Document Detail


Antithrombotic effects of FK419, a novel nonpeptide platelet GPIIb/IIIa antagonist, in a guinea pig photochemically induced middle cerebral artery thrombosis model: comparison with ozagrel and argatroban.
MedLine Citation:
PMID:  14634048     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.
Authors:
Akira Moriguchi; Toshiaki Aoki; Kayoko Mihara; Nobuteru Tojo; Nobuya Matsuoka; Seitaro Mutoh
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Publication Detail:
Type:  Journal Article     Date:  2003-11-21
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  308     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2004 Mar 
Date Detail:
Created Date:  2004-02-26     Completed Date:  2004-04-06     Revised Date:  2004-12-08    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1094-101     Citation Subset:  IM    
Affiliation:
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co, Ltd, Osaka, Japan. akira_moriguchi@po.fujisawa.co.jp
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MeSH Terms
Descriptor/Qualifier:
Animals
Antithrombins / therapeutic use*
Blood Coagulation / drug effects
Blood Platelets / drug effects,  physiology
Brain Ischemia / complications,  drug therapy
Disease Models, Animal
Guinea Pigs
Infarction, Middle Cerebral Artery / drug therapy*
Male
Methacrylates / therapeutic use
Pipecolic Acids / therapeutic use
Platelet Aggregation Inhibitors / therapeutic use*
Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
Reperfusion Injury / prevention & control
Thromboxane B2 / metabolism
Chemical
Reg. No./Substance:
0/Antithrombins; 0/Methacrylates; 0/Pipecolic Acids; 0/Platelet Aggregation Inhibitors; 0/Platelet Glycoprotein GPIIb-IIIa Complex; 54397-85-2/Thromboxane B2; 74863-84-6/argatroban; 82571-53-7/ozagrel

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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