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Journal of the American College of... Jan 1985Human tissue plasminogen activator holds promise for the dissolution of coronary thrombi by intravenous administration and without systemic anticoagulation. Prior animal... (Comparative Study)
Comparative Study
Human tissue plasminogen activator holds promise for the dissolution of coronary thrombi by intravenous administration and without systemic anticoagulation. Prior animal experiments have been conducted only in vessels without disease. To test the thrombolytic efficacy of recombinant tissue plasminogen activator in the presence of diseased intima, an established model of atherosclerosis was utilized. The aorta of 16 New Zealand white rabbits (2 to 3 kg) was made atherosclerotic by balloon endothelial denudation and concurrent 1% cholesterol feeding for 8 weeks. An aged (24 hour) heterologous (human) clot, labeled with I-125 fibrinogen was injected into the distal aorta and produced thrombotic occlusion. After 1 hour of thrombosis (control period), recombinant tissue plasminogen activator (100,000 IU approximately equal to 1 mg protein, n = 6) or streptokinase (100,000 IU, n = 5) or saline solution (n = 5) was systemically infused over 30 minutes. Serial blood samples, obtained to determine fractional change in blood radioactivity over time, showed a fourfold increase of blood radioactivity after tissue plasminogen activator and streptokinase infusion compared with the control period (47,400 +/- 3,300 [mean +/- standard error] versus 11,800 +/- 300 counts/min, p less than 0.001). Time to 50% of maximal thrombolysis was 41 +/- 14 minutes (+/- standard deviation) for tissue plasminogen activator versus 63 +/- 16 minutes for streptokinase (p less than 0.01). In six of six rabbits receiving tissue plasminogen activator and four of five rabbits receiving streptokinase, reestablishment of distal aortic flow was detected via the indwelling catheter within 25 minutes of drug infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Hemorrhage; Humans; Infusions, Parenteral; Male; Perfusion; Plasminogen Activators; Rabbits; Streptokinase; Thrombosis
PubMed: 4038373
DOI: 10.1016/s0735-1097(85)80088-7 -
Sangre 1984
Review
Topics: Animals; Blood Vessels; Dogs; Endothelium; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; Myocardial Infarction; Plasminogen Activators; Streptokinase; Thrombosis; Urokinase-Type Plasminogen Activator; alpha-2-Antiplasmin
PubMed: 6393389
DOI: No ID Found -
Critical Reviews in Biotechnology 1988The mammalian serine protease zymogen, plasminogen, can be converted into the active enzyme plasmin by vertebrate plasminogen activators urokinase (uPA), tissue... (Review)
Review
The mammalian serine protease zymogen, plasminogen, can be converted into the active enzyme plasmin by vertebrate plasminogen activators urokinase (uPA), tissue plasminogen activator (tPA), factor XII-dependent components, or by bacterial streptokinase. The biochemical properties of the major components of the system, plasminogen/plasmin, plasminogen activators, and inhibitors of the plasminogen activators, are reviewed. The plasmin system has been implicated in a variety of physiological and pathological processes such as fibrinolysis, tissue remodeling, cell migration, inflammation, and tumor invasion and metastasis. A defective plasminogen activator/inhibitor system also has been linked to some thromboembolic complications. Recent studies of the mechanism of fibrinolysis in human plasma suggest that tPA may be the primary initiator and that overall fibrinolytic activity is strongly regulated at the tPA level. A simple model for the initiation and regulation of plasma fibrinolysis based on these studies has been formulated. The plasminogen activators have been used for thrombolytic therapy. Three new thrombolytic agents--tPA, pro-uPA, and acylated streptokinase-plasminogen complex--have been found to possess better properties over their predecessors, urokinase and streptokinase. Further improvements of these molecules using genetic and protein engineering tactics are being pursued.
Topics: Amino Acid Sequence; Animals; Base Sequence; Fibrinolysin; Fibrinolysis; Glycoproteins; Humans; Molecular Sequence Data; Plasminogen; Plasminogen Activators; Plasminogen Inactivators
PubMed: 2976309
DOI: 10.3109/07388558809150542 -
Advances in Cancer Research 1985
Review
Topics: Amino Acid Sequence; DNA; Enzyme Precursors; Fibrinolysin; Genes; Humans; Neoplasms; Phenotype; Plasminogen; Plasminogen Activators; RNA, Messenger; Urokinase-Type Plasminogen Activator
PubMed: 2930999
DOI: 10.1016/s0065-230x(08)60028-7 -
Thrombosis and Haemostasis Apr 2005
Topics: Congresses as Topic; History, 20th Century; History, 21st Century; Humans; Plasminogen Activators; Research; Tissue Plasminogen Activator
PubMed: 15841304
DOI: 10.1160/TH05-02-0110 -
[Rinsho Ketsueki] the Japanese Journal... Jul 1984
Comparative Study
Topics: Animals; Cell Line; Dogs; Fibrinolysis; Fibrinolytic Agents; Humans; Melanoma; Plasminogen Activators; Rabbits; Thrombosis; Urokinase-Type Plasminogen Activator
PubMed: 6542154
DOI: No ID Found -
Endocrinology May 1990We have investigated the content of plasminogen activators in the rat ventral prostate during castration. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis...
We have investigated the content of plasminogen activators in the rat ventral prostate during castration. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and zymography demonstrated two major Mr-forms of plasminogen activators that were found to be strongly increased by castration; inclusion of quenching antibodies in the zymography and immunoblotting analysis identified these as urokinase-type plasminogen activator (u-PA) and its Mr 30,000 degradation product, respectively. A third, less abundant form, which was identified as tissue-type plasminogen activator, was also increased by castration. The induction of the plasminogen activators was prevented by treating the rats with 5 alpha-dihydrotestosterone. The increase in u-PA antigen was quantitated by the use of enzyme-linked immunosorbent assay. The increases in u-PA activity and antigen were traced back to a corresponding increase in u-PA messenger RNA (mRNA). By immunohistochemical methods, the u-PA was found to be present in scattered single cells at the surface of the epithelium facing the lumen of the glandular ducts. Such cells were present in control as well as in castrated rats, but their number increased after castration. In addition, after castration, u-PA immunoreactivity appeared in cells throughout the epithelium. These results suggest a role for plasminogen activation in castration-induced involution of the rat ventral prostate, and a role in the normal turnover of the rat ventral prostate epithelium.
Topics: Animals; Blotting, Western; Dihydrotestosterone; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Kinetics; Male; Molecular Weight; Nucleic Acid Hybridization; Orchiectomy; Plasminogen Activators; Prostate; RNA, Messenger; Rats; Rats, Inbred Strains; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator
PubMed: 2109689
DOI: 10.1210/endo-126-5-2567 -
Cardiovascular & Hematological Agents... Jul 2008First generation thrombolytics (streptokinase and urokinase) had no fibrin binding capabilities and caused systemic plasminogen activation with concomitant destruction... (Review)
Review
First generation thrombolytics (streptokinase and urokinase) had no fibrin binding capabilities and caused systemic plasminogen activation with concomitant destruction of haemostatic proteins. A primary driving force behind the development of the second generation plasminogen activator tissue plasminogen activator (tPA or alteplase) was its ability to bind to fibrin and target thrombolysis. Although in vitro assays highlighted advantages of fibrin binding, clinical trials were disappointing, showing only small benefits in mortality with tPA versus streptokinase, but also with some increase in haemorrhagic stroke. Third generation thrombolytic agents (reteplase, tenecteplase and pamiteplase) are variants of tPA engineered to have improved structure/function, such as longer half life and resistance to inhibitors. However, clear therapeutic advantages of third generation thrombolytics in clinical trials have also been difficult to demonstrate. Although fibrin binding is critical in regulating the activity of tPA, it is not clear how important it is for thrombolytic treatment. Advances are needed in our understanding of the relationship between structure/binding and activity of PAs in vivo under normal conditions and when administered in pharmacological doses. Clearly the impact of fibrin structure and the other components in fibrin clots must also be considered. Ultimately these studies may lead to better engineered therapeutics or optimised mixtures of molecules. With a more detailed understanding of the regulation of plasminogen activation and fibrinolysis it might be possible to tailor thrombolytic therapy to different situations such as myocardial or cerebrovascular treatment or to the patient's age and sex and other characteristics.
Topics: Fibrin; Fibrinolysis; Fibrinolytic Agents; Models, Biological; Plasminogen Activators
PubMed: 18673235
DOI: 10.2174/187152508784871945 -
Annales de Biologie Clinique 1988The mammalian fibrinolytic system comprises a proenzyme, plasminogen, which can be converted to the active enzyme plasmin, which will degrade fibrin. Plasminogen... (Review)
Review
The mammalian fibrinolytic system comprises a proenzyme, plasminogen, which can be converted to the active enzyme plasmin, which will degrade fibrin. Plasminogen activation is mediated by plasminogen activators which are classified as either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). t-PA and single-chain u-PA (scu-PA) induce clot-specific thrombolysis, however via entirely different mechanisms. t-PA is relatively inactive in the absence of fibrin, but fibrin strikingly enhances the activation rate of plasminogen by t-PA. This is explained by an increased activity of fibrin-bound t-PA for plasminogen and not by alteration of the catalytic efficiency of the enzyme. scu-PA has a high affinity for plasminogen but, however, does not activate plasminogen in plasma in the absence of a fibrin clot, due to competitive inhibition. Fibrin-specific thrombolysis appears to be due to the fact that fibrin reverses the competitive inhibition, but this does not seem to occur via specific binding of scu-PA to fibrin. The thrombolytic efficacy and fibrin-specificity of natural and recombinant t-PA has been demonstrated in animal models of pulmonary embolism, venous thrombosis and coronary artery thrombosis. In all these studies thrombolysis and relative fibrinogen sparing effect of t-PA was recently confirmed in several multicenter clinical trials in patients with acute myocardial infarction. Specific thrombolysis by scu-PA has also been demonstrated in animal models of pulmonary embolism, venous thrombosis and coronary artery thrombosis.
Topics: Humans; Plasminogen Activators
PubMed: 3044205
DOI: No ID Found -
Proceedings of the National Academy of... Jul 1981A preparation of fibrin precipitated over a solid Celite (diatomaceous earth) matrix that selectively binds 50-70% of the plasminogen activator present in human blood...
A preparation of fibrin precipitated over a solid Celite (diatomaceous earth) matrix that selectively binds 50-70% of the plasminogen activator present in human blood plasma is described. Affinity chromatography of plasma on fibrin/Celite followed by gel filtration led to a 29,000-fold purification of the plasminogen activator. The activator, referred to as the high-affinity plasminogen activator, is characterized by its ability to be strongly adsorbed by fibrin. Smaller amounts of other plasminogen activators and essentially all plasminogen were not bound to fibrin. The high-affinity plasminogen activator is a single-chain unstable protease with a molecular weight of 65,000-70,000. The high-affinity plasminogen activator has a low specific activity (500 CTA units/mg) compared to tissue or urine plasminogen activators (100,000-200,000 CTA units/mg) (CTA, Committee on Thrombolytic Agents).
Topics: Chromatography, Affinity; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Fibrin; Humans; Isoflurophate; Molecular Weight; Plasminogen Activators; Plasminogen Inactivators; Silicon Dioxide
PubMed: 6270665
DOI: 10.1073/pnas.78.7.4265