Platelets and Anti-platelet Therapy

McNicol, Archibald; Israels, Sara J.

doi:10.1254/jphs.93.381

Cited by 97 publications

(99 citation statements)

References 166 publications

(120 reference statements)

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“…After activation, platelets release secondary agonists such as thromboxane A 2 and adenosine diphosphate (ADP), which in combination with thrombin generated by the coagulation cascade result in stimulation and recruitment of additional platelets. 1,2 With this pathophysiological background, it is not surprising that antiplatelet therapy is a cornerstone of the management of patients with ACS, especially those undergoing PCI. [3][4][5] See p 3171…”

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confidence: 99%

Clopidogrel Resistance

2004

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A lthough platelets lack nuclei and are the smallest circulating human cells, they play an integral and complex role in the process of thrombosis, both physiological and pathophysiological. Activation and aggregation of platelets play a central role in the propagation of intracoronary thrombi after (1) spontaneous atherosclerotic plaque disruption that results in myocardial ischemia or infarction in the acute coronary syndromes (ACS), or (2) the mechanical disruption that results from percutaneous coronary intervention (PCI). Platelets initially adhere to collagen and von Willebrand factor at the site of the disrupted plaque, resulting in an initial platelet monolayer. After activation, platelets release secondary agonists such as thromboxane A 2 and adenosine diphosphate (ADP), which in combination with thrombin generated by the coagulation cascade result in stimulation and recruitment of additional platelets. 1,2 With this pathophysiological background, it is not surprising that antiplatelet therapy is a cornerstone of the management of patients with ACS, especially those undergoing PCI. [3][4][5] See p 3171 Antiplatelet AgentsAspirin inhibits cyclooxygenase (COX) by irreversible acetylation, which prevents the production of thromboxane A 2 . The antithrombotic effect of aspirin results from the decreased production of this prothrombotic, vasoconstrictive substance. Aspirin is effective in the short-and long-term prevention of adverse vascular events in high-risk patient groups, including those with ACS, stroke and peripheral arterial disease. 6 Aspirin also has been shown to reduce the frequency of ischemic complications after PCI. 7,8 Despite the impressive and consistent effects of aspirin in reducing adverse events in a variety of ischemic heart disease states, a significant rate of such events persists, and more potent antiplatelet agents, glycoprotein IIb/IIIa inhibitors, and thienopyridines have been developed. The thienopyridines irreversibly inhibit ADP binding to the P2Y 12 receptor on the platelet surface. By blocking this receptor, these agents interfere with platelet activation, degranulation, and-by inhibiting the modification of the glycoprotein IIb/IIIa receptor-aggregation. Currently available thienopyridine antiplatelet agents include ticlopidine and clopidogrel. Both agents are rapidly absorbed prodrugs that are modified hepatically to active metabolites. 2 The agents have similar platelet effects and have been shown to be clinically efficacious. However, clopidogrel has largely replaced ticlopidine because of an improved safety profile, with a lower incidence of hematologic complications (neutropenia and pancytopenia) than ticlopidine. 9 The effects of clopidogrel are time and dose dependent, with a ceiling effect at approximately 50% to 60% inhibition of platelet aggregation. 2 Loading doses of clopidogrel of 300 to 600 mg reach near steady-state levels of platelet aggregation by 4 to 24 hours, whereas daily maintenance dosing with 75 mg daily without a preload results in steady-state leve...

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Clopidogrel Resistance

2004

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“…Platelets, also called trombocytes, play an essential role in hemostasis and pathological thrombosis [1][2][3] . Platelet activation and aggregation are important necessities in the pathogenesis of athero thrombotic events characteristic of the acute coronary syndromes (ACSs) or due to mechanical disruption of plaque by percutaneous coronary interventions (PCIs).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of some dibenzofuran-piperazine derivatives

Yurttaş

Mohsen

Özkan

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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In the present paper, a novel series of dibenzofuran-piperazine derivatives were synthesized via the treatment of N-(2-methoxy-3-dibenzofuranyl)-2-chloroacetamide with substituted piperazine derivatives. The chemical structures of the compounds were elucidated by 1 H NMR, 13C NMR, mass spectral data; elemental analysis and HPLC analysis. Each derivative was evaluated for antiplatelet activity and anticholinesterase activity. Compound 2 m with 2-furoyl moiety exhibited high percentage inhibition as much as standard drug aspirin on arachidonic acid (AA)-induced platelet aggregation. None of the compounds presented significant inhibitor effect on collagen-induced platelet aggregation. Furthermore, the anticholinesterase activity of the compounds was determined and they did not show promising inhibitor activity compared with standard drug donepezil.

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“…Hepatic biotransformation into at least one active metabolite is required for drug activation because TCL itself does not inhibit ADP-induced platelet aggregation. The mechanism of antiplatelet action appears to be an irreversible alteration of the platelet surface P2Y12 ADP receptor, resulting in a reduced ADP-induced platelet aggregation (1). However, there are few reports on the metabolic activation of TCL.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Effects of Omeprazole and Rabeprazole on Ticlopidine Metabolism In Vitro

et al. 2011

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Abstract. The thienopyridine derivative ticlopidine (TCL) is an inhibitor of adenosine diphosphate-induced platelet aggregation. Combination therapy with a thienopyridine derivative and aspirin is standard after coronary stenting, although more hemorrhagic complications occur with the combination therapy than with aspirin alone. A proton pump inhibitor (PPI) is required for prevention or treatment of upper gastrointestinal bleeding in such cases. We examined the effects of PPIs [omeprazole (OPZ) and rabeprazole (RPZ)] on TCL metabolism using pooled human liver microsomes prepared from various human liver blocks and 12 individual human liver microsomes. We calculated the K i values of each PPI for TCL metabolic activity and compared the inhibitory effect of each PPI on TCL metabolism. The K i values of OPZ and RPZ were 1.4 and 12.7 μM, respectively. The inhibitory effect of OPZ (78.6 ± 0.05%) was significantly greater than that of RPZ (24.2 ± 0.05%) (P < 0.001). Interestingly, a negative correlation existed between the inhibitory effect of OPZ and CYP2C19 activity (r = −0.909, P < 0.001). These results suggest that the inhibitory effect of OPZ is more potent than that of RPZ in vitro. In conclusion, RPZ appears preferable when administering TCL, aspirin, and a PPI in combination.

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Platelets and Anti-platelet Therapy

Cited by 97 publications

References 166 publications

Clopidogrel Resistance

Clopidogrel Resistance

Synthesis and biological evaluation of some dibenzofuran-piperazine derivatives

Comparison of the Effects of Omeprazole and Rabeprazole on Ticlopidine Metabolism In Vitro

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