Randomized Comparison of Coronary Thrombolysis Achieved With Double-Bolus Reteplase (Recombinant Plasminogen Activator) and Front-Loaded, Accelerated Alteplase (Recombinant Tissue Plasminogen Activator) in Patients With Acute Myocardial Infarction

Bode, Christoph; Smalling, Richard W.; Berg, Günter; Burnett, Curtis; Lorch, Gerald S.; Kalbfleisch, John M.; Chernoff, Robert W.; Christie, Leonard G.; Feldman, Robert L.; Seals, A. Allen; Weaver, W. Douglas

doi:10.1161/01.cir.94.5.891

Cited by 331 publications

(141 citation statements)

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“…nattokinase [7] and lumbrokinase [8] which can directly degrade the fibrin of blood clots, thereby dissolving the thrombi rapidly and completely [9]. However, these enzymes are expensive and patients may suffer from undesirable side effects such as gastrointestinal bleeding, allergic reaction, and resistance to repercussion [10,11]. Therefore, antithrombotic, anticoagulant and thrombolytic reagents from various sources have been investigated [12].…”

Section: Introductionmentioning

confidence: 99%

Fibrin(ogen)olytic and antiplatelet activities of a subtilisin-like protease from Solanum tuberosum (StSBTc-3)

et al. 2016

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a b s t r a c tPlant serine proteases have been widely used in food science and technology as well as in medicine. In this sense, several plant serine proteases have been proposed as potential anti-coagulants and antiplatelet agents. Previously, we have reported the purification and identification of a plant serine protease from Solanum tuberosum leaves. This potato enzyme, named as StSBTc-3, has a molecular weight of 72 kDa and it was characterized as a subtilisin like protease. In this work we determine and characterize the biochemical and medicinal properties of StSBTc-3. Results obtained show that, like the reported to other plant serine proteases, StSBTc-3 is able to degrade all chains of human fibrinogen and to produces fibrin clot lysis in a dose dependent manner. The enzyme efficiently hydrolyzes b subunit followed by partially hydrolyzed a and g subunits of human fibrinogen. Assays performed to determine StSBTc-3 substrate specificity using oxidized insulin b-chain as substrate, show seven cleavage sites: Asn3-Gln4; Cys7-Gly8; Glu13-Ala14; Leu15-Tyr16; Tyr16-Leu17; Arg22-Gly23 and Phe25-Tyr26, all of them were previously reported for other serine proteases with fibrinogenolytic activity. The maximum StSBTc-3 fibrinogenolytic activity was determined at pH 8.0 and at 37 C. Additionally, we demonstrate that StSBTc-3 is able to inhibit platelet aggregation and is unable to exert cytotoxic activity on human erythrocytes in vitro at all concentrations assayed. These results suggest that StSBTc-3 could be evaluated as a new agent to be used in the treatment of thromboembolic disorders such as strokes, pulmonary embolism and deep vein thrombosis.

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Section: Introductionmentioning

confidence: 99%

Fibrin(ogen)olytic and antiplatelet activities of a subtilisin-like protease from Solanum tuberosum (StSBTc-3)

et al. 2016

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“…4,5 Early treatment and complete TIMI grade 3 flow have been facilitated by faster delivery regimens for accelerated alteplase 3 and double-bolus reteplase. [6][7][8] Simpler effective regimens, such as a single-bolus injection, may offer additional benefits through earlier achievement of reperfusion and by reduction in the risk of dosing errors. Efforts to improve thrombolytic efficacy are tempered by the risk of serious bleeding, particularly hemorrhagic stroke.…”

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confidence: 99%

Evaluation of a Weight-Adjusted Single-Bolus Plasminogen Activator in Patients With Myocardial Infarction

et al. 1998

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Background —Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase. Methods and Results —InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the dose-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects, P <0.001). Similar results were observed at 90 minutes (26.1% to 57.1%, P <0.001). At 90 minutes, coronary patency (TIMI 2 or 3) increased across the dose range up to 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. Thus, at this dose, lanoteplase was superior to alteplase in restoring coronary patency (difference, 12%; 95% CI, 1% to 23%). The early safety experience in this study suggests that lanoteplase was well tolerated at all doses with safety comparable to that of alteplase. Conclusions —Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent.

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“…A double bolus regimen (10 C 10 mega units after 30 min) of r-PA administered to patients with AMI helped in complete, speedy, and sustained thrombolysis in comparison with the standard dose of t-PA (front-loaded accelerated infusion or standard infusion). 85,86 This strategy helped to overcome the necessity of a continuous intravenous infusion. The double bolus regimen of r-PA was found to be as effective as the standard dosage of streptokinase (1.5 million units given intravenously over 60 min) for the treatment of AMI (The INJECT Trial, 1995).…”

Section: Third Generation Plasminogen Activatorsmentioning

confidence: 99%

“…The molecule bears 21-23% sequence similarity with the u-PA and t-PA catalytic domains. It contains 6 disulfide bonds and His 41 , Asp 86 and Ser 180 form the catalytic triad in TSV-PA. Further, TSV-PA lacks the sequences responsible for interaction of t-PA (KHRR; Lys-His-Arg-Arg) and u-PA (RRHR; ArgArg-His-Arg) with PAI-1. The recombinant form of this molecule has been produced using E. coli.…”

Section: (Iv) Monteplase (E6010)mentioning

confidence: 99%

The evolution of recombinant thrombolytics: Current status and future directions

Adivitiya

Khasa

2016

Bioengineered

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Cardiovascular disorders are on the rise worldwide due to alcohol abuse, obesity, hypertension, raised blood lipids, diabetes and age-related risks. The use of classical antiplatelet and anticoagulant therapies combined with surgical intervention helped to clear blood clots during the inceptive years. However, the discovery of streptokinase and urokinase ushered the way of using these enzymes as thrombolytic agents to degrade the fibrin network with an issue of systemic hemorrhage. The development of second generation plasminogen activators like anistreplase and tissue plasminogen activator partially controlled this problem. The third generation molecules, majorly t-PA variants, showed desirable properties of improved stability, safety and efficacy with enhanced fibrin specificity. Plasmin variants are produced as direct fibrinolytic agents as a futuristic approach with targeted delivery of these drugs using liposome technlogy. The novel molecules from microbial, plant and animal origin present the future of direct thrombolytics due to their safety and ease of administration.

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Randomized Comparison of Coronary Thrombolysis Achieved With Double-Bolus Reteplase (Recombinant Plasminogen Activator) and Front-Loaded, Accelerated Alteplase (Recombinant Tissue Plasminogen Activator) in Patients With Acute Myocardial Infarction

Cited by 331 publications

References 32 publications

Fibrin(ogen)olytic and antiplatelet activities of a subtilisin-like protease from Solanum tuberosum (StSBTc-3)

Fibrin(ogen)olytic and antiplatelet activities of a subtilisin-like protease from Solanum tuberosum (StSBTc-3)

Evaluation of a Weight-Adjusted Single-Bolus Plasminogen Activator in Patients With Myocardial Infarction

The evolution of recombinant thrombolytics: Current status and future directions

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