Comparative effects of anti-platelet agents as adjuncts to tissue plasminogen activator in a dog model of occlusive coronary thrombosis.
1. This study compares a cyclo-oxygenase inhibitor (aspirin), a 5-HT2 antagonist (ZM170809) and a combined thromboxane synthase inhibitor/receptor antagonist (ZD1542) as adjuncts to tissue plasminogen activator (rt-PA). 2. Application of an anodal current (332 +/- 4.1 microA) to the stenosed left circumflex coronary artery of 20 anaesthetized dogs produced a stable platelet-rich occlusive thrombus. 3. After initial i.v. administration of recombinant human tissue type plasminogen activator (rt-PA, 3 mg bolus +2 mg kg-1 h-1 for 30 min) thrombolysis occurred in 15 out of 20 dogs. All 15 dogs reoccluded. 4. The second i.v. administration of rt-PA in the presence of either aspirin, ZM170809, ZD1542 or saline resulted in thrombolysis in all 20 dogs. 5. Both the combined thromboxane synthase inhibitor/receptor antagonist (ZD1542) and 5-HT2 antagonist (ZM170809) significantly (P < 0.05) reduced the time taken to lyse the thrombus compared with the saline group. The times were 14.4 +/- 2.7 min, 18.0 +/- 3.9 min and 36.8 +/- 6.2 min for ZD1542, ZM170809 and saline respectively. 6. Aspirin did not offer any additional benefit to using rt-PA alone. The times to thrombolysis were 36.8 +/- 8.4 min for aspirin and 36.8 +/- 6.2 min for the saline group. 7. The number of dogs in which the circumflex coronary artery reoccluded within 60 min of terminating the second infusion of rt-PA were five for saline, four for aspirin, two for ZD1542 and two for ZM170809. 8. These results indicate that both ZD1542 and ZM170809 are more effective adjuncts than aspirin in thrombolysis and may provide an improvement in current clinical practice.
McAuliffe
S J
SJ
Vascular inflammatory and Musculoskeletal Research Department, ZENECA Pharmaceuticals, Mereside, Macclesfield, Cheshire.
Moors
J A
JA
Jones
H B
HB
D000818:Animals; D001241:Aspirin / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003328:Coronary Thrombosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004146:Dioxanes / Q000627:therapeutic use*; D004285:Dogs; D004357:Drug Synergism; D004562:Electrocardiography / Q000187:drug effects; D008297:Male; D010960:Plasminogen Activators / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012702:Serotonin Antagonists; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D016861:Cyclooxygenase Inhibitors; D004146:Dioxanes; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D011804:Quinolines; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; C081036:ICI D1542; C060632:ICI 170809; D010960:Plasminogen Activators; D013930:Thromboxane-A Synthase; D001241:Aspirin