Preclinical evaluation of S18886 in an experimental model of coronary arterial thrombosis
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Ting-Ting Hong1, Jinbao Huang, Edward Driscoll
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA. thongz@umich.edu
Abstract:
The specific thromboxane receptor antagonist, S18886, was evaluated for prevention of coronary arterial thrombosis and myocardial ischemia-reperfusion in anesthetized canines. For the primary thrombosis study in left circumflex (LCX) coronary artery, 26 dogs were randomized to receive either vehicle (n = 7) or intravenous S18886 (0.3 mg/kg, n = 6; 1.0 mg/kg, n = 6; and 3.0 mg/kg, n = 7). The respective times to occlusion after S18886 were as follows: 56.8 +/- 9.3, 83.5 +/- 14.9, and 92.4 +/- 15.7 minutes compared to 43.3 +/- 8.2 minutes after vehicle. S18886 caused a minimal increase in tongue bleeding time and a significant decrease in ex vivo platelet aggregation to arachidonic acid or U46619. Another 37 dogs were randomized to receive placebo (n = 12), clopidogrel 1.0 mg/kg p.o. QDX3 (n = 9), clopidogrel + S18886 0.3 (n = 9) or 1.0 (n = 7) mg/kg intravenous. Clopidogrel produced a 50% reduction in adenosine diphosphate-induced platelet aggregation and a slight increase in the time to occlusion. However, clopidogrel + S18886 1.0 mg/kg prevented occlusive thrombus formation in most of the coronary vessels over 6 hours. S18886 did not alter myocardial infarct size in the ischemia-reperfusion model. In conclusion, S18886 alone caused a dose-dependent prolongation in the time to primary occlusive coronary artery thrombosis, whereas S18886 + clopidogrel displayed effective in preventing occlusive thrombus formation with only a moderate increase of tongue-bleeding time.
Insights
The thromboxane receptor antagonist S18886 effectively delayed coronary artery thrombosis in dogs. Combining S18886 with clopidogrel prevented occlusive thrombus formation with minimal bleeding risk.
Area of Science:
- Cardiovascular Pharmacology
- Thrombosis Research
Background:
- Coronary artery thrombosis is a critical factor in myocardial infarction.
- Thromboxane receptor antagonists offer a potential therapeutic strategy.
- Evaluating novel antithrombotic agents is crucial for cardiovascular disease management.
Purpose of the Study:
- To assess the efficacy of S18886, a thromboxane receptor antagonist, in preventing coronary arterial thrombosis.
- To investigate the combined effect of S18886 and clopidogrel on thrombosis and bleeding.
- To evaluate S18886's impact on myocardial ischemia-reperfusion injury.
Main Methods:
- Anesthetized canines underwent studies for coronary thrombosis and ischemia-reperfusion.
- Dogs were randomized to receive vehicle, S18886 at various doses, clopidogrel, or combinations.
- Primary endpoint was time to coronary artery occlusion; secondary endpoints included platelet aggregation and bleeding time.
Main Results:
- S18886 demonstrated a dose-dependent prolongation of time to coronary artery occlusion.
- Combination therapy with S18886 and clopidogrel effectively prevented occlusive thrombus formation.
- S18886 showed minimal increase in tongue bleeding time and reduced platelet aggregation.
- S18886 did not affect myocardial infarct size in the ischemia-reperfusion model.
Conclusions:
- S18886 alone significantly delays occlusive coronary artery thrombosis in a dose-dependent manner.
- The combination of S18886 and clopidogrel is highly effective in preventing occlusive thrombus formation.
- This combination therapy offers a promising approach for managing thrombotic cardiovascular events with a manageable bleeding profile.
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