Selected Investigational Fibrinolytics

Prourokinase

In the early 1980s, a glycosylated, single chain form of UK-type plasminogen activator (scuPA) was isolated from human urine and cell culture media and characterized biochemically as a proenzyme form of the active two-chain urokinase (tcuPA). Prourokinase (proUK) was of interest in part because it appeared to be more fibrin-specific than UK. This effect is believed to be mediated by the preferential conversion of scuPA to active tcuPA at the fibrin surface (11). The circulating half-life of natural and recombinant scuPA is 4 and 8 min, respectively, with predominant hepatic clearance (84). A phase 2 study of glycosylated proUK produced in mouse hybridoma cells suggested promising coronary patency rates (85), but further development for AMI has not been undertaken.

Saruplase

Saruplase is a recombinant nonglycosylated form of human proUK with less fibrin specificity and stability than glycosylated proUK (11). Elimination is biphasic, with an initial half-life of 6-9 min. Administration has been by bolus (20 mg) plus infusion (60

mg/60 min). Saruplase has undergone comparative clinical studies with SK and tPA (86-88). Saruplase achieves early (60-90 min) coronary patency rates greater than SK and similar to 3-h tPA infusions. Mortality rates were at least equivalent to SK but intracranial hemorrhage rates were greater. An application for clinical use was rejected by the European Medical Evaluation Agency (EMEA).

Lanoteplase

Lanoteplase (nPA) is a tPA mutant with deletions of the epidermal growth factor, the fibronectin finger domain, and the amino acid 117 glycosylation site (11). The result is slower clearance (half-life, 37 min), allowing for bolus injection, but decreased fibrin specificity. In comparative studies with tPA, nPA achieved equivalent patency rates (89) and similar 30-d mortality rates (90), but an increase in intracranial hemorrhage was observed (1.13 vs 0.62%). It is believed that the dosing strategy of both nPA and heparin may have contributed, but further development of nPA is uncertain.

Staphylokinase

Staphylokinase (SAK) is a single-chain, 136 amino-acid protein secreted by strains of Staphylococcus aureus and manufactured for clinical use by recombinant DNA technology (91,92). The SAK-plasmin complex is fibrin selective, efficiently activating plasminogen while bound to fibrin at the thrombus surface. SAK has shown at least equivalent reperfusion potential and greater fibrin specificity than accelerated dose tPA in phase 2 studies. SAK is antigenic, inducing neutralizing antibodies within 1 wk. A peglyated form has been generated to increase half-life and allow for bolus dosing.

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