Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of treatment of this illness should be recovery of the circulation, i.e. the suppression of thrombi in the deep venous network. This goal may currently be reached, in the same way as embolic lysis, by the early administration of streptokinase and urokinase, whose mechanisms, dosage-problems and chances of success are discussed here. This thrombolytic treatment is charged with major risks. If it is not to be used then anticoagulants are indicated. These have only a prophylactic effect, that is: they prevent the growth of thrombi. Heparin is the most active anticoagulant but it can only be administered parenterally. The author discusses the mechanism and efficiency of heparin and the antagonists of vitamin K1. Anti-aggregates rather show prophylactic action in the formation of arterial thromboses. Their spectacular effect in vitro on coagulation in vivo has not always been clearly proved in the venous system. It can be seen from the varied effects on thrombocytes and the vascular wall why anti-aggregates are not ideal anti-coagulants.
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PMID:[Possibilities of drug therapy in the fight against deep venous thrombosis]. 729 19

The PTCA procedure fails in 30-50% of patients due to late restinosis, meaning that this is a problem of 100,000-150,000 people per year in the USA alone. It has been found that heparin and low-molecular-weight heparin (LMWH) have an inhibitory effect on smooth muscle cell (SMC) proliferation and migration, the major causes of restinosis. However, little is known about the toxicity and side effects of these drugs when used for a long period as may be required for prophylaxis of PTCA restinosis. To investigate possible side effects, non-human primates received daily injections of 1 mg/kg s.c. LMWH (Mono-Embolex) over a 12-week period. The hemostatic system was monitored through measurement of ACT-celite, APTT, Heptest, TT(10U/mL), TFPI, Anti-IIa activity, Anti-Xa activity, ACA-Heparin, AT III, factor VIII R:Ag, fibrinogen, and thrombomodulin levels. Elisa tests for t-PA, PAI-1, u-PA, FgDP, TDP, and D-Di levels were used for measurements of fibrinolytic activity. Increased values of ACT, APTT, Heptest, TT, Anti-IIa, Anti-Xa, ACA-Heparin, and TFPI were observed four hours after LMWH injections. AT III, vWFAg, fibrinogen and thrombomodulin showed no change from the pre-study baseline. An accumulation effect was seen in the APTT and Heptest over the 12 weeks. After the first week the blood levels of Anti-IIa activity remained elevated at 20% inhibition rather than 0% 24 hrs after drug administration. This activity slowly decreased after discontinuation of drug. The Anti-Xa blood level activity remained elevated at 40% inhibition 24 hrs after drug administration 2 weeks into the study, and this activity was detectable even 2 weeks after cessation of drug administration. There was increasing activity of the fibrinolytic system with LMWH treatment. After two weeks t-PA increased two-fold to 6 ng/mL but returned to baseline at six weeks. There was a corresponding increase of the TDP but not a clear increase in D-Di and FgDP. The increase of u-PA was limited to the first days of LMWH treatment only. The PAI-1 activity increased gradually over the entire study period. No bleeding complications occurred throughout the study. The long-term administration of Mono-Embolex as projected for the use in the prophylaxis of restinosis following PTCA appears to be safe for patients.
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PMID:Evaluation of hemostatic and fibrinolytic alterations associated with daily administration of low-molecular-weight heparin for a 12-week period. 766 Jan 45

In addition to fibrinolysis, plasminogen activators may be involved in other processes relevant to atherogenesis such as smooth muscle cell migration, proliferation and extracellular matrix remodeling. Because mitogens such as basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF) are positive regulatory factors and heparin is a negative regulatory factor for smooth muscle cell proliferation and migration, we have looked at the effects of these factors (plus serum and phorbol ester) on urokinase (uPA) and tissue plasminogen activator (tPA) of smooth muscle cells. PDGF, bFGF and serum increased tPA (serum > PDGF > FGF). Heparin inhibited the effect of serum, but not PDGF on tPA. Heparin actually increased the stimulatory effect of bFGF on tPA. Of interest, heparin was also able to inhibit mitogenesis mediated by serum, but not by PDGF or bFGF. Serum decreased and phorbol ester increased uPA, while PDGF and bFGF had no effect Heparin shifted uPA from the cell layer to the medium of serum or phorbol ester treated but not PDGF or bFGF treated cells. These data demonstrate that PDGF, bFGF and serum can differentially regulate smooth muscle cell plasminogen activators and that heparin can either increase or decrease levels of tPA or shift the localization of uPA depending on the mitogen used.
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PMID:Regulation of baboon arterial smooth muscle cell plasminogen activators by heparin and growth factors. 770 77

Heparin and heparan sulfate, exhibiting wide biological interactions, are constituted of block structures. A defined pentasaccharide motif was found responsible for the enhancement of the rate of inactivation of factor Xa by antithrombin III. Heparin also interacts with other serine proteinase inhibitors as protease nexin I, and thus possibly modulates extracellular matrix proteolysis by serine proteinases in the pericellular environment. Human neutrophil elastase (HNE) activity is inhibited by heparin with Ki = 75 pM. This strong interaction is electrostatic, involving HNE/arginine residues disposed in a "cluster shoe" arrangement on the surface of the molecule and mainly OSO3- groups of heparin. HNE-heparin interactions also interfere with HNE associations with its natural inhibitors: it decreases the rate of association of HNE with alpha 1 proteinase inhibitor (alpha 1 P(i)) by 3 orders of magnitude, while increasing kass between HNE and mucus bronchial inhibitor (MBI) by > 10 fold. In vivo experiments demonstrated that heparin fragments lacking anticoagulant activity were able to nearly completely abolish emphysematous lesions induced in mice by a single intratracheal administration of 200 micrograms HNE. Long chain unsaturated fatty acids peptide conjugates were described as competitive HNE inhibitors (Hornebeck W. et al. 1985). We synthesized N-oleoyl heparin derivative (3 oleoyl groups/one molecule of heparin); such a lipophilic glycosaminoglycan (LipoGAG), although acting as an elastin protecting agent, possessed lower HNE inhibitory capacity as compared with heparin. In contrast, however, it was able to inhibit other serine proteinases such as urokinase, plasmin, porcine pancreatic apha-chymotrypsin and elastase. Such Lipo GAG's can be therefore useful to control matrix metalloproteinases (MMPs) during tissue remodeling or tumor invasion.
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PMID:Heparin and its derivatives modulate serine proteinases (SERPS) serine proteinase inhibitors (SERPINS) balance. Physiopathological relevance. 789 38

Newly developed synthetic and recombinant thrombin inhibitors possess strong anticoagulant effects. Despite these effects, interactions of these agents with enzymes in the fibrinolytic network result in the modulation of such proteases as t-PA, u-PA and streptokinase. The inhibitory spectrum of several thrombin inhibitors [D-Phe-Pro-Arg-H(GYKI 14166), D-MePhe-Pro-Arg-H(GYKI 14766), Boc-D-Phe-Pro-Arg-H (GYKI 14451), Ac-D-Phe-Pro-boroArg-OH (DuP 714), recombinant hirudin (r-Hir) and unfractionated porcine mucosal heparin complexed with antithrombin III (Heparin/AT-III)] was studied towards various serine proteases such as tissue plasminogen activator (t-PA), plasmin, plasminogen/streptokinase complex, urokinase and kallikrein. Aprotinin was also studied in the same systems as the thrombin inhibitors. All four tripeptide derivatives were found to inhibit t-PA, plasmin and plasminogen/streptokinase complex at micromolar concentrations (IC50: 0.57 mM-3.3 microM). Boc-D-Phe-Pro-Arg-H and Ac-D-Phe-Pro-boroArg-OH also inhibited urokinase, while Ac-D-Phe-Pro-boroArg-OH inhibited kallikrein as well (IC50: 0.15 mM-16 microM). In contrast, r-Hir and Heparin/AT-III did not inhibit any of these enzymes at millimolar concentrations (IC50 > or = 1 mM). Aprotinin inhibited plasmin, plasminogen/streptokinase complex and kallikrein at micromolar concentrations (IC50: 3.1-0.85 microM). In a rabbit thrombolysis model, where pre-formed clots are lysed by streptokinase, simultaneous administration of D-MePhe-Pro-Arg-H or Ac-D-Phe-Pro-boroArg-OH, at concentrations approximately 1 mumol/kg, i.v. resulted in complete inhibition of the fibrinolytic process. Aprotinin at 0.1 mumol/kg, i.v. produced similar inhibition. These results demonstrate that thrombin inhibitors may exert significant antiprotease actions against various fibrinolytic enzymes.
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PMID:Fibrinolytic compromise by simultaneous administration of site-directed inhibitors of thrombin. 804 88

Binding of urinary protein C inhibitor (PCI) to cultured human epithelial kidney tumor cells (TCL-598) was studied. Binding was dose-dependent, time-dependent, and saturable. Heparin interfered in a dose-dependent way with PCI binding to TCL-598 as did heparan sulfate and to a lesser degree also dermatan sulfate. Pretreatment of TCL-598 with protamine sulfate inhibited subsequent binding of PCI in a dose-dependent manner and > 100 micrograms/ml protamine sulfate reduced binding of PCI to < 10% of the control. Binding of 125I-PCI was specific, and bound 125I-PCI was recovered from the cells by heparin treatment or detached together with intact cells by EDTA treatment, migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with the same mobility (M(r) = 57,000) as unbound 125I-PCI. Furthermore, cell-bound PCI was functionally active as judged from its ability to inhibit the amidolytic activity of urokinase, and its inhibitory activity was stimulated approximately 3-4-fold as compared to fluid-phase PCI. Immunogold electron microscopy revealed that PCI-antigen presented to the cells from the luminal side bound exclusively to that surface in native as well as in prefixed cells. This binding of PCI was abolished in the presence of heparin (50 micrograms/ml) and after pretreatment of the cells either with protamine sulfate (400 micrograms/ml) or with heparinase III (0.5 unit/ml). A slight decrease in PCI binding was seen after pretreatment of the cells with chondroitinase ABC and chondroitinase AC. In contrast, binding of PCI to extracellular matrices of TCL-598 was decreased to approximately 70% after chondroitinase ABC treatment of the extracellular matrices, whereas both heparinase III or chondroitinase AC treatment only reduced matrix-bound PCI to approximately 95%. These data suggest that heparan sulfate-containing proteoglycans are predominantly involved in binding of PCI to the luminal side of TCL-598, while dermatan sulfate-containing proteoglycans, the overall predominant PCI-binding proteoglycans in TCL extracts, are responsible for PCI binding to the extracellular matrix. Heparan sulfate, however, exposed to an environment containing PCI under physiological conditions, might localize PCI and modulate its target enzyme specificity in vivo.
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PMID:Binding of urinary protein C inhibitor to cultured human epithelial kidney tumor cells (TCL-598). The role of glycosaminoglycans present on the luminal cell surface. 818 78

By microcatheterization of the ophthalmic artery it was possible to test a controlled retinal fibrinolysis in the rabbit. Heparin, tolazoline and urokinase were applied through the microcatheter. By continuous administration of highly diluted fluorescein (0.1%), on-line control of the therapeutic effects was available. Treatment was carried out in cycles of enforced perfusion. In 12 main vessel occlusions the rates of flow could nearly be normalized after mobilization of thrombi by combined emergency therapy. An average of 14 cycles of treatment was necessary. The time needed was 40-60 min. With this technique drug therapies of ocular circulation disturbances are testable and controlled emergency treatment of the eye begins to become feasible.
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PMID:[Technique of selective, controlled retinal fibrinolysis in a model]. 821 34

The history of the antithrombotic agents--aspirin, heparin, warfarin, and the thrombolytics--is a rich and lively odyssey of serendipity, perseverance, vision, and conflict involving a number of striking personalities. The history of aspirin spans ages and continents from Hippocrates' analgesic for women in labor to the rediscovery of the white willow bark by English country scholar Reverend Edward Stone. Bayer chemist Felix Hoffmann reinvented aspirin for his ailing father; suburban physician L.L. Craven pioneered the prophylactic antithrombotic uses of aspirin; and Sir John Vane elucidated aspirin's mechanism of action as the inhibition of prostaglandin synthetase. Heparin was discovered by McLean, working as a medical student in 1915 in search of a pure procoagulant in dog liver. His original impure material differed somewhat from today's heparin, but purified heparin was rapidly accepted for a myriad of clinical uses; to this day, diverse new properties of this complex glycosaminoglycan continue to be elucidated. The oral anticoagulants emerged from veterinary research in the 1920s on a hemorrhagic disorder afflicting cattle that consumed spoiled sweet clover hay. Several chance encounters led Karl Link and his University of Wisconsin team to the identification of dicumarol as the offending agent in 1939 and its widespread therapeutic use by Wright and others in the 1940s. Link later developed warfarin as a rodenticide, but its use in humans soon followed in the 1950s. Vitamin K was discovered in the 1930s; its involvement in the mechanism of the anticoagulant agents was not delineated until the 1970s. The intrinsic ability of clotted blood to liquify and the fibrinolytic properties of normal urine were noted in the 1800s. Tillett and Sherry's group stumbled on the fibrinolytic properties of streptokinase in the 1930s and pioneered the therapeutic use of streptokinase in the 1940s and of urokinase in the 1960s. Several teams found tissue-type plasminogen activator in various body sites beginning in the 1940s, leading to its cloning and widespread use in the 1980s; anisoylated plasminogen-streptokinase activator complex is an example of rational drug design. The discoverers of these diverse agents have not only provided physicians with a potent armamentarium of antithrombotic drugs but also helped elucidate much basic science and vividly demonstrated the merits of perseverance, independent thought, and adherance to the scientific method.
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PMID:History of drugs for thrombotic disease. Discovery, development, and directions for the future. 828 78

In the absence of significant symptoms and signs the diagnosis of pulmonary embolism remains difficult. Sensitivity and specificity of laboratory tests, chest x-ray, ECG, echocardiography and venous studies on their own is low. Ventilation-perfusion scanning establishes or excludes the diagnosis only in those patients with "high-probability" or "normal" scanning results. The diagnosis of pulmonary embolism should be made by combining clinical assessment, several diagnostic techniques, and, finally, pulmonary angiography in doubtful cases. Heparin remains the standard therapy for patients with stable hemodynamics. Thrombolytic therapy is recommended in hemodynamically compromised patients. In short-term dose regimens the thrombolytic agents urokinase and rt-PA seem to be equally effective. So far, however, no study has proven that thrombolytic therapy significantly reduces mortality in pulmonary embolism.
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PMID:[Acute pulmonary embolism]. 832 7

The absence of significant symptoms and signs makes the diagnosis of pulmonary embolism difficult. Sensitivity and specificity of laboratory tests, chest X-ray, ECG, echocardiography and venous studies is low. Ventilation-perfusion scanning is also often not diagnostic. The combination of several diagnostic techniques, however, and pulmonary angiography confirm the diagnosis. Heparin remains the standard therapy for patients with stable haemodynamics. Thrombolytic therapy is recommended in haemodynamically compromised patients, since it yields accelerated clot lysis and pulmonary reperfusion. In standard dose regimes streptokinase, urokinase and t-PA are equally efficient. t-PA, however, acts more rapidly than the other agents. So far there is no study to prove that thrombolytic therapy significantly reduces mortality in pulmonary embolism.
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PMID:[Thrombolytic therapy in pulmonary embolism. Indications and therapeutic strategies]. 833 30


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