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Tytuł:
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Antithrombotic activity of F 16618, a new PAR1 antagonist evaluated in extracorporeal arterio-venous shunt in the rat.
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Autorzy:
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Létienne R; Centre de Recherche Pierre Fabre, Castres, France.
Leparq-Panissié A
Calmettes Y
Nadal-Wollbold F
Perez M
Le Grand B
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Źródło:
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Biochemical pharmacology [Biochem Pharmacol] 2010 Jun 01; Vol. 79 (11), pp. 1616-21. Date of Electronic Publication: 2010 Feb 25.
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Typ publikacji:
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Comparative Study; Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.
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MeSH Terms:
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Fibrinolytic Agents/*therapeutic use
Piperazines/*pharmacology
Pyridines/*pharmacology
Receptor, PAR-1/*antagonists & inhibitors
Thrombosis/*drug therapy
Animals ; Arterial Occlusive Diseases/drug therapy ; Arteriovenous Shunt, Surgical ; Aspirin/administration & dosage ; Aspirin/pharmacology ; Bleeding Time ; Clopidogrel ; Dose-Response Relationship, Drug ; Fibrinolytic Agents/pharmacology ; Humans ; Male ; Piperazines/administration & dosage ; Piperazines/therapeutic use ; Platelet Aggregation/drug effects ; Pyridines/administration & dosage ; Pyridines/therapeutic use ; Rats ; Ticlopidine/administration & dosage ; Ticlopidine/analogs & derivatives ; Ticlopidine/pharmacology
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Substance Nomenclature:
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0 (2-(5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)penta-1,3-dienyl)benzonitrile)
0 (Fibrinolytic Agents)
0 (Piperazines)
0 (Pyridines)
0 (Receptor, PAR-1)
A74586SNO7 (Clopidogrel)
OM90ZUW7M1 (Ticlopidine)
R16CO5Y76E (Aspirin)
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Entry Date(s):
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Date Created: 20100302 Date Completed: 20100513 Latest Revision: 20181201
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Update Code:
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20240104
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DOI:
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10.1016/j.bcp.2010.02.006
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PMID:
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20188709
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The purpose of the present work was the evaluation of the antithrombotic activity of a new PAR1 antagonist, F 16618 in arterio-venous shunt in the rat. Arterial thrombosis was induced by insertion of a silk thread (thrombogenic substrate) into an extracorporeal shunt. F 16618 was administered either by intravenous route (0.63-2.5mg/kg) or by oral route (20-80mg/kg). Oral activity of F 16618 was compared to that of aspirin (20-80mg/kg) and clopidogrel (0.63-10mg/kg). Finally, F 16618 was associated to aspirin and/or clopidogrel to test for possible antithrombotic activity and its effects on bleeding time. SFLLR-induced human platelet aggregation was evaluated in the presence of F 16618, demonstrating the anti-aggregant activity of this compound. F 16618 (1.25mg/kg) significantly delayed the time leading to occlusion by 52+/-17%, without affecting bleeding time and in absence of hemodynamic effects. F 16618 given orally dose-dependently increased the time to occlusion. The maximal effect was observed at 40mg/kg (984+/-95s versus 644+/-17s in vehicle group). Aspirin and clopidogrel also dose-dependently lengthened time to occlusion, but this effect was associated with an increase of bleeding time. F 16618 (20mg/kg) orally associated with either aspirin (40mg/kg) or with clopidogrel (1.25mg/kg) potentiated the antithrombotic effects of both compounds without further increasing of bleeding time. In conclusion, F 16618 exerted a potent antithrombotic activity by intravenous and oral routes, without affecting bleeding time. Furthermore, the antithrombotic activity was potentiated when combined with aspirin or clopidogrel.
(2010 Elsevier Inc. All rights reserved.)