Ticlopidine: A Promise for the Prevention and Treatment of Thrombosis and Its Complications

Panak, E.; Maffrand, J.P.; Picard-Fraire, C.; Vallee, E.; Blanchard, J; Roncucci, R.

doi:10.1159/000214831

Cited by 73 publications

(67 citation statements)

References 56 publications

(96 reference statements)

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“…This suggests that the antiaggregation effect might be due to active metabolites. 26 The mechanism by which ticlopidine inhibits platelet aggregation is completely different from the mechanism of aspirin because it does not have any effects on cyclooxygenase.27 Recent studies indicate that ticlopidine inhibits ADP-mediated platelet aggregation15 and antagonizes the interaction of fibrogen with its platelet receptor, the membrane glycoprotein IIb-IIIa. 16 Ticlopidine has been given to patients with several clinical forms of atherosclerosis, such as transient ischemic attack, stroke, and peripheral vascular disease.…”

Section: Ticlopidine: Mode Ofaction and Clinical Usementioning

confidence: 99%

Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio della Ticlopidina nell'Angina Instabile Group.

et al. 1990

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We conducted a controlled multicenter trial with central randomization and evaluation of events under blind conditions involving 652 patients with unstable angina. Patients were treated either with conventional therapy alone (group C) (n =338) or with conventional therapy combined with an inhibitor of platelet aggregation, ticlopidine 250 mg b.i.d. (group C+T) (n=314). Patients were assigned randomly within 48 hours of admission and followed up for 6 months. With the "intention-to-treat" approach, the primary end points, vascular death and nonfatal myocardial infarction, were observed in 13.6% of the patients in group C and in 7.3% of the patients in group C+T, which is a reduction in risk of 46.3% (p=0.009). Vascular mortality was 4.7% in patients in group C and 2.5% in patients in group C+T, which is a reduction in risk of 46.8% (p=0.139). The risk of nonfatal myocardial infarction was reduced by 46.1% (p=0.039), with a frequency of 8.9o in patients in group C and 4.8% in patients in group C+T. New Q wave myocardial infarction occurred with a frequency of 6.8% in patients in group C and 3.8% in patients in group C+T, which is a reduction in risk of 44.1% (p=0.091). Fatal and nonfatal myocardial infarction was 10.91% in patients in group C and 5.1% in patients in group C+T, which is a reduction in risk of 53.2% (p=0.006). These findings confirm the importance of platelets in the pathogenesis of unstable angina and the usefulness of antiplatelet treatment for the prevention of cardiovascular events.

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Section: Ticlopidine: Mode Ofaction and Clinical Usementioning

confidence: 99%

Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio della Ticlopidina nell'Angina Instabile Group.

et al. 1990

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“…Furthermore, a large difference was observed between the total radioactivity and unchanged ticlopidine level in the plasma (Panak et al, 1983). In the 1980s, metabolic studies suggested that N-dealkylation, N-oxidation, and oxidation of the thiophene ring followed by ring opening appeared to be the main routes, but numerous highly polar urinary and biliary metabolites in both humans and animals remained unidentified (Tuong et al, 1981;Panak et al, 1983). More recently, novel ticlopidine metabolites such as the S-oxide form (Ha-Duong et al, 2001) and the pharmacologically active metabolite (Yoneda et al, 2004) have been detected.…”

mentioning

confidence: 93%

“…For example, less than 1% of the parent compound was detected in urine, whereas approximately 60 and 25% of radioactivity was recovered in urine after a single oral administration of [ 14 C]ticlopidine to humans (Noble and Goa, 1996) and rats (Tuong et al, 1981), respectively. Furthermore, a large difference was observed between the total radioactivity and unchanged ticlopidine level in the plasma (Panak et al, 1983). In the 1980s, metabolic studies suggested that N-dealkylation, N-oxidation, and oxidation of the thiophene ring followed by ring opening appeared to be the main routes, but numerous highly polar urinary and biliary metabolites in both humans and animals remained unidentified (Tuong et al, 1981;Panak et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

Metabolism of Ticlopidine in Rats: Identification of the Main Biliary Metabolite as a Glutathione Conjugate of TiclopidineS-Oxide

Shimizu¹,

Atsumi²,

Nakazawa³

et al. 2009

Drug Metab Dispos

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ABSTRACT:We have identified several novel metabolites of ticlopidine, a well known antiplatelet agent and have revealed its metabolic route in rats. The main biliary metabolite of ticlopidine was characterized as a glutathione (GSH) conjugate of ticlopidine S-oxide, in which conjugation had occurred at carbon 7a in the thienopyridine moiety. Quantitative analysis revealed that 29% of the dose was subjected to the formation of reactive intermediates followed by conjugation with GSH after oral administration of ticlopidine (22 mg/ kg) to rats. In vitro incubation of ticlopidine with rat liver 9000g supernatant fraction (S9) fractions led to the formation of multiple metabolites, including 2-oxo-ticlopidine, the precursor for the pharmacologically active ticlopidine metabolite, [1-(2-chlorobenzyl)-4-mercaptopiperidin-(3Z)-ylidene] acetic acid. A novel thiophene ring-opened metabolite with a thioketone group and a carboxylic acid moiety has also been detected after incubation of 2-oxo-ticlopidine with rat liver microsomes or upon incubation of ticlopidine with rat liver S9 fractions.Ticlopidine is a well known antiplatelet agent (Quinn and Fitzgerald, 1999) and has been widely used for the secondary prevention of atherothrombosis (Jacobson, 2004). The metabolism of ticlopidine is complex because of extensive oxidation in the liver (Saltiel and Ward, 1987). For example, less than 1% of the parent compound was detected in urine, whereas approximately 60 and 25% of radioactivity was recovered in urine after a single oral administration of [ 14 C]ticlopidine to humans (Noble and Goa, 1996) and rats (Tuong et al., 1981), respectively. Furthermore, a large difference was observed between the total radioactivity and unchanged ticlopidine level in the plasma (Panak et al., 1983). In the 1980s, metabolic studies suggested that N-dealkylation, N-oxidation, and oxidation of the thiophene ring followed by ring opening appeared to be the main routes, but numerous highly polar urinary and biliary metabolites in both humans and animals remained unidentified (Tuong et al., 1981;Panak et al., 1983). More recently, novel ticlopidine metabolites such as the S-oxide form (Ha-Duong et al., 2001) and the pharmacologically active metabolite (Yoneda et al., 2004) have been detected. However, the whole metabolism of ticlopidine has remained unclarified.In the present study, we have identified several novel metabolites of ticlopidine and revealed the metabolic pathways of ticlopidine quantitatively. Moreover, an in vitro experiment was conducted to elucidate the whole metabolic route of ticlopidine including the biotransformation to the pharmacologically active metabolite.

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“…Although the exact mechanism for the inhibitory effect of ticlopidine on platelet aggregation remains unclear, it may involve the production of cyclic AMP (2,13,14). Ticlopidine has been found to potentiate the stimulation by prostaglandin El of adenylate cyclase activity in rat platelets, suggesting that ticlopidine stimulates the adenylate cyclase system by its action on the N regulatory subunit of the enzyme as GTP does (37).…”

Section: Platelet Aggregationmentioning

confidence: 99%

Spin Label Study of the Effect of Ticlopidine on Platelets

Hongo

Setaka

Kwan

1985

Japanese Journal of Pharmacology

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Abstract-The effect of ticlopidine on platelet membrane fluidity was investigated using a spin label technique.Ticlopidine, when orally administered to rats, in creased both the order parameter and the motion parameter, indicating a decrease in the membrane fluidity of platelets.On the other hand, the order parameter and the motion parameter decreased markedly when the platelets were aggregated by thrombin.Ticlopidine inhibited the thrombin-induced aggregation of platelets and caused a slight increase in order parameter and motion parameter in thrombin aggregated platelets.Judging from sodium dodecyl sulfate polyacrylamide gel electrophoresis, ticlopidine did not modify the electrophoretic pattern of platelet proteins appreciably.Ticlopidine decreased cholesterol/phospholipids molar ratio and increased slightly total amounts of proteins of the platelets.These results indicate that the inhibitory action by ticlopidine was accompanied by changes in membrane fluidity, and these changes were due to a perturbation of the mem brane phospholipid core of the platelets by ticlopidine and/or its metabolites.

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Ticlopidine: A Promise for the Prevention and Treatment of Thrombosis and Its Complications

Cited by 73 publications

References 56 publications

Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio della Ticlopidina nell'Angina Instabile Group.

Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio della Ticlopidina nell'Angina Instabile Group.

Metabolism of Ticlopidine in Rats: Identification of the Main Biliary Metabolite as a Glutathione Conjugate of TiclopidineS-Oxide

Spin Label Study of the Effect of Ticlopidine on Platelets

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