotide 400 mg (1 cps) b.i.d. for 6 months, defibrotide 400 mg o.d., or placebo. Absolute walking distance (AWD, treadmill) and ankle-arm pressure ratio (Winsor Index, WI) were evaluated at the beginning and after 30, 90, and 180 days after therapy. Two hundred twenty seven patients were recruited and 193 patients were included in the final analysis (800 mg: 67; 400 mg: 60; placebo: 66). All treatments brought about an increase in AWD placebo = +17%; 400 mg = +47%, 800 mg = +52%); however, patients treated with defibrotide exhibited a significantly better AWD at the end of treatment in comparison with placebo (p less than 0.01). AWD was not significantly different in the 400-mg and 800-mg groups. There was a trend indicating a possible improvement of WI after defibrotide, with higher WI in 800-mg patients in comparison with placebo (p less than 0.05). However, this difference was partly due to a decrease in arterial blood pressure elicited by the drug. The tolerability in all groups was optimal. These results indicate that orally administered defibrotide exerts symtomatic benefit in PAD patients and daily doses of 400 or 800 mg seem to be equivalent.

Administration, Oral↗

PubMed1991

Fibrinolytic effects of defibrotide in atherosclerotic patients.

Defibrotide is a polydeoxyribonucleotide salt that shows antithrombotic activity through a suggested profibrinolytic mechanism. To study the effectiveness of defibrotide in atherosclerosis, we evaluated the fibrinolytic and coagulation behavior in normal subjects and patients with atherosclerotic disease, before and after single or repeated intravenous defibrotide infusion. A significant shortening of the ELT was found in all subjects. However, since neither t-PA increase nor PAI decrease was observed, we suggest that the profibrinolytic response to defibrotide may be due to mechanisms other than t-PA stimulation. Our results provide further evidence for the usefulness of defibrotide antithrombotic prophylaxis in atherosclerosis.

Arteriosclerosis↗