Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of PRAP-1, a Fab-fragment of a PAI-1-inhibiting polyclonal antibody, on thrombus size and arterial blood flow was studied in a rat model of arterial thrombosis. It was shown that exposure of the carotid artery to FeCl3 led to the rapid formation of an occlusive thrombus with a morphology similar to that of arterial thrombi found in humans. Tranexamic acid (50 mg/kg), an inhibitor of fibrinolysis, increased thrombus size (p = 0.014) when given intravenously (i.v.) prior to the FeCl3-exposure. Heparin (1000 U), when given i.v. after FeCl3, did not affect the thrombus size per se, but caused a reduction in the interindividual variation of the size of the thrombus (p < 0.05). Thus, heparin was included in all the subsequent experiments. An i.v. infusion of t-PA (1 mg/kg/h), starting before thrombus formation, induced a 3.3 fold increase in the perfusion rate (p = 0.006) and a 67% reduction in the thrombus size (P < 0.001). PRAP-1, an inhibitor of rat PAI-1 activity, was given i.v. as a bolus followed by an infusion. Two doses of PRAP-1 were studied (7.5 and 15 mg/kg/h), and the administration of the PAI-1 inhibitor was started 10 min before FeCl3. The lower PRAP-1 dose caused a 3.8 fold increase in perfusion rate (p = 0.036), a 1.44 fold increase in the time to occlusion (p = 0.034), and the thrombus size was decreased by 18% (p = 0.104). The corresponding effects of the high PRAP-1 dose were a 6.5 fold increase in perfusion rate (p < 0.001), a 1.6 fold increase in time to occlusion (p = 0.038) and a 32% reduction in thrombus size (p = 0.016). It is concluded that an inhibitor of PAI-1 activity, PRAP-1, caused a moderate decrease in thrombus size and partly restores blood flow in a rat model of arterial thrombus. This finding suggests a potential role for an inhibitor of PAI-1 in the treatment of arterial thrombosis.
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PMID:The Fab-fragment of a PAI-1 inhibiting antibody reduces thrombus size and restores blood flow in a rat model of arterial thrombosis. 918 11

Previous works suggest the interesting possibility of an effect of heparin on vascular smooth muscle cell (SMC) replication and migration via a selective inhibition of the expression of t-PA and u-PA both of which may play major roles during intimal hyperplasia following endothelial injury. The present study was undertaken to evaluate in vitro the effect of heparin on the growth and migration of aortic SMC isolated from transgenic mice showing single inactivations of the t-PA and u-PA genes comparatively to SMC isolated from control mice. With regard to serum-induced proliferation and migration, all cell types showed similar responses. On control cells, heparin inhibited in a dose-dependent manner the expression of both t-PA and u-PA protein and mRNA. Heparin however, similarly affected the mitogenic and chemotactic activity of FCS for SMC isolated from control, t-PA or u-PA-deficient mice therefore showing that heparin inhibits FCS-induced SMC proliferation via mechanism(s) other than single inhibition of t-PA or u-PA expression by smooth muscle cells.
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PMID:The inhibitory effect of heparin for vascular smooth muscle cell proliferation or migration is not mediated by u-PA and t-PA. 918 19

The effect of Desmin 370 (D370), a low molecular weight dermatan sulfate, on the extent of lysis of radiolabelled pulmonary emboli in rats was evaluated. 125I-fibrin labelled blood clots were embolized into the lungs via a jugular vein, and the degree of lysis was calculated, at predetermined intervals, by the residual radioactivity in the lungs. A single i.v. injection of D370 (50 mg/kg) caused a significant increase in the rate of lysis, which was visible at 30 min and persisted for the whole experimental period (2 h). This effect was prevented by epsilon-aminocaproic acid (1 g/kg). At comparable antithrombotic dosages, heparin (2 mg/kg) also produced a significant enhancement of thrombolysis while hirudin (2 mg/kg) was totally ineffective. Heparin, however, produced a much more pronounced anticoagulant effect than D370. No changes in the plasma levels of plasminogen activator and plasminogen activator inhibitor activities were observed after treatment with D370. Moreover, the dermatan sulfate failed to enhance the blood fibrinolytic activity measured by a solid phase 125I-fibrin assay. These results extend previous data indicating that D370 may be efficient also in the therapy of thrombosis and provide direct evidence that this effect occurs, at least in part, via degradation of thrombus associated fibrin.
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PMID:Thrombolysis enhancing activity of a low molecular weight dermatan sulfate (Desmin 370) in experimental pulmonary embolism in rats. 930 18

Basic fibroblast growth factor (bFGF) and its specific receptors have diverse roles on a variety of cell types, such as the induction of vascular smooth-muscle cell proliferation which contributes to restenosis after coronary balloon angioplasty. bFGF is also known to interact with heparan sulphate proteoglycans present on the cell surface or in the extracellular matrix. In this study, the binding of 125I-bFGF to human aortic smooth-muscle cells was investigated. 125I-bFGF binding to these cells was reversible and saturable. Scatchard analysis revealed the presence of two distinct binding sites: a high-affinity receptor (Kd=38+/-7 pM; 1480+/-220 sites/cell) and a low-affinity non-saturable binding site (Kd=8. 0+/-2.0 nM). Pretreatment of the cells with heparinase resulted in a large reduction of 125I-bFGF binding to its low-affinity receptors, suggesting that they are heparin-like molecules. The specificity of the low- and high-affinity binding sites for bFGF was determined with acidic FGF, platelet-derived growth factor-BB and epidermal growth factor, which did not compete for 125I-bFGF binding. Expression of FGF receptor isoforms analysed by reverse transcriptase-PCR revealed the presence of only the type-1 receptor. Binding to low-affinity binding sites was antagonized by heparin, suramin, protamine sulphate and platelet factor 4. Unexpectedly, these molecules also reduced the binding of 125I-bFGF to its high-affinity sites. Consistent with these results, heparin, suramin, protamine sulphate and platelet factor 4 inhibited bFGF-induced proliferation of human aortic smooth-muscle cells. Heparin abrogated bFGF-induced release of tissue-type plasminogen activator by these cells. These observations suggest that the interaction of bFGF with human aortic smooth-muscle cells is different from that described for other cells such as endothelial cells, in which heparin acts as a potentiating factor of the mitogenic activity of bFGF.
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PMID:Heparin inhibits the binding of basic fibroblast growth factor to cultured human aortic smooth-muscle cells. 930 14

Fibrinolytic therapy substantially reduces mortality from acute myocardial infarction. Patient selection is, however, important. The patient must present within 12 hours of the onset of ischaemic symptoms, have definite ECG changes of ST elevation or left bundle branch block and no contraindications. The major contraindications are those for risk of an intracerebral bleed, recent stroke, intracranial tumour or risk of a major systemic bleed. Age and hypertension are not contraindications but may modify the regimen used. Heparin is required with recombinant tissue plasminogen activator but is optional with streptokinase. The recent COBALT trial suggests that the accelerated weight related t-PA regimen given over 90 minutes is more satisfactory than double bolus t-PA. However, in patients under 75 years of age, the two regimens were equivalent. For patients suffering acute myocardial infarction, practitioners should now individualise choice of therapy, rather than give the same cocktail to all patients. The choice of regimen will depend on the cardiac risk, the stroke risk, the bleeding risk and the cost.
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PMID:The current status of thrombolytic therapy. 944 5

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 occurence of severe bleeding indicates that TL should be halted and coagulation factors should be replaces 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:[In Process Citation] 966 37

Heparin-binding growth factors have been implicated in central nervous system development, regeneration and pathology. To assess the expression pattern and possible function in multiple sclerosis, the heparin-binding growth factors pleiotrophin (PTN), midkine (MK), basic fibroblast growth factor (FGF-2) and one of its receptors (FGFR1/flg) mRNA and protein levels were examined in an experimental autoimmune encephalomyelitis (EAE) model in the Lewis rat. We assessed the time course of expression of PTN, MK and FGF-2 during EAE and determined the cellular origin of FGF-2 and FGFR1 in normal spinal cord and during inflammatory demyelination. Basal expression of PTN and MK mRNAs in normal spinal cords was significantly upregulated after induction of EAE. MK expression was upregulated two to threefold correlating with disease progression, whereas PTN expression reached peak levels threefold above basal levels during the clinical recovery period. FGF-2 mRNA expression was low in normal spinal cord and dramatically increased in correlation with progressive demyelination. FGF-2 was confined to neurons in normal tissue and shifted dramatically to microglia, paralleling their activation during EAE. Double immunohistochemistry revealed colocalization of FGF-2 to activated microglia/macrophages with strongest expression in the macrophage-rich perivascular core area and microglial expression at the edges of white and gray matter perivascular regions. FGFR1, like its ligand, was induced in activated macrophages/microglia. Growth factor expression in demyelinating diseases could serve several functions, e.g., to modulate the activity of microglia/macrophage in an autocrine fashion, to induce the expression of other factors like insulin-like growth factor 1 or plasminogen activator, which can effect regeneration or degeneration, respectively, and finally to stimulate directly localized proliferation and/or regeneration of oligodendrocytes within the lesion area.
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PMID:Basic FGF and FGF receptor 1 are expressed in microglia during experimental autoimmune encephalomyelitis: temporally distinct expression of midkine and pleiotrophin. 981 19

Stroke is a very common medical emergency that, until recently, had no specific treatment. Following the results of several major trials (including 2 'mega-trials'), aspirin (acetylsalicylic acid) can be recommended for the majority of patients with acute ischaemic stroke. While the benefit of aspirin is only modest, i.e. an increase of 11 per 1000 long term independent survivors, the public health benefit in the world will be substantial as this treatment could be given to millions of patients with acute ischaemic stroke each year. Heparin is associated with a reduction in early recurrent ischaemic stroke, but there is no net benefit because of a similar sized excess of recurrent haemorrhagic stroke (even for those in atrial fibrillation). Thrombolytic therapy has not been so widely tested and the results of the small trials to date have yielded conflicting results. The only positive publication to date (comprised of 2 related trials) evaluated the recombinant tissue plasminogen activator alteplase, but such treatment is probably only indicated for highly selected patients. Further trials are almost certainly required and it would be unwise to change clinical practice based on the current evidence. No other stroke treatments have been shown to be beneficial, and much larger trials will be required to confirm or refute possible moderate benefits of treatment. A well organised stroke service and participation in clinical trials will improve the future care of patients with acute ischaemic stroke.
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PMID:Drug therapy for acute ischaemic stroke: risks versus benefits. 982 50

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

Thin flexible sheets composed of poly(lactic acid) (PLA) laminated polyanhydride, poly(erucic acid dimer-sebacic anhydride) (P(EAD-SA)), loaded with heparin were evaluated in vitro and in vivo. PLA was used for coating the polyanhydride to improve the release profile and improve the strength of the films. Heparin was released constantly for 20 days from PLA-coated 2% loaded P(EAD-SA). The uncoated film of P(EAD-SA) released heparin for only 4 days. The localized delivery of heparin around the carotid artery was investigated by implanting polymer loaded with [3H]heparin around the carotid artery of rats and the heparin release and tissue distribution was monitored. The maximum heparin concentration in the artery exposed to the drug was on day 4 for the P(EAD-SA) uncoated device (fast releasing system) and day 11 for the coated devices. The control artery, the uncovered segments of the artery, and the surrounding tissue contained negligible amounts of radioactivity. These data confirm that heparin was delivered locally without systemic exposure. Two independent animal studies were conducted to evaluate the effectiveness of these heparin-releasing devices. In both studies the balloon catheter injury in a rat model was used. After inflicting an injury to the common carotid, a matrix oriented with its long axis along the artery was placed under the injured portion of the vessel. In both studies the treated rats showed a very thin layer of neointima where the control group showed a significant reduction of the artery internal diameter with SMC neointima ratio greater than 1.
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PMID:Perivascular delivery of heparin for the reduction of smooth muscle cell proliferation after endothelial injury. 1037 Jan 77


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