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Eptifibatide is a cyclical heptapeptide with anticoagulant activity. Eptifibatide selectively and reversibly binds to and blocks the platelet glycoprotein IIb/IIIa receptor. This prevents the binding of fibrinogen, von Willebrand factor, and other adhesive ligands and leads to an inhibition of platelet aggregation and prevents thrombus development. Eptifibatide Acetate is a cyclic heptapeptide constructed from 6 amino acids and a mercaptopropionyl residue. A disulfide bridge forms between mercaptopropionyl and cysteine.
Protein disulfide isomerase (PDI) catalyzes the oxidation reduction and isomerization of disulfide bonds. We have previously identified an important role for extracellular PDI during thrombus formation in vivo. Here, we show that endothelial cells are a critical cellular source of secreted PDI, important for fibrin generation and platelet accumulation in vivo. Functional PDI is rapidly secreted from human umbilical vein endothelial cells in culture upon activation with thrombin or after laser-induced stimulation. PDI is localized in different cellular compartments in activated and quiescent endothelial cells, and is redistributed to the plasma membrane after cell activation. In vivo studies using intravital microscopy show that PDI appears rapidly after laser-induced vessel wall injury, before the appearance of the platelet thrombus. If platelet thrombus formation is inhibited by the infusion of eptifibatide into the circulation, PDI is detected after vessel wall injury, and fibrin deposition is normal. Treatment of mice with a function blocking anti-PDI antibody completely inhibits fibrin generation in eptifibatide-treated mice. These results indicate that, although both platelets and endothelial cells secrete PDI after laser-induced injury, PDI from endothelial cells is required for fibrin generation in vivo.
Jasuja, R., Furie, B., & Furie, B. C. (2010). Endothelium-derived but not platelet-derived protein disulfide isomerase is required for thrombus formation in vivo. Blood, 116(22), 4665-4674.
The objective of the study was to determine the identity of a new impurity detected in HPLC chromatograms of research samples of eptifibatide manufactured by a new process and formulated into drug product. The identification of the unknown impurity was required in order to understand the mechanism of its formation. The analysis was performed by using tandem mass spectrometers coupled with a reversed-phase gradient HPLC system. The unknown compound was then structurally elucidated by matrix-assisted laser desorption ionization (MALDI) tandem mass spectrometry. The mass spectrometric results showed that the protonated molecular ion of the unknown compound was m/z 862.3347 with molecular formula: C(36)H(52)N(11)O(10)S(2). The unknown compound was a linear peptide and was related to Asp-clipped eptifibatide. It was formed from Asp-clipped eptifibatide by the reaction of the amino group of tryptophan moiety with formaldehyde followed by electrophilic attack on the nitrogen of indole.
Wang, R., Feder, D., & Hsieh, F. (2003). Characterization of eptifibatide during drug formulation stability assays. Journal of pharmaceutical and biomedical analysis, 33(5), 1181-1187.