Clinical pharmacology in patients with evolving myocardial infarction of tissue-type plasminogen activator produced by recombinant DNA technology

A. J. Tiefenbrunn, A. K. Robinson, P. B. Kurnik, P. A. Ludbrook, B. E. Sobel

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

This study was performed to characterize selected pharmacologic properties and effects on the fibrinolytic system of tissue-type plasminogen activator synthesized by recombinant DNA technology (rt-PA) in 12 patients treated for coronary thrombosis. rt-PA was infused parenterally (by the intracoronary route in four patients and intravenously in eight) in doses of 8.3, 12.5, or 16.7 μg/kg/min for 30 to 60 min, yielding a total dosage of 20 to 40 mg/patient. The drug induced coronary thrombolysis in 10 of the 12 patients treated (83%), including six of the eight given rt-PA intravenously. No bleeding complications were encountered. Serial blood samples were obtained before, during, and after infusion of rt-PA and analyzed for t-PA antigen (i.e., immunoassayable rt-PA protein), functional fibrinolytic activity attributable to rt-PA, fibrinogen, plasminogen, α2-antiplasmin, fibrinogen degradation products, prothrombin time, activated partial thromboplastin time, and protamine-corrected thrombin time. Pretreatment plasma t-PA antigen levels averaged 16.5 ± 5 (SD) ng/ml. Peak plasma values were generally proportional to dose, averaging 3330 ± 1201 ng/ml. Approximately 90% of peak level was reached in 30 min, with a plateau at peak reached within 40 min. Functional t-PA activity increased monotonically in a comparable fashion. Curves for disappearance of both t-PA antigen and functional activity from plasma were monoexponential for at least two half-lives (r = .99 for both) and were concordant. The observed half-lives were similar, averaging 8.3 and 9.1 min, respectively. Changes in concentrations of fibrinogen were transient and modest (17 ± 6% of baseline). Plasminogen and α2-antiplasmin levels declined moderately to 51 ± 6% and 32 ± 7% of pretreatment values at the end of infusion of rt-PA. Prothrombin time, protamine-corrected thrombin time, and assay of fibrinogen degradation products corroborated the lack of a lytic state. Thus, desirable levels of rt-PA can be achieved consistently with short-term infusions of appropriately selected doses without induction of a systemic lytic state predisposing to bleeding.

Original languageEnglish
Pages (from-to)110-116
Number of pages7
JournalCirculation
Volume71
Issue number1
DOIs
StatePublished - Jan 1 1985
Externally publishedYes

Fingerprint Dive into the research topics of 'Clinical pharmacology in patients with evolving myocardial infarction of tissue-type plasminogen activator produced by recombinant DNA technology'. Together they form a unique fingerprint.

  • Cite this