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)

Thrombosis, a major cause of hemodialysis catheter dysfunction, can be treated with urokinase. We compared protocols using full strength urokinase to the volume of the catheter with low dose therapy. Clotting episodes and successful declottings (blood flow > 200 ml/min) were tracked for 6 months. One hundred four clotting episodes were treated with 5,000 U/ml urokinase to the volume of the catheter lumen for a 1 hr dwell. If unsuccessful, a second dose of 5,000 U/ml was administered and, if needed, a third dose of 125,000 U/lumen. Post treatment, catheters were locked with 5,000 U/ml heparin to the volume of the lumen. Using new protocols, clotting episodes were treated with 2,500 U/lumen urokinase, followed by saline to the volume of the lumen for a 1 hr dwell. A mid dwell injection of 0.2 ml/lumen saline was added to advance the front of active urokinase. If unsuccessful, a second 2,500 U/lumen dose was administered. Heparin lock was 10,000 U/ml heparin to the volume of the lumen. Revised protocols decreased clotting episodes 60% and urokinase charges 81%, while maintaining successful declottings at 74%. Low dose urokinase was as effective as full strength when the active front was advanced mid dwell.
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PMID:Effectiveness of low dose urokinase on dialysis catheter thrombolysis. 980 94

The data gained from clinical studies in the past years have indicated that the thrombolytic therapy (TL) has favourable effect on patients with acute myocardial infarction (AMI). It is aimed at reperfusion in the ischaemic area, a decrease in the extent of infarction site and a decrease in mortality. TL administered within the initial hours after the onset of AMI leads to better results than when administered after several hours. Currently, TL is not limited by age. The patients who were given streptokinase (SK) or anistreplase (APSAC) prior to more than 4 days, if necessary, urokinase or alteplase (rt-PA) should be given. There are differences in the opinions as to the optimal selection of thrombolytic drugs. However, all currently used drugs lead to a significant decrease in mortality due to AMI. The preferential use of accelerated administration of rt-PA in contrast to SK is justified in younger patients with extensive AMI of the anterior wall, in whom the therapy has begun within 4 hours since its onset. The occurrence of severe bleeding indicates that TL should be halted and coagulation factors should be replaced by freshly frozen plasma or fibrinogen concentrate, if necessary, transfusion of full blood should take place. If the severe bleeding occurs shortly after the administration of SK, the persisting plasminaemia can be arranged by antifibrinolytic drugs. An improvement in TL results can be achieved by adjuvant antithrombotic therapy. At the same time, in addition to acetylsalicylic acid, the patient treated with rt-PA should be given heparin. Heparin administration is not necessary in patients treated with SK or APSAC. However, heparin is indicated in patients at risk due to systemic embolization in congestive heart disease, extensive infarction or atrial fibrillation. (Tab. 1, Ref. 28.)
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PMID:[Thrombolytic therapy in acute myocardial infarct]. 991 45

In February 2000, a 70-year-old man was admitted to our hospital complaining of back pain and dyspnea on exertion. Pulmonary thromboembolism was diagnosed, and he was treated with intravenous urokinase and heparin. The pulmonary thromboembolism improved, though heparin-induced thrombocytopenia (HIT) was subsequently observed. The thrombocytopenia was then improved by withdrawing the intravenous heparin, but thrombosis appeared extending from both femoral veins to the inferior vena cava. The thrombosis was dispersed by catheter-directed thrombolysis. There have been few reports of HIT in Japan. Heparin is frequently used for the treatment of pulmonary thromboembolism, but special care must be taken, since severe thrombotic complications are associated with HIT.
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PMID:[A case of pulmonary thromboembolism with heparin-induced thrombocytopenia]. 1143 14

An 80-year-old woman was admitted to the Traumatologic Hospital of Florence because of bilateral post-traumatic humeral fractures. Subcutaneous calcium heparin was immediately administered to prevent deep venous thrombosis. Nine days later, the patient was referred to the Internal Medicine Unit because of severe immune-mediated heparin-induced thrombocytopenia and bilateral deep venous thrombosis. Heparin therapy was immediately discontinued, and the patient was switched to warfarin therapy. Diagnosis of heparin-induced thrombocytopenia was confirmed by positivity of anti-heparin-PF4 antibodies. On the second day of warfarin therapy, bilateral limb venous gangrene with a high risk of limb amputation appeared. To reduce thrombin generation, i.e., the mechanism by which heparin-induced thrombocytopenia induces thrombotic events, intravenous treatment with dermatan sulphate and low-dose urokinase was initiated. After 10 days of treatment, the limb venous gangrene disappeared, and low-dose warfarin therapy was again introduced. The patient was discharged 40 days after admission, and a Doppler ultrasound study showed only minimal signs of deep vein thrombosis in the right popliteal veins. Although in Italy the use of dermatan sulphate has been limited to the prevention of deep vein thrombosis, this case shows that it should be considered a useful agent for the treatment of thrombotic complications secondary to heparin-induced thrombocytopenia. Patients with acute immune-mediated heparin-induced thrombocytopenia should not be treated with warfarin alone. Frequent platelet count monitoring from day 5 of heparin treatment remains the best means of early detection of immune-mediated heparin-induced thrombocytopenia.
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PMID:[Calcium heparin-induced immunologic thrombocytopenia complicated with venous gangrene of the legs. Report of a clinical case]. 1169 2

Although the urokinase receptor (uPAR) binds to vitronectin (VN) and promotes the adhesion of cells to this matrix protein, the biochemical details of this interaction remain unclear. VN variants were employed in BIAcore experiments to examine the uPAR-VN interaction in detail and to compare it to the interaction of VN with other ligands. Heparin and plasminogen bound to VN fragments containing the heparin-binding domain, indicating that this domain was functionally active in the recombinant peptides. However, no significant binding was detected when uPAR was incubated with this domain, and neither heparin nor plasminogen competed with it for binding to VN. In fact, uPAR only bound to fragments containing the somatomedin B (SMB) domain, and monoclonal antibodies (mAbs) that bind to this domain competed with uPAR for binding to VN. Monoclonal antibody 8E6 also inhibited uPAR binding to VN, and this mAb was shown to recognize sulfated tyrosine residues 56 and 59 in the region adjacent to the SMB domain. Destruction of this site by acid treatment eliminated mAb 8E6 binding but had no effect on uPAR binding. Thus, there appears to be a single binding site for uPAR in VN, and it is located in the SMB domain and is distinct from the epitope recognized by mAb 8E6. Inhibition of uPAR binding to VN by mAb 8E6 probably results from steric hindrance.
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PMID:Kinetic analysis of the interaction between vitronectin and the urokinase receptor. 1177 78

Degradation of the extracellular matrix leads to the release of fragments, which elicit biological responses distinct from intact molecules. We have reported that alpha1:Ser(2091)-Arg(2108), a peptide derived from the alpha1-chain of laminin-1, triggers protein kinase C-dependent activation of MAPK(erk1/2), leading to the up-regulation of macrophage urokinase type plasminogen activator and matrix metalloproteinase (MMP)-9 expression. Since intact laminin-1 failed to trigger these events, we hypothesized that alpha1:Ser(2091)-Arg(2108) is cryptic or assumes a conformation not recognized by macrophages. Here we demonstrate that elastase cleavage of laminin-1 generates fragments, which stimulate proteinase expression by RAW264.7 macrophages and peritoneal macrophages. In contrast, fragments generated by MMP-2, MMP-7, or plasmin had no effect on macrophage proteinase expression. Elastase-generated laminin-1 fragments were fractionated by heparin-Sepharose chromatography. Heparin-binding fragments stimulated macrophages' proteinase expression severalfold greater than nonbinding fragments. The heparin binding fragments reacted with antibodies directed against regions of the alpha1-chain including alpha1:Ser(2091)-Arg(2108) and the globular domain. A peptide from the first loop of the globular domain (alpha1:Ser(2179)-Ser(2198)) triggered the phosphorylation of MAPK(erk1/2) and stimulated the expression of macrophage urokinase type plasminogen activator and MMP-9. Moreover, a heparin-binding fraction isolated from an aortic aneurysm contained fragments of alpha1-chain and stimulated macrophages' proteinase expression. Based on these data, we conclude that cryptic domains in the COOH-terminal portion of the alpha1-chain of laminin are exposed by proteolysis and stimulate macrophages' proteinase expression.
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PMID:Exposure of cryptic domains in the alpha 1-chain of laminin-1 by elastase stimulates macrophages urokinase and matrix metalloproteinase-9 expression. 1182 68

In failed flap transfers and in burn injuries, superoxides and thrombi generated in the microcirculation are considered responsible for tissue injury. A dynamic and morphologic analysis of thrombus formation was conducted in a model of microvessel injury, and an analysis was made of the different antithrombotic effects of heparin, urokinase, and prostaglandin E(1). The dye-light method was used (i.e., injury of the endothelium by reactive oxygen species) to induce thrombus formation in both the arterioles and venules of the rabbit ear chamber under an intravital microscope-television system. The dynamic course of thrombus formation was observed, and the period from irradiation to complete obstruction of blood flow (i.e., time to stasis) was measured and compared in relation to various treatment conditions. Arteriolar thrombi were formed by platelet aggregation. Venular thrombi were composed of platelets and erythrocytes that gathered and adhered around leukocytes stuck to the vessel wall. Heparin treatment prolonged the time to stasis in both the arterioles and the venules. Urokinase extended the time to stasis in the venules but not in the arterioles. Prostaglandin E(1)-treatment significantly prolonged the time to stasis in the arterioles, but only high-dose prostaglandin E(1) prolonged the time to stasis in the venules. The results of this study show that endothelial damage caused by superoxides promotes the formation of thrombi that differ in composition between the arteriole and the venule and that the effectiveness of each drug varies accordingly. The authors believe that these agents can be used with increased efficacy if the two types of thrombi and the specific antithrombotic effects of each agent are considered.
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PMID:The features of thrombus in a microvessel injury model and the antithrombotic efficacy of heparin, urokinase, and prostaglandin E1. 1279 73

A 65-year-old male underwent iliocecal excision and hepatic posterior segmentectomy for cecum cancer and synchronous liver hepatic metastasis in September and October 2001, respectively. A reservoir was implanted by the GDA-coil method from the right femoral artery in November, and WHF (5-FU 1,000 mg/m2) was administered 8 times. Because of the remnant liver recurrence, WHF was restarted in April 2002. Left leg paralysis appeared suddenly after the 3rd administration. Heparin and urokinase were administrated continuously after hospitalization. Also, liver function tests showed a worsening condition. The bile duct necrosis in the liver was examined with abdominal CT scan. The anti-coagulation therapy was changed to an oral drug on the 7th day after hospitalization. The liver function tests normalized gradually. Although the rehabilitation for leg paralysis performed during hospitalization was continued after discharge from the hospital, the patient is unable to walk and uses a wheelchair. Hepatic arterial infusion chemotherapy is considered safe for blood and non-blood toxicity compared with systemic chemotherapy. However, there are also complications as in this case, where QOL is reduced remarkably, and caution is required.
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PMID:[A case of spinal infarction related to hepatic arterial infusion chemotherapy]. 1461 12

Receptors for plasminogen activators present on endothelial cell (EC) surface regulate local plasmin activity. Plasmin generation by human ECs, derived from cerebral cortex, skin and lung, iliac artery, iliac vein, aorta and coronary artery, was studied. The respective ECs were treated with recombinant tissue plasminogen activator (rt-PA) or with recombinant urokinase-type plasminogen activator (ru-PA), washed, plasminogen added and the plasmin generated then assayed. The largest amounts of plasmin were generated by cerebral ECs, under baseline conditions or after exposure to rt-PA or ru-PA (P < 0.0001). Exposure to rt-PA also resulted in more plasmin generation than ru-PA in the cerebral ECs (P < 0.0001) but not in the other ECs. Heparin enhanced plasmin generation by both rt-PA and ru-PA. Specific antibody against annexin II, a t-PA receptor, blocked plasmin generation by rt-PA. Western blotting showed higher amounts of annexin II on the cell membrane in cerebral ECs. This suggests that expression of annexin II in ECs depends on their location, being greatest in cerebral ECs. In contrast, expression of u-PA receptor was the same for all ECs. This has implications for higher risk of intracranial bleeding during thrombolytic therapy, and for a role of t-PA in neurological development and function.
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PMID:Expression of receptors for plasminogen activators on endothelial cell surface depends on their origin. 1499 94

The pulmonary-renal cascade may regulate the respiration and skeletal muscle contractility. To evaluate this working hypothetical model, we conducted experiments to ascertain the skeletal muscle tone of the Swiss mice (20-35 g). The animals were evaluated for their skeletal muscle tone via several techniques i.e. inclined plane test, grip strength test and swim test. Groups of mice (n=6) were pre-treated with mefenamic acid (60 mg/kg, i.p), carbenoxolone (100 mg/kg i.p) or vehicle only 15 minutes before the treatment with heparin (500 U/kg, i.v), urokinase (5500 U/kg, i.v) and erythropoietin (150 U/kg, i.v). Heparin potentiated the loss of skeletal muscle tone induced by mefenamic acid and carbenoxolone while urokinase & erythropoietin significantly enhanced the skeletal muscle tone as evaluated by all or one of the tests. Other groups of mice (n=6) were pretreated with mefenamic acid (1 mg i.c.v), carbenoxolone (160 microg i.c.v) or minoxidil (30 microg i.c.v) and the effects of heparin & urokinase and erythropoietin on skeletal muscle tone were evaluated. To study the effects of heparin and urokinase on nerve regeneration, two groups of mice underwent a sham and sciatic nerve crush procedure. The mice treated with urokinase recovered much faster as compared to those treated with heparin or saline. These experimental results suggest that gap junction blockers and potassium channel openers interact with heparin, urokinase and erythropoietin to control the skeletal muscle tone.
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PMID:Renal humoral modulation of skeletal muscle tone in mice: implications for 'the pulmonary-renal cascade'. 1657 93


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