Exploring new non-sugar sulfated molecules as activators of antithrombin.

New non-sugar, small, sulfated molecules, based on our de novo rationally designed activator (-)-epicatechin sulfate (ECS), were investigated to bind and activate antithrombin, an inhibitor of plasma coagulation enzyme factor Xa. For the activators studied, the equilibrium dissociation constant (K(D)) of the interaction with plasma antithrombin varies nearly 53-fold, with the highest affinity of 1.8 microM observed for morin sulfate, while the acceleration in factor Xa inhibition varies 2.6-fold. The results demonstrate that antithrombin binding and activation is a common property of these small sulfated molecules and suggests plausible directions for designing more potent activators.

Fondaparinux sodium.

black triangle Fondaparinux sodium, a selective factor Xa inhibitor, is the first in a new class of antithrombotics. It binds selectively with high affinity to antithrombin III and specifically catalyses the inactivation of factor Xa. The elimination half-life of fondaparinux sodium permits once daily treatment. black triangle A randomised, double-blind, parallel-group, dose-ranging, multicentre phase IIb study in 933 eligible patients established that a subcutaneous dose of between 1.5 and 3mg of fondaparinux sodium has the optimum efficacy and safety profile for prophylaxis of venous thromboembolism in patients undergoing major orthopaedic surgery. black triangle Fondaparinux sodium, given to more than 3600 patients undergoing major orthopaedic surgery who participated in prospective, randomised, double-blind, multicentre phase III clinical trials, significantly reduced the incidence of venous thromboembolism, with an overall risk reduction of 55.2% compared with enoxaparin. black triangle Fondaparinux sodium was well tolerated by patients undergoing major orthopaedic surgery, and at the recommended clinical dose of 2.5mg has a similar tolerability profile, including bleeding events, to standard enoxaparin regimens. Fondaparinux sodium has not been reported to cause antibody-induced thrombocytopenia.

Pharmacokinetic properties of LMW-heparin-tyramine fractions with high or low affinity to antithrombin III in the rat.

We have recently presented evidence that a macrophage scavenger receptor-mediated pathway is responsible for the hepatic uptake of unfractionated heparins and low-molecular-weight heparins (LMWHs) in the rat. The same receptor-mediated pathway was partially responsible for the removal of oxidized low-density lipoprotein. Unfractionated and fractionated LMWHs exert their anticoagulatory effects predominately by reversibly binding to the plasma glycoprotein antithrombin III. In this study LMWHs modified by endpoint attachment of tyramine were radiolabeled and their fractions with low or high affinity to AT-III studied in vivo in rats. The high-affinity fraction was predominately cleared from the circulation by a hepatic uptake mechanism. About 25% of the injected high-affinity tracer material was recovered, whereas only about 8% of the low-affinity material was found in the liver after 180 minutes. Blocking the scavenger receptor-mediated liver RES uptake mechanism by maleylated bovine serum albumin led to a considerable decline in liver uptake (9 versus 25%). The low-affinity material was rapidly eliminated into the urine after 180 minutes. About 45% of the low-affinity material was excreted versus 23% of the high-affinity material. Tight binding to AT-III prevented LMWH-tyramine from being rapidly cleared from the circulation via the kidneys into the urine; instead, the scavenger receptor-mediated hepatic uptake mechanism seemed to be more dominant in removing material with high affinity to AT-III from blood.

New data on the pharmacology of heparin and low molecular weight heparins.

Studies on the pharmacological and pharmacodynamic properties of heparins are complicated by the heterogeneity of heparin preparations. It is important to consider the molecular weight distribution, which may differ from one preparation to another. Molecules with a molecular weight ranging from about 2000 to 5000D are abundant in low molecular weight heparins (LMWHs), while they are present at a very low concentration in standard heparin. The clinical relevance of this difference is not fully understood. Recent work from our laboratory demonstrates that factor VII activation to factor VIIa in vitro is significantly inhibited by heparins. This is another aspect of some importance in understanding the mechanism of action of heparins. The bioavailability and plasma clearance of anti-Xa activity are well documented. In contrast, clear results regarding the bioavailability of anti-IIa activity are still missing. Recent data indicate that the anti-Xa activity of different molecules of heparin does not increase in parallel with the molecular weight of the heparin chain. In contrast, the anti-IIa activity of different molecules of heparin increases in parallel with the molecular weight. This could explain why activated partial-thromboplastin time is less prolonged with LMWHs than with standard heparin. There is growing evidence that anti-Xa activity contributes to the antithrombotic effect of heparins, although it is generally accepted that anti-IIa activity plays a major role. There have been 3 important findings from recent work on the pharmacology of heparins: i) heparin at a very low dose has thrombopoietic activity; ii) in hip surgery, the incidence of heparin-induced thrombocytopenia is significantly lower in patients receiving subcutaneous LMWHs for 2 weeks compared with patients receiving unfractionated heparin; and iii) the risk of osteoporosis with long term treatment with LMWHs seems lower than with standard heparin.