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Biomedical subjects

M Mantovani

Publications and source records attributed to M Mantovani.

At least 19 recordsLinked to original sources
PubMed1992

Defibrotide has antiischemic activity in perfused rabbit hearts, preventing tissue Ca++ overloading.

Defibrotide (D), a polydeoxyribonucleotide obtained from mammalian lungs, reduced the ischemic contracture due to low perfusion (0.2 ml/min) of the isovolumic left heart of the rabbit and abolished the irregularity of the rhythm of the heart, thereby restoring the cardiomechanical activity upon reperfusion (20 ml/min). D stimulated the release of PG-like material. Indomethacin infusion completely prevented both the antiischemic activity of D and its ability to increase the generation of prostaglandins in the rabbit heart. Measurement by atomic absorption spectroscopy of calcium content in ischemic heart tissue and its mitochondrial fraction indicated that the ischemic procedure significantly increased tissue calcium content in both. D, Prostacyclin (PGI2) and Nifedipine protected the heart from ischemic ventricular contracture and prevented accumulation of calcium in the heart. The effect of D on preventing Ca++ overload was completely abolished by indomethacin infusion. The results indicate that the beneficial effects of Defibrotide in experimental ischemia are primarily due to a release of Prostaglandin E2 (PGE2) and PGI2, which in turn may inhibit the detrimental effects of calcium overload in myocytes and mitochondria.

Animals↗
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↗
PubMed1991

Enhancement by defibrotide of prostanoid neosynthesis from arachidonic acid: an adenosine receptor-mediated effect?

The antithrombotic and anti-ischemic drug defibrotide is known to enhance PGI2 and prostaglandin E2 release and to interact competitively and agonistically with adenosine A1 and A2 receptors. To elucidate a possible molecular mechanism of action of this drug, we measured prostanoid neosynthesis from exogenous AA in isolated, intraluminally perfused RbA (5 to 10 preparations/group). Defibrotide (30 micrograms/ml) almost doubled the conversion rate of AA (15 micrograms) into PGI2-la (quantitated by a bioassay system): 56.8 +/- 5.3 versus 32.9 +/- 7.8 ng, compared with controls. The adenosine receptor antagonist 8-PT, at concentrations of 0.625, 1, and 1.6 micrograms/ml, dose-dependently and up to 100% inhibited the effect of defibrotide; however, a higher concentration of this latter (100 micrograms/ml) shifted to the right the 8-PT inhibition curve. A second AA bolus given into RbA caused homologous desensitization: 43 and 62% reduction of AA conversion after two versus one bolus was observed in controls receiving 15 and 30 micrograms AA. This phenomenon was inhibited by 30 micrograms/ml defibrotide (32% reduction only at two boluses, instead of 62% displayed by comparable controls), but this effect was abolished by 1.6 micrograms/ml 8-PT; once again, 100 micrograms/ml defibrotide overcame the antagonism by 8-PT. We conclude that defibrotide enhances prostanoid neosynthesis from AA and reduces homologous desensitization of the cyclooxygenase pathway through a mechanism possibly linked to stimulation of adenosine receptors.

Animals↗
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

Plasmapheresis in the therapy of hyperthyroidism associated with leukopenia.

Surgery, the treatment of choice for hyperthyroidism due to nodular goiter, requires an euthyroid state, which is generally achieved with thionamides. Leukopenia is the most serious toxic effect of thionamides, and it causes controindication. We report a 50-year old woman with severe hyperthyroidism and leukopenia, in whom an euthyroid state before thyroidectomy was obtained with the use of therapeutic plasmapheresis. This procedure was carried out immediately before surgery using an intermittent flow separator; three sessions removed a total of 6,300 cc of plasma. Plasmapheresis caused a rapid reduction of both total and free thyroid hormone levels. Thyroidectomy was performed without any complications. Plasmapheresis can be considered a valid and safe method to prepare hyperthyroid patients for thyroidectomy when other therapies are ineffective or counterindicated.

Antithyroid Agents↗
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↗
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↗
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↗
PubMed1976

Hypersomnia with periodic apneas in acquired micrognathia. A bird-like face syndrome.

We describe a syndrome characterized by acquired micrognathia, hypersomnia, and periodic apneas during sleep. Six patients affected with the syndrome underwent nocturnal and diurnal polygraphic recordings that demonstrated that during sleep there is an uninterrupted succession of apneas, primarily the obstructive type, analogous to those observed in Pickwickian syndrome. Simultaneous recording of pulmonary and systemic arterial pressure during sleep and repeated blood gas analyses have shown that as soon as the apneas appear there is a decisive increase in pulmonary and systemic pressure and serious alveolar hypoventilation. The hemodynamic and ventilatory changes are even more intense during rapid eye movement sleep. Tracheostomy, performed on five of our patients, is the only treatment producing complete clinical remission of the syndrome.

Adult↗