Intravenous and Endobronchial Administration of G4120, a Cyclic Arg‐Gly‐Asp‐Containing Platelet GPIIb/IIIa Receptor‐Blocking Pentapeptide, Enhances and Sustains Coronary Arterial Thrombolysis With rt‐PA in a Canine Preparation
作者:
Tsunehiro Yasuda,
Herman Gold,
Chikashi Kohmura,
Luis Guerrero,
Hiroyuki Yaoita,
John Fallon,
Stuart Bunting,
Desire Collen,
期刊:
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology
(OVID Available online 1993)
卷期:
Volume 13,
issue 5
页码: 738-747
ISSN:1049-8834
年代: 1993
出版商: OVID
关键词: acute myocardial infarction;thrombolytic therapy;arterial reocclusion;template bleeding time;glycoprotein IIb/IIIa receptor
数据来源: OVID
摘要:
G4120, L-cysteine, A$mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-tt-aspartyl-cyclic(l-»5)-sulfide, 5-oxide, a synthetic cyclic Arg-Gly-Asp-containing pentapeptide, has a high affinity (dissociation constant of 4 nM) for the platelet glycoprotein (GP) Ilb/IIIa receptor. The effects of its intravenous or endobronchial administration on thrombolysis, reocclusion, and bleeding time prolongation induced with 0.45 mg/kg bolus injections of recombinant tissue-type plasminogen activator in combination with intravenous heparin (4,000-unit bolus and 1,000 units each hour) were studied in a canine model consisting of an erythrocyte-rich blood clot in the left anterior descending coronary artery. Coronary patency was monitored for 3 hours both by ultrasonic flow probe and by repeat coronary angiography. Four groups of six to 10 dogs were studied with intravenous infusions of 0, 0.1, 0.2, or 0.3 mg/kg G4120 over 60 minutes. G4120 at a dose of 0.3 mg/kg reduced the time to reflow from a mean control value of 45 to 8 minutes (p=0.036) and delayed reocclusion (p=0.001). Four groups of five or six dogs were studied with endobronchial instillation of G4120 in a randomized, blinded study design using 0,0.13,0.25, or 0.5 mg/kg G4120. Endobronchial G4120 at a dose of 0.5 mg/kg reduced the time to reflow from a mean control value of 52 to 7 minutes (p=0.039) and abolished cyclic reocclusion and reflow (p=0.008). G4120 induced a dose-related transient prolongation of the template bleeding time and inhibition of ADP-induced platelet aggregation. G4120, a synthetic low-molecular-weight GPIIb/IIIa inhibitor that may be produced by chemical synthesis, may be of clinical value as a conjunctive agent for thrombolysis in patients with ischemic coronary syndromes.
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