Beneficial Effects of Defibrotide against Myocardial Ischemia and Decline of β-Adrenoceptor Function in the Rabbit

Berti, F.; Rossoni, Giuseppe; Niada, R; Omini, C.; Pretolani, Marina; Mandelli, C.

doi:10.1159/000215334

Cited by 4 publications

(2 citation statements)

References 7 publications

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“…Defibrotide is a polydeoxyribonucleotide of mammalian origin with antithrombotic activity in arterial and venous experimental thrombosis. 1,2 The effect was related at least partly to the enhancement of prostanoid metabolism, in particular to the in crease of prostacyclin generation from arterial wall, 2,3 but this effect was not definitely proved in human beings. 4 More attractive is the activation of the fibrinolytic system that was demonstrated by the shortening of uglobulin lysis times after intravenous defibrotide administration.…”

mentioning

confidence: 99%

Inhibition of Tissue Plasminogen Activator Inhibitor by Defibrotide in Atherosclerotic Patients

Violi

Ferro²,

Alessandri³

et al. 1989

Semin Thromb Hemost

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Defibrotide, an antithrombotic drug, was previously shown to activate fibrinolysis. In order to elucidate the relationship between defibrotide treatment and fibrinolysis, ten atherosclerotic patients were given 1200 mg/day defibrotide intravenously for 7 days and then 400 mg/day intramuscularly for another 20 days. t-PA antigen assessed before and after venous occlusion was not affected by the treatment. Tissue PAI activity significantly decreased and t-PA activity, measured after venous occlusion, increased after 8 and 28 days of treatment; both these changes disappeared after defibrotide was discontinued. No particular side effects were detected throughout the investigation. The study suggests that defibrotide increases t-PA activity by reducing PAI activity.

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mentioning

confidence: 99%

Inhibition of Tissue Plasminogen Activator Inhibitor by Defibrotide in Atherosclerotic Patients

Violi

Ferro²,

Alessandri³

et al. 1989

Semin Thromb Hemost

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“…Thus, all further experiments were carried out according to our standard procedure in which calcium and magnesium are used at the final concen tration of 1 mM each. In other studies, dif ferent times of preincubation (1,4, and 20 h) were employed. It was observed that the maximum effect of D could be observed when monocytes were pretreated with the drug for 20 h before adding FMLP or A23187 (in 3 determinations in response to 1 pMFMLP, inhibition was 16 ± 4, 23 ± 2 and 37 ± 5% at 1,4 and 20 h, respectively; likewise, inhibition of A23187-induced O2 generation was 10 ± 2, 13 ± 6 and 22 ± 5 % at 1, 4 and 20 h, respectively).…”

Section: Effect O F Defibrotide On Monocyte Oj Generationmentioning

confidence: 99%

In vitro Inhibition by Defibrotide of Monocyte Superoxide Anion Generation: A Possible Mechanism for the Antithrombotic Effect of a Polydeoxyribonucleotide-Derived Drug

Cirillo¹,

Margaglione²,

Vecchione³

et al. 1991

Pathophysiol Haemos Thromb

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In an attempt to elucidate the antithrombotic potential of defibrotide (D) we have evaluated several functions of monocytes from 7 healthy subjects before and after in vitro incubation of the cells with increasing concentrations of this drug. At concentrations as high as 40 μg/ml, D hardly affected the expression of both the procoagulant activity of monocytes and the formation of superoxide anion in response to 1 mg/ml zymosan (STZ). In contrast, at concentrations that may be achieved in vivo following the administration of the drug (5–20 μg/ml), D impaired in a dose-dependent manner (p < 0.05) the generation of O^-₂ in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP, 1 μM) or calcium ionophore A23187 (10 μM). Regardless of the agonist employed, at concentrations between 1 and 5 mM, extracellular Ca²⁺ had little effect on the impairment of superoxide anion generation by D. In contrast, the inhibitory effect was time-dependent, the maximum impairment ( > 30%) being observed when the cells were preincubated with the drug for 20 h. These data support the concept that the antithrombotic potential of D involves the ability of the drug to affect the generation of free radicals by leukocytes and suggest that future in vivo studies for the evaluation of the activity of D should take into account the role of monocytes in hemostasis and thrombosis.

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Novel mechanism of action of a prostacyclin enhancing agent in haemorrhagic shock

Bitterman

Lefer

1988

Naunyn-Schmiedeberg's Arch Pharmacol

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Prostacyclin (PGI2) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane stabilizing agent with beneficial effects in ischemia and shock. We studied defibrotide, a new agent which enhances PGI2 release from vascular tissue, to determine its effects in a murine model of hemorrhagic shock. Hemorrhaged rats treated with defibrotide maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving the vehicle (final MABP, 100 +/- 3 vs. 69 +/- 7 mm Hg, p less than 0.01). Defibrotide attenuated the release of the lysosomal hydrolase cathepsin D (p less than 0.02), and the plasma accumulation of free amino-nitrogen groups (p less than 0.02). The plasma activity of a myocardial depressant factor (MDF) was significantly lower in defibrotide treated shocked rats than in the vehicle group (29 +/- 4 vs. 61 +/- 8 U/ml, p less than 0.01). Moreover, plasma i6-keto-PGF1 alpha concentrations increased 3-fold above haemorrhaged rats receiving only the vehicle. This, as well as the improved MABP, was abolished by indomethacin. Additionally, defibrotide exerts an anti-proteolytic action in pancreatic homogenates, and a lysosomal stabilizing effect in large granule fractions of rat liver homogenates. Moreover, defibrotide enhanced the recovery from norepinephrine induced vasoconstriction in rat aortic rings having an intact endothelium (p less than 0.01 from vehicle), and augmented the release of i6-keto-PGF1 alpha, the stable metabolite of PGI2, from isolated rat aortae. Our results indicate that enhancement of endogenous vascular PGI2 release coupled with direct, or PGI2 mediated antiproteolytic and membrane stabilizing actions may be important physiological mechanisms counteracting the deleterious effects of hemorrhagic shock.

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Beneficial Effects of Defibrotide against Myocardial Ischemia and Decline of β-Adrenoceptor Function in the Rabbit

Cited by 4 publications

References 7 publications

Inhibition of Tissue Plasminogen Activator Inhibitor by Defibrotide in Atherosclerotic Patients

Inhibition of Tissue Plasminogen Activator Inhibitor by Defibrotide in Atherosclerotic Patients

In vitro Inhibition by Defibrotide of Monocyte Superoxide Anion Generation: A Possible Mechanism for the Antithrombotic Effect of a Polydeoxyribonucleotide-Derived Drug

Novel mechanism of action of a prostacyclin enhancing agent in haemorrhagic shock

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