Antiplatelet therapy

Gershlick, AH

doi:10.12968/hosp.2000.61.1.1267

Cited by 7 publications

(9 citation statements)

References 21 publications

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“…Endothelial injury caused by shear stress, hypertension, diabetes or smoking is an important factor in the initiation and progression of arterial disease [1, 2]. Lipids and monocytes accumulate on the intima of damaged arteries.…”

Section: Pathophysiology Of Atherosclerosis and Atherothrombosismentioning

confidence: 99%

“…These atheromatous plaques, usually located at vessel ostia, branches or regions where blood flow changes in velocity or direction, causing high shear stress, later become calcified. High shear stress occurring in the atherosclerotic small arteries and arterioles induces platelet activation, aggregation and enhances platelet thrombus formation [1, 2].…”

Section: Pathophysiology Of Atherosclerosis and Atherothrombosismentioning

confidence: 99%

“…The disruption of atherosclerotic plaques triggers platelet adhesion, activation and aggregation, causing cerebrovascular, coronary and peripheral vascular ischaemic syndromes that may progress to infarction [1–3]. Platelet adhesion is mediated by the interaction of platelet glycoprotein Ib/IX with subendothelial von Willebrand's factor under high shear conditions, and by platelet glycoprotein Ia/IIb binding to collagen under low shear conditions.…”

Section: Pathophysiology Of Atherosclerosis and Atherothrombosismentioning

confidence: 99%

“…Atherothrombosis associated with pre‐existing atherosclerotic plaques involves platelet activation, aggregation and thrombus formation. Long‐term antiplatelet therapy is effective in the secondary prevention of vascular events in patients with acute coronary or cerebrovascular events who are at a high risk of subsequent thrombotic events [1]. The recent development of drugs with greater selectivity, efficacy and decreased side effects resulted from a better understanding of the mechanisms of atherosclerosis, platelet aggregation, coagulation and thrombolysis.…”

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confidence: 99%

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The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments

2003

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SummaryThe thienopyridines, ticlopidine and clopidogrel, are antiplatelet drugs. They are prodrugs and are metabolised in the liver to active metabolites that are non-competitive antagonists of the platelet adenosine diphosphate receptor, P2Y 12 . Inhibition of platelet aggregation by these drugs is delayed until 24-48 h after administration, with maximal inhibition achieved after 3-5 days. Recovery of platelet function after drug withdrawal is slow (7-14 days). Ticlopidine and clopidogrel are effective in preventing atherothrombotic events in cardiovascular, cerebrovascular and peripheral vascular disease. Gastrointestinal side effects and skin rashes are common. However, neutropenia and thrombotic thrombocytopenic purpura are significant and sometimes fatal adverse effects of ticlopidine. Clopidogrel appears to offer several advantages over ticlopidine: a more rapid onset of action and a lower incidence of neutropenia and thrombotic thrombocytopenic purpura. A combination of clopidogrel and aspirin has become standard for antithrombotic therapy in cardiovascular disease. The anaesthetic considerations of patients taking the thienopyridine compounds are discussed.

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Section: Pathophysiology Of Atherosclerosis and Atherothrombosismentioning

confidence: 99%

Section: Pathophysiology Of Atherosclerosis and Atherothrombosismentioning

confidence: 99%

Section: Pathophysiology Of Atherosclerosis and Atherothrombosismentioning

confidence: 99%

mentioning

confidence: 99%

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The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments

2003

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“…Release of ADP from activated platelets is one of the primary mediators of platelet aggregation, leading to a sustained response via activation of P2Y 12 receptors (Schrör, 1995;Gershlick, 2000). Inhibition of platelet aggregation with a combination of aspirin and a thienopyridine antiplatelet drug, such as clopidogrel, is an important strategy for preventing ischemic events in patients with acute coronary syndromes (Yusuf et al, 2001;Bassand et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Disposition and Metabolism of Ticagrelor, a Novel P2Y₁₂ Receptor Antagonist, in Mice, Rats, and Marmosets

Landqvist²,

Grimm³

2011

Drug Metab Dispos

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ABSTRACT:Ticagrelor is a reversibly binding and selective oral P2Y 12 antagonist, developed for the prevention of atherothrombotic events in patients with acute coronary syndromes. The disposition and metabolism of [ 14 C]ticagrelor was investigated in mice, rats, and marmosets to demonstrate that these preclinical toxicity species showed similar metabolic profiles to human. Incubations with hepatocytes or microsomes from multiple species were also studied to compare with in vivo metabolic profiles. The routes of excretion were similar for both oral and intravenous administration in mice, rats, and marmosets with fecal excretion being the major elimination pathway accounting for 59 to 96% of the total radioactivity administered. Urinary excretion of drug-related material accounted for only 1 to 15% of the total radioactivity administered. Milk samples from lactating rats displayed significantly higher levels of total radioactivity than plasma after oral administration of ticagrelor. This demonstrated that ticagrelor and/or its metabolites were readily transferred into rat milk and that neonatal rats could be exposed to ticagrelor-related compounds via maternal milk. Ticagrelor and active metabolite AR-C124910 (loss of hydroxyethyl side chain) were the major components in plasma from all species studied and similar to human plasma profiles. The primary metabolite of ticagrelor excreted in urine across all species was an inactive metabolite, AR-C133913 (loss of difluorophenylcyclopropyl group). Ticagrelor, AR-C124910, and AR-C133913 were the major components found in feces from the three species examined. Overall, in vivo metabolite profiles were qualitatively similar across all species and consistent with in vitro results.

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A peripherally restricted P2Y 12 receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism

et al. 2014

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BackgroundTicagrelor is an orally available, direct acting and reversible P2Y12 receptor antagonist approved for treatment of acute coronary syndrome. The objectives of these studies were to (1) evaluate the Ticagrelor 2-year rat carcinogenicity bioassay data; (2) investigate potential mode of action (MOA) and (3) interpret human relevance.MethodsThe following studies were done (1) rat two-year carcinogenicity study in male and female rats, (2) in vitro and in vivo genotoxicity assays, (3) quantitative whole body autoradiography (QWBA; male and female rats), (4) in vitro pharmacological profiling for more than 300 assays, and (5) in vivo ovariectomized rat assay.ResultsThe carcinogenicity study indicated Ticagrelor increased uterine tumor incidence while decreasing mammary and pituitary tumors/hyperplasia incidences in only high dose female rats. However, this altered tumor incidences were not P2Y12 target related since marketed non-reversible P2Y12 receptor antagonists were not associated with alter tumor incidences. MOA studies determined Ticagrelor exposure in the anterior pituitary and Ticagrelor was (1) non-genotoxic, (2) peripherally-restricted, (3) a dopamine transport (DAT) inhibitor with an IC50 lower than systemic free exposure in the rat carcinogenic study and more than a log higher than the free systemic exposure seen in clinical trials and (4) an inhibitor of estradiol-induced prolactin secretion.DiscussionSimilar to Ticagrelor, centrally active dopamine agonists induce the same altered tumor incidence patterns that according to literature do not translate into the clinical setting, with a MOA involving decreased prolactin secretion. The Ticagrelor MOA data and literature suggest that altered dopamine levels in the hypophyseal part of the hypothalamus–hypophyseal axis (by Ticagrelor) will result in similar altered tumor incidences in rat that do not translate into the clinical setting, based on qualitative species differences. In conclusion Ticagrelor increased uterine tumors in the rat carcinogenesis study by a MOA consistent with reduced dopamine inhibition of prolactin, which is not a patient safety risk.

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Antiplatelet therapy

Abstract: Within the last few years antiplatelet therapy has developed exponentially, with new agents being tested in an increasing number of clinical scenarios. The mechanism of action of these newer agents and evidence of benefit is prevented in this review.

Cited by 7 publications

References 21 publications

The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments

The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments

Disposition and Metabolism of Ticagrelor, a Novel P2Y₁₂ Receptor Antagonist, in Mice, Rats, and Marmosets

A peripherally restricted P2Y 12 receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism

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Antiplatelet therapy

Abstract: Within the last few years antiplatelet therapy has developed exponentially, with new agents being tested in an increasing number of clinical scenarios. The mechanism of action of these newer agents and evidence of benefit is prevented in this review.

Cited by 7 publications

References 21 publications

The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments

The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments

Disposition and Metabolism of Ticagrelor, a Novel P2Y12 Receptor Antagonist, in Mice, Rats, and Marmosets

A peripherally restricted P2Y 12 receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism

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Disposition and Metabolism of Ticagrelor, a Novel P2Y₁₂ Receptor Antagonist, in Mice, Rats, and Marmosets