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 stability, activity, and compatibility of alteplase with eight drugs frequently used in cardiovascular disease were studied. Alteplase 1 mg/mL was mixed with each of the following: heparin sodium 80 units/mL in 0.9% sodium chloride injection, dobutamine 10 mg/mL (as the hydrochloride salt) in 0.9% sodium chloride injection or 5% dextrose injection, dopamine hydrochloride 1.6 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection, morphine sulfate 2 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection, lidocaine hydrochloride 8 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection, propranolol hydrochloride 1 mg/mL, metoprolol tartrate 1 mg/mL, or nitroglycerin 0.8 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection. Each mixture was assayed immediately and after storage for 24 hours at 25 degrees C; mixtures containing heparin were also assayed at 4 hours. The alteplase concentration and percentage of the single-chain molecule in each mixture were analyzed by using size-exclusion high-performance liquid chromatography (HPLC). Alteplase bioactivity was determined by a clot-lysis assay. Drug concentrations were assayed by HPLC, pH values of the mixtures were determined, and the mixtures were visually inspected. Instability was defined as a > 10% decrease in concentration; inactivity was defined as a > 10% decrease in activity; incompatibility was defined as detection of a precipitate, opalescence, or color change. Alteplase was not stable in the presence of heparin sodium, morphine sulfate, or dobutamine and was not active in the presence of dopamine hydrochloride. Alteplase was compatible with and stable and active (in vitro) in the presence of lidocaine hydrochloride, propranolol hydrochloride, metoprolol tartrate, or nitroglycerin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stability and activity of alteplase with injectable drugs commonly used in cardiac therapy. 852 54

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

We investigated whether the clinical evolution of symptoms in patients admitted with unstable angina is associated with changes in t-plasminogen activator antigen (t-PA) and von Willebrand (vW) factor levels. Concentrations of vW factor antigen and t-PA antigen were measured by an enzyme-linked immunoassay method in 10 patients who became clinically stable within 24 h of admission and remained so for 5 days. A significant rise in morning t-PA plasma level occurred 24 h after the admission (15.15 +/- 2.1 ng/ml, P < 0.05), whereas the vW factor remained unchanged. No significant changes were found in the night concentration in t-PA and vW factor during the 5 day period. Thus t-PA level is significantly raised 24 h after admission in patients with unstable angina who stabilize in response to medical treatment.
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PMID:t-Plasminogen activator and von Willebrand factor in patients with unstable angina. 879 92

Reteplase (drug code: BM 06.022) is an unglycosylated recombinant plasminogen activator variant derived from human tissue-type plasminogen activator. The main metabolic organs of reteplase are the kidneys, liver, and blood, whereas human tissue-type plasminogen activator is predominantly cleared by the liver. Recent studies showed that reteplase plasma concentrations were significantly increased in severe acute renal failure. The purpose of the present study was to evaluate whether the degree of renal failure influences the pharmacokinetic properties of reteplase. Subacute renal failure in rats was induced by bilateral 1-hr clamping of the renal arteries and recovery for 3 or 6 days. Acute renal failure was induced by bilateral surgical nephrectomy. Renal function was assessed by inulin clearance. The plasma concentration of functionally active reteplase was measured by an indirect spectrophotometric assay. Reteplase was administered as a double-bolus intravenous injection of 140 + 140 kU/kg, 30 min apart. In comparison with sham surgery, 1-hr clamping plus recovery for 6 days had the least effect on inulin clearance, followed by clamping and recovery for 3 days and bilateral nephrectomy (20.2 +/- 1.8 vs. 13.0 +/- 1.3, 8.3 +/- 0.8, and 3.1 +/- 0.2 ml center dot min-1 center dot kg-1, p < 0.01). Total plasma clearance of reteplase was significantly reduced, compared with sham surgery after 1-hr clamping plus 3-day recovery and bilateral nephrectomy (3.65 +/- 0.26 vs. 2.6 +/- 0.23 and 2.18 +/- 0.14 ml center dot min-1 center dot kg-1, p < 0.05 and p < 0.01, respectively), but not after 1-hr clamping plus 6-day recovery (3.33 +/- 0.34 ml center dot min-1 center dot kg-1, NS vs. sham surgery). There was a significant (p < 0.0001) linear correlation (r = 0.713) between the decrease of inulin clearance and the decrease of reteplase clearance. These data indicate that slight impairment of renal function does not significantly influence pharmacokinetic properties of reteplase, whereas severe renal dysfunction does.
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PMID:Influence of the degree of renal dysfunction on the pharmacokinetic properties of the novel recombinant plasminogen activator reteplase in rats. 882 Apr 18

Direct interactions of plasminogen activators with arterial endothelial cells are important in the pathogenesis of vascular complications associated with thrombolytic therapy. We investigated the direct effects of various plasminogen activators on human aortic and pulmonary artery endothelial cell functions in vitro. The effects of plasminogen activators on endothelial cells were not caused by generation of plasmin, as shown by the absence of plasminogen and alpha(2)-plasmin inhibitor-plasmin complex both before and after addition of plasminogen activators to endothelial cells. High concentrations of plasminogen activators increased the permeability of aortic endothelial cells to albumin. Alteplase (50 x 10(3) IU/ml), a recombinant tissue-type plasminogen activator (t-PA), increased prostaglandin I(2) (PGI(2)) production by aortic endothelial cells from 175.5 +/- 13.8 to 870.8 +/- 131.0 pg/mg cellular protein during a 2-h incubation; other plasminogen activators increased PGI(2) production to a lesser extent. Alteplase (100 x 10(3) IU/ml) also increased PGI(2) production from 152.0 +/- 16.2 to 1,080 +/- 95.1 pg/mg cellular protein in human pulmonary artery endothelial cells. High concentrations of urokinases decreased the amount of endothelin-1 in the medium of aortic or pulmonary artery endothelial cells by as much as 93%; part of this decrease was attributable to degradation of endothelin-l by urokinases. Other plasminogen activators either had no effect on or slightly increased the production of endothelin-1. These changes in the function of human arterial endothelial cells induced by plasminogen activators may affect regional vascular tone, endothelial permeability, and platelet aggregability, all of which are important in the efficacy of thrombolysis and in the pathogenesis of such vascular complications as rethrombosis and hemorrhage.
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PMID:Direct interactions of plasminogen activators with human aortic and pulmonary artery endothelial cells in vitro: implications for thrombolytic therapy. 885 31

Reteplase is a protein consisting of the kringle-2 and protease domains of tissue-type plasminogen activator (t-PA). Because intravenous heparin will be used as an adjunct to thrombolytic therapy with reteplase, we investigated the interactions in vitro between heparin and reteplase as well as between heparin and recombinant t-PA (alteplase) as a control. Reteplase and alteplase bound completely to a heparin-agarose column and eluted respectively at 0.39 M and 0.60 M in a NaCl gradient. Two-chain derivatives of reteplase and alteplase eluted at 0.31 M and 0.52 M NaCl respectively. Plasminogen activation by the two-chain derivatives of reteplase and alteplase in a purified system at low ionic strength were stimulated by heparin up to 13- and 22-fold, respectively. However, reteplase required five times more heparin for maximal stimulation than alteplase. In addition, the heparin stimulation of reteplase was more salt sensitive than that of alteplase. In conclusion, both heparin binding and heparin stimulation experiments showed that heparin interacts with reteplase, but the interaction is weaker than with alteplase.
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PMID:Interaction of reteplase with heparin. A comparison between reteplase and alteplase. 887 67

Although the ability of a thrombolytic agent to lyse a clot has been recognized for over 50 years, it was not until recently that this form of therapy was used to treat acute myocardial infarction. The need for rapid diagnosis and timely treatment to provide optimum outcomes and prognosis is now well established. Numerous clinical trials continue to examine alternative therapeutic regimens as well as the efficacy and safety of new agents to improve short- and long-term outcomes further. Reteplase is a new recombinant tissue-type plasminogen activator with potential advantages over currently available agents.
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PMID:Controlled trials comparing reteplase with alteplase and streptokinase in patients with acute myocardial infarction. 888 1

Reteplase (BM 06.022; r-PA) is a recombinant peptide which consists of the kringle 2 and protease domains of human tissue-type plasminogen activator. It has been developed as a thrombolytic treatment for acute myocardial infarction (AMI). The half-life of reteplase allows administration as a double-bolus injection (second injection given 30 minutes after the first) rather than by the prolonged and, in some cases, more complex intravenous infusion regimens that are required for most other thrombolytic agents. Reteplase produced rapid and effective coronary artery thrombolysis in a number of dose-finding and comparative studies. Double-bolus administration of reteplase 10U + 10U produced significantly higher coronary artery patency rates than accelerated alteplase (100mg as a 1.5-hour infusion) in patients with AMI in the RAPID-II study. The 10U + 10U reteplase regimen produced a 35-day survival rate at least equivalent to that seen with a 1-hour infusion of streptokinase 1.5 million units in 5986 patients in the INJECT study, which was designed to demonstrate equivalence between treatments. As with other thrombolytics, bleeding was the most common adverse event seen in reteplase recipients. No significant differences in the overall risk of haemorrhage were observed between reteplase and either accelerated alteplase or standard streptokinase treatment in clinical trials. The risk of stroke in reteplase recipients appears to be similar to that for other thrombolytic agents [1.2% incidence in 3288 patients treated with reteplase 10U + 10U in clinical trials (0.76% for haemorrhagic stroke)], although accurate statistical assessment of the relative risk is not possible for the data available to date. Thus, reteplase is an effective thrombolytic agent which can be administered as a double-bolus injection regimen rather than as a prolonged infusion. Together with acquisition cost and general pharmacoeconomic data (which are not yet available), the results of GUSTO-III (a trial comparing double-bolus reteplase with accelerated alteplase in 15 000 patients) will have a major influence on the pattern of use of reteplase. In the meantime, data from the available clinical trials suggest that reteplase is a fast-acting and effective thrombolytic treatment for patients with AMI.
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PMID:Reteplase. A review of its pharmacological properties and clinical efficacy in the management of acute myocardial infarction. 889 69

Elderly patients have the highest absolute risk of death following an acute myocardial infarction (MI); 16.1% for those aged between 65 and 74 years, and 25.3% for those older than 75 years. Therefore, this age-group potentially may benefit most from the use of thrombolytic therapy. Cost-effectiveness analysis of streptokinase therapy has estimated that in patients aged 70 to 80 years, the cost per life-year saved is between $US21,200 and $US22,400 (1990 dollars) compared with placebo treatment. Additional mortality benefits have been shown for accelerated alteplase compared with streptokinase-treated patients (30-day mortality for alteplase and streptokinase was 6.3% and 7.3%, respectively; p = 0.001). A prospective cost-effectiveness study for all age groups concluded that the cost of an additional year of life saved with alteplase compared with streptokinase was $US32,678 (1993 dollars). This extra cost of alteplase treatment declined to $US13,410 and $US16,246 with patients older than 75 years with anterior and inferior MI, respectively. In patients aged 40 years or younger with an anterior or inferior MI, and for those aged up to 60 years with an inferior infarction, the accepted cost-effectiveness ratio of $US50,000 was exceeded. Alteplase appears to be a cost-effective therapy for the treatment of elderly patients with acute MI.
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PMID:Thrombolytic therapy in the elderly. Pharmacoeconomic considerations. 892 Jan 73

Optimal thrombolytic therapy in acute myocardial infarction must aim to achieve early and complete reperfusion of the infarct related coronary artery. Establishment of normal coronary flow (Thrombolysis in Myocardial Infarction [TIMI] grade 3) is the key correlate of improved survival. Three large-scale clinical trials, the Reteplase Angiographic Phase II International Dose-finding Study (RAPID 1), the Reteplase vs Alteplase Patency Investigation During Acute Myocardial Infarction Study (RAPID 2), and the International Joint Comparison of Thrombolytics Study (INJECT), have evaluated the comparative efficacy and safety of reteplase, a new, rapid-acting thrombolytic agent that offers the practical clinical convenience of bolus dosing. RAPID 1 and 2 demonstrated that reteplase was associated with superior early coronary artery patency rates compared with alteplase, whether alteplase was infused over 3 h or over 90 min. Further, the TIMI 3 flow rates achieved in reteplase-treated patients at 60 min were comparable to those achieved at 90 min with the accelerated alteplase dosing regimen. The INJECT trial showed that reteplase resulted in comparable mortality and clinical benefits to those achieved with streptokinase. All three studies demonstrated that reteplase therapy was not associated with an increase in bleeding complications or other adverse clinical events. The simple double-bolus regimen of reteplase administration may permit earlier initiation of thrombolysis with fewer dosing errors than with continuous infusion regimens and thus afford a reduction in the morbidity and mortality risks in patients with acute myocardial infarction.
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PMID:The role of thrombolytic drugs in the management of myocardial infarction. Comparative clinical trials. 896 Apr 43


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