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.