Thrombolytic activity of a novel plasminogen activator, LY210825, compared with recombinant tissue-type plasminogen activator in a canine model of coronary artery thrombosis.

Abstract

With the technical assistance of Jack D. Frank 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. (Circulation 1990;82:930-940) Since the approval of streptokinase and recombinant tissue-type plasminogen activator (rtc PA) for intravenous administration in acute myocardial infarction, there has been significant growth in the acceptance of thrombolytic therapy for

Comparison of desulfatohirudin (REVASC) and heparin as adjuncts to thrombolytic therapy with reteplase in a canine model of coronary thrombosis

“…The role , randomized of prostacyclin which is inhibited by high dose acetylsalicylic as effective as acid may be negligible in the present experimental setting because the vessel occluder mechanically limits the reactivity of the injured coronary artery. The canine model of coronary artery thrombosis induced by electrolytic injury is known to produce stable coronary artery occlusion for hours without thrombolytic therapy (Jackson et al, 1990), even in the presence of heparin alone (Martin et al, 1991) and of heparin or hirudin alone (Martin et al, 1992c).…”

Blood Clearance and Activity of Erythrocyte-Coupled Fibrinolytics

“…Considerable effort has been expended to improve the clinical profile of PAs themselves (Verstraete et al, 1985;Jackson et al, 1992;Benedict et al, 1995;Collen and Lijnen, 2004). For example, Retavase (rPA, a mutant tPA derivative lacking the finger, extracellular growth factor, and kringle-1 domains) is more susceptible to inhibitors and has lower affinity for fibrin than wild-type tPA.…”

Thrombolytic Effects of a Novel Modified Tissue Plasminogen Activator, E6010, on Coronary Thrombosis in the Pig.

“…Benedict et al (24) demon strated that an occlusive coronary thrombus could occur spontaneously after the discon tinuation of electrical stimulation in anesthe tized open-chest dogs. Although canine mod els of coronary thrombosis have been widely used for the evaluation of thrombolytic agents (25)(26)(27), there have been few reports in pigs. We have recently reported a pig model of coronary thrombosis with spontaneous cyclic coronary flow variations induced by electrical stimulation of the intima of the coronary artery (12).…”

“…Two t-PA variants lacking the finger-like and growth factor-like domains (26) and LY210825 (27), which possess longer plasma half lives than native t-PA, were shown to produce rapid recanalization of a coronary thrombus and prevent reocclusion in a canine model of coronary artery thrombosis.…”