Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034065 (pulmonary embolism)
 14,979 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twelve centers participated in a double-blind study in which 63 patients with angiographically documented acute massive pulmonary embolism were randomly assigned to treatment with either urokinase (4,400 U/kg as an intravenous bolus infusion, then 4,400 U/kg per h over 12 h; n = 29) or alteplase (10 mg as an intravenous bolus infusion, then 90 mg over 2 h) followed by heparin (n = 34). The primary objective was to compare the resolution of pulmonary embolism as judged by the change in total pulmonary resistance over the initial 2 h. Further objectives were to evaluate the changes in total pulmonary resistance over the next 10 h and the degree of angiographic resolution at 12 to 18 h. At 2 h, total pulmonary resistance decreased by 18 +/- 22% in the urokinase group and by 36 +/- 17% in the alteplase group (p = 0.0009). Continuous monitoring of pulmonary artery mean pressure, cardiac index and total pulmonary resistance revealed that these variables improved faster in the alteplase group, with consistently significant intergroup differences from 30 min up to 3 to 4 h. After 12 h, the decrease in total pulmonary resistance was 53 +/- 19% in the urokinase group compared with 48 +/- 17% in the alteplase group and the reduction in the angiographic severity score was 30 +/- 25% compared with 24 +/- 18%, respectively, with no significant intergroup differences. Bleeding was equally frequent in the two treatment groups, except that more urokinase-treated patients experienced hematomas at puncture sites.
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PMID:Effects of intravenous urokinase versus alteplase on total pulmonary resistance in acute massive pulmonary embolism: a European multicenter double-blind trial. The European Cooperative Study Group for Pulmonary Embolism. 173 48

A hybrid hybridoma (FU1-74), secreting a bispecific monoclonal antibody (bs mAb), was obtained by fusion of a murine hybridoma secreting a monoclonal antibody (mAb) specific for human fibrin with a murine hybridoma secreting a mAb against urokinase-type plasminogen activator (u-PA). The bs mAb (MA-FU1-74), purified to homogeneity from mouse ascitic fluid, migrated as a single band with apparent Mr 150,000 on nonreduced SDS-PAGE and had an affinity for both human fibrin (Ka = 2 x 10(7) M-1) and for u-PA (Ka = 10(8) M-1) comparable to that of the mAbs obtained from the respective parental hybridomas. MA-FU1-74 did not influence the enzymatic activity of two-chain u-PA (tcu-PA) towards plasminogen or towards a chromogenic substrate. The complex of MA-FU1-74 with recombinant single chain u-PA (rscu-PA) or with tcu-PA (urokinase) enhanced the fibrinolytic potency of the plasminogen activator towards clotted human plasma 20-fold and 5-fold, respectively. In a hamster pulmonary embolism model, the rscu-PA/MA-FU1-74 complex had a 13- to 17-fold increased thrombolytic potency (percent lysis per mg/kg u-PA administered) relative to that of rscu-PA. The specific thrombolytic activity (percent lysis per microgram/ml steady state plasma level of u-PA antigen) of the complex was, however, not significantly different from that of rscu-PA. The complex of rscu-PA with the parental anti-u-PA mAb (MA-UK1-3) had only a 2-fold enhanced thrombolytic potency relative to that of rscu-PA and had a 5-fold decreased specific thrombolytic activity. The plasma clearance rates of the complexes of rscu-PA with both MA-FU1-74 and MA-UK1-3 were about 10-fold lower than that of rscu-PA. In a rabbit jugular vein thrombosis model, the rscu-PA/MA-FU1-74 complex had a 4-fold enhanced thrombolytic potency, an unchanged specific thrombolytic activity and 20-fold reduced plasma clearance. In both animal models, the rscu-PA/MA-FU1-74 complex did not cause more extensive systemic activation of the fibrinolytic system than rscu-PA. It is concluded that the bispecific anti-fibrin/anti-u-PA mAb MA-FU1-74 targets u-PA to the fibrin clot, resulting in a significantly enhanced thrombolytic potency of the plasminogen activator.
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PMID:Enhancement of clot lysis in vitro and in vivo with a bispecific monoclonal antibody directed against human fibrin and against urokinase-type plasminogen activator. 179 14

The incidence of deep vein thrombosis (DVT) and pulmonary embolism was studied prospectively in patients undergoing elective total hip replacement. 96 patients were randomly allocated to receive either low molecular weight heparin (LMWH) or unfractionated heparin (UFH). All patients had bilateral phlebography and pulmonary perfusion/ventilation scintigraphy 10-12 days after surgery. The following fibrinolytic variables were analysed in plasma and related to thromboembolism: tissue plasminogen activator (t-PA) activity, t-PA antigen (t-PA Ag), plasminogen activator inhibitor (PAI-1) activity and PAI-1 antigen (PAI-1 Ag). No significant difference was found, regarding the fibrinolytic response to surgery, between patients treated with LMWH and UFH. The level of PAI-1 activity was significantly increased before operation in patients developing DVT as compared to non-DVT patients (p less than 0.03). Immediately after surgery and in the morning the first postoperative day the levels of PAI-1 activity, PAI-1 Ag and t-PA Ag were positively correlated to thromboembolism. PAI-1 activity was the only preoperative fibrinolytic variable correlated to thromboembolism.
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PMID:Impaired fibrinolysis and postoperative thromboembolism in orthopedic patients. 185 6

Two patients with significant relative contraindications to fibrinolysis, and with refractory shock caused by acute pulmonary embolism, who were successfully treated with recombinant tissue-type plasminogen activator (rt-PA) are reported. The role of rt-PA in the management of pulmonary embolism is discussed, and pertinent literature is reviewed.
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PMID:Tissue-plasminogen activator for pulmonary embolism resulting in shock: two case reports and discussion of the literature. 189 67

A 65-year-old man was admitted to our hospital because of shortness of breath on exertion. As the results of examinations including pulmonary angiography, pulmonary perfusion scan and pulmonary ventilation scan, we diagnosed the case as chronic recurrent pulmonary embolism. Although the patient received thrombolytic therapy by a tissue plasminogen activator (t-PA), there was no noticeable improvement. However, oxygen and vasodilator therapy had marked effective on the hemodynamics. In chronic pulmonary embolism, vasodilators are generally not considered to be effective for improvement of hemodynamics. However, if the acute effects of vasodilators were confirmed, we should try to administer them while paying attention to possible adverse effects.
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PMID:[Acute and chronic effects of vasodilators in a case of chronic recurrent pulmonary embolism]. 190 16

A pulmonary embolism model in hamsters was used for the quantitative evaluation of the thrombolytic and pharmacokinetic properties of variants of tissue-type plasminogen activator (t-PA). A 25 microliters 125I-fibrin labeled human plasma clot was made in vitro and injected into the jugular vein of heparinized hamsters. The extent of thrombolysis within 90 min was determined as the difference between the radioactivity injected in the jugular vein and that recovered in the heart and lungs. Recombinant t-PA (home-made rt-PA or Activase) infused intravenously over 60 min caused dose-dependent progressive thrombolysis. The results of thrombolytic potency (clot lysis in percent versus dose administered in mg/kg) and of specific thrombolytic activity (clot lysis in percent versus steady state plasma level in microgram/ml) were fitted with an exponentially transformed sigmoidal function y = 100 c/(1 + e-a(ax-eh] and the maximal percent lysis (c), the dose or plasma level at which maximal rate of lysis is achieved (b) and the maximal rate of lysis (z = 1/4 ac.eb) were determined. With rt-PA, these parameters were c = 72 +/- 6% (mean +/- SEM), b = 0.19 +/- 0.08 mg/kg, z = 68 +/- 25% lysis per mg/kg, with corresponding values of 87 +/- 5%, 0.07 +/- 0.03 mg/kg and 150 +/- 38% lysis per mg/kg for Activase (p = NS). Deletion of the finger and growth factor domains in rt-PA (rt-PA-delta FE) was not associated with marked alteration of the thrombolytic potency (c = 90 +/- 30%, b = 0.34 +/- 0.35 mg/kg, and z = 54 +/- 14% per mg/kg), but was associated with a significant reduction of the specific thrombolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thrombolytic and pharmacokinetic properties of human tissue-type plasminogen activator variants, obtained by deletion and/or duplication of structural/functional domains, in a hamster pulmonary embolism model. 190 70

The recombinant chimeric plasminogen activator, rt-PA-delta FE/scu-PA-e, consisting of amino acids 1 to 3 and 87 to 274 of tissue-type plasminogen activator (t-PA) and amino acids 138 to 411 of single-chain urokinase-type plasminogen activator (scu-PA), has a markedly increased thrombolytic potency following its continuous intravenous infusion in animal models of venous thrombosis (Collen et al, Circulation, in press). In the present study, the thrombolytic potencies of intravenous bolus injections of rt-PA-delta FE/scu-PA-e, of recombinant t-PA (rt-PA), and of recombinant scu-PA (rscu-PA), given alone or in combination, were compared with those of intravenous infusions in a hamster pulmonary embolism model. Dose-dependent clot lysis was obtained in the absence of systemic activation of the fibrinolytic system and fibrinogen breakdown. In bolus injection experiments, the maximal rate of clot lysis, expressed in percent clot lysis per milligrams per kilogram compound administered, was 120 +/- 10 for rt-PA, 54 +/- 8 for rscu-PA, and 2,100 +/- 500 for rt-PA-delta FE/scu-PA-e (P less than .01 v rt-PA or rscu-PA). Comparative results with continuous infusion over 1 hour were 270 +/- 64, 99 +/- 18, and 1,500 +/- 250 (P less than .01 v rt-PA or rscu-PA) percent lysis per mg/kg compound infused for rt-PA, rscu-PA, and rt-PA-delta FE/scu-PA-e, respectively. Thus, rt-PA and rscu-PA are more potent when administered as an infusion than as a bolus, whereas rt-PA-delta FE/scu-PA-e is at least as potent when administered as a bolus. Combined bolus injections of rt-PA and rscu-PA had a 2.2-fold synergistic effect on clot lysis, but no synergism was observed with combined bolus injections or with combined infusions of rt-PA and rt-PA-delta FE/scu-PA-e, or of rscu-PA and rt-PA-delta FE/scu-PA-e. The present study thus shows that rt-PA-delta FE/scu-PA-e is much more potent for clot lysis than rt-PA or rscu-PA when administered as a bolus injection, but no synergistic interaction is observed between the chimera and either rt-PA or rscu-PA.
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PMID:Comparative thrombolytic properties of bolus injections and continuous infusions of a chimeric (t-PA/u-PA) plasminogen activator in a hamster pulmonary embolism model. 190 51

We report a series of seven patients (age: 43-77 years, preoperative American Society of Anesthesiologists (ASA) physical status II-III) with perioperative, life-threatening pulmonary embolism and severe cardiogenic shock treated with recombinant tissue type plasminogen activator (rt-PA). Diagnosis was established by ECG (n = 7), arterial blood gas analysis (n = 7), massive elevation of mean pulmonary arterial pressure (MPAP: 40 +/- 6 mmHg SD, n = 7), echocardiography (n = 3), increased arterial/end-tidal CO2 difference (30 +/- 16 mmHg, n = 3), and pulmonary angiography (n = 4). All patients had to be ventilated, six with an FIO2 of 1.0. To achieve a mean arterial pressure of above 60 mmHg all patients received norepinephrine 0.4 +/- 0.2 microgram.kg-1.min-1 in combination with dopamine 11 +/- 5 micrograms.kg-1.min-1 (n = 6), epinephrine 0.13 +/- 0.04 microgram.kg-1.min-1 (n = 5) or dobutamine 14 +/- 6 micrograms.kg-1.min-1 (n = 3). In addition, six of seven patients had to be resuscitated by external chest compression (duration of resuscitation: 5 to 40 min) prior to or during the thrombolytic therapy. The dosages of rt-PA ranged from 10 to 150 mg, and the duration of administration up to 31 h. Six patients survived neurologically intact. In these six patients MPAP had decreased from 41 +/- 6 mmHg to 33 +/- 6 mmHg (P less than 0.05, Wilcoxon rank test) 2 h after the start of thrombolytic therapy, with concomitant reduction of vasopressor and inotropic support.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Recombinant tissue-type plasminogen activator for the emergency treatment of perioperative life-threatening pulmonary embolism (stage IV). Results in 7 patients]. 190 1

The effects of both clot-bound and circulating plasminogen activator inhibitor-1 (PAI-1) on endogenous fibrinolysis were investigated in a rat model of pulmonary embolism. Iodine-125 fibrin(ogen)-labeled blood-clot homogenates were delivered through the left jugular vein to the lung microvasculature, and the subsequent extent of the clot lysis was monitored by measuring the release of 125I-fibrin degradation products (FDPs) into the blood. Clots that had incorporated activated PAI-1 ex vivo were subsequently protected from dissolution in vivo in a dose-responsive manner (half-maximal concentration [IC50] = 4.3 micrograms/ml). PAI-1-containing clots also resisted lysis, as measured by the release of the specific FDP D-dimer. Plasma levels of plasminogen activator (PA) and PAI activity were unaltered by administration of PAI-1-containing clots, and the clot-protective effects of clot-bound PAI-1 were reversed by exogenous tissue-type plasminogen activator administration. Clot lysis was also inhibited in a dose-responsive manner (IC50 = 58 micrograms/kg) by intravenous bolus delivery of activated PAI-1 to the circulation. The clot-protective effects of circulating PAI-1 were correlated with dose-dependent increases in plasma PAI-1 antigen and activity levels and decreases in plasma PA levels (IC50 = 37 micrograms/ml). There was no evidence of any accumulation of circulating PAI-1 in the lungs. Latent PAI-1, whether delivered with or delivered after the clot homogenates, did not affect the clot-lytic process. Activated and latent PAI-1 was cleared from the circulation in a monophasic manner, with a half-life of approximately 32 and 7 minutes, respectively. The results indicate that both clot-bound and circulating PAI-1 are potent inhibitors of fibrinolysis in vivo. Clot-bound PAI-1 may inhibit PAs in the immediate vicinity of the clots, whereas circulating PAI-1 may act systemically by controlling overall levels of PAs present in the blood.
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PMID:Both circulating and clot-bound plasminogen activator inhibitor-1 inhibit endogenous fibrinolysis in the rat. 191 13

More than 10 years ago, thrombolytic therapy with urokinase and streptokinase for pulmonary embolism was found to have considerable advantages over standard heparin therapy. After the introduction of alteplase, a recombinant tissue plasminogen activator, further studies confirmed this benefit. However, thrombolytic therapy for pulmonary embolism has not gained universal acceptance, even though it now has U.S. Food and Drug Administration approval. Clear advantages of thrombolytic therapy over conventional heparin therapy are improved pulmonary capillary blood volume, accelerated clot lysis and accelerated pulmonary perfusion. Earlier reversal of right-sided heart failure, a lower incidence of recurrent pulmonary embolism, a reduced risk of chronic pulmonary hypertension and reduced mortality have been claimed as advantages, but these have not been adequately proved. A recent survey suggests that about half of all patients with pulmonary embolism are potential candidates for thrombolytic therapy. In a subset of patients with hemodynamic compromise, thrombolysis has definite advantages over heparin therapy.
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PMID:Thrombolysis for pulmonary embolism. 192 47


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