Influence of heparin and systemic lysis on coronary blood flow after reperfusion induced by the novel recombinant plasminogen activator BM 06.022 in a canine model of coronary thrombosis

Intracoronary thrombus resulting in acute myocardial ischemia can be lysed by thrombolytic agents, such as, streptokinase or t-PA. We examined the potential of a recombitant tissue-plasminogen activator (rt-PA)and a fibrin (ogen)-degradation productpentapeptide 6A, Ala-Arg-Pro-Ala-Lys, corresponding to aminoacids 43-47 in the BB-chain of fibrinogen, which causes marked increase in coronary blood flow and stimulates prostacyclin release, in restoring coronary blood flow in dqgs with experimentally-induced thrombus. An occlusive thrombus was created in the circumflex (Cx) coronary artery in 8 dcgs by electricalstimulation of the endothelial surface. The electrically-induced Cx thrombus consisted primarily of platelets and fibrin. After the occlusive thrcmbus was stable without electrical currant, rt-PA (10ug/kg/minute for 30 minutes intravenously)or peptide 6A (5 unoles/minute for 20 minutes intracorcnary) were randomly administered. Infusion of t-PA restored coronar blood flow (peak 22 ±12 ml/minute, mean ±SD) in five of seven animlas. The time to flow restoration was 12.3 ± 9.1 minutes and the reflow persistedfor20.0 ± 10.9 minutes. Peptide 6A administration also restored coronary blood flow (peak 20 ± 4 ml/ minute) in seven of eight animals with occlusive coronary thrombus. Mean time to blood flow restoration (4.3 ±2.9 minutes) wasshorter(P>0.05) than with rt-PA, but thereflow persisted only for the duration of tine infusion (16.3 ± 10.2 minutes).Peptide 6A adninistration was associatedwith a significant (P±0.05) increase in plasma 6-keto-PGF1α indicating stimulation of prostacyclin release. In addition, plasma t-PA concentrations also increased (F>0.01) at the peak effect of peptide 6A indicating releaseof endogenous t-PA as another potentialmechanism of the thrombolytic effects of peptide 6A. This study demonstrates that peptide 6A exerts coronary thrombolytic effectsccmpa rable to those of t-PA in a canine model of coronary thrombosis.

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The New Nitroderivative ITF 296 Improves Collateral Blood Flow in a Canine Model of Coronary Thrombosis

Journal of Cardiovascular Pharmacology ◽

10.1097/00005344-199506264-00007 ◽

1995 ◽

Vol 26 ◽

pp. S31-36

Author(s):

Maria Giovanna Trivella ◽

Graziano Barsotti ◽

Roberta Cereda ◽

Francesca Chiaverini ◽

Gianni Gromo ◽

...

Keyword(s):

Blood Flow ◽

Coronary Thrombosis ◽

Canine Model ◽

Collateral Blood Flow

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173 Restoration of microvascular patency with recombinant double chain tissue plasminogen activator (BW t-PA) in a canine model of coronary thrombosis

Fibrinolysis and Proteolysis ◽

10.1016/0268-9499(88)90520-6 ◽

1988 ◽

Vol 2 ◽

pp. 75

Author(s):

D.J. Longridge ◽

M.P. Maxwell ◽

A.J. Ford ◽

M. Follenfant ◽

B. Hughes

Keyword(s):

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Coronary Thrombosis ◽

Canine Model ◽

Double Chain ◽

Tissue Plasminogen

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The New Nitroderivative ITF 296 Improves Collateral Blood Flow in a Canine Model of Coronary Thrombosis

Journal of Cardiovascular Pharmacology ◽

10.1097/00005344-199526004-00007 ◽

1995 ◽

Vol 26 (Sup 4) ◽

pp. S31-36

Author(s):

Maria Giovanna Trivella ◽

Graziano Barsotti ◽

Roberta Cereda ◽

Francesca Chiaverini ◽

Gianni Gromo ◽

...

Keyword(s):

Blood Flow ◽

Coronary Thrombosis ◽

Canine Model ◽

Collateral Blood Flow

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Encapsulation of a plasminogen activator speeds reperfusion, lessens infarct and reduces blood loss in a canine model of coronary artery thrombosis

Thrombosis and Haemostasis ◽

10.1160/th03-11-0704 ◽

2004 ◽

Vol 91 (06) ◽

pp. 1213-1218 ◽

Cited By ~ 15

Author(s):

J. Leach ◽

Eugene Patterson ◽

Edgar O’Rear

Keyword(s):

Blood Flow ◽

Coronary Artery ◽

Blood Loss ◽

Plasminogen Activator ◽

Canine Model ◽

Arterial Blood Flow ◽

Bleeding Complications ◽

Arterial Blood ◽

Artery Thrombosis ◽

Coronary Artery Thrombosis

SummaryIn the present study, a polymer-encapsulated plasminogen activator was investigated as an alternative to restore blood flow more effectively than free plasminogen activator. While current fibrinolytic agents have limited efficacy, attributable to delayed onset of sustained reperfusion and bleeding complications, encapsulated plasminogen activators have shown promise in addressing these shortcomings. A polymer-encapsulated plasminogen activator could offer an effective formulation with a prolonged shelf-life. In this study, coronary artery thrombosis was produced in the anesthetized dog by the injection of thrombin + whole blood, and then one of five randomly selected formulations was administered intravenously: saline, blank microcapsules, free streptokinase (FREE SK), streptokinase and blank microcapsules (FREE SK + BLANK), or streptokinase entrapped in polymer microcapsules (MESK). MESK significantly accelerated the time to reperfusion compared to FREE SK or FREE SK + BLANK. Additionally, substantial reductions were observed in residual clot mass, infarct mass, reocclusion episodes, fibrinogen depletion and blood loss with MESK compared to FREE SK. The results of this study demonstrate that MESK accelerates thrombolysis and the restoration of blood flow compared to identical dosages of FREE SK while also reducing systemic fibrinogenolysis and blood loss. Microencapsulation may produce an improved dosage form for restoring arterial blood flow and reducing bleeding complications with thrombolytic therapy.

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