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)

Recombinant tissue-type plasminogen activator (rt-PA) was produced in Escherichia coli cells in order to obtain an unglycosylated rt-PA (BM 06.021) with increased thrombolytic potency due to altered pharmacokinetic properties. The pharmacokinetics were studied in rabbits upon intravenous infusion of 200 kU/kg over 30 min. The thrombolytic dose-response effects were evaluated in a rabbit model with 125I-labeled venous thrombi upon intravenous infusion over 4 h. The thrombolytic effects after intravenous bolus injection of 200 kU/kg BM 06.021 were investigated in a canine model of coronary artery thrombosis. All studies were performed comparing BM 06.021 with glycosylated rt-PA (alteplase). BM 06.021 demonstrated a longer (p less than 0.05) half-life (5.6 +/- 2.6 vs. 2.1 +/- 0.3 min) and a lower (p less than 0.05) clearance rate (7.5 +/- 0.8 vs. 22.2 +/- 3.1 ml.min-1.kg-1) than alteplase in rabbits upon intravenous infusion. The dose-response curve of BM 06.021 for thrombolysis in a rabbit model of jugular vein thrombosis was located to the left of that for alteplase with a 2.1-fold lower effective dose of 50% thrombolysis (ED50) of BM 06.021 (207 vs. 436 kU/kg). Intravenous bolus injection of 200 kU/kg BM 06.021 induced the same reperfusion rate (4/6) as intravenous infusion of 800 kU/kg alteplase over 90 min in a canine model of coronary artery thrombosis. The residual thrombus wet weight did not significantly differ between BM 06.021 and alteplase (5.7 +/- 1.8 vs. 6.3 +/- 1.1 mg). The results indicate that unglycosylated rt-PA (BM 06.021) has a higher in vivo thrombolytic potency than glycosylated rt-PA (alteplase).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacokinetic and thrombolytic properties of unglycosylated recombinant tissue-type plasminogen activator (BM 06.021) produced in Escherichia coli. 140

We measured levels of tissue plasminogen activator (t-PA) antigen in 100 patients within six hours of the onset of acute myocardial infarction, in 34 patients with chronic angina but no recent infarction, and in 36 normal subjects. We also assayed von Willebrand factor in the acute patients and in the normal subjects. Measurements were repeated in 40 acute patients at three weeks after myocardial infarction. Although resting levels of t-PA antigen were not significantly different from normal during myocardial infarction, the capacity of the vascular endothelium to release t-PA after five minutes of venous occlusion was impaired (p less than 0.01). The acute phase vessel wall release of von Willebrand factor was increased during acute infarction (p less than 0.01). We conclude that impairment of t-PA production is associated with acute coronary thrombosis, although it is not possible to differentiate between a causative role or a secondary response due to exhaustion of the t-PA producing mechanism.
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PMID:Reduced synthesis of tissue plasminogen activator by vascular endothelium during acute myocardial infarction. 149 53

This study was conducted to compare the thrombolytic effect of a novel modified tissue plasminogen activator, E6010, with that of recombinant human tissue plasminogen activator (t-PA), administered by single intravenous bolus injection in pigs with occlusive coronary thrombosis. Thrombosis was induced by electrical stimulation of the intimal surface of the left circumflex coronary artery. Coronary blood flow velocity and hemodynamic parameters were observed for 1 hr after complete cessation of coronary flow. Ten minutes after heparin injection (300 U/kg), E6010, t-PA or placebo was intravenously administered as a bolus. E6010 at 0.2 and 0.4 mg/kg caused recanalization of the occluded coronary artery in 1 of 6 and 5 of 5 pigs, respectively. The time to recanalization after 0.4 mg/kg of E6010 was 22 +/- 11 min (mean +/- S.E.M.). t-PA (0.4 mg/kg) caused recanalization in only 1 of 5 pigs. Recanalization did not occur in any of the 6 animals administered placebo. Plasma clearance of E6010 was smaller than that of t-PA (4.9 +/- 0.3 vs. 9.4 +/- 3.8 ml/min/kg). There were no significant differences in plasma levels of fibrinogen, alpha 2-plasmin inhibitor and plasminogen among the placebo, E6010 and t-PA groups. These results suggest that the slower clearance of E6010 from plasma contributes to the effective thrombolytic action of E6010 following single intravenous bolus injection.
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PMID:Thrombolytic effects of a novel modified tissue plasminogen activator, E6010, on coronary thrombosis in the pig. 151 78

Although the benefits of coronary thrombolysis are well established, the optimal therapeutic strategy for ensuring rapid and sustained coronary artery patency remains controversial. The available data suggest that the success of coronary thrombolysis depends not only on the induction of clot lysis, but also on the extent to which procoagulant activity that promotes recurrent thrombosis is inhibited. Procoagulant activity increases almost immediately in patients treated with fibrinolytic agents, and persistent increases in thrombin activity have been associated with recurrent coronary thrombosis. Heparin administered intravenously appears to markedly attenuate the thrombin activity associated with thrombolysis and, in patients treated with tissue plasminogen activator (t-PA), prevents early recurrent coronary thrombosis. The results of clinical trials of coronary thrombolysis indicate that conjunctive treatment of patients with heparin improves survival compared with treatment with fibrinolytic agents alone. Although recent clinical trials in which patients were treated with streptokinase suggested that 12,500 units of heparin administered subcutaneously twice daily decreases mortality, this dosage regimen does not induce therapeutic levels of anticoagulation within the first 24 h in most patients. The failure to achieve early therapeutic anticoagulation may account for the lack of mortality benefit in trials in which patients given t-PA were treated with conjunctive subcutaneous heparin therapy. Thus, the available experimental and clinical data suggest that intravenous heparin should be given to patients treated with fibrinolytic agents for acute myocardial infarction.
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PMID:Role of heparin in coronary thrombolysis. 155 78

Reocclusion of coronary arteries is a major problem after successful thrombolysis in patients with acute myocardial infarction. We evaluated in a canine model of coronary thrombosis which is known to elicit reocclusion, whether an increased single i.v. bolus dose or two boli of the novel t-PA variant BM 06.022 improved coronary blood flow after reperfusion compared to i.v. injection of a standard single dose of BM 06.022. Double bolus administration, but not an increased single bolus dose of BM 06.022 significantly increased the maximum achieved coronary blood flow, prolonged the cumulative patency time, maintained blood flow at the end of the experiments, and reduced residual thrombus wet weight. Thus, double bolus administration improves coronary blood flow after reperfusion in the dog.
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PMID:Double bolus administration of the novel recombinant plasminogen activator BM 06.022 improves coronary blood flow after reperfusion in a canine model of coronary thrombosis. 160 85

Coronary artery reocclusion after thrombolysis with human recombinant tissue-type plasminogen activator (rt-PA) is related to the short half-life of this agent in plasma. K2P, a mutant of rt-PA lacking the fibronectin fingerlike, epidermal growth factor-like and first kringle domains (amino acids 6 to 173) and having the glycosylation site Asn184 mutagenized to Gln, has been produced in Chinese hamster ovary cells. In this study we compared the thrombolytic effect of K2P and rt-PA in dogs with electrically induced coronary artery thrombosis. Both agents were given intravenously in equimolar amounts over 20 min after the occlusive thrombus was stable for 30 min; dogs were monitored for 1 h after reperfusion if flow occurred. Coronary blood flow was restored by rt-PA in 6 (60%) of 10 dogs. The restored flow lasted for 49 +/- 12 min and mean flow at 60 min from the start of reperfusion was 7 +/- 3 ml/min. The reocclusion rate was 50% (three of six dogs). Flow was restored in five (100%) of five dogs by K2P. The restored blood flow lasted during the entire 1-h observation period in all but one dog and mean flow at 60 min was 49 +/- 16 ml/min (p less than 0.02 vs. flow in rt-PA-treated dogs). Restored coronary blood flow showed marked cyclic flow variations in rt-PA-treated but not in K2P-treated dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sustained reflow in dogs with coronary thrombosis with K2P, a novel mutant of tissue-plasminogen activator. 160 30

We examined the effect of coronary thrombolysis by recombinant tissue-plasminogen activator (rtPA) on infarct size using a thrombin-induced thrombosis model of open-chest anesthetized dog. Occlusive thrombus was induced by injection of thrombin (100 U) in the left anterior descending coronary artery (LAD). The intravenous infusion of rtPA (10 micrograms/kg/min) was started at 30 min (30 min-ischemia group) or at 60 min (60 min-ischemia group) after the formation of thrombus, and was continued for 30 min. Spontaneous thrombolysis was not observed in the 360 min-ischemia (vehicle-treated) group. Intravenous infusion of rtPA elicited thrombolysis within 30 min in all the dogs except in one in the 60 min-ischemia group. The infarct size was significantly reduced by rtPA-induced thrombolysis. The shorter the duration of the ischemia, the longer the effect of the drug, and the infarct size after thrombolysis was smaller in the 30 min-ischemia group than in the 60 min-ischemia group. Ischemia-induced changes in ST-segment of electrocardiogram (ECG) were significantly ameliorated after thrombolysis in both 60 min- and 30 min-ischemia group. These results suggest that early reperfusion of coronary thrombosis by rtPA is beneficial to the ischemic myocardium.
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PMID:Early thrombolysis by recombinant tissue-plasminogen activator is beneficial to the ischemic myocardium. 160 39

Inhibition of thromboxane (TX) A2 with aspirin enhances the response to coronary thrombolysis. However, experimental evidence suggests that platelet activation during coronary thrombolysis is mediated by a number of agonists, in addition to TXA2. As a consequence, greater benefit would be expected with antiplatelet agents that have a broader spectrum of activity. However, a recent clinical trial, combining tissue plasminogen activator (t-PA) with the prostacyclin analog, iloprost, did not detect such a benefit. To address the mechanism of this response, we compared the effect of iloprost, a stable analog of prostacyclin, with GR32191, a TXA2/prostaglandin endoperoxide receptor antagonist, on the response to i.v. t-PA in a closed chest, canine model of coronary thrombosis. GR32191 reduced the time to reperfusion by 47% (n = 6, P less than .05), consistent with a role for TXA2-mediated platelet activation in impairing thrombolysis. In contrast, iloprost increased the time to reperfusion by 50% (n = 5, P = NS) and in four of nine animals reperfusion failed to occur despite inhibition of platelet aggregation. In a separate series of experiments, steady-state plasma t-PA clearance increased by 38% (407 +/- 49 vs. 294 +/- 42 ml/min; n = 8, P less than .02) during infusion of iloprost and recovered after its withdrawal. This appeared to be a specific effect, as infusion of nitroglycerin at a dose which induced a similar fall in blood pressure altered neither the time to reperfusion nor plasma t-PA. Iloprost impairs the thrombolytic response to t-PA via an increase in the clearance of this agent.
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PMID:A prostacyclin analog impairs the response to tissue-type plasminogen activator during coronary thrombolysis: evidence for a pharmacokinetic interaction. 170 25

We studied the thrombolytic dose-response relationship of a recombinant plasminogen activator (rPA) (BM 06.022) compared with alteplase in a canine model of coronary artery thrombosis. BM 06.022 consists of the kringle 2 and protease domains of human tissue PA (tPA) and lacks oligosaccharide side chains because of its expression in Escherichia coli. Thrombus formation in anesthetized, open-chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery in the presence of a critical stenosis. Intravenous bolus injection of BM 06.022 (50, 100, 140, and 200 kU/kg) or of alteplase (200, 800, 1,130, and 1,600 kU/kg) 30 min after coronary occlusion to six heparinized dogs per group achieved a dose-dependent increase in reperfusion rate and decrease in residual thrombus wet weight. Vehicle-treated dogs did not reperfuse. Semilogarithmic regression analysis showed that the effective dose that produced 50% reperfusion of BM 06.022 (83 kU/kg) was 11.6-fold lower than that of alteplase (951 kU/kg). Comparison with infusion experiments showed that intravenous bolus injection of 140 kU/kg of BM 06.022 was equieffective to a 90-min infusion of 800 kU/kg (= 1 mg/kg) of alteplase as a standard treatment regarding reperfusion rate (66%) and time to reperfusion (15 +/- 6 vs. 18 +/- 8 min). Pharmacokinetic analysis for functionally active BM 06.022 or alteplase in plasma revealed a total plasma clearance of 4.1-6.6 ml/min/kg for BM 06.022 and of 12.6-42.3 ml/min/kg for alteplase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coronary thrombolytic properties of a novel recombinant plasminogen activator (BM 06.022) in a canine model. 171 79

The thrombolytic and systemic effects of BM 06.022 were evaluated and compared with those of alteplase, anistreplase, streptokinase and urokinase in a canine model of coronary artery thrombosis. BM 06.022 consists of the kringle-2 and protease domains of human tissue plasminogen activator (t-PA) and is unglycosylated because of its expression in Escherichia coli cells. Thrombus formation in anesthetized open chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery at a high level site of obstruction. In heparinized dogs, none of six vehicle-treated animals exhibited reperfusion. Reperfusion was achieved in four of six dogs at 18.3 +/- 6 min after intravenous bolus injection of 140 kU/kg (0.24 mg/kg) of BM 06.022, whereas four of six dogs exhibited reperfusion later (p less than 0.05) at 76.5 +/- 16.1 min during infusion of 1.33 mg/kg of alteplase (0.13 mg/kg as initial bolus injection, followed by 0.66 mg/kg over 1 h and 0.53 mg/kg over 2 h). Significantly later (p less than 0.05) reperfusion than that achieved with BM 06.022 was achieved in five of six dogs at 57.8 +/- 12.1 min after intravenous injection of 0.4 U/kg of anistreplase. Streptokinase (21,000 IU/kg over 60 min) and urokinase (20,000 IU/kg as an intravenous bolus injection, followed by 20,000 IU/kg over 89 min) each induced reperfusion in three of six dogs but at 67 +/- 12 and 84.3 +/- 17.1 min (p less than 0.05 vs. BM 06.022), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evaluation of thrombolytic and systemic effects of the novel recombinant plasminogen activator BM 06.022 compared with alteplase, anistreplase, streptokinase and urokinase in a canine model of coronary artery thrombosis. 173 72


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