Randomized coronary patency trial of double-bolus recombinant staphylokinase versus front-loaded alteplase in acute myocardial infarction

Vanderschueren, Steven; Dens, Jo; Kerdsinchai, Pitsanu; Desmet, Walter; Vrolix, Mathias; Man, Filip De; Heuvel, Paul Van den; Hermans, L. J. F.; Collen, D.; Werf, Frans Van de

doi:10.1016/s0002-8703(97)70127-3

Cited by 60 publications

(27 citation statements)

References 19 publications

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“…The fibrin-specific property of SAK underlies an interesting observation in clinical trials. The fibrinogen levels in patients treated with SAK remain close to 100%, whereas patients treated with tPA have 32% of fibrinogen cleaved and degraded in their plasma (9,10).…”

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confidence: 98%

“…Staphylokinase (SAK), a 136-amino acid protein from certain lysogenic Staphylococcus aureus strains, is a plasminogen activator and a promising blood clot-dissolving agent with clinical potency that is at least as good as tPA (9,10). In addition, it has some desirable features that are superior to tPA (11).…”

mentioning

confidence: 99%

“…In addition, it has some desirable features that are superior to tPA (11). Notably, SAK mediates the lysis of platelet-rich and retracted clots efficiently (12,13) and shows exceptional fibrin specificity (9,10,14,15). These properties can help minimize reocclusion and bleeding complications.…”

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confidence: 99%

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A Fast-acting, Modular-structured Staphylokinase Fusion with Kringle-1 from Human Plasminogen as the Fibrin-targeting Domain Offers Improved Clot Lysis Efficacy

Wong

2003

Journal of Biological Chemistry

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To develop a fast-acting clot dissolving agent, a clottargeting domain derived from the Kringle-1 domain in human plasminogen was fused to the C-terminal end of staphylokinase with a linker sequence in between. Production of this fusion protein in Bacillus subtilis and Pichia pastoris was examined. The Kringle domain in the fusion protein produced from B. subtilis was improperly folded because of its complicated disulfidebond profile, whereas the staphylokinase domain produced from P. pastoris was only partially active because of an N-linked glycosylation. A change of the glycosylation residue, Thr-30, to alanine resulted in a non-glycosylated biologically active fusion. The resulting mutein, designated SAKM3-L-K1, was overproduced in P. pastoris. Each domain in SAKM3-L-K1 was functional, and this fusion showed fibrin binding ability by binding directly to plasmin-digested clots. In vitro fibrin clot lysis in a static environment and plasma clot lysis in a flowcell system demonstrated that the engineered fusion outperformed the non-fused staphylokinase. The time required for 50% clot lysis was reduced by 20 to 500% under different conditions. Faster clot lysis can potentially reduce the degree of damage to occluded heart tissues.

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confidence: 98%

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confidence: 99%

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A Fast-acting, Modular-structured Staphylokinase Fusion with Kringle-1 from Human Plasminogen as the Fibrin-targeting Domain Offers Improved Clot Lysis Efficacy

Wong

2003

Journal of Biological Chemistry

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“…130 Double bolus staphylokinase (15 mg C 15 mg given 30 min apart) was found to be more efficient and fibrin-specific than an accelerated regimen of rt-PA. Further, it did not induce any allergic reactions. 131 The therapeutic potential of staphylokinase has also been confirmed by the CAPTORS I and II trials (Collaborative Angiographic Patency Trial of Recombinant Staphylokinase). 132,133 Other Thrombolytics/Plasminogen activators Plasminogen activators from snakes Snake venoms contain a great variety of proteases exhibiting fibrinolytic properties.…”

Section: (Iv) Monteplase (E6010)mentioning

confidence: 90%

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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“…The resulting SAK-plasmin complex can then function as the plasminogen activator to convert plasminogen to plasmin for clot lysis. Although SAK has comparable thrombolytic potency as tPA, several multicenter clinical trials demonstrate that staphylokinase shows a superior fibrin specificity in comparison to tPA (11)(12)(13). This high fibrin specificity (14) is accomplished by a mechanism whereby the plasminogen activation activity of any non-fibrin bound SAK-plasmin complex is inhibited by circulating ␣ 2 -antiplasmin.…”

mentioning

confidence: 99%

Engineering of a Staphylokinase-based Fibrinolytic Agent with Antithrombotic Activity and Targeting Capability toward Thrombin-rich Fibrin and Plasma Clots

Lian¹,

Szarka²,

et al. 2003

Journal of Biological Chemistry

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Current clinically approved thrombolytic agents have significant drawbacks including reocclusion and bleeding complications. To address these problems, a staphylokinase-based thrombolytic agent equipped with antithrombotic activity from hirudin was engineered. Because the N termini for both staphylokinase and hirudin are required for their activities, a Y-shaped molecule is generated using engineered coiled-coil sequences as the heterodimerization domain. This agent, designated HE-SAKK, was produced and assembled from Bacillus subtilis via secretion using an optimized co-cultivation approach. After a simple in vitro treatment to reshuffle the disulfide bonds of hirudin, both staphylokinase and hirudin in HE-SAKK showed biological activities comparable with their parent molecules. This agent was capable of targeting thrombin-rich fibrin clots and inhibiting clot-bound thrombin activity. The time required for lysing 50% of fibrin clot in the absence or presence of fibrinogen was shortened 21 and 30%, respectively, with HE-SAKK in comparison with staphylokinase. In plasma clot studies, the HE-SAKK concentration required to achieve a comparable 50% clot lysis time was at least 12 times less than that of staphylokinase. Therefore, HE-SAKK is a promising thrombolytic agent with the capability to target thrombin-rich fibrin clots and to minimize clot reformation during fibrinolysis.

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Randomized coronary patency trial of double-bolus recombinant staphylokinase versus front-loaded alteplase in acute myocardial infarction

Cited by 60 publications

References 19 publications

A Fast-acting, Modular-structured Staphylokinase Fusion with Kringle-1 from Human Plasminogen as the Fibrin-targeting Domain Offers Improved Clot Lysis Efficacy

A Fast-acting, Modular-structured Staphylokinase Fusion with Kringle-1 from Human Plasminogen as the Fibrin-targeting Domain Offers Improved Clot Lysis Efficacy

The evolution of recombinant thrombolytics: Current status and future directions

Engineering of a Staphylokinase-based Fibrinolytic Agent with Antithrombotic Activity and Targeting Capability toward Thrombin-rich Fibrin and Plasma Clots

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