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)

Reocclusion following thrombolysis is a major limitation of thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA). We investigated the effects of vapiprost ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-7-(5-((1,1'-biphenyl)-4-yl-methoxy)- 3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, a thromboxane A2 receptor antagonist); argatroban ((2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfon yl] - L-arginyl)]-2-piperidine-carboxylic acid, a specific thrombin inhibitor) and MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid, a specific leukotriene biosynthesis inhibitor) on the thrombolytic efficacy of rt-PA. The guinea pig femoral artery was thrombotically occluded by photochemical reaction between rose bengal and green light. Thirty min after the occlusion, rt-PA was administered and the time (T1) for reopening of the vessel and the frequency of reocclusion (Fro) 24 h after thrombolysis were monitored. With rt-PA alone, T1 was 28 +/- 7 min (n = 10) and Fro was 70%. T1 was reduced to 9 and 20 min by a combination of rt-PA with vapiprost and argatroban respectively. Fro was reduced by all three adjuvants. Histological observations revealed extensive adherence of polymorphonuclear leucocytes to the damaged endothelium at the site of thrombolysis. It is concluded that thromboxane A2, thrombin and leucocytes are involved in reocclusion after thrombolysis.
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PMID:Enhancement of thrombolytic efficacy of tissue-type plasminogen activator by adjuvants in the guinea pig thrombosis model. 785 82

An early, complete, and sustained patency of the infarct related artery achieved by thrombolytic therapy reduces mortality in patients with acute myocardial infarction. In the ISIS-3-study there was no difference in mortality between t-PA, APSAC, and streptokinase. In contrast, in the GUSTO-trial, a "front-loaded" regimen of t-PA (100 mg/90 min) lead to a reduced inhospital mortality compared to streptokinase. This was most likely due to the higher early patency-rate of the infarct-related artery after the front-loaded t-PA. The search for new, more effective, thrombolytic regimens lead to a double-bolus injection of t-PA (2 x 50 mg) which revealed high early patency rates (> 80% TIMI-3 after 90 min). R-PA, a new recombinant plasminogen activator with a prolonged half-life, given as double bolus (2 x 10 MU), also produced high patency rates after 90 min without an increased incidence of reocclusions. Acetylsalicylic acid should be given routinely in every thrombolytic therapy. An anticoagulation with heparin seems to improve the efficacy of the more fibrin-specific thrombolytics t-PA, r-PA, and pro-urokinase. In dose-finding studies the specific thrombin inhibitor hirudin has been shown to significantly reduce reocclusions and reinfarctions compared to heparin. An "optimal thrombolysis" most likely can only be achieved by a thrombolytic agent with a very high early patency combined with an effective adjunctive therapy with platelet aggregation- and thrombin-inhibition.
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PMID:[Different therapeutic regimens in thrombolysis of acute myocardial infarct]. 786 5

Coagulation and fibrinolysis were investigated in 14 claudicants undergoing percutaneous transluminal angioplasty (PTA) for femoropopliteal artery lesions. Cross-linked fibrin degradation products (XL-FDP), tissue plasminogen activator (t-PA) antigen, fibrinopeptide A (FPA), and plasminogen activator inhibitor-1 (PAI-1) activity were measured in peripheral blood. XL-FDP and t-PA increased, and FPA and PAI-1 decreased significantly after angioplasty. XL-FDP increased from baseline 266 +/- 72 ng/ml to 481 +/- 239 ng/ml (p < 0.0005) 30 min after PTA, indicating mural thrombus formation in spite of the significant fall in FPA influenced by heparin. A groin haematoma developed after PTA in 4/6 patients, who received more than 5600 IU heparin and in 1/8 patients receiving smaller dosages. The alterations in PAI-1 showed no correlation with those of t-PA, whereas heparin had a sparing effect on PAI-1 consumption. These findings may indicate that PAI-1 acts as a thrombin inhibitor following deep vessel wall injury by angioplasty. In two patients, who had signs of rethrombosis on the next day, residual FPA was relatively high, XL-FDP peaked at 3530 +/- 1170 ng/ml, and t-PA increased by 2.6 +/- 1.0 ng/ml. The corresponding values in patients with an uncomplicated course were 406 +/- 89 ng/ml (p < 0.0001) and 0.1 +/- 0.5 ng/ml (p < 0.02). We conclude that thrombin promotes activation of coagulation and fibrinolysis in femoropopliteal PTA. Instability between these counteracting systems resulting in thrombosis is not prevented by conventional heparin administration at dosages causing bleeding complications.
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PMID:Thrombosis and intrinsic fibrinolysis in percutaneous transluminal angioplasty. 801 75

An experimental disseminated intravascular coagulation (DIC) was induced in female CD rats by the intravenous administration of living bacteria (9.5 x 10(7) cfu Klebsiella pneumoniae), sublethal (5 mg/kg) or lethal (50 mg/kg) lipopolysaccharide (LPS), or tissue factor (1.5 micrograms/kg i.v. bolus or 0.4 micrograms/kg x hr i.v. infusion). We used a new fibrin monomer (FM) assay to follow the course of DIC. FM were detected by their ability to stimulate the tissue-type (t-PA) plasminogen activator dependent conversion of plasminogen to plasmin by a chromogenic assay. Miniplasminogen was used instead of plasminogen to avoid interference of the assay by alpha 2-antiplasmin. As a marker of DIC, elevated levels of FM were observed with all DIC-inducing agents (plasma levels were up to 90 micrograms/ml). The kinetics of FM formation were similar to the course of thrombin-antithrombin III (TAT) levels (maximal plasma levels 70 ng/ml); however, in the bacterial infection group, both parameters rose after a lag phase of about 1 hr. A 4 hr infusion of the highly specific thrombin inhibitor recombinant (rec.) hirudin (0.125 mg/kg x hr) resulted in a decrease of FM levels from 89.2 +/- 14.4 micrograms/ml in the LPS group (n = 10) to 27.4 +/- 11.2 micrograms/ml in the rec. hirudin group (n = 10; P < 0.001). The respective values for TAT levels were 73.1 +/- 19.7 micrograms/ml in the LPS group and 52.7 +/- 15.7 ng/ml in the rec. hirudin group (P < 0.001). Other coagulation parameters, such as platelets, fibrinogen, and fibrin(ogen) degradation products, were ameliorated accordingly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Formation of fibrin monomers in experimental disseminated intravascular coagulation and its inhibition by recombinant hirudin. 805 64

The clotting and fibrinolytic systems are activated by tissue factor and by tissue-type plasminogen activator in the pericardial cavity, where the thrombogenicity is greater than that of the surface of modern extracorporeal circuits. This local activation may have consequences for the systemic activation processes during cardiopulmonary bypass. To test this hypothesis, we investigated blood activation by interrupting the blood suction from the pericardial cavity during cardiopulmonary bypass in clinical coronary artery bypass operations. In blood collected in the pericardial cavity, thrombin-antithrombin III complex (p < 0.01), tissue-type plasminogen activator antigen (p < 0.05), fibrinogen degradation products (p < 0.01), and fibrin degradation products (p < 0.01) were significantly higher than in the systemic blood. Plasma heparin was significantly consumed in the pericardial cavity (p < 0.01). Once the pericardial blood was returned to the systemic circulation after resumed suction during cardiopulmonary bypass, thrombin-antithrombin III complex (p < 0.05), fibrinogen degradation products (p < 0.05), and fibrin degradation product (p < 0.05) concentrations increased significantly in the systemic blood. The effects of pericardial tissue on activation of clotting and fibrinolysis were also studied in vitro. When human plasma was incubated for 5 minutes with rabbit pericardium at reduced heparin concentrations, we found significant generation of thrombin (p < 0.05) and plasmin (p < 0.05). If the thrombin inhibitor hirudin was added, plasmin generation was also inhibited (p < 0.05). The results of the clinical and experimental study are in agreement with our hypothesis that tissue factor and tissue-type plasminogen activator accelerate the activation of clotting and sequentially of fibrinolysis under conditions of low heparin concentrations in the pericardial cavity and that this local activation contributes highly to the systemic activation, affecting hemostasis during cardiopulmonary bypass. Topical use of heparin in the pericardial cavity therefore seems indicated to reduce blood activation during cardiopulmonary bypass.
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PMID:Activation of fibrinolysis in the pericardial cavity during cardiopulmonary bypass. 823 Dec 4

Recombinant hirudin, a specific thrombin inhibitor, has been shown to accelerate thrombolysis and reduce reocclusions in experimental models. In a pilot trial recombinant hirudin (HBW 023) was used as an adjunctive therapy to thrombolysis with front-loaded tissue plasminogen activator (t-PA) (100 mg.90 min-1) in 40 patients with acute myocardial infarction whose duration of symptoms was less than 6 h. Patients received a bolus of r-hirudin of 0.07 mg.kg-1 b.w. followed by an infusion of 0.05 mg.kg-1.h-1 over 48 h. Complete patency (TIMI grade 3) of the infarct-related artery at 30, 60 and 90 min after the start of thrombolytic therapy was seen in 38.5%, 64.1% and 71.0% of patients, respectively. After 24-48 h, 80% of patients had a complete patent infarct vessel. A very early, complete and sustained patency (TIMI grade 3 at 60 and 90 min and at 24-48 h) was observed in 55% of patients. Reocclusions during the hirudin therapy appeared in six (16.1%) patients, two of whom had a PTCA at 90 min. The only reinfarction was seen after 6 h; this was successfully treated with additional thrombolysis. Major bleedings, mostly related to the invasive procedure, were observed in three patients. Spontaneous organ bleedings and intracerebral haemorrhages did not occur. There was one in-hospital death due to a late retroperitoneal bleeding. In was concluded that, with regard to safety and efficacy, the general feasibility of r-hirudin as adjunctive therapy to thrombolysis with front-loaded t-PA, has been demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Recombinant hirudin and front-loaded alteplase in acute myocardial infarction: final results of a pilot study. HIT-I (hirudin for the improvement of thrombolysis). 854 68

For use as an antithrombotic agent, a thrombin inhibitor must be potent and specific, i.e., it should not significantly inhibit the proteases of the anticoagulation (activated protein C) and fibrinolytic systems (plasminogen activator and plasmin). Previous evaluation of potency and specificity has been based on inhibition constants (Ki values). However, consideration of the kinetic parameters for natural plasma serine protease inhibitors indicates that a low Ki value with thrombin is not sufficient; the inhibited complex must also form rapidly. Moreover, potent inhibition of activated protein C and plasmin could be tolerated providing the inhibited complex only forms slowly. An ideal profile of kinetic parameters with thrombin, activated protein C and plasmin is formulated and discussed in relation to various classes of thrombin inhibitors. Examination of kinetic data for thrombin inhibitors currently in clinical trials (hirudin and hirulog) indicates that they possess this ideal profile of kinetic parameters.
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PMID:Thrombin inhibitors as antithrombotic agents: the importance of rapid inhibition. 856 65

1. We compared the direct thrombin inhibitor, desulfatohirudin (REVASC) and the indirect thrombin inhibitor, heparin, as adjuncts to thrombolytic therapy with reteplase in a canine model of coronary artery thrombosis. 2. Reteplase (BM 06.022) is a recombinant unglycosylated variant of human tissue-type plasminogen activator. Thrombus formation in anaesthetized open chest dogs was induced by electrical injury. Left circumflex coronary artery blood flow was monitored for 210 min with an electromagnetic flow probe. Twenty eight dogs were randomized to receive i.v. heparin (120 iu kg-1 bolus plus 80 iu kg-1 per h) or i.v. hirudin (2.0 mg kg-1 bolus plus 2.0 mg kg-1 per h) 10 min before thrombolysis preceded by i.v. acetylsalicyclic acid (20 mg kg-1) 5 min prior to anticoagulation. Every dog received an i.v. double bolus injection of 0.14 + 0.14 u kg-1 ( = 0.24 + 0.24 mg kg-1) reteplase, 30 min apart, 1 h after thrombus formation. 3. At comparable reperfusion rates (12 out of 12 vs. 15 out of 16 dogs), hirudin enhanced time to reperfusion (14.3 +/- 1.4 vs. 23.2 +/- 3.4 min; P < 0.05) and completely prevented reocclusion after reperfusion in contrast to heparin (0 out of 11 vs. 7 out of 11 dogs; P < 0.05). Coronary blood flow quality was improved by hirudin as shown by a higher maximum blood flow after reperfusion (130 +/- 14.3 vs. 83 +/- 9.3% of baseline; P < 0.05), a higher blood flow level at 20, 30, 40, and 50 min after onset of thrombolysis (P < 0.05) and a longer cumulative patency time (195 +/- 1.7 vs. 166 +/- 12 min; P < 0.05). Activated partial thromboplastin time and buccal mucosa bleeding time were prolonged (P < 0.05) by either anticoagulant, but did not differ significantly between groups. 4. The direct thrombin inhibitor, desulfatohirudin, enhanced thrombolysis, prevented reocclusion and increased blood flow as compared with the indirect thrombin inhibitor, heparin, when investigated at one dose level each and used in conjunction with reteplase.
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PMID:Comparison of desulfatohirudin (REVASC) and heparin as adjuncts to thrombolytic therapy with reteplase in a canine model of coronary thrombosis. 873 26

Enhanced thrombin activity has been associated with coronary thrombosis and with acute and long-term complications following coronary balloon angioplasty. Blocking thrombin activity with specific inhibitors is proposed as a promising antithrombotic therapy. We describe the anticoagulant and antithrombotic properties of hirunorm, a novel synthetic 26-aminoacid peptide thrombin inhibitor, in comparison with r-hirudin and hirulog-1. Hirunorm was equipotent to hirulog-1 and 1/30 as potent as r-hirudin in blocking alpha-thrombin amidolytic activity (IC50 = 10 +/- 2, 15 +/- 1 and 0.3 +/- 0.1 nM, respectively), but it did not affect trypsin, plasmin and t-PA activities at 10 microM. All the compounds inhibited clot-bound thrombin to clots prepared by thrombin hydrolysis of purified fibrinogen in buffer. Hirunorm and hirulog-1 showed similar species-dependent potency in doubling basal in vitro clotting times of human, rat and rabbit plasma (EC200 varied 70 to 200 nM for TT, 0.7 to 16 microM for aPTT and 0.8 to 17 microM for PT), while r-hirudin was always at least three times more active. When assayed by HPLC or by bioassay of the intact peptide, hirunorm was stable against alpha-thrombin and plasma hydrolases, but it was catabolized by rat liver and kidney enzymes. Venous thrombosis was produced in anaesthetized rats by vena cava ligation following a procoagulant serum injection. Intravenous and subcutaneous hirunorm inhibited venous thrombosis at doses (< or = 0.3 mg/kg) two-three times higher than those of r-hirudin. Hirulog-1 was as active as hirunorm only after i.v. infusion. Arterial thrombosis was obtained in the anaesthetized rat by chemical (FeCl2) stimulation of a common carotid and i.v. infused hirunorm (1-3 mg/kg/30 min) inhibited it dose-dependently; r-hirudin was partly active only at 3 mg/kg, but hirulog-1 was inactive at either dose. Full antithrombotic doses of hirunorm did not affect the bleeding time as measured from punctured mesenteric vessels, in anaesthetized rats. In conclusion, hirunorm is a potent peptide thrombin inhibitor endowed with antithrombotic activity in models of venous and arterial thrombosis.
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PMID:Experimental pharmacology of hirunorm: a novel synthetic peptide thrombin inhibitor. 888 75

The thrombin inhibitor inogatran is a synthetic peptidomimetic with a molecular weight of 439 dalton. In vitro studies have shown that inogatran is a classical competitive inhibitor of the active site of thrombin with a Ki of 15 x 10(-9) mol/l. Inogatran doubles the thrombin clotting time in human plasma at 20 x 10(-9) mol/l, APTT at 1.2 x 10(-6) mol/l, and prothrombin time at 4 x 10(-6) mol/l. The effects on rat and dog plasma are similar although slightly weaker. IC50 for inhibition of thrombin-induced aggregation of human platelets is 17 x 10(-9) mol/l. Inogatran has no effect on platelet aggregation induced by ADP or collagen. Up to a concentration of 10 x 10(-6) mol/l inogatran does not inhibit t-PA-induced fibrinolysis as seen in an ECLT system. Inogatran has good selectivity for thrombin as compared to several other serine proteases occurring in the blood. It is concluded that the properties of inogatran in vitro make the compound suitable for further studies in animals and man.
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PMID:In vitro effects of inogatran, a selective low molecular weight thrombin inhibitor. 905 87


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