Augmented and sustained plasma concentrations after intramuscular injections of molecular variants and deglycosylated forms of tissue-type plasminogen activators

Circulation
B E SobelD A Nachowiak

Abstract

We have previously explored induction of coronary thrombolysis with tissue-type plasminogen activator (t-PA) administered intramuscularly. Absorption-enhancing agents that rendered the approach feasible were identified, but large amounts of activator were required and initial elevations of concentrations in plasma could not be sustained. The present study was designed to determine whether more therapeutically favorable plasma concentrations could be induced by genetically engineering or chemically modifying t-PA to prolong its half-life based on the hypothesis that the ratio of absorption to clearance would be increased. Each of four genetically engineered variants (one variant with growth factor and kringle 1 domains deleted and kringle 2 duplicated, a second variant with a cysteine for Arg substitution in the growth factor domain, a third variant with an additional urokinase kringle inserted, and a fourth variant with the growth factor domain deleted) and enzymatically deglycosylated t-PA exhibited prolonged half-life after bolus intravenous injection in rabbits. Each elicited substantially higher and more sustained elevations in plasma after intramuscular injection in rabbits or dogs with absorption-enhancing agents as compa...Continue Reading

References

Oct 1, 1989·Journal of the American College of Cardiology·B E Sobel
Jun 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·B E SobelS J Sarnoff
Mar 8, 1984·The New England Journal of Medicine·F Van de WerfB E Sobel

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Citations

Sep 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·J S StamlerJ Loscalzo

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