Role of abciximab in the treatment of coronary artery disease
Unidade de Cardiologia de Intervenção Joaquim Oliveira, Serviço de Cardiologia, Hospital de Santa Maria, Avenida Egas Moniz, 1649-035 Lisboa, Portugal. Expert opinion on biological therapy
(Impact Factor: 3.74).
10/2006; 6(9):935-42. DOI: 10.1517/147125220.127.116.115
Glycoprotein IIb/IIIa complex is a crucial membrane receptor for platelet aggregation, binding platelets to fibrinogen and establishing interplatelet bridges. This receptor is the common end point of the multiple activation pathways of a platelet. Antiplatelet agents, such as aspirin or thienopyridines, including ticlopidine and clopidogrel, inhibit one or more but not all, of these pathways. Inhibitors of the receptor are powerful platelet antiaggregants and include two groups of agents: non-competitive receptor blockers, such as abciximab, and competitive antagonists, such as tirofiban and eptifibatide. Abciximab is a monoclonal antibody that binds to the glycoprotein IIb/IIIa complex, thus blocking the interaction with fibrinogen. It is used for treatment of coronary artery disease, being well-studied in the setting of acute coronary syndromes and percutaneous coronary intervention, in which a rapid and effective antiaggregation is clinically important.
Available from: Yoshi Takada
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ABSTRACT: The integrins are a superfamily of cell adhesion receptors that bind to extracellular matrix ligands, cell-surface ligands, and soluble ligands. They are transmembrane alphabeta heterodimers and at least 18 alpha and eight beta subunits are known in humans, generating 24 heterodimers. Members of this family have been found in mammals, chicken and zebrafish, as well as lower eukaryotes, including sponges, the nematode Caenorhabditis elegans (two alpha and one beta subunits, generating two integrins) and the fruitfly Drosophila melanogaster (five alpha and one beta, generating five integrins). The alpha and beta subunits have distinct domain structures, with extracellular domains from each subunit contributing to the ligand-binding site of the heterodimer. The sequence arginine-glycine-aspartic acid (RGD) was identified as a general integrin-binding motif, but individual integrins are also specific for particular protein ligands. Immunologically important integrin ligands are the intercellular adhesion molecules (ICAMs), immunoglobulin superfamily members present on inflamed endothelium and antigen-presenting cells. On ligand binding, integrins transduce signals into the cell interior; they can also receive intracellular signals that regulate their ligand-binding affinity. Here we provide a brief overview that concentrates mostly on the organization, structure and function of mammalian integrins, which have been more extensively studied than integrins in other organisms.
Available from: circle.ubc.ca
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ABSTRACT: RGD (arginine-glycine-aspartic acid) is a known peptide sequence that binds platelet integrin GPIIbIIIa and disrupts platelet-fibrinogen binding and platelet cross-linking during thrombosis. RGD peptides are unsuitable for clinical applications due to their high 50% inhibitory concentration (IC50) and low in vivo residence times. We addressed these issues by conjugating RGD peptides to biocompatible macromolecular carriers: hyperbranched polyglycerols (HPG) via divinyl sulfone. The GPIIbIIIa binding activity of RGD was maintained after conjugation and the effectiveness of the HPG-RGD conjugate was dependent upon molecular weight and the number of RGD peptides attached to each HPG molecule. These polyvalent inhibitors of platelet aggregation decreased the IC50 of RGD in an inverse linear manner based on the number of RGD peptides per HPG. Since HPG-RGD conjugates do not cause platelet activation by degranulation and certain substitution ratios do not increase fibrinogen binding to resting platelets, HPG-RGD may serve as a model for a novel class of antithrombotics.
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