Effect of time of 7E3 administration on rt-PA-induced reperfusion: study in a canine model of thrombus-based occlusion-reperfusion.
Chimeric version of the murine monoclonal antibody, 7E3 has been proposed for the early restoration of coronary artery patency during thrombolytic therapy. We determined the optimal time for administration of 7E3 during recombinant tissue plasminogen activator (rt-PA)-induced thrombolysis using a canine model of coronary artery thrombosis. After 30 min of thrombotic occlusion, microspheres were injected to assess regional myocardial blood flow, followed by a 90-min rt-PA infusion. Dogs were randomized to three groups wherein 7E3 (0.8 mg kg(-1), i.v.) was administered either 5 min before rt-PA (Group I), at the first evidence of thrombolysis (Group II), or after the completion of rt-PA infusion (Group III). Hemodynamic parameters were monitored for 6 h after which infarct size was estimated. Time to occlusion/reperfusion was similar in all groups. In the rt-PA alone group, 78% arteries reoccluded after 60 min of reperfusion. The incidence of reocclusion was lower in Groups II (25%, P = 0.04) and III (0%. P < 0.01). All arteries (100%) were patent at the end of the protocol in Group III vs 50% remaining patent in Group I (P = 0.01). Arterial patency was maintained longer in Group III (301 min, n = 10), compared with Groups I (124 min, n = 5) and II (124 min, n = 6). Arterial flow was greater in Group III (82%) compared with Groups I (27%) and II (35%) (P < 0.01). Regional myocardial blood flow and infarct size were similar in all groups. The data indicate that the time of administration of 7E3 in conjunction with rt-PA-induced thrombolysis influences patency status. The experimental results suggest that in the absence of aspirin and heparin, optimal thrombolysis is obtained when 7E3 is administered after the completion of rt-PA infusion regimen.
Rebello
S S
SS
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, USA. sam.rebello@rp-rorer.com
Huang
J
J
Saito
K
K
Saucedo
J F
JF
Bates
E R
ER
Lucchesi
B R
BR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D015425:Myocardial Reperfusion; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000627:therapeutic use; D012039:Regional Blood Flow / Q000187:drug effects; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator