Pharmacodynamics of ticlopidine in man in relation to plasma and blood cell concentration

Perri, T. Di; Pasini, F. Laghi; Frigerio, Carlo Sala; Blardi, Patrizia; Centini, F.; Messa, G. L.; Ghezzi, Angelo; Volpi, L.

doi:10.1007/bf00626364

Cited by 36 publications

(16 citation statements)

References 18 publications

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“…As already demonstrated for ticlopidine (39), clopidogrel acted in an irreversible manner on the platelets, for no antiaggregating activity remained in plasma from treated subjects. Such results are compatible with those previously obtained in the rat, showing that clopidogrel, inactive in vitro, is metabolically transformed by the liver into a transient, antiaggregating compound (22).…”

Section: Bleeding Timementioning

confidence: 62%

Clopidogrel: An Antithrombotic Drug Acting on the ADP-dependent Activation Pathway of Human Platelets

Savi

Heilmann

Nurden

et al. 1996

Clin Appl Thromb Hemost

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The aim of the study was to determine the effect of clopidogrel on adenosine diphosphate (ADP)-induced platelet activation in human volunteers. Platelets from human volunteers before and after a 7-day treatment with clopidogrel (75 mg/kg), were tested for their sensitivity to ADP by measuring ADP-induced aggregation, adenylyl cyclase downregulation, and [ 3 H]-2-MeS-ADP binding. Platelet membrane glycoprotein (GP IIb-IIIa; GP Ib, GMP-140) expression was measured by flow cytometry using fluorescent-labeled antibodies or fibrinogen. After oral administration to human volunteers (75 mg/day for 7 days), clopidogrel, a novel ADP-selective antiplatelet agent, inhibited ADP-induced aggregation of platelets ex vivo. This effect was irreversible in nature, and no activity could be detected in the plasma of treated subjects. Although clopidogrel did not modify ADPinduced shape change, it prevented the inhibitory effect of ADP (but not that of epinephrine) on the prostoglandin-E 1 (PGE 1 )-induced increase in platelet cAMP. The number of binding sites for [ 3 H]-2-MeS-ADP, a stable analogue of ADP that labels ADP binding sites linked to the inhibition of stimulated adenylyl cyclase, was reduced from 525 ± 62 sites/cell in the controls to 32 ± 5 sites/cell after treatment with clopidogrel (p < 0.001). This effect occurred with no consistent change in the binding affinity of [ 3 H]-2-MeS-ADP, indicating that inhibition of platelet functions by clopidogrel was mainly due to a selective and irreversible reduction of ADP binding sites on platelets. Flow cytometry experiments showed that clopidogrel selectively inhibited ADP-inducing binding of fibrinogen to platelets. This effect occurred through a major reduction of the ADP-induced activation of the GP IIb-IIIa complex. These findings therefore indicate that clopidogrel downregulates platelet responses via a selective and direct interaction with the ADP receptors, mediating the inhibition of stimulated adenylyl cyclase activity in human platelets.

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Section: Bleeding Timementioning

confidence: 62%

Clopidogrel: An Antithrombotic Drug Acting on the ADP-dependent Activation Pathway of Human Platelets

Savi

Heilmann

Nurden

et al. 1996

Clin Appl Thromb Hemost

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“…The daily recommended dose of ticlopidine is 250–500 mg, demonstrated plasma concentrations of the drug in low microgram/mL range [37], and concentrations of 10–30 μ g/mL are pharmacologically irrelevant. The MTT assay was performed to investigate whether ticlopidine affect the growth of HUVECs.…”

Section: Resultsmentioning

confidence: 99%

Reduction of Monocyte Chemoattractant Protein‐1 and Interleukin‐8 Levels by Ticlopidine in TNF‐α Stimulated Human Umbilical Vein Endothelial Cells

Lee

Shih

et al. 2009

BioMed Research International

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Atherosclerosis and its associated complications represent major causes of morbidity and mortality in the industrialized or Western countries. Monocyte chemoattractant protein-1 (MCP-1) is critical for the initiating and developing of atherosclerotic lesions. Interleukin-8 (IL-8), a CXC chemokine, stimulates neutrophil chemotaxis. Ticlopidine is one of the antiplatelet drugs used to prevent thrombus formation relevant to the pathophysiology of atherothrombosis. In this study, we found that ticlopidine dose-dependently decreased the mRNA and protein levels of TNF-α-stimulated MCP-1, IL-8, and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Ticlopidine declined U937 cells adhesion and chemotaxis as compared to TNF-α stimulated alone. Furthermore, the inhibitory effects were neither due to decreased HUVEC viability, nor through NF-kB inhibition. These results suggest that ticlopidine decreased TNF-α induced MCP-1, IL-8, and VCAM-1 levels in HUVECs, and monocyte adhesion. Therefore, the data provide additional therapeutic machinery of ticlopidine in treatment and prevention of atherosclerosis.

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“…16 This is the first reported study of plasma measurement of ticlopidine using HPLC/MS/MS. Our method allows a suitable sensitivity (LOQ 1.0 ng ml 1 ) and can be carried out in a shorter time (retention time 1.8 min for ticlopidine compared with 4.8 min for GC/NPD, 9.5 min for GC/MS and 10.5 min for LC/(C)ES-MS. 7,9,10,16 The last method as described by Langana et al 16 also shows good sensitivity but a longer retention time (10.5 min) for the measurement of ticlopidine in human plasma. Furthermore, our method involves a simple liquid-liquid extraction as opposed to the solid-phase extraction described by Langana et al…”

Section: Discussionmentioning

confidence: 96%

Ticlopidine quantification in human plasma by high‐performance liquid chromatography coupled to electrospray tandem mass spectrometry. Application to bioequivalence study

et al. 2004

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A rapid, sensitive and specific method to quantify ticlopidine in human plasma using clopidogrel as the internal standard (IS) is described. The analyte and the IS were extracted from acidified plasma by liquid-liquid extraction using diethyl ether-hexane (80 : 20, v/v). The extracts were analyzed by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry (HPLC/MS/MS). Chromatography was performed isocratically on a Jones Genesis C(8) 4 microm analytical column (150 x 4.1 mm i.d.). The method had a chromatographic run time of 3.0 min and a linear calibration curve over the range 1.0-1000 ng ml(-1) (r(2) > 0.999427). The limit of quantification was 1.0 ng ml(-1). This HPLC/MS/MS procedure was used to assess the bioequivalence of two ticlopidine 250 mg tablet formulations (ticlopidine test formulation from Apotex do Brasil, Brazil, and Ticlid from Sanofi-Synthelabo, standard reference formulation). A single 250 mg dose of each formulation was administered to healthy volunteers. The study was conducted using an open, randomized, two-period crossover design with a 2 week washout interval. Since the 90% confidence interval for C(max) and area under the curve ratios were all inside the 80-125% interval proposed by the US Food and Drug Administration, it was concluded that ticlopidine formulation from Apotex do Brasil is bioequivalent to Ticlid formulation with respect to both the rate and the extent of absorption.

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Pharmacodynamics of ticlopidine in man in relation to plasma and blood cell concentration

Cited by 36 publications

References 18 publications

Clopidogrel: An Antithrombotic Drug Acting on the ADP-dependent Activation Pathway of Human Platelets

Clopidogrel: An Antithrombotic Drug Acting on the ADP-dependent Activation Pathway of Human Platelets

Reduction of Monocyte Chemoattractant Protein‐1 and Interleukin‐8 Levels by Ticlopidine in TNF‐α Stimulated Human Umbilical Vein Endothelial Cells

Ticlopidine quantification in human plasma by high‐performance liquid chromatography coupled to electrospray tandem mass spectrometry. Application to bioequivalence study

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