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)

Several lines of research towards improvement of thrombolytic agents are being explored, including the construction of mutants of plasminogen activators, chimeric plasminogen activators, conjugates of plasminogen activators with monoclonal antibodies, and plasminogen activators from animal or bacterial origin. Some of these new thrombolytic agents have shown promise in animal models of venous or arterial thrombosis; only those which are being investigated in clinical studies are briefly discussed. Monteplase is a modified tissue type-plasminogen activator (t-PA) constructed by substituting only one amino acid in the epidermal growth factor domain (Cys84-->Ser) and expressed in baby Syrian hamster kidney cells. It has a prolonged half-life of more than 20 min, as compared to 4 min for native t-PA. TNK-t-PA differs from t-PA by 3 mutations. This mutant has increased thrombolytic potency, slower clearance and enhanced resistance to the inhibitor PAI-1. Reteplase is a non-glycosylated deletion mutant of wild-type human t-PA which contains only kringle 2 and the protease domain but lacks its kringle 1 and the finger and growth factor domains. The structural changes in reteplase translate into a decreased fibrin binding, a lower affinity to endothelial and liver cells resulting in an extended half-life. Lanoteplase is a deletion mutant of t-PA with a half-life that is circa 10 times greater than alteplase, making it suitable for single bolus injection. YM866 is another mutant of t-PA in which the aminoacids 92 to 173 of kringle 1 were deleted and arginine275 replaced by glutamic acid which confers a longer half-life to the mutant. Recombinant glycosylated prourokinase has a greater stability than recombinant unglycosylated pro-urokinase, is rapid acting and safe in the clinical doses used. Staphylokinase (SAK) is produced by Staphylococcus aureus. It induces efficient and rapid recanalization, also after bolus injection, but is immunogenic. There are only a few large scale clinical trials published directly comparing fibrin-selective thrombolytic drugs. In patients with acute myocardial infarction, reteplase, administered in bolus injections, is associated with a similar mortality and bleeding rate as front loaded t-PA. Bolus TNK-t-PA has a similar incidence of cerebral bleeding as front loaded t-PA and is associated with the same survival rate after acute myocardial infarction in a large mortality trial.
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PMID:Newer thrombolytic agents. 1057 30

In acute myocardial infarction rapid, complete, and sustained reperfusion of the infarct-related coronary artery is the most important therapeutic principle. Lanoteplase or n-PA, a third-generation plasminogen activator consisting of a deletion and point mutant of tissue-type plasminogen activator (t-PA), is a promising agent to approach this therapeutic goal. The molecule exhibits an increased plasma half-life allowing single-bolus administration. In this article, after characterizing the n-PA molecule, the currently available pharmacokinetic and pharmacodynamic data including the results of the InTIME study are reviewed.
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PMID:Pharmacokinetics and pharmacodynamics of lanoteplase (n-PA). 1069 1

New bolus fibrinolytic agents derived from the recombinant human tissue plasminogen activator (t-PA) have emerged as a new means of dissolution of the occlusive thrombosis associated with acute myocardial infarction. Lanoteplase is a fibrinolytic drug derived from t-PA by deleting its fibronectin finger-like and epidermal growth factor domains and mutating Asn(117) to Gln(117). Lanoteplase has a reduced plasma clearance and a prolonged half-life such that it can be administered as a single bolus. In the InTIME I trial, patency (TIMI grade 2 or 3 flow) with the 120 KU/kg dose was higher compared with front-loaded t-PA. The InTIME II trial demonstrated that lanoteplase was as effective as alteplase with regard to mortality. However, the rate of intracranial haemorrhage was significantly higher in lanoteplase-treated patients and further development of this compound has been halted.
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PMID:Pharmacology and clinical trial results of lanoteplase in acute myocardial infarction. 1106 Aug 30

Lanoteplase, a modified form of a tissue plasminogen activator (t-PA) lacking fibronectin finger-like and epidermal growth factor domains, was developed by the Genetics Institute for the potential treatment of thromboembolic disorders. Suntory, the Japanese licensee, has filed an NDA in Japan for the treatment of acute myocardial infarction (MI) [301222]. It was also licensed to Bristol-Myers Squibb (BMS) for worldwide development (excluding Japan, China, South Korea and Taiwan) [178225]. BMS conducted phase III trials for acute MI [272490] but discontinued development and returned the license to Genetics Institute during 1999 [359688]. In February 1999, Lehman Brothers predicted the drug had a 60% probability of reaching market, with an estimated first launch date in 2000. The analysts predicted peak sales would occur in 2006, with peak sales of $200 million in the US and US $100 million in the rest of the world at that time [319225].
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PMID:Lanoteplase Genetics Institute. 1124 1

Lanoteplase is a recombinant mutant of tissue-type plasminogen activator (t-PA) that was developed with an aim to overcome the drawback of rapid systemic elimination of t-PA. In this study, we examined the disposition profile of lanoteplase in vivo and the kinetics of receptor-mediated endocytosis (RME) of this recombinant t-PA in vitro to kinetically characterize the mechanism(s) underlying its tissue distribution and elimination. Integration plot analysis of the initial-phase tissue distribution in rats revealed a much lower uptake clearance (CL(uptake)) of lanoteplase in the liver than that of t-PA. Rate constants for cell surface binding, internalization, and degradation of lanoteplase were also lower than those for t-PA in primary cultured rat hepatocytes. These results suggest that the improved stability of lanoteplase in vivo could be accounted for by the delay in the RME of this recombinant protein. The CL(uptake) in the liver decreased with coadministration of lactoferrin, a ligand for the low-density lipoprotein receptor-related protein (LRP) and the asialoglycoprotein (ASGP) receptors in normal mice, and in lrpap1((-/-)) mice, which have a hereditary deficiency of LRP; In contrast, CL(uptake) was not affected by mannose, whereas that of t-PA decreased with both ligands and in the lrpap1((-/-)) mice. Thus, the hepatic disposition of lanoteplase seems to be mediated by common specific receptors for t-PA, including LRP and the ASGP receptors, whereas the mannose receptor seems to be only minimally involved in the disposition of lanoteplase.
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PMID:Characterization of the hepatic disposition of lanoteplase, a rationally designed variant of tissue plasminogen activator in rodents. 1717 68

Lanoteplase is a recombinant plasminogen activator, which when administered as a single bolus intravenous injection, displays thrombolytic activity. In the phase II InTIME trial, lanoteplase dose-dependently increased reperfusion rates at 60 and 90 minutes in patients with acute myocardial infarction and at 90 (but not 60) minutes lanoteplase 120 kU/kg was significantly superior to alteplase in restoring TIMI grade 2 and 3 flow (in 83.0 and 71.4% of patients, respectively). Preliminary results from the phase III InTIME-II study showed that lanoteplase was as effective as alteplase in decreasing 30-day mortality. At 30 days, the combined incidence of death, reinfarction, major bleeding and heart failure was lower with lanoteplase 120 kU/kg than with alteplase 100mg. From preliminary results of the large InTIME-II study, lanoteplase 120 kU/kg showed a greater incidence of intracranial haemorrhage and mild bleeding than alteplase <or=100mg, but a similar incidence of stroke. The smaller InTIME study showed a tendency for fewer adverse events with lanoteplase.
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PMID:Lanoteplase. 1803 26