Anti-thrombotic action of ticlopidine, a new platelet aggregation inhibitor

Tomikawa, Munehiro; Ashida, Shinji; Kakihata, Koji; Abiko, Yasushi

doi:10.1016/0049-3848(78)90070-1

Cited by 36 publications

(10 citation statements)

References 15 publications

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“…The minimal effective dose of ticlopidine in arterioles was similar to that reported by Ashida et al [10], although a lower concentra tion (10 mg/kg) was found to be effective by Seiffge and Weithmann [11], In addition, the present effective dose in venules was similar to that reported by others using different tech niques [ 1,3,4,12,13]. It should be empha sized, however, that the antithrombotic effect of ticlopidine in models based on venous sta sis [12,13] might be influenced by inhibition of blood coagulation, where coagulation is normally enhanced by coexisting platelets [14],…”

Section: Discussionsupporting

confidence: 76%

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Antithrombotic Effect of Ticlopidine on He-Ne Laser-Induced Thrombus Formation in Rat Mesenteric Microvessels

Yamamoto¹,

Ishii²,

Sasaki³

et al. 1992

Pathophysiol Haemos Thromb

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The inhibitory effects of ticlopidine and acetylsalicylic acid (ASA) on thrombus formation in rat mesenteric microvessels were studied. The results were compared with the effect of the drugs on platelet aggregation in citrated whole blood. He-Ne laser-induced thrombus formation in arterioles and in venules was significantly inhibited by 100 mg/kg ticlopidine. In contrast, a higher dose of ASA (300 mg/kg) was needed to inhibit thrombus formation and the effects of ASA were observed only in arterioles and not in venules. In addition, although the inhibition by ASA in arterioles was not strong it followed a dose-dependent manner, suggesting that the differential effect of ASA on platelets and endothelium may not be evident in vivo. Ticlopidine and ASA strongly inhibited ADP-induced whole blood platelet aggregation, but not collagen- or thrombin-induced platelet aggregation.

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Section: Discussionsupporting

confidence: 76%

“…The antithrombotic effect of antiplatelet drugs has been reported in a variety of animal models [1][2][3][4]. For example, Weichert et al [5] used argon and ruby laser-induced thrombus formation to investigate the effect of ticlopi dine on hemostasis in venules.…”

Section: Introductionmentioning

confidence: 99%

Antithrombotic Effect of Ticlopidine on He-Ne Laser-Induced Thrombus Formation in Rat Mesenteric Microvessels

Yamamoto¹,

Ishii²,

Sasaki³

et al. 1992

Pathophysiol Haemos Thromb

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“…It has been shown that ticlopidine has long‐lasting effects on platelet aggregation ex vivo ( Nunn & Lindsay, 1980 ), and the duration of the action of ticlopidine is equal to the lifespan of platelets in the rat ( Tomikawa et al ., 1978 ). These results suggest that ticlopidine interacts with platelets in an irreversible manner.…”

Section: Discussionmentioning

confidence: 99%

Identification of the active metabolite of ticlopidine from rat in vitro metabolites

Yoneda

Iwamura

Kishi

et al. 2004

British J Pharmacology

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1 Ticlopidine is a well-known anti-platelet agent, but is not active by itself in vitro. We identified a metabolite with anti-platelet activity, which was generated after incubation of 2-oxo-ticlopidine with phenobarbital-induced rat liver homogenate in vitro. 2 An active moiety (UR-4501) was isolated by high-performance liquid chromatography after largescale preparation of metabolites. 3 The chemical structure of UR-4501 was determined by a combination of liquid chromatography mass/mass spectrometry (LC/MS/MS) and nuclear magnetic resonance (NMR) analysis. 4 UR-4501 produced a concentration-dependent inhibition (3-100 mM) of ADP (10 mM)-induced human platelet aggregation, whereas 2-oxo-ticlopidine (3-100 mM) did not elicit inhibitory responses. 5 UR-4501 (10-100 mM) strongly inhibited ADP-and collagen-induced aggregation and slightly inhibited thrombin-induced aggregation. 6 The inhibition of rat washed platelet aggregation by UR-4501 (100 mM) persisted, even after the platelets had been washed twice. 7 These results suggest that UR-4501 is the molecule responsible for the in vivo activities of ticlopidine.

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“…2) was the first clinically available thienopyridine. It was initially discovered in 1972 through in vivo screening tests directed at identifying new antiinflammatory compounds [33] and was subsequently found to be antithrombotic in rat models of pulmonary thrombosis [36]. Since only the metabolites, and not the parent compound, possess significant antiplatelet activity, early characterization was performed in animals.…”

Section: Antagonists Of Platelet Gpcrs P2y 12 Receptor Antagonistsmentioning

confidence: 99%

Targeting Platelet G-Protein Coupled Receptors (GPCRs): Looking Beyond Conventional GPCR Antagonism

Dowal¹,

Flaumenhaft

2010

CVP

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Platelets are key mediators of thrombosis. Drugs that interfere with platelet activation substantially improve survival in arterial thrombotic disease. One attractive family of drug targets which has already been exploited in the development of antiplatelet agents are G-protein coupled receptors (GPCRs). Yet limitations of present antiplatelet agents, including incomplete efficacy, bleeding and drug resistance, have spurred the development of new drugs directed at alternative platelet GPCRs. Compounds that target platelet receptors including P2Y(12), protease-activated receptor-1 (PAR1), the thromboxane A(2) receptor (TP receptor), the prostaglandin receptor (EP3 receptor), and the serotonin receptor (5-HT(2A) receptor) have been identified and are in various phases of clinical development and use. Yet, improving the clinical profile of reagents targeting platelet GPCRs may not be only a matter of blocking alternative GPCRs. A more detailed understanding of GPCR function is leading to the development of pharmacophores with novel mechanisms of drug action. Identifying compounds that work by alternative mechanisms may be equally or more valuable than developing reagents targeting different GPCRs. Pharmacological concepts such as GPCR oligomerization, allosterism, and targeting GPCR-G protein interactions may ultimately provide opportunities to more effectively control platelet activation in the clinical setting. In this review, we will discuss the utility and limitations of GPCR-targeted antiplatelet therapies in clinical use and development. We will also consider emerging concepts in GPCR pharmacology that have the potential to foster the development of GPCR-targeted reagents with novel mechanisms of action and improved clinical profiles.

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Anti-thrombotic action of ticlopidine, a new platelet aggregation inhibitor

Cited by 36 publications

References 15 publications

Antithrombotic Effect of Ticlopidine on He-Ne Laser-Induced Thrombus Formation in Rat Mesenteric Microvessels

Antithrombotic Effect of Ticlopidine on He-Ne Laser-Induced Thrombus Formation in Rat Mesenteric Microvessels

Identification of the active metabolite of ticlopidine from rat in vitro metabolites

Targeting Platelet G-Protein Coupled Receptors (GPCRs): Looking Beyond Conventional GPCR Antagonism

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