Studies of chemical and biologic properties of a fraction of sulodexide, a heparin-like glycosaminoglycan.

The chemical composition and biologic properties of a fraction (f) of Sulodexide, a heparin-like GAG, were studied and compared with those of two sulfated GAG preparations and heparin from intestinal mucosa. f-Sulodexide and the sulfated GAG preparations were fractionated on a Dowex-1Cl- column and subsequently on an antithrombin III affinity column. Low affinity and high affinity fractions had similar chemical composition and lipoprotein lipase releasing ability, but they varied in anticoagulant activity. Low affinity fractions from f-Sulodexide had negligible anticoagulant activity while high affinity fractions had one-half the activity of mucosal heparin. When compared to heparin, both fractions had one third amount of lipoprotein lipase releasing activity. The low anticoagulant activity of f-Sulodexide suggests a suitability for long-term use as an antiatherogenic agent.

Heparinizable materials (III). Heparin retention power of a poly(amido-amine) either as crosslinked resin, or surface-grafted on PVC.

The retentive power of a poly(amido-amine), in the form of a highly hydrophilic crosslinked resin, has been evaluated at different pH's. The resin releases heparin quantitatively in a very narrow pH range (10.8-11.4). This poly(amido-amine) has also been grafted on PVC tubes, and the heparin-adsorbing capacity of the materials so obtained has been tested biologically. In this case heparin is only released at pH greater than 10 so confirming the strong interaction between our polymer and heparin.

Antithrombotic activity of a glycosaminoglycan (sulodexide) in rats.

Glycosaminoglycans extracted from various sources are extensively utilized in the treatment of occlusive vascular disease. These products have shown to possess antithrombotic activity in some experimental thrombosis (1,2). Our purpose was to study the activity of Sulodexide, an heparin-like compound (3,4), on rat model of arterial thrombosis and to study its interaction with platelets.

Prostaglandins and cyclic nucleotides as effectors in non-lymphocyte mediated surveillance processes ( short review).

This paper reviews the evidence pointing to a role of prostaglandins and cyclic AMP in the regulation of surveillance processes against transformed cells carried out by activated monocytes macrophages and natural killer (NK) cells. Specific topics of discussion include: (a) the regulation of monocyte/macrophage system and NK cells by prostaglandins and cyclic AMP; and (b) the possible immunomodulatory role of thromboxanes generated by activated monocytes and macrophages. Also the role of cyclic AMP dependent and independent protein kinases as well as their link with oncogenes is briefly reviewed.

The effect of 6-keto-prostaglandin E1 on human lymphocyte cAMP levels.

6-keto-PGE1 was capable of increasing cyclic AMP levels of peripheral human blood lymphocytes in a dose and time dependent fashion. The response was maximal after 30 min of incubation at 37 degrees C; 1 microgram per ml of 6-keto-PGE1 elevated cyclic AMP levels 5 fold which compares with a 10 fold increase due to PGE1. Thus 6-keto-PGE1 may play a role as a modulator of lymphocyte function.

Interaction of a new low molecular weight heparin (OP/LMWH) with human platelets.

In vitro platelet proaggregating effect of unfractionated heparin (H) and OP/LMWH were studied with human platelets. OP/LMWH produced a significant less potentiation of ADP and PAF induced aggregation and slightly counteracted the antiaggregating effect of PGI2, in comparison with H. The proaggregating effect of both heparins was neutralized by equal contemporaneous amount of protamine sulfate.

Comparison of the antithrombotic and haemorrhagic effects of heparin and a new low molecular weight heparin in rats.

A new low molecular weight heparin (LMWH) and a conventional unfractionated heparin (H) were tested in rats for venous antithrombotic activity and bleeding tendency after intravenous administration. Both drugs showed antithrombotic activity, but LMWH at the low dosages tested (0.1 and 0.25 mg/kg) demonstrated significantly higher activity than H. In a rat bleeding time test (transection model) both heparins produced a prolonged bleeding time, but LMWH possessed significantly less potency than H at all the dosages tested. Ex vivo coagulation parameters (activated partial thromboplastin time and antiXa activity) were also evaluated: LMWH presented very low activity on the APTT test and a sustained antiXa activity, comparable to that of H.

Pharmacokinetics and distribution of a fluoresceinated glycosaminoglycan, sulodexide, in rats. Part I: Pharmacokinetics in rats.

Fluorescein-labelled sulodexide pharmacokinetics and urinary excretion were studied in the rat after intravenous administration. The compound showed a pharmacokinetic pattern similar to that of heparin and the plasmatic levels were linearly correlated with anti-factor Xa activity and logarithmically with lipoprotein lipase activation. The compound is well eliminated by urinary route; the urinary recovery was 50% in 24 h and 67% 48 h after administration. The results obtained indicate that fluorescein labelling of glycosaminoglycans may be a valid tool for pharmacokinetics and distribution studies in the laboratory animals.

Regulation of cyclic AMP levels in human lymphocytes and lymphoblasts by prostaglandins.

The sensitivity of human lymphocytes to prostaglandins was compared to that of two lines of cultured lymphoblasts. It was found that 25 nM PGE1 increased lymphocyte cyclic AMP levels twofold, but had no effect on lymphoblasts. At 2.8 micrometers PGE1 the increase of cyclic AMP in lymphocytes was 14 fold versus a 1-3 fold increase in lymphoblasts. Lymphoblasts maintained a response to 6-keto-PGE1, isoproterenol and histamine similar to that observed in lymphocytes. Thus, it appears that the rapidly proliferating lymphoblasts excape signals inhibiting proliferation by impairing the function of the PGE receptor.

Antithrombotic effect of OP/LMWH by subcutaneous route in rats.

The aim of this study was to compare the antithrombotic and haemorrhagic effects of unfractionated heparin and OP/LMWH, a new low molecular weight heparin fragment, after subcutaneous administration in rats. Both heparins showed antithrombotic efficacy in a model of acute venous thrombosis even at 1 mg/kg; furthermore OP/LMWH presented a significantly higher activity in subacute venous thrombosis of the rat. At all the dosages tested OP/LMWH showed a significantly shorter bleeding time in the rat by the "transection" method, compared with unfractionated heparin. This study suggests the possibility of dissociating the antithrombotic and haemorrhagic effects of some heparin fractions.

Pharmacokinetics and organ distribution in rats of a low molecular weight heparin.

Fluorescein-labelled low molecular weight heparin (OP/LMWH) pharmacokinetics and organ distribution were studied in the rat after intravenous administration at doses of 3 and 15 mg/kg. The pharmacokinetics of labelled OP/LMWH was dose-dependent like heparin, however, the anticoagulant activity such as anti-Xa was more prolonged. The rapidity of the disappearance of the fluorescence was quicker than the biological activity. The fluorescence was observed mainly in the liver and kidney as a diffuse aspect in the short time and as a globular aspect in the long time, mainly in Disse's space of the liver. These results confirm that the liver is important in the regulation of heparin metabolism and activity.

Pharmacokinetics and distribution of a fluoresceinated glycosaminoglycan, sulodexide, in rats. Part II: Organ distribution in rats.

Fluorescein-labelled sulodexide tissue distribution was studied in the rat after intravenous administration at the dosage of 15 mg/kg. A globular fluorescence was observed mainly in the extracellular matrix and a diffuse one was present in liver and kidney parenchyma lasting for a long time, up to 4 h after administration. In particular in the kidney cortex the fluorescent material was present at the higher time intervals. Fluorescence was also observed in the spleen and in the perivascular areas and in the media of the aortic wall.

Effect of SAS 650 (Furofenac) on malondialydehyde production by platelets.

The activity of SAS 650, a new anti-inflammatory drug, on ex vivo and in vitro MDA production by platelets was compared to that of aspirin. The drug induced dose-dependent inhibition of in vitro MDA production by rat and guinea-pig platelets and also had good activity after 30 second of incubation in rat platelets, quicker than aspirin. SAS 650 preincubation reduced the in vitro inhibitory effect of ASA, as shown also by ex vivo experiments. The results of the present study support the involvement of SAS 650 in the platelet cyclooxygenase pathway.