PubMed Health⌕ Search

Biomedical subjects

R Pescador

Publications and source records attributed to R Pescador.

At least 19 recordsLinked to original sources
PubMed2001

Antithrombin activity of an algal polysaccharide.

In an effort to reduce the risks of a possible iatrogenic transmission of bovine spongiform encephalitis (BSE) through the use of bovine-derived medicinal products, we patented in the USA in 1999 a polysaccharide from brown algae, endowed with interesting pharmacological activities: (a) concentration-dependent inhibition of thromboplastin or cephalin-kaolin-induced thrombin generation from platelets, (b) concentration-dependent inhibition of thrombin-induced platelet aggregation, (c) thrombin has hypotensive effect, which was blunted and zeroed by our fucansulfate in a dose-dependent way, (d) when aortae are stimulated with thrombin, they become stickier for polymorphonucleated leukocytes (PMNs); our fucansulfate decreased concentration-dependently, PMNs sticking to autologous rabbit aortae, (e) dose-dependent inhibition of thrombin-induced thrombosis. All the above data suggest that our fucansulfate could be a heparin substitute endowed with antithrombotic and anti-inflammatory activities, devoid or the problems caused to heparin by its animal origin, i.e., possible prion protein contamination.

Animals↗
PubMed2000

Defibrotide normalizes cardiovascular function hampered by established atherosclerosis in the rabbit.

In a previous paper we gave evidence that chronic oral defibrotide antagonizes the noxious effect of developing atherosclerosis in the cardiovascular system. In the present paper we give evidence that defibrotide is still capable of exerting beneficial effects on cardiovascular function once atherosclerosis is established. In fact, there was statistically significant amelioration by defibrotide infusion in the following, all of which were hampered by established atherosclerosis: in rabbit aorta relaxation to acetylcholine, prostaglandin E2, and 6-keto-prostaglandin F1alpha generation from rabbit aortas, rabbit heart left ventricular end-diastolic pressure, coronary perfusion pressure, and left ventricular developed pressure, vasopressor activity of acetylcholine and endothelin-1 on coronary perfusion pressure, and 6-keto-prostaglandin F1alpha generation from the rabbit heart. Since prostacyclin takes part in NO generation, is cellular protective, and inhibits 5-lipoxygenase product synthesis, its increase, caused by defibrotide, could explain defibrotide cardioprotective activity. Prostacyclin activity could be backed by prostaglandin E2, another cardioprotective prostaglandin.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Chronic oral defibrotide counteracts hypercholesterolemia noxious effects on cardiovascular function in the rabbit.

The aim of the present work was to assess if the cardioprotective drug defibrotide could counteract the hypercholesterolemia noxious effects on cardiovascular function. Aortas and hearts from normal- or cholesterol-fed rabbits, treated or not with chronic oral defibrotide (100 mg/kg/day) for 45 days, were used in in vitro tests throughout the experiment. Hypercholesterolemia worsened: aorta stickiness toward polymorphonuclear leukocytes, aorta relaxation to acetylcholine, heart left ventricular end-diastolic pressure and coronary perfusion pressure, heart left ventricular diastolic pressure, acetylcholine and endothelin-1 activity on coronary perfusion pressure, and heart generation of 6-Keto-prostaglandin F1alpha. Oral defibrotide counteracted and/or obliterated the above hypercholesterolemia noxious effects. Particularly, oral defibrotide counteracted the parameters associated with early endothelial cell disfunction: that is, increased adherence of leukocytes to endothelium and endothelial vasorelaxation induced by acetylcholine, which acts through the release of endothelium-derived relaxing factor. These activities of defibrotide are probably exerted through the increased generation of prostacyclin. The fact that acetylcholine induced vasorelaxation is partially protected by oral defibrotide points to a partial rescue of endothelial ability to generate endothelium-derived relaxing factor, as acethylcoline acts through the release of endothelium-derived relaxing factor, by defibrotide itself. Defibrotide's endothelial protection could, in turn, explains why defibrotide protected cardiovascular function. This is not surprising as, in a few cases, endothelial dysfunction, observed in hypercholesterolemia, was found to be prevented or reversed, pharmacologically, by PN-2001-10, a calcium channel blocker, dipyridamole, and lovastatin.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Pharmacokinetics, absorption, distribution and disposition of [125I]-oligotide following intravenous or oral administration in the rat.

Oligotide (O) was labelled with 125I. The radiolabelled compound ([125I]-Oligotide ([125I]-O)) retained the biological activity of parent O. Following single intravenous administration the half lives of radioactivity associated with O and/or O related components in plasma were 9-10 min and 9-10 h for alpha and beta phases respectively. Following single oral administration the half life of radioactivity associated with O and/or O related components in plasma was 11.45-12.76 h for beta fase. Following multiple oral administration once daily for 7 days, the half life of radioactivity associated with O and/or O related components following the 7th dose was 10-12 h for beta phase. The areas under plasma total radioactivity versus time curves were dose-dependent. Following single intravenous administration the major proportion of the administered dose was excreted via urine, while following single oral administration excretion via urine and faeces accounted for similar proportions of the administered dose. Following both single and oral administration the levels of radioactive components derived from [125I]-O in organs examined were generally highest in highly perfused organs.

Absorption↗
PubMed1996

Study on pharmacokinetics of radioactive labelled defibrotide after oral or intravenous administration in rats.

Defibrotide (D) was labelled with 125I or with 32P. The radiolabelled compounds ([125I]-Defibrotide ([125I]-D), [32P]-Defibrotide ([32P]-D) retained the same profibrinolytic activity, in vitro, as the parent drug, suggesting that the labelling procedures had not modified the pharmacological properties of D and hence that its chemical structure was not affected significantly. After single intravenous or oral administration of [125I]-D or [32P]-D the pharmacokinetic parameters for the two labels were generally in good agreement (75%). t 1/2 alpha was in the range of minutes while t 1/2 beta was in the range of hours. Bioavailability, following single oral administration of [125I]-D or [32P]-D, was in the range of 58-70%. These data suggest that D, in spite of its macromolecular nature, is absorbed, after oral administration, fairly well.

Administration, Oral↗
PubMed1996

An integrated view of the activities of defibrotide.

Defibrotide is a polydeoxyribonucleotide sodium salt extracted from mammalian organs. Its mean molecular weight is 15,000-30,000 daltons. Defibrotide contains aptamers, i.e., single-stranded polynucleotides with a well-defined base sequence and composition (5'-GGTTGG-ATT-GGTTGG-3' and 5'-GGTTGG-ATC-GGTTGG-3') that bind thrombin. For the time being, these aptamers are the only ones that have been identified in defibrotide, but there may also be other aptamers that bind proteins other than thrombin. Defibrotide has no anticoagulant activity, but in some other aspects it probably parallels heparin. Heparin is a sulfated polysaccharide sodium salt with a mean molecular weight ranging from 5,000 to 40,000 daltons extracted from mammalian organs. It contains disaccharide sequences of well-defined structure and frequency. Heparin binds an array of proteins, enzymes, and growth factors and shows inhibitory or stimulatory or protective activity. Defibrotide has a spectrum of interesting pharmacological properties that make this drug very useful for the treatment of arterial and venous thrombotic diseases. In fact, defibrotide has profibrinolytic, antithrombotic-thrombolytic, anti-ischemic, and antiatherosclerotic activity and protective activity in shock. What have all the above activities to do with a single drug? The explanation is that atherosclerosis, myocardial, renal, and liver ischemia, hemorrhagic and septic shock, and shock induced by occlusion of splanchnic artery and thrombosis are different facets of the same entity: the polyhedric inflammatory process.

Fibrinolytic Agents↗
PubMed1995

Is defibrotide's activity on leukocytes adenosine-receptor mediated? An "in vitro"--"ex vivo" appraisal.

Defibrotide both "in vitro" and "ex vivo" decreases PMN adhesion to nylon columns. This activity is blunted by 8-phenyltheophylline, a known blocker of adenosine A1/A2 receptors, suggesting that Defibrotide acts on that kind of receptors. Indomethacin, a blocker of PGI2 synthesis, did not cancel DFT's activity, suggesting that PGI2 is not involved in DFT's activity, at least under our experimental conditions. Non-PMN leukocytes behaved differently "ex vivo" than PMNs. DFT's activity was not blunted by 8-phenyltheophylline, suggesting that DFT acts on this kind of cell through a different mechanism. The "in vitro" experiment did not confirm "ex vivo" studies suggesting that in the "in vitro" experiment "something" is missing that is present in "ex vivo" experiments.

Animals↗
PubMed1995

Oligotide, a new single-stranded oligodeoxyribonucleotide, preserves postsynaptic beta-adrenergic and cholinergic receptor functions in rabbit hearts after acute infarction.

Acute myocardial infarction was induced in New Zealand male albino rabbits. 3 days after surgery, the mortality rate and plasma CPK activity were reduced by 64% and 66% respectively by intravenous infusion of Oligotide (32 mg/kg/h for 6h), a single-stranded oligodeoxyribonucleotide of mammalian origin. Perfused hearts, obtained from Oligotide-treated rabbits 3 days after surgery, showed a strength of contraction in the range of that of hearts of sham-operated animals and an ameliorated postsynaptic beta-adrenergic and cholinergic receptor function. In addition, in these hearts, "ex vivo" treatment with Oligotide resulted in almost complete preservation of both adrenergic and cholinergic responses to their specific agonists. These data suggest that Oligotide by protecting the hearts from the ischemic damage and possibly by restricting left ventricular tissue necrosis may have normalized the biological responses of this organ to isoproterenol and preserved the integrity of coronary endothelial-dependent relaxant function.

Acetylcholine↗
PubMed1995

Defibrotide's activity on leukocytes and platelets in rabbits with diet-induced atherosclerosis.

Oral Defibrotide decreased leukocyte and platelet counts, raised by cholesterol diet, and the area (%) of aorta endothelial surface involved in atherosclerosis. Frequency of intimal thickening in blood vessels of kidneys and hearts and in cardiac valves was reduced by oral Defibrotide by 47%, 29% and 17%. It is suggested that oral Defibrotide reduced the involvement of the aorta in the atherosclerotic process by acting on leukocytes and platelets, to both reduce their number and deactivate them.

Administration, Oral↗
PubMed1995

Effects of defibrotide on leukocytosis in rabbits with diet-induced atherosclerosis.

The antithrombotic drug Defibrotide (DFT) (a polydeoxyribonucleotide with a mean MW of 20,000 Daltons) reduces the number of leukocytes and platelets in thrombi. Because leukocytes and platelets are of importance in the genesis of endothelial lesions leading to atherosclerosis, DFT was given to challenge leukocytosis in rabbits with diet-induced atherosclerosis (0.25% cholesterol for 16 weeks). After 9 weeks of cholesterol feeding and at the end of experiment, oral DFT (60 mg/Kg per day) had decreased the leukocyte count raised by the cholesterol diet. Leukocyte stickiness and leukocyte differential counts were not modified by either oral cholesterol or by oral cholesterol plus oral DFT. At the end of experiment, oral DFT had normalized the platelet count increased by cholesterol diet. The red blood cell count decreased by oral cholesterol at 9 weeks and at the end of experiment was normalized by DFT. The % of aortae endothelial surface involved in the atherosclerotic process was decreased by oral DFT. The frequencies of intimal thickening in blood vessels of kidneys and hearts and in cardiac valves were reduced by oral DFT by 47%, 29% and 17%, although these reductions were not statistically significant. It is suggested that DFT, by preventing the increase in the number of leukocytes and platelets and deactivating them, as demonstrated in papers already published, was able to counteract against the atherosclerotic process.

Animals↗
PubMed1995

Action of CCK on CDE diet-induced acute pancreatitis in rats treated with hydrocortisone.

The present work studies the effect of previous hydrocortisone administration (10 mg/kg/day) over 7 days on the later development of diet-induced acute pancreatitis in the rat. Acute pancreatitis was induced by feeding a diet deficient in choline and supplemented with 0.5% ethionine (CDE diet) over 10 days. Hydrocortisone pretreatment exacerbated CDE-induced acute pancreatitis. There was a significant increase in serum amylase, pancreatic edema, and haematocrit levels and an insignificant decrease in pancreatic mass in rats pretreated with hydrocortisone. Pancreatic enzyme secretion was strongly reduced in the rats subjected to acute pancreatitis, and although the drop in enzyme levels did not reach statistical significance, the values of secretion were even further reduced in the animals treated with hydrocortisone, pointing to the absence of pancreatic functionality. This effect can be attributed to enzyme storage elicited by previous hydrocortisone administration; activated intracellularly, these enzymes could aggravate the pathology. Administration of the cholecystokinin octapeptide (CCK-8) (10 micrograms/kg/day) during the development of acute pancreatitis in animals pretreated with hydrocortisone substantially improved the general state of the animals' pancreases. There was a significant decrease in serum amylase, pancreatic edema and haematocrit levels in rats injected with CCK, which was accompanied by an increase in pancreatic functionality. Conversely, the administration of L-364,718 (0.1 mg/kg/day), a CCK antagonist, did not improve pancreatic functionality and did not appreciably affect the general state of the organ. It is concluded that in rats with storage levels increased by hydrocortisone administration that are subjected to acute pancreatitis, the secretagogue effect of CCK is more beneficial than the repose of the gland induced by L-364,718.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1995

Effect of chronic administration of hydrocortisone on the induction and evolution of acute pancreatitis induced by cerulein.

The effects of chronic administration of hydrocortisone (10 mg/kg/day) on the development and evolution of acute pancreatitis induced by supramaximal stimulation with cerulein were examined in the rat. In these circumstances the potentially therapeutic effect of L-364,718, a CCK-receptor antagonist, was assayed. Administration of hydrocortisone over 7 days did not increase the severity of edematous acute pancreatitis induced by cerulein, since the reduction in pancreatic secretion, the hyperamylasemia and the increase in the levels of hematocrit and fluid in the pancreatic tissue were similar in rats with acute pancreatitis treated and untreated with hydrocortisone previously. When hydrocortisone was administered chronically, before administration of supramaximal doses of cerulein, a spontaneous regression of acute pancreatitis occurred. However, when hydrocortisone administration was continued after inducing pancreatitis, pancreatic recovery was prevented, observing a significantly depressed acinar secretion and elevated values of hematocrit and tissue fluid (edema). L-364,718 administration proved to be detrimental in the evolution of edematous acute pancreatitis when the rats had been treated chronically with hydrocortisone because the blockade exerted on secretion prevented the draining of enzymes stored in excess by hydrocortisone administration.

Acute Disease↗
PubMed1994

Comparable beneficial effects of defibrotide and nifedipine in calcium induced atherosclerosis.

The present study demonstrates the antiatherosclerotic property of Defibrotide (DFT) in an experimental model in which the pathology is secondary to calcium deposition in the vessel wall and various organs. Rats were treated by gavage for 21 consecutive days with Vitamin D3 and/or, twice a day, with DFT or Nifedipine (N). The calcium contents of aorta, heart and kidney were determined by atomic absorption spectrometry. Specimens of these tissues were examined histologically. DFT or N administered alone did not modify the calcium contents of aorta, heart or kidney. On the contrary, Vitamin D3 caused a huge increase in the calcium concentration in the aorta and in the kidney, whereas the heart content was only double that of control animals. In rats treated with Vitamin D3, contemporaneous administration of DFT or N sharply and highly significantly reduced the aorta calcium concentration and there were less striking, although still significant, reductions in the other two tissues. Histological examination paralleled these data; the effect of DFT or N in reducing the mineralization of aorta and heart was very evident, and more pronounced for DFT. These results confirm that DFT, even though not belonging to the class of the calcium antagonists, has comparable antiatherosclerotic properties, possibly due to its endothelial protective efficacy, as evidenced by the lesser amount of calcium in the aortic tissue.

Animals↗
PubMed1994

Human pharmacokinetics of glycosaminoglycans using deuterium-labeled and unlabeled substances: evidence for oral absorption.

In the present study, the pharmacokinetics of extractive GAGs used as therapeutic agents have been studied after intravenous and oral administration on volunteers. The use of native or deuterium-labeled compounds, followed by HPLC/MS detection, allowed the quantitation of exogenous heparin and DS as major disaccharide fragments, obtained either by enzymatic or chemical depolymerization. In particular the high level of labeling reached in DS allowed its differentiation from structurally related endogenous species. The estimated plasmatic bioavailability was about 18% for DS. Notwithstanding the impossibility of evaluating the same parameters for heparin species, due to the interferences of endogenous GAGs, the results obtained provided clear evidence of oral availability of heparin and DS through detection and quantitation of structures specifically related to these GAGs. Due to the selectivity of the lyases used, the enzymatic degradation specifically allowed the detection of both DS and heparin species still retaining the original sulfation pattern. Additionally, the chemical degradation could detect the main metabolites of the drugs, consisting of partially to totally desulfated GAGs showing a more or less marked reduction in their molecular weight.

Administration, Oral↗
PubMed1993

Pharmacokinetics, absorption, distribution and disposition of [125I]-defibrotide following intravenous or oral administration in the rat.

Defibrotide (D) was labelled with 125I. The radiolabelled compound ([125I]-Defibrotide ([125I]-D)) retained the same profibrinolytic activity as the parent drug. Following single intravenous administration of [125I]-D the half lives of radioactivity associated with D components in plasma were 9.45 min and 11.27 h for alpha and beta phases respectively. Following single oral administration of [125I]-D the half life of radioactivity associated with D components in plasma was 12.83 h for the elimination phase. Bioavailability was apparently 58%. The areas under plasma total radioactivity versus time curves were dose-dependent following both intravenous and oral administration. No significant accumulation of total radioactivity in plasma was observed following multiple oral administration of [125I]-D. Following single intravenous administration of [125I]-D a larger proportion of administered radioactivity was excreted via urine than faeces while following single oral administration excretion via urine and faeces accounted for similar proportions of administered radioactivity. Following both single and oral administration the levels of total radioactivity in tissues and organs examined were generally highest in highly perfused organs and were very high in the thyroid despite pretreatment with non-radiolabelled potassium iodide. Radioactivity was also found to be associated with the aorta wall.

Absorption↗
PubMed1992

High-performance liquid chromatography determination of polydeoxyribonucleotides in plasma: its application to the determination of defibrotide's pharmacokinetics in the rabbit.

We describe an HPLC method for the determination of whole polydeoxyribonucleotides in animal plasma. This method was compared to a colorimetric method, which evaluates the sugar moiety of polydeoxyribonucleotides, and to an agarose gel electrophoresis method, which evaluates the whole polydeoxyribonucleotides as does the HPLC method, and was found to give results very close to those obtained with these two other methods. A pharmacokinetic study of the antithrombotic, profibrinolytic, polydeoxyribonucleotidic drug defibrotide was carried out by evaluating the plasma drug levels by these three methods. The pharmacokinetic parameters calculated from the data are very similar.

Animals↗
PubMed1992

A novel insight into the mechanism of the antithrombotic action of defibrotide.

Defibrotide is a polydeoxyribonucleotide sodium salt with antithrombotic properties. These properties have been attributed to its profibrinolytic activity [increase of tissue plasminogen activator (t-PA) activity, concomitant decrease of that of plasminogen activator inhibitor (PAI)], but there could conceivably be other factor(s). To look for these, we studied Defibrotide in a thrombosis model (pulmonary thromboembolism in mice) in which free radicals play a pivotal role. Defibrotide was found to be active after both intravenous and oral administration. Defibrotide behaved in vitro like a scavenger of H2O2 but not of O2.- in cell-free systems. Defibrotide added in vitro to cellular systems decreased the stimulated release of beta-glucuronidase from polymorphonuclear cells (PMNs), the luminol chemiluminescence induced by oxygen species generated by stimulated PMNs and the generation of O2.- from stimulated macrophages. We think that the antithrombotic activity of Defibrotide is based on other factor(s) in addition to profibrinolytic activity, i.e., some scavenger activity and desensitization of cells involved in thrombus formation must also be taken into account.

Animals↗