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Thromb Haemost 1992; 67(06): 686-691
DOI: 10.1055/s-0038-1648523
Original Articles
Schattauer GmbH Stuttgart

G4120, an Arg-Gly-Asp Containing Pentapeptide, Enhances Arterial Eversion Graft Recanalization with Recombinant Tissue-Type Plasminogen Activator in Dogs

Hua Rong Lu
The Center for Thrombosis and Vascular Research, the Laboratory of Experimental Cardiology and the Department of Histopathology, University of Leuven, Belgium, the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA and the Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Herman K Gold
The Center for Thrombosis and Vascular Research, the Laboratory of Experimental Cardiology and the Department of Histopathology, University of Leuven, Belgium, the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA and the Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Zaomin Wu
The Center for Thrombosis and Vascular Research, the Laboratory of Experimental Cardiology and the Department of Histopathology, University of Leuven, Belgium, the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA and the Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Tsunehiro Yasuda
The Center for Thrombosis and Vascular Research, the Laboratory of Experimental Cardiology and the Department of Histopathology, University of Leuven, Belgium, the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA and the Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Patrick Pauwels
The Center for Thrombosis and Vascular Research, the Laboratory of Experimental Cardiology and the Department of Histopathology, University of Leuven, Belgium, the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA and the Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Hansjörg J Rapold
The Center for Thrombosis and Vascular Research, the Laboratory of Experimental Cardiology and the Department of Histopathology, University of Leuven, Belgium, the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA and the Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Mary Napier
The Center for Thrombosis and Vascular Research, the Laboratory of Experimental Cardiology and the Department of Histopathology, University of Leuven, Belgium, the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA and the Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Stuart Bunting
The Center for Thrombosis and Vascular Research, the Laboratory of Experimental Cardiology and the Department of Histopathology, University of Leuven, Belgium, the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA and the Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
,
Désiré Collen
The Center for Thrombosis and Vascular Research, the Laboratory of Experimental Cardiology and the Department of Histopathology, University of Leuven, Belgium, the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA and the Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA, USA
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Publikationsverlauf

Received 11. Oktober 1991

Accepted after revision 18. Dezember 1991

Publikationsdatum:
03. Juli 2018 (online)

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Summary

The effects of G4120, a cyclic Arg-Gly-Asp (RGD) containing peptide which inhibits fibrinogen binding to the platelet receptor GPIIb/IIIa, on thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) were investigated in a combined arterial and venous thrombosis model in heparinized dogs. The arterial thrombus model consisted of a 3 cm everted (inside-out) carotid arterial segment inserted into a transsected femoral artery which occludes within 30 min with platelet-rich material and which is resistant to recanalization with 0.5 mg/kg rt-PA. The venous thrombus was a 125I-fibrin labeled whole blood clot produced in the contralateral femoral vein.

In 5 dogs given an intravenous bolus of 0.05 mg/kg G4120 followed by a continuous infusion of 0.05 mg/kg per hour for 3 h (group I), arterial occlusion persisted throughout a 4 h observation period and was still present at 24 h in all dogs; the extent of venous clot lysis after 120 min was 27 ± 7%. In 5 dogs given the same infusion of G4120 in combination with 0.5 mg/kg rt-PA over 60 min, recanalization of the arterial graft occurred in all dogs, within 13 ± 2 min and persisted throughout the observation period of 4 h (p = 0.01 versus G4120 or rt-PA alone); at 24 h, however, all grafts were occluded. Venous clot lysis in this group was 75 ± 8% (p = 0.002 versus G4120 alone andp NS versus rt-PA alone). Pathologic analysis revealed platelet-rich or mixed thrombus with platelet-rich and erythrocyte-rich zones. The last 6 dogs were given a reduced dose of G4120 consisting either of a 0.05 mg/kg bolus followed by an infusion of 0.05 mg/kg over 1 h in 3 dogs (group III) or of a single 0.05 mg/kg bolus in 3 dogs (group IV), both given in combination with 0.5 mg/kg rt-PA infused over 60 min. These protocols produced recanalization within 15 ± 2 and 34 ± 8 min, respectively, which was maintained throughout the 4 h observation period. Venous lysis in these groups was 63 ± 4 and 97 ± 1% respectively. Bleeding times prolonged from 1 to 2 min to >30 min with G4120, but returned towards baseline within 2 h after the end of the infusion. Platelet aggregation with ADP was completely inhibited with G4120 but partially recovered within 1 h after the end of the infusion. No fibrinogen breakdown was observed in association with the rt-PA infusion.

Thus, G4120, a synthetic GPIIb/IIIa receptor antagonist, enhances and accelerates lysis of platelet-rich arterial thrombosis with rt-PA and prevents reocclusion during and within 3 h after the infusion. It may be useful for the conjunctive use with thrombolytic agents in patients with arterial thromboembolic disease.

 

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