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Biomedical subjects

R Pescador

Publications and source records attributed to R Pescador.

At least 37 records · Page 2Linked to original sources
PubMed1991

Absorption through the peritoneum of the macromolecular profibrinolytic drug defibrotide in the rabbit.

Defibrotide is the sodium salt of a polydeoxyribonucleotide extracted from mammalian lungs by controlled depolymerization. This macromolecular compound (mean molecular weight 20,000 d) has profibrinolytic activity. It also is antithrombotic after both intravenous and oral administration. The purpose of this study was to see whether defibrotide could activate the fibrinolytic system after intraperitoneal administration, because it has been observed that in ascitic patients treated intraperitoneally with defibrotide, no occlusion of the peritoneal-jugular catheter valve draining the ascitic fluid (according to LeVeen et al.) occurred. The profibrinolytic activity of defibrotide and its plasma levels were dose dependent, with a statistically significant correlation between the fibrinolytic activities and the AUC of the plasma levels of defibrotide. No rebound effect was observed during the duration of the experiments (24 hours). We hypothesize that the fibrinolytic activity elicited by defibrotide prevented the deposition of fibrin in the catheter valve, enabling normal drainage of the ascitic fluid. The lack of rebound makes defibrotide a safe drug. The mechanism by which this macromolecular compound is absorbed is still unknown.

Animals↗
PubMed1991

Novel beneficial mechanisms of defibrotide, a prostacyclin enhancing agent in splanchnic artery occlusion and reperfusion in rats.

To further clarify the protective mechanism(s) of defibrotide in splanchnic artery occlusion (SAO) shock, we observed the effect of defibrotide on polymorphonuclear leukocyte (PMN) accumulation in the intestinal tissue, gastric lysosomal hydrolases and endothelial function of the ischemia-reperfused superior mesenteric artery (SMA). Pentobarbital anesthetized rats were subjected to occlusion of both the celiac and superior mesenteric arteries for 90 min followed by 2 h reperfusion. The rats receiving only the vehicle for defibrotide exhibited a marked increase in intestinal myeloperoxidase (MPO) activity and a significant endothelial dysfunction manifested by the loss of endothelium-dependent vasorelaxation. Only 2 of 6 rats (33%) survived 2 h of reperfusion. In contrast, those rats treated with defibrotide exhibited significantly attenuated PMN accumulation in intestinal tissue, enhanced endothelium-dependent vasorelaxation in SMA rings, prolonged survival time and increased survival rate to 6 of 7 (i.e., 86%). However, addition of defibrotide in vitro had no direct effect on LTB4 activated PMN adherence to vascular endothelium. Moreover, defibrotide preserved gastric lysosomal membranes in vitro. These results indicate that the protective effect of intravenous administration of defibrotide on SAO shock may be related to its endothelial preserving effect reducing PMN adherence and protection of endothelial and lysosomal membrane integrity.

Animals↗
PubMed1990

Defibrotide affects the anticoagulant and lipase-releasing activities of heparin.

Defibrotide (DEF), an antithrombotic drug with no anticoagulant activity, given concomitantly with heparin potentiates its effects on thrombin time and lipase-releasing activity. Unlike heparin, DEF has hardly any lipase-releasing activity of its own. Most likely DEF interferes with pharmacokinetics of heparin. It is clear from the data reported here that when used in combination with DEF heparin should be administered at low doses and the coagulation parameters carefully followed.

Animals↗
PubMed1990

7-Substituted theophyllines. Part VI--N-[2-(4-chlorophenoxy)-1-phenyl-alkyl]-alkylamido derivatives.

The new amides are inhibitors of cholesterol biosynthesis in vitro as well as in vivo. These compounds are also inhibitors in vivo of triglyceride biosynthesis and of platelet aggregation. All tests showed activity (values expressed as percentage variation) much greater than clofibrate. Besides, all compounds have no effect on coagulation or diuresis and showed low acute toxicity.

Animals↗
PubMed1989

Profibrinolytic activities of chemically modified heparins with very low anticoagulant activities.

Many evidences indicate that heparin is an activator of fibrinolysis, but the most important side effect of heparin is bleeding which is a problem particularly in the high risk patient. Here we describe how chemical modifications, associated with separation techniques, can sharply reduce the anticoagulant activities of a heparin while its ability to stimulate fibrinolysis is retained.

Animals↗
PubMed1989

Defibrotide decreases cholesterol amount in hypercholesterolemic rabbit aorta, with no modification of plasma or lipoprotein cholesterol.

Defibrotide, (D) an antithrombotic agent, when administered i.v. to cholesterol-fed rabbits decreased cholesterol in the aorta without changing total plasma cholesterol, triglyceride or phospholipid, nor the cholesterol, triglyceride, phospholipid and protein of plasma lipoproteins. Platelet aggregation was decreased in rabbits treated with D. There were fewer vascular lesions in the hearts and kidneys of animals treated with D than in animals fed cholesterol and treated with placebo. These data suggest that the antithrombotic activity of D and its ability to reduce platelet sensitivity could help to reduce the amount of cholesterol in the cardiovascular system in atherosclerosis-prone situations.

Adenosine Diphosphate↗
PubMed1989

Thrombolytic activity of defibrotide against old venous thrombi.

The age of the thrombus is probably a very important determinant of the outcome of thrombolysis. The clinical potential for rapidly dissolving thrombi by thrombolytic therapy is considerable because restoration of the blood flow can rescue the jeopardized district served by the occluded vessel such as for myocardial infarction, deep vein thrombosis, arterial thrombosis, pulmonary embolism, and occlusion of retinal vessels. Defibrotide was effective against 3-, 7-, or 10-day-old thrombi; its ED50s were 32, 65, or 118 mg/kg-1 hour-1, respectively, suggesting that the age of the thrombus could play a role in the outcome of thrombolysis. A similar pattern was also shown for urokinase.

Animals↗
PubMed1987

The anticoagulant, hepatic lipase-releasing and lipoprotein lipase-releasing activities of several natural and chemically modified heparins differ.

Several 'natural' heparins have been found to have different potencies for releasing hepatic lipase and lipoprotein lipase. These differences can also be obtained by treating heparins with physical and chemical methods, which also affect the anticoagulant activity. These differences in potency in hepatic lipase-releasing activity are discussed in terms of the role of this lipase in lipoprotein and cholesterol metabolism.

Animals↗
PubMed1986

Protective activity of defibrotide against lethal acute myocardial ischemia in the cat.

Defibrotide (D) is a natural polydeoxyribonucleotide from mammalian lungs with profibrinolytic and antithrombotic activities. D also has PGI2-stimulating and tissue plasminogen activator (TPA)-releasing activities, but has no anticoagulant properties. The protective effects of D were demonstrated very recently in a model for non-lethal ischemia in the cat. In the experiments reported here Defibrotide was tested in a model for acute myocardial ischemia leading to ventricular fibrillation (VF) and death of the cat. Occlusion of the coronary artery (LAD) at its origin induced VF and death in 17 of 20 control cats. When cats were treated with D (32 mg Kg-1, bolus i.v., + 32 mg Kg-1 h-1, i.v., after LAD occlusion) 19 of 20 animals survived until the end of experiments. D also prevented changes in plasma and myocardial CPK, hemodynamics and ECG. D was compared with a variety of pharmacological agents which are used clinically for specific cardiovascular diseases. The ability of D to promote considerable generation of PGI2 from vascular walls plus its ability to prevent the decreases in CPK-activity and ATP in the myocardial tissue may have roles in its beneficial effects against ischemic heart in the cat. However, the mechanism/s of the substantial protective effect of D against cardiac death has still to be clarified.

Animals↗
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

Cardioprotective effects of defibrotide in acute lethal and nonlethal myocardial ischemia in the cat.

We evaluated the effects of defibrotide (D), a natural profibrinolytic and antithrombotic agent with endogenous PGI2-stimulating properties, on acute lethal and nonlethal myocardial ischemia (L-AMI and NL-AMI) in the cat. The coronary artery was occluded at 12-14 mm from its origin. In L-AMI, 12 of 15 control cats developed ventricular fibrillation and died; D (32 mg kg-1, bolus intravenously plus infusion) provided total protection against death and showed protective effects on plasma and myocardial creatine phosphokinase (CPK), hemodynamics and ECG. In NL-AMI, pretreatment of cats with D at the same dosage (intravenous infusion) reduced AMI-ST segment increases and AMI changes in hemodynamics. AMI-induced changes in lactate adenosine triphosphate and CPK in ischemic tissues were prevented by D. The beneficial effects of D in NL-AMI could be partly attributed to its stimulatory effect on vascular PGI2 release; the mechanism of the impressive protection by D observed in L-AMI has still to be elucidated.

Adenosine Triphosphate↗
PubMed1986

Retention of antilipemic activity by periodate-oxidized non-anticoagulant heparins.

Heparin preparations with different anticoagulant and antilipemic (fat-clearing) activities were oxidized with periodate under conditions of cleavage of all the C(2)-C(3) bonds of non-sulfated uronic acid residues, while preserving the original molecular weight of the polysaccharide. Periodate-oxidised heparins (oxyheparins, O-HEP) and the corresponding borohydride-reduced products (reduced oxyheparins, RO-HEP) were compared with the original heparins for their content in trisulfated disaccharide sequences (as determined by 13C-nuclear magnetic resonance) and in active sites for antithrombin-III (as determined indirectly by affinity chromatography), and for their anticoagulant and antilipemic (lipoprotein lipase-releasing) activities. The drop of anticoagulant activity induced by periodate oxidation was paralleled by a substantial decrease of affinity for antithrombin, and is thought to arise from glycol splitting at the level of the D-glucuronic acid residue that is part of the active site for antithrombin. The trisulfated disaccharide sequences and the associated antilipemic activities were substantially unaffected by periodate oxidation. The residual anticoagulant activity of periodate-oxidized heparins obtained from preparations - such as those from beef lung - rich in trisulfated disaccharide sequences is discussed in terms of the influence of charge density on heparin-protease interactions not mediated by antithrombin.

Animals↗