Pentobarbital-anesthetized dogs (total of 25) were used in which acute damage of the proximal left circumflex coronary artery, together with mechanical
stenosis, produced an occlusive
thrombosis. When the platelet plug was removed by rubbing the vessel, the occlusion returned reproducibly for at least 2 hours in control studies. To evaluate the antithrombotic efficacy of
DTTX30, a reproducible pattern of occlusive coronary thrombi was first established over a period of one hour. Thereafter,
DTTX30 (0.12 mg/kg i.v. bolus plus 0.29 mg/kg/hr),
acetylsalicylic acid (ASA, 5 mg/kg, i.v. bolus),
vapiprost (1.0 mg/kg i.v. bolus plus 1.0 mg/kg/ hr), or vehicle was administered and observations continued for one additional hour. At the end of the one hour observation period,
epinephrine (0.3 microgram/kg/min i.v.) was infused (with continued
DTTX30,
vapiprost or vehicle infusion) and observations were continued for an additional 30 min.
DTTX30 eliminated the recurrent arterial
thrombus formation in all dogs without significant systemic or left ventricular hemodynamic effects. Infusion of
epinephrine to further provoke
thrombus formation produced a significant enhancement of left ventricular pressure development (LV dP/dt) and arterial diastolic and systolic pressures but failed to initiate
thrombus formation.
DTTX30 inhibited fully
collagen-induced platelet aggregation ex vivo and produced an approximate 3-fold prolongation of the sublingual bleeding time. ASA eliminated
thrombus formation in 4 of 5 dogs, but the additional prothrombotic stimulus of
epinephrine infusion produced recurrent
thrombus formation in all dogs.
Collagen-induced platelet aggregation ex vivo was inhibited by
acetylsalicylic acid, but sublingual bleeding time was unaffected.
Vapiprost inhibited arterial
thrombus formation in all dogs, but
thrombus formation returned with the addition of
epinephrine. There was a tendency for prolonged bleeding times with
vapiprost administration and
collagen-induced platelet aggregation ex vivo was effectively inhibited.
CONCLUSION: