Comparison of the thrombolytic activity of the novel plasminogen activator, LY210825, to anisoylated plasminogen-streptokinase activator complex in a canine model of coronary artery thrombolysis.
We have compared the thrombolytic efficacy of a novel single-chain, recombinant tissue-type plasminogen activator variant, LY210825, containing the second kringle and serine protease domains of native tissue-type plasminogen activator, with anisoylated plasminogen-streptokinase activator complex (APSAC). Male hounds (16-22 kg) were anesthetized, the left circumflex coronary artery was isolated and an electromagnetic flow probe was placed around the artery proximal to the first main branch for the measurement of coronary blood flow. An occlusive thrombus was formed after electrolytic injury of the intima of the coronary artery. After an occlusion period of 1 hr, either LY210825 (n = 8) or APSAC (n = 6) was administered as a single i.v. injection of 0.45 mg/kg. Blood was drawn (3.8% citrate) for determination of plasma fibrinogen, plasminogen and alpha-2 antiplasmin. Time to reperfusion was significantly faster with LY210825 than with APSAC, 20 +/- 2 vs. 54 +/- 8 min, respectively. The incidence of reocclusion was similar for both agents. APSAC produced significant depletion of alpha-2 antiplasmin, plasminogen and circulating fibrinogen, whereas LY210825 caused only slight consumption of plasminogen and only small decreases in fibrinogen. After a single injection of LY210825, thrombolytic concentrations of plasminogen activator were available immediately, whereas there was a significant delay in lytic concentrations of active streptokinase-plasmin complex. Consequently, LY210825 reperfused the coronary artery faster than did APSAC. In addition, LY210825 spared plasma fibrinogen, plasminogen and alpha-2 antiplasmin and therefore, could potentially minimize the risk of bleeding complications.
Jackson
C V
CV
Department of Cardiovascular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Frank
J D
JD
Craft
T J
TJ
Sundboom
J L
JL
Smith
G F
GF
D000818:Animals; D016255:Anistreplase / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D005340:Fibrinogen / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D010958:Plasminogen / Q000187:drug effects / Q000378:metabolism; D010960:Plasminogen Activators / Q000494:pharmacology; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000979:alpha-2-Antiplasmin / Q000187:drug effects / Q000378:metabolism
D000979:alpha-2-Antiplasmin; C065621:LY 210825; D016255:Anistreplase; D005340:Fibrinogen; D010958:Plasminogen; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator