LY210825, a recombinant
tissue-type plasminogen activator (rt-PA), which contains the kringle-2 and
serine protease functional domains of native
tissue-type plasminogen activator, was previously produced by site-directed mutagenesis in a Syrian hamster cell line. We studied the thrombolytic potential of this molecule in a canine
thrombosis model. Male hounds (16-22 kg) were anesthetized; a 2.0-cm segment of the left circumflex coronary artery (LCX) was isolated proximal to the first main branch, and the dogs were instrumented with an electromagnetic flow probe to measure coronary blood flow. An occlusive
thrombus was formed after injury of the intimal surface of the LCX with an electrical current applied by a needle-tipped
anode placed distal to the electromagnetic flow probe. After 1 hour of occlusion, either
LY210825 or rt-PA was administered intravenously according to the following protocols: 1) a 1-hour infusion of either 0.25 mg/kg
LY210825 or 0.4 mg/kg rt-PA, 2) single
injections of 0.15-0.6 mg/kg
LY210825, and 3) a single injection of 0.45 mg/kg
LY210825 and a 3-hour infusion of 1.0 or 1.7 mg/kg rt-PA. Plasma half-lives of
LY210825 and rt-PA were 58 +/- 7 and 3.3 +/- 0.3 minutes, respectively.
LY210825 produced more rapid reperfusion of the LCX than did rt-PA. In the third study, 90% of the rt-PA-treated vessels reoccluded within 1 hour after cessation of
drug, whereas only 25% of the
LY210825-treated vessels reoccluded during a 4-hour washout period. There were significant, but relatively small, reductions produced by both
plasminogen activators on plasma
fibrinogen and
plasminogen (25-35% decreases). Because of its longer plasma half-life,
LY210825 could be administered intravenously as a single injection. In a canine model of coronary artery
thrombosis,
LY210825 was a more effective
thrombolytic agent than was rt-PA.