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.
G4120, L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-alpha- aspartyl-cyclic(1-->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) IIb/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.
Yasuda
T
T
Cardiac Unit, Massachusetts General Hospital, Boston 02114.
Gold
H K
HK
Kohmura
C
C
Guerrero
L
L
Yaoita
H
H
Fallon
J T
JT
Bunting
S
S
Collen
D
D
D000818:Animals; D001980:Bronchi; D003326:Coronary Circulation; D003327:Coronary Disease / Q000473:pathology / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D004285:Dogs; D004357:Drug Synergism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006487:Hemostasis; D007275:Injections, Intravenous; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D012008:Recurrence; D013454:Sulfoxides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D014654:Vascular Patency / Q000187:drug effects
D005343:Fibrinolytic Agents; D010456:Peptides, Cyclic; D010980:Platelet Membrane Glycoproteins; D013454:Sulfoxides; C074915:G 4120; D010959:Tissue Plasminogen Activator