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Antiplatelet therapy in interventional cardiology
Published in John Edward Boland, David W. M. Muller, Interventional Cardiology and Cardiac Catheterisation, 2019
Eptifibatide is a non‐immunogenic cyclic heptapeptide that reversibly inhibits the platelet IIb/IIIa receptor as a competitive inhibitor of the fibrinogen‐binding site. It is rapid but short acting (2–4 hours) with a half-life of 2.5 hours. It should be used with caution in patients with renal impairment as it is renally excreted. The PURSUIT study examined the role of eptifibatide in acute coronary syndromes.50 The dose used was a 180 µg/kg bolus followed by a 2.0 µg/kg/min infusion. There was a small but significant reduction in death or non-fatal MI (14.2% vs. 15.7% p = 0.004).50
Percutaneous coronary intervention in the elderly
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Use of glycoprotein (GP) IIb/IIIa inhibitors in the elderly has both significant anti-ischemic benefits as well as possible increased risk of bleeding. Limited data from a subgroup analysis of the ADMIRAL trial (85) found that the benefit with GP IIb/IIIa inhibitors was greater in STEMI patients >65 years of age than in younger patients (RR 0.35 (0.12–0.98), with the composite endpoint of death, MI, or revascularization at 6 months being 7.6% with abciximab versus 21.7% without. In NSTEMI, age was not a significant determinant of the benefit of GP IIb/IIIa inhibitors in one meta-analysis (86). In the ESPRIT study (87), patients undergoing PCI for acute or chronic coronary disease with eptifibatide had a lower composite risk of death, MI, urgent target-vessel revascularization, or thrombotic use of GP IIb/IIIa inhibitors versus placebo, and this was predominantly in the subgroup of patients >65 years of age (RR 0.47, 95% CI 0.31–0.72) rather than in younger patients (RR 0.84, 95% CI 0.56–1.25).
Adjunctive pharmacotherapy and coronary intervention
Published in Ever D. Grech, Practical Interventional Cardiology, 2017
Daniel M Shivapour, Derek P Chew, A Michael Lincoff
Glycoprotein IIb/IIIa receptor inhibitors (GPI) are intravenous medications that inhibit platelet aggregation and thrombus formation by preventing the binding of fibrinogen or circulating vWF on the platelet surface. The three agents currently approved by the US FDA are abciximab, eptifibatide and tirofiban. Abciximab is a Fab fragment of a humanised murine antibody that exhibits a very strong affinity for the glycoprotein receptor. Whilst it has a short plasma half-life (approximately 30 minutes), abciximab's strong binding results in platelet inhibition, which continues for hours to days after the infusion is stopped. Eptifibatide, a small-molecule cyclic heptapeptide and tirofiban, a synthetic non-peptide antagonist, both reversibly inhibit the IIb/IIIa receptors on the platelet surface with a shorter duration of action (half-life approximately 2 hours with platelet activity normalising approximately 4 hours after discontinuation).
How not to discover a drug - integrins
Published in Expert Opinion on Drug Discovery, 2021
One of the disintegrins was barbourin, a disintegrin from Sistrurusm.barbouri. Unusually, barbourin had a KGD sequence rather than an RGD sequence. Modification of barbourin led to the cyclic peptide eptifibatide [41,42], which was commercialized as Integrilin® [43]. This maintained the KGD sequence from barbourin. Another disintegrin was echisatin, a disintegrin from Echis carinatus [44], which was used to guide the drug discovery process in Merck. However, rather than making a peptide they used it as a starting point for discovering a small molecule. Echistatin was purified, expressed in cells [45], synthesized, crystalised and subjected to NMR analysis to determine the conformation of the RGD sequence [46]. This was then mapped onto chemical scaffolds and used to discover small molecule, peptide-mimetics [47,48]. This led to the discovery of tirofiban (see Figure 2), which was commercialized as Aggrestat® [49]. Although both tirofiban and eptifibatide are very potent, neither of them are orally active and thus are only useful for acute conditions – acute myocardial infarction, stenting etc.
Sushi Domain Containing 2 (SUSD2) inhibits platelet activation and binding to high-grade serous ovarian carcinoma cells
Published in Platelets, 2018
Tyson W. Lager, Jessica J. Roetman, Jacob Kunkel, Megan Thacker, Jordan N. Sheets, Kristi A. Egland, Cecelia M. Miles, Mark K. Larson, Jennifer A. A. Gubbels
A lower activation state of the platelets is reflected in a lower binding of the platelets to the OVCAR3 NT cells. Other studies have previously shown that the GPIIb/IIIa receptor is crucial in tumor/platelet activation pathways [10,11]. Because nearly all agonist pathways in the platelet lead to GPIIb/IIIa activation [16], we used an inhibitor of the GPIIb/IIIa receptor on platelets to see if blocking this receptor would inhibit platelet binding (Figure 2b). Eptifibatide treatment reduced platelet binding levels in the OVCAR3 sh1 and sh2 cell lines to the level observed in OVCAR3 NT cells. Therefore, this receptor’s activation followed by platelet binding can be mediated by the presence of SUSD2 on the cell surface. It is also likely that there are other receptors involved in the platelet activation because the level of binding after eptifibatide treatment in Figure 2b was not completely abrogated by inhibiting the GPIIb/IIIa receptor. Future studies warrant the investigation of the protein repertoire on the cancer cell surface that may contribute to this differential binding and activation of platelets, which may be important for enhancing patient survival.
Kounis syndrome presenting as ST elevation acute myocardial infarction
Published in Baylor University Medical Center Proceedings, 2021
Michael Engheta, Jonathan Urbanczyk, Erica Fidone, Yissela Escobedo, Timothy Mixon
Case 1. A 65-year-old woman presented for outpatient robotic total knee replacement. She had a history of coronary artery disease and had had drug-eluting stents placed in the left anterior descending (LAD) artery and right coronary artery. During a preoperative infusion of vancomycin, she developed acute anaphylactic shock. An electrocardiogram (ECG) revealed inferolateral ST-segment elevation. Emergent coronary angiography (Figure 1a) revealed culprit thrombosis within the previous LAD stent, which was successfully treated with aspiration thrombectomy and intravascular ultrasound-guided balloon angioplasty. Eptifibatide was administered by double bolus followed by continuous infusion for 6 hours after the procedure.