Antiplatelet action of R‐99224, an active metabolite of a novel thienopyridine‐type G<sub>i</sub>‐linked P2T antagonist, CS‐747

Sugidachi, Atsuhiro; Asai, Fumitoshi; Yoneda, Kenji; Iwamura, Ryo; Ogawa, Taketoshi; Otsuguro, Ken-ichi; Koike, Hiroyuki

doi:10.1038/sj.bjp.0703761

Cited by 116 publications

(96 citation statements)

References 27 publications

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“…Preclinical studies indicate that like clopidogrel, prasugrel is a prodrug that requires metabolic conversion to an active metabolite [19]. Following oral dosing of prasugrel, there is a rapid and potent inhibition of ADP-induced platelet activation and aggregation [19,22,23]. These early studies demonstrated that the dose required to achieve a given degree of platelet inhibition or inhibition of thrombus formation in preclinical models was approximately one-tenth and one-hundredth that of clopidogrel and ticlopidine, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, a novel thienopyridine P2Y 12 inhibitor, prasugrel (CS-747, LY640315), has been identified and profiled [19][20][21][22][23]. Preclinical studies indicate that like clopidogrel, prasugrel is a prodrug that requires metabolic conversion to an active metabolite [19].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans

Jakubowski

Matsushima²,

Asai³

et al. 2006

Brit J Clinical Pharma

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130

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AimsThis double-blind, placebo-controlled trial was designed to evaluate the pharmacodynamics, pharmacokinetics, safety, and tolerability of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 ADP receptor antagonist compared with clopidogrel, during multiple oral dosing in healthy subjects. MethodsThirty subjects received placebo, prasugrel 5 mg, 10 mg, or 20 mg, or clopidogrel 75 mg orally, daily for 10 days. Platelet aggregation, bleeding time, and prasugrel metabolites were measured and adverse events were recorded. ResultsInhibition of ADP-induced platelet aggregation reached steady state by day 3 following prasugrel 10 and 20 mg compared with 5 days for clopidogrel 75 mg or prasugrel 5 mg. Compared with placebo, at 24 h after the last dose of study drug, inhibition of platelet aggregation using (20 mm) ADP was significantly higher in the prasugrel 10 mg group (58.2 Ϯ 4.9% vs. 9.2 Ϯ 4.0%, P < 0.001) with no difference in the clopidogrel group (15.7 Ϯ 6.8% vs. 9.2 Ϯ 4.0%, P = 0.78). With 5 mm ADP, inhibition of platelet aggregation with prasugrel 10 mg and clopidogrel 75 mg was significantly higher than with placebo (prasugrel 10 mg, 70.5 Ϯ 4.7%; clopidogrel 75 mg, 36.5 Ϯ 9.0%; vs. placebo, 11.3 Ϯ 5.1%; P < 0.0001 and P = 0.02). On day 10 at 4 h postdose, bleeding time was prolonged with prasugrel 10 mg (prasugrel 10 mg, 706 Ϯ 252 s vs. placebo, 221 Ϯ 38 s, P = 0.05) but not with clopidogrel (283 Ϯ 56 s, P = 0.98). There were no clinically significant bleeding events, serious adverse events, or discontinuations of the study drug. ConclusionsCompared with clopidogrel 75 mg, prasugrel 10 mg and 20 mg daily for 10 days resulted in more rapid, more consistent, and higher levels of platelet inhibition.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans

Jakubowski

Matsushima²,

Asai³

et al. 2006

Brit J Clinical Pharma

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130

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“…1 Recently, it was shown that cytochrome P-450, isoform 3A4 (CYP3A4), is primarily responsible for the metabolism and activation of clopidogrel in vivo. 2 Several studies have shown that clopidogrel decreases the incidence of coronary artery stent thrombosis and is approved for reduction of myocardial infarction, stroke, and vascular death in patients with atherosclerotic vascular disease. 3 Patients with symptomatic coronary artery disease and hypercholesterolemia are frequently given clopidogrel in conjunction with the HMG-CoA inhibitors (statins).…”

mentioning

confidence: 99%

Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes

Mitsios¹,

Papathanasiou²,

Rodis³

et al. 2004

ACC Current Journal Review

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Background-The antiplatelet effect of clopidogrel may be attenuated by short-term coadministration of lipophilic statins.We investigated whether the coadministration of atorvastatin for 5 weeks in patients with acute coronary syndromes (ACS) could affect the antiplatelet potency of clopidogrel. Methods and Results-Forty-five hypercholesterolemic patients with the first episode of an ACS were included in the study. Patients were randomized to receive daily either 10 mg of atorvastatin (nϭ21) or 40 mg of pravastatin (nϭ24). Thirty patients who underwent percutaneous coronary intervention (PCI) received a loading dose of 375 mg of clopidogrel, followed by 75 mg/d for at least 3 months. In the remaining 15 patients who refused to undergo PCI, clopidogrel therapy was not administered. Eight normolipidemic patients with the first episode of an ACS were also included and received only clopidogrel. The serum levels of soluble CD40L and the adenosine 5Ј-diphosphate-or thrombin receptor activating peptide-14 -induced platelet aggregation, as well as P-selectin and CD40L surface expression, were studied at baseline (within 30 minutes after admission) and 5 weeks later. Neither atorvastatin nor pravastatin significantly influenced the clopidogrel-induced inhibition of platelet activation, nor did clopidogrel influence the therapeutic efficacy of atorvastatin. Conclusions-Atorvastatin does not affect the antiplatelet potency of clopidogrel when coadministered for 5 weeks in ACS patients.

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“…Another antiplatelet drug, CS-747, neutralizes P2Y 12 by the same mechanism [76,77]. P2Y 12 also is irreversibly antagonized by the thiol reagent pCMBS [69,78].…”

Section: The P2y 12 Receptormentioning

confidence: 99%

The Platelet ATP and ADP Receptors

Oury

Tóth-Zsámboki

Vermylen

et al. 2006

CPD

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Adenine nucleotides, ADP and ATP, are coreleased from dense granules during platelet activation, as well as from endothelial cells and damaged red blood cells following vascular injury. Through autocrine and paracrine mechanisms, these extracellular signaling molecules interact with the platelet P2 receptors to amplify ongoing platelet activation. Two receptors for ADP, the G q -protein-coupled P2Y 1 and G i -protein-coupled P2Y 12 and one receptor for ATP, the P2X 1 ion channel, have been identified on platelets. Due to distinct pharmacological properties and differential regulation, the P2Y and P2X receptors essentially operate on different scales of time and distance and trigger selective intracellular signaling cascades. Recent advances in the understanding of the P2Y receptor physiology have reinforced the concept of these receptors as useful targets for antithrombotic therapy. The function of P2X 1 in platelet activation only recently started to be unraveled. This review focuses on recent findings on the physiology of these platelet ADP and ATP receptors, their distinct downstream intracellular signaling pathways as well as on the available agonists, antagonists and inhibitors that allow their pharmacological discrimination.Key Words: Hemostasis, thrombosis, adenine nucleotides, P2Y 1 , P2Y 12 , P2X 1 , antithrombotic therapy. HISTORY AND CLASSIFICATION OF PURINERGIC RECEPTORSThe first report about the potent actions of an adenine compound, AMP, extracted from heart muscle, was published by Drury and Szent-Györgyi in 1929. Initial investigations focused on effects of adenosine and ATP on the heart and vasculature, or concerned the effects of purines on platelets [1] and on mast cells. Further insights into the physiological role of extracellular purines and pyrimidines were provided via the study of their biological sources [2]. In this respect, the detection of nucleotide release from the heart during hypoxia [3] or from skeletal muscle during contraction indicated that secretion of purine compounds might be coupled to metabolic demand to regulate local blood flow. ATP release from sensory nerves suggested that adenine nucleotides play a role as neurotransmitter or neuromodulator in the central and peripheral nervous system [4].These early publications established that purinergic nucleotides act as extracellular signaling molecules [5]. Nucleotides are now documented to contribute to a diverse range of physiological responses such as smooth muscle contraction, neurotransmission, exocrine and endocrine secretion, immune response, inflammation, platelet aggregation, male reproduction, nociception and modulation of cardiac function [6].Purines and pyrimidines mediate their effects by interacting with distinct cell-surface receptors. Purinergic receptors were first formally recognized by Burnstock in 1978 [7]. They were divided into two classes: at P1-purinoceptors adenosine is the principal natural ligand, while P2-purinoceptors recognize both purine and pyrimidine nucleotides Based on an increasin...

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Antiplatelet action of R‐99224, an active metabolite of a novel thienopyridine‐type G_i‐linked P2T antagonist, CS‐747

Cited by 116 publications

References 27 publications

A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans

A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans

Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes

The Platelet ATP and ADP Receptors

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Antiplatelet action of R‐99224, an active metabolite of a novel thienopyridine‐type Gi‐linked P2T antagonist, CS‐747

Cited by 116 publications

References 27 publications

A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans

A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans

Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes

The Platelet ATP and ADP Receptors

Contact Info

Product

Resources

About

Antiplatelet action of R‐99224, an active metabolite of a novel thienopyridine‐type G_i‐linked P2T antagonist, CS‐747

A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans

A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans