sanorg-34006 and Thrombosis

The elucidation of the structure of the antithrombin binding sequence in heparin has given a large impulse to the rational design of heparin related drugs. De novo chemical synthesis of the corresponding pentasaccharide as well as simplified analogues has provided very specific, antithrombin-mediated inhibitors of factor Xa with various pharmacokinetic profiles. Fondaparinux and idraparinux are examples of such compounds that have found clinical application as antithrombotics. Because of the very specific binding to antithrombin the pharmacokinetics of pentasaccharides can be predicted and transferred to other molecules covalently bound to them. The new chemical entities thus obtained display a wide array of antithrombotic activities, giving improved heparin molecules as well as new anticoagulants, devoid of the undesired side effects of heparin and with unprecedented pharmacological profiles. In this context, a direct thrombin inhibitor was covalently coupled to a pentasaccharide by an inert spacer. This compound, EP42675 exerts antithrombin mediated anti-factor Xa activity together with direct thrombin inhibiting capacity. It displays favourable pharmacokinetics as imposed by the pentasaccharide. EP42675 was further modified by the introduction of a biotin moiety in its structure. The new entity obtained, EP217609 exerts the same pharmacological profile as EP42675 and it can be instantaneously neutralised by injection of avidin. Due to this unprecedented mechanism of anticoagulant activity and its ability to be neutralised, EP217609 deserves to be investigated in clinical settings where direct thrombin inhibition is required.

Topics: Animals; Anticoagulants; Antithrombin III; Avidin; Binding Sites; Biotin; Drug Design; Factor Xa Inhibitors; Fondaparinux; Heparin; Heparin Antagonists; Humans; Molecular Structure; Oligosaccharides; Polysaccharides; Rabbits; Structure-Activity Relationship; Thrombosis

Idraparinux is an analogue of fondaparinux binding with high affinity to antithrombin. It was designed for weekly, rather than daily, administration, with an exceptionally long half-life. One potential problem with small heparin-like fragments of this type is the difficulty of neutralising excessive activity in the case of side-effects or overdose. The efficacy of idraparinux was was proven in clinical studies with patients suffering from venous thromboembolism (VTE) or atrial fibrillation. Due to major bleeding events during treatment for more than six months the development of idraparinux was stopped. Idrabiotaparinux has an attached biotin moiety at the non-reducing end unit, which allows its neutralisation with avidin, an egg-derived protein with low antigenicity. This compound is currently investigated in clinical trials for prevention of recurrent VTE in patients with acute pulmonary embolism. The future of idrabiotaparinux depends also on the safety and efficacy of avidin.

Topics: Animals; Anticoagulants; Antithrombin III; Atrial Fibrillation; Avidin; Biotin; Carbohydrate Conformation; Carbohydrate Sequence; Drug Design; Drug Evaluation, Preclinical; Fondaparinux; Hemorrhage; Heparin Antagonists; Humans; Molecular Sequence Data; Molecular Structure; Oligosaccharides; Polysaccharides; Randomized Controlled Trials as Topic; Structure-Activity Relationship; Thrombosis; Treatment Outcome

Indirect systemic and direct oral factor Xa and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Glycine; Humans; Infusions, Parenteral; Morpholines; Oligosaccharides; Piperazines; Prothrombin; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Thrombosis; Venous Thromboembolism

Shortcomings of the existing anticoagulants, vitamin K antagonists and heparins, have led to the development of newer anticoagulant therapies. In particular, Vitamin K antagonists' slow onset of action, numerous drug interactions, narrow therapeutic window and need for frequent monitoring make it the most obvious target for replacement. Targeting specific coagulation enzymes or steps in the coagulation pathway, new anticoagulants have been or are under evaluation in clinical trials for a number of clinical indications, namely the prevention and treatment of venous thromboembolism, the prevention of ischemic stroke in patients with atrial fibrillation, and in acute coronary syndromes. Following a brief review of pharmacological aspects, this article will summarize the results of Phase III clinical trials evaluating the novel anticoagulants fondaparinux, ximelagatran and idraparinux. At present, most attention is directed at developing an oral anticoagulant to replace vitamin K antagonists for prevention of systemic thromboembolism. A number of newer agents are in both early and advanced stages of investigation.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Thromboembolism; Thrombosis; Venous Thrombosis

Modern approaches to prevention of venous thromboembolic complications in patients with chronic heart failure are analyzed in this review which contains results of large studies of low molecular weight heparins. In MEDENOX trial the use of enoxaparin in medical patients was associated with 63% reduction of risk of thrombosis. The authors own experience showed that 2 weeks of therapy with enoxaparin in patients with chronic stage IIB-III heart failure caused significant lowering of soluble fibrin-monomer complexes, fibrinogen, and index of turbo-dynamic potential. These changes evidenced for decreased intravascular blood coagulation. Thus enoxaparin can be effectively used for prevention of thrombosis and thromboembolism in patients with chronic heart failure. Novel antithrombotic agents fondaparinux, idraparinux, ximelagatran, recombinant thrombomodulin are perspective medications for prevention of venous thromboses and embolism in medical patients.

Topics: Anticoagulants; Azetidines; Benzylamines; Dalteparin; Double-Blind Method; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Heart Failure; Humans; Multicenter Studies as Topic; Oligosaccharides; Placebos; Polysaccharides; Randomized Controlled Trials as Topic; Risk Factors; Thromboembolism; Thrombomodulin; Thrombosis; Time Factors; Venous Thrombosis

Antithrombotic drugs: heparins and oral vitamin K antimetabolites are connected with many side effects, which delimit their application in clinical practise. Continuous research has led to synthesis of new drugs which are safer and easier in use. Actually used antithrombotic drugs with their faults are discussed. Mechanism of action and data from trials relating to efficacy and safety of new drugs: fondaparinux, idraparinux and ximelagatran are presented.

Topics: Azetidines; Benzylamines; Fibrinolytic Agents; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Thrombosis

Idraparinux sodium [SANORG 34006, SR 34006], a synthetic, anti Xa pentasaccharide and analogue of SR 32701 and fondaparinux sodium, was in development with Sanofi (now Sanofi-Synthélabo) and Organon (Akzo Nobel) in Europe and the USA (now Sanofi-Synthélabo alone). It may have potential in the treatment and secondary prevention of thrombosis, especially deep-vein thrombosis (DVT). Because of the long duration of action of idraparinux sodium, it may be suitable for once-weekly administration. In January 2004, Sanofi-Synthélabo announced it was to acquire, before the end of the first quarter 2004, all the rights of Organon relating to idraparinux sodium, subject to approval of the regulatory authorities. Sanofi-Synthélabo is to make payments to Organon based on future sales. Idraparinux sodium has completed phase IIb development with the PERSIST study and it is in phase III clinical trials. In June 2003, Organon announced the initiation of pivotal phase III studies as a once-weekly treatment of DVT and pulmonary embolism (PE), and for the prevention of stroke in patients with atrial fibrillation. The AMADEUS study will focus on patients with atrial fibrillation while the Van Gogh PE, Van Gogh DVT and the Van Gogh extension (EXT) will focus on patients with DVT or PE.

Topics: Animals; Drugs, Investigational; Fibrinolytic Agents; Humans; Oligosaccharides; Thrombosis

In order to obtain a neutralizable antithrombotic, a chimeric molecule (SSR126517E) containing the sequence of a long-lasting antithrombin (AT)-dependent anti-factor Xa pentasaccharide, idraparinux, linked to a biotin molecule was synthesized and tested for anticoagulant and antithrombotic activity.. SSR126517E was tested in several models in vitro and in vivo for its pharmacological properties as well as its ability to be neutralized by avidin.. SSR126517E displayed exactly the same properties as idraparinux. In vitro, SSR126517E had a very high affinity for AT (K(d) < 1 nm) and showed a potent anti-FXa effect and inhibition of thrombin generation with IC(50) values similar to those of idraparinux. Ex vivo, after intravenous administration to rats, SSR126517E produced a potent and long-lasting anti-FXa effect comparable to that obtained with idraparinux; as with idraparinux, the subcutaneous bioavailability was 100%. In vivo, SSR126517E was a potent antithrombotic in rat and mouse venous and arterial thrombosis models. Direct comparison in rats showed that SSR126517E was as active as idraparinux, when administered at the same molar dose. Furthermore, injection of avidin triggered the immediate elimination of SSR126517E from the bloodstream, resulting in complete neutralization of the antithrombotic activity of SSR126517E.. These results show for the first time that coupling an oligosaccharide with biotin has no effect on the former's pharmacokinetic and pharmacologic properties and renders neutralization easy by injection of avidin.

Topics: Animals; Anticoagulants; Antithrombin III; Avidin; Biotinylation; Factor Xa Inhibitors; Fibrinolytic Agents; Mice; Oligosaccharides; Rats; Thrombin; Thrombosis

Idraparinux sodium, a long-acting anti-Factor Xa synthetic pentasaccharide, is under development by Sanofi-Aventis for the potential prevention and treatment of venous thromboembolic events in patients with deep vein thrombosis or pulmonary embolism.

Topics: Animals; Clinical Trials as Topic; Fibrinolytic Agents; Humans; Oligosaccharides; Structure-Activity Relationship; Thrombosis

Topics: Antineoplastic Agents; Azetidines; Benzylamines; Blood Coagulation Factors; Clinical Trials as Topic; Endothelium, Vascular; Fibrinolytic Agents; Fondaparinux; Hemostasis; Humans; Neoplasms; Neovascularization, Pathologic; Oligosaccharides; Polysaccharides; Stilbenes; Thrombosis

SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the "synthetic pentasaccharide" (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 +/- 0.3 v 48 +/- 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 +/- 15 anti-factor Xa U/mg v 850 +/- 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti-factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti-factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50 values = 40.0 +/- 3.4 and 105.0 +/- 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti-factor Xa activity. SANORG 34006 enhanced rt-PA-induced thrombolysis and inhibited accretion of 125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

Topics: Animals; Carbohydrate Sequence; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Molecular Sequence Data; Oligosaccharides; Papio; Partial Thromboplastin Time; Rabbits; Rats; Thrombin; Thromboplastin; Thrombosis