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Biomedical subjects

M Mantovani

Publications and source records attributed to M Mantovani.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1986

Gastroprotection and lysosomal membrane stabilization by sulglicotide.

Well-known agents that induce gastric ulcers cause a decrease in lysosomal stability, with release of lytic enzymes. Some antiulcer and cytoprotective agents have lysosomal membrane stabilizing activity when tested in vitro and ex vivo. Sulglicotide (Gliptide), a polysulfated glycopeptide with antiulcer and cytoprotective activities, was able to stabilize lysosomal membranes in vitro at concentrations between 9 and 36 micrograms/ml. The ratio of potency of sulglicotide to that of carbenoxolone was 12.2. In ex vivo experiments in rats, it was found that sulglicotide stabilized lysosomes after oral treatment. The effect was dose-dependent after intravenous treatment. Carbenoxolone, injected i.v. under the same experimental conditions, was less active (potency ratio 0.65). 16,16-dimethyl-PGE2, administered at a dose of 10 micrograms/kg orally or intravenously, had an activity equivalent to that of sulglicotide at a dose of 12.5 mg/kg i.v. or 200 mg/kg p.o. Sulglicotide (200-400 mg/kg p.o.) was also able to prevent the release of acid phosphatase from stomachs challenged for 10 min or 3 h with absolute ethanol. The same result was obtained with 200 mg/kg p.o. of carbenoxolone. These data show that sulglicotide is a potent lysosomal membrane stabilizer in vitro and ex vivo, and could explain the cytoprotective activity of this compound in different experimental models of ulcer.

Animals↗
PubMed1985

Cardioprotective effects of defibrotide in acute myocardial ischemia in the cat.

We investigated the effects of Defibrotide (D), a natural polydeoxyribonucleotide, on acute myocardial ischemia (AMI) in anesthetized cats. A permanent ligature was placed around the left anterior descending coronary artery (LAD) 12-14 mm from its origin. Ventricular fibrillation and death were exceptional and when they occurred the cats were not included in the evaluation. Pretreatment of cats with D, 32 mg Kg-1 h-1, i.v. infusion, maintained throughout the 5 h occlusion period, reduced AMI-ST segment increases and increased the diminished pressure-rate index (PRI). AMI-induced changes in lactate, ATP and CPK in ischemic tissue were prevented by D. PGI2 gave the same results as D. Atenolol prevented the loss of myocardial CPK, but had no favourable effects on lactate and ATP in ischemic tissue. The beneficial effects of D in AMI reported here could be partly attributed to its ability to enhance PGI2 release from vascular walls; D might also relieve ischemia by improvement of local tissue oxygenation, energy supplies and platelet function by its ability to deaggregate platelet clumps.

Acute Disease↗
PubMed1985

[The hormonal response to hypercalcemic stimulation: the difference between male and female young people].

The aim of our study was to evaluate the pattern of response of thyroid Calcitonin (CT) secretory cells in young healthy people after specific stimulation. For this purpose, test of 60'' i.v. calcium infusion in a dose of 4 mg/Kg lean body mass was employed. Blood samples were taken at times-5', 0', 2', 5', 10', 15', and 30' after the infusion, to determine total Calcium (Ca), ionized calcium (Ca++) and CT concentrations. As a result, plasma CT increased significantly (f = 24.51, p less than 0.000001) in both sexes, while males showed stimulated CT values about double than the female ones: the difference was statistically significant throughout the test. In males too, we observed a strong and significant (r = 0.92, p less than 0.01) correlation between ionized calcium increases and CT responses. This correlation was found neither in males as regards total calcium, nor in females. In conclusion, our data confirm the higher CT secretion in males, indicating also a more constant pattern of response in this sex. Eventually, ionized calcium proves to be the real effective provocative stimulus for CT secretion.

Adult↗
PubMed1983

Pharmacokinetics of Defibrotide and of its profibrinolytic activity in the rabbit.

An extensive study of the pharmacokinetics and the pharmacokinetics of the profibrinolytic activity of Defibrotide (D) in the rabbit has been made. a two compartment model was used to describe D's pharmacokinetics. The parameters of drug disposition and the rate constant of release from tissues to central compartment were closely dose-dependent. The dose-response curves for elimination parameters were powers with a negative exponent indicating considerable saturation of this process. As a consequence, the T1/2, Co and AUC were also dose-dependent, as were the parameters describing the decrease in profibrinolytic activity in the blood stream.

Animals↗
PubMed1983

Correlation between structure, fat-clearing and anticoagulant properties of heparins and heparan sulphates.

Heparins and heparan sulphates from different organs, of high purity by accepted criteria, were characterized by chemical and physical (including electrophoretic and 13C-NMR spectroscopic) methods. The fat-clearing activity of these preparations was shown to be correlated with their content of the trisulphated disaccharide units I2S-ANS,6S (L-iduronic acid 2-O-sulphate-N-sulphated D-glucosamino 6-O sulphate). Species with low anti-lipemic activity contained significant proportions (greater than or equal to 30%) of nonsulphated uronic acids (especially D-glucuronic acid), and of D-glucosamino residues undersulphated at C-6, these latter residues being partially N-acetylated. Heparins from beef lung and sheep mucosa, predominantly consisting of trisulphated disaccharide units, displayed consistently higher antilipemic activity than the more heterogeneous pig mucosal heparins. The anticoagulant activity (as determined by the U.S.P., APTT and anti-Xa tests) was not a simple function of the measured physicochemical parameters. Trends were confirmed for pig mucosal heparins being more anticoagulant than beef lung preparations, and low molecular weight (usually undersulphated) species being more active in the anti-Xa test than in the U.S.P. and APTT tests.

Amino Acids↗
PubMed1983

Sulglycotide displays cytoprotective activity in rat gastric mucosa.

Sulglycotide, a well known antisecretory and antiulcer compound, has been further investigated for its ability to protect rat gastric mucosa against extensive necrosis induced by absolute ethanol, NaOH (0.2N) and NaCl (30%). Sulglycotide, which has been compared with cimetidine, displays a dose-dependent cytoprotective activity against the above necrotizing agents. The results obtained indicate that Sulglycotide requires a normal prostaglandin biosynthetic process in order to manifest its antiulcer activity. In fact gastric mucosa from animals treated with Sulglycotide releases in vitro a greater amount of PGl2-like activity; and furthermore no protection was observed against gastric lesions induced by indomethacin. As far as the mode of action of Sulglycotide is concerned it is tempting to speculate that the compound may interfere with prostaglandin degradation or it may trigger an adaptive cytoprotection which is important in maintaining the cellular integrity of rat gastric mucosa.

Animals↗
PubMed1982

An intrauterine progesterone contraceptive system (52 mg) used in pre- and peri-menopausal patients with endometrial hyperplasia.

An intrauterine progesterone contraceptive system (IPCS) (52 mg) was inserted in 25 women with cystic endometrial hyperplasia. Among these women, 11 complained of heavy climacteric symptoms and also received an oestrogen replacement therapy consisting of conjugated oestrogens (0.625 mg/day) administered cyclically for 3 out of 4 wk. Prior to the therapy and after 6 mth of treatment, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), oestrone (E1) and oestradiol (E2) plasma levels were measured and endometrial histology was evaluated. In the women receiving IPCS treatment alone, there were no significant changes in FSH, LH, PRL, E1 and E2 plasma levels. However, there were remarkable changes found in their endometrial histology. In the remaining women receiving both treatments there was a sharp decrease in FSH and LH plasma levels and an increase in E1 and E2 plasma levels, while the prolactin levels remained unchanged. With the exception of two of these women, the endometrial histology changed remarkably. The endometrial morphology of the two exceptions remained unchanged. All climacteric symptoms disappeared after the administration of both IPCS and the oestrogen replacement therapy. The remarkable changes which did occur in the endometrial histology resulted in a less active glandular epithelium and stromal decidual formation, thus proving a useful effect of treatment.

Adult↗