Platelets receptors

Volume 169. Platelets Receptors, Adhesion, Secretion (Part A)... 

The balance of opposing pro- and anti-platelet forces determines the overall hemostatic response. Successful hemostasis is achieved when assorted signal-transduction systems, mediators, white blood cells, and platelet receptors for agonists and adhesion molecules overcome the local resistance against platelet activation to generate... 

Clopidogrel (Plavix, Hematology Platelet receptor inhibitor... 

Mechanism of Action A thienopyridine derivative that inhibits binding of the enzyme adenosine phosphate (ADP) to its platelet receptor and subsequent ADP-mediated activation of aglycoprotein complex. Therapeutic Effect Inhibits platelet aggregation. Pharmacokinetics ... 

A. General description Eptifibatide is a cyclic heptapeptide containing six amino acids and one mercaptopropionyl residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Eptifibatide binds to the platelet receptor glycoprotein (gp) Ilb/IIIa of human platelets and inhibits platelet aggregation. The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophifized. 

A second example of protease inhibitor design that properly illustrates the peptide scaffold-based approach is that of thrombin inhibitors. Work with these compounds led to the identification of highly potent, selective, and in vivo-effective lead compounds. A member of the serine protease family, thrombin cleaves a number of substrates (e.g., fibrinogen) and activates its platelet receptor (a G-protein-coupled receptor) by proteolysis of the extracellular N-terminal domain which results in self-activation (for a review see Reference 66). Initial lead inhibitors of thrombin were substrate-based, including the fibrinogen P3-Pi Phe-Pro-Arg sequence [67] and simple Arg derivatives such as Tos-Arg-OMe [68]. 

Platelet receptors for adenine nucleotides and thromboxane A2. Semin Thromb Hemost. 2004 30 411-418. 

Agonist stimulation of platelet receptors induces various internal signaling pathways transduced from the membrane into the cytoplasm, which result in platelet receptors GPIIb/llla activation. 

Inhibitor of platelet vWF receptors Inhibits the link of vWF with their platelet receptor GPIb inhibiting platelet adhesion... 

Blockade of fibrinogen y-chain Inhibits fibrinogen link to their platelets receptors... 

Blockers/inhibitors of platelets receptors GP Ilb/IIIa (integrin allb(33) (abeiximab, tirofiban, eptifibatide) Prevent the link of fibrinogen with platelet receptors inhibiting platelet aggregation in front of different agonists... 

Suboptimal platelet response to clopidogrel may be due to an increased number of platelet P2Y 2 receptors or polymorphism of platelet receptors. Genetic polymorphisms of platelet GPIIb/llla, GPIa/lla, or P2Y 2 receptors have been reported to affect platelet function and may influence dopidogrel response variability (103-105). Recently, it was reported that an increased percentage of patients with peripheral arterial disease have the P2Y 2 receptor H2 haplotype (104). However, in another study, the relation of this haplotype to clopidogrel responsiveness could not be demonstrated (105). Since the relation... 

All of the data mentioned earlier strongly support insufficient metabolite generation as the primary explanation for nonresponsiveness rather than genetic polymorphisms of platelet receptors or intracellular signaling mechanisms. The latter mechanisms may be relevant in those patients who may remain resistant and with high platelet reactivity to ADP even after treatment with high doses of clopidogrel. 

Samara WM, Gurbel PA. The role of platelet receptors and adhesion molecules in coronary artery disease. Coron Artery Dis 2003 14 65-79. 

Beer JH, Pederiva S, Pontiggia L. Genetics of platelet receptor single-nucleotide polymorphisms clinical implications in thrombosis. Ann Med 2000 32 10-14. 

I 14 Greenbaum AB, Grines CL, Bittl JA, Becker RC, Initial experience with an intravenous P2YI2 platelet receptor antagonist in patients undergoing percutaneous coronary intervention results from a 2-part, phase II, multicenter, randomized,... 

These biomarkers represent a response to injury and may reflect the degree of ischemia. In a substudy of the platelet receptor inhibition for ischemic syndrome management (PRISM) trial, Heeschen et al. found that ACS patients with low... 

The enhanced suppression of platelet receptor llb/llla using integrilin therapy (ESPIRIT) trial of nonurgent PCI demonstrated a significant reduction in the incidence of post-PCI Ml at 30 days but not death or urgent target vessel revascularization using eptifibatide in terms of MACE (34). However, this trial randomized patients to receive placebo in the control arm. 

Duda SH, Tepe G, Luz O, et al. Peripheral artery occlusion treatment with abciximab plus urokinase versus with urokinase alone—a randomized pilot trial (the PROMPT Study). Platelet receptor antibodies in order to manage peripheral artery thrombosis, radiology 2001 221 (3) 689—696. 

Yoon HC, Miller FJ Jr, Using a peptide inhibitor of the glycoprotein llb/llla platelet receptor initial experience in patients with acute peripheral arterial occlusions. AJRAmJ Roentgenol 2002 178(3) 617—622. 

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