New parenteral anticoagulants in development

Abstract

The therapeutic armamentarium of parenteral anticoagulants available to clinicians is mainly composed by unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux, recombinant hirudins (i.e. bivalirudin, desirudin, lepirudin) and argatroban. These drugs are effective and safe for prevention and/or treatment of thromboembolic diseases but they have some drawbacks. Among other inconveniences, UFH requires regular anticoagulant monitoring as a result of variability in the anticoagulant response and there is a risk of serious heparin-induced thrombocytopaenia (HIT). LMWH, fondaparinux and recombinant hirudins are mainly cleared through the kidneys and their use in patients with severe renal insufficiency may be problematic. LMWH is only partially neutralized by protamine while fondaparinux and recombinant hirudins have no specific antidote. Novel anticoagulants in development for parenteral administration include new indirect activated factor Xa (FXa) inhibitors (idrabiotaparinux, ultra-low-molecular-weight heparins [semuloparin, RO-14], new LMWH [M118]), direct FXa inhibitors (otamixaban), direct FIIa inhibitors (flovagatran sodium, pegmusirudin, NU172, HD1-22), direct FXIa inhibitors (BMS-262084, antisense oligonucleotides targeting FXIa, clavatadine), direct FIXa inhibitors (RB-006), FVIIIa inhibitors (TB-402), FVIIa/tissue factor inhibitors (tifacogin, NAPc2, PCI-27483, BMS-593214), FVa inhibitors (drotrecogin alpha activated, ART-123) and dual thrombin/FXa inhibitors (EP217609, tanogitran). These new compounds have the potential to complement established parenteral anticoagulants. In the present review, we discuss the pharmacology of new parenteral anticoagulants, the results of clinical studies, the newly planned or ongoing clinical trials with these compounds, and their potential advantages and drawbacks over existing therapies.

Large inter-individual variation of the pharmacodynamic effect of anticoagulant drugs on thrombin generation

“…[8][9][10] For a fixed-dose treatment to be safe and effective one would like the pharmacodynamic response to be predictable and stable within the population as well. We, therefore, measured the response of thrombin generation to a fixed concentration of different anticoagulants in a series of individual normal plasmas (n=44).…”

Monocyclic β-Lactams: New Structures for New Biological Activities

“…This new compound has the potential to complement established parenteral anticoagulants [60]. In a recent review, the pharmacology of some new parenteral anticoagulants, the results of clinical studies, the newly planned or ongoing clinical trials with these compounds, and their potential advantages and drawbacks over existing therapies were discussed [61].…”

Chemoenzymatic Synthesis Of The Next Generation of Ultralow MW Heparin Therapeutics

“…There are a number of different LMWHs currently in use that are prepared by the controlled chemical or enzymatic degradation of heparin [28,29]. Since the LMWHs are derivatives of heparin, they are polydisperse and structurally heterogeneous and, as a result of their preparation by a chemical or enzymatic process, they often carry an unnatural anhydromannitol, 1,6-anhydro sugar or unsaturated uronic acid residues at the ends of their chains.…”