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aAccelerated tPA given as follows: 15 mg bolus, then 0.75 mg/kg over 30 min (maximum, 50 mg), then 0.50 mg/kg over 60 min (maximum 35 mg). bTNK is dosed by weight (supplied in 5 mg/mL vials): <60 kg = 6 mL; 61-70 kg = 7 mL; 71-80 kg = 8 mL; 81-90 kg = 9 mL; >90 kg = 10 mL. cBased on Granger et al. (94) and Bode et al. (74) dPatients with STE or BBB, treated in <6 h.

eBased on the finding from the GUSTO trial that tPA saves 1 more additional life/100 treated than does SK.

aAccelerated tPA given as follows: 15 mg bolus, then 0.75 mg/kg over 30 min (maximum, 50 mg), then 0.50 mg/kg over 60 min (maximum 35 mg). bTNK is dosed by weight (supplied in 5 mg/mL vials): <60 kg = 6 mL; 61-70 kg = 7 mL; 71-80 kg = 8 mL; 81-90 kg = 9 mL; >90 kg = 10 mL. cBased on Granger et al. (94) and Bode et al. (74) dPatients with STE or BBB, treated in <6 h.

eBased on the finding from the GUSTO trial that tPA saves 1 more additional life/100 treated than does SK.

on plasminogen in the activator complex is activated, leading to conversion of free circulating plasminogen in the region of the activator complex to plasmin. Similarly, the SK-plasminogen complex itself is autocatalytically cleaved to form SK-plasmin, but this form of the complex retains its activator activity. The in vivo half-life of the SK-plas-minogen-plasmin activator complex is approx 23 min.

SK is antigenic and has little fibrin specificity, so that substantial systemic lytic effect occurs in clinically applied doses. The generation of circulating fibrinogen degradation products (FDPs) (which exert antiplatelet and antithrombotic effects) and the depletion of circulating fibrinogen and a-1-antiplasmin, along with other clotting factors, provide long-acting (up to 1 to 2 d) antithrombotic actions that far exceed the time-course of fibrinolytic effects. This may explain why the addition of IV heparin to SK and aspirin increases bleeding risk but provides little additional benefit.

Urokinase

A native protein responsible for part of the proteolytic activity in human urine was first reported in 1861 and was shown to have specificity for fibrin (64,65). It was later established that renal parenchymal cells are responsible for UK production. Contemporary clinical formulations of UK have been obtained from human kidney cells grown in culture and are primarily of the low molecular weight form (33,000 Da), whereas that purified from human urine is of higher molecular weight (55,000 Da). The therapeutic efficacy of the two molecular species in clinical applications is very similar. UK, unlike SK, is a direct-acting proteolytic agent (trypsin-type serine proteinase). UK contains 410 amino acid residues in two polypeptide chains connected by a disulfide bridge.

UK activity is not found in the circulation under normal conditions. When present, UK directly converts plasminogen to plasmin through enzymatic cleavage at the L-argi-nine 560-valine 561 site (the identical site of attack of SK); no additional cofactors are required. A single bolus of UK is cleared from the circulation with a half-life of 14-16 min by degradation to inert metabolites in the liver. UK is nonantigenic.

For AMI, UK has been approved only for IC use in a dose of 6000 IU a minute for periods up to 2 h or until lysis of the coronary arterial thrombus is observed. Heparin therapy is recommended concurrently with UK. UK also has been tested by the iv route in doses of 2 to 3 MU (generally administered as a bolus plus a short-term infusion regimen). However, iv UK is less well studied than iv SK or tissue-type plasminogen activator (tPA), and its mortality benefits have been less well-established (66). Hence, tPA is generally used when a nonantigenic agent with less systemic-fibrinolytic activity than SK is desired.

Clinically, UK has been most frequently used in catheter-directed infusions to remove thrombus and restore patency in appropriately selected cases of venous, arterial, and graft thromboses, and intravenously for massive pulmonary embolism (64). Recently, however, UK has become unavailable in the U.S. market.

Anistreplase

Anistreplase (anisoylated plasminogen streptokinase activator complex, or APSAC) was the first custom-designed biochemically modified fibrinolytic agent to be developed (67,68). It was designed to allow rapid delivery (a 2- to 5-min injection), rapid onset, more prolonged duration of action, and improved plasma stability and fibrin binding compared with SK. However in doses used clinically, it retains the antigenic and nonspecific systemic thrombolytic effects of SK.

APSAC is synthesized by complexing SK with lys-plasminogen and reversibly acy-lating the complex by reacting it with the anisoyl group of a special acylating agent, producing a molecule of 131,000-Da molecular weight. Placed in aqueous solution or plasma, APSAC deacylates by a simple ester hydrolysis reaction, a rate-limiting process that follows first-order kinetics. APSAC's fibrinolytic activity has a half-life of approx 105 min in plasma. The commonly used clinical dosage of 30 U of APSAC corresponds to approx 1.1 MU of SK.

Tissue-Type Plasminogen Activator tPA is the primary physiologic (intrinsic) plasminogen activator in the circulation (69). A two-subunit form can be generated by limited proteolytic cleavage. Both single and two-chain forms activate plasminogen with approx similar catalytic efficacy and biologic potency (70). tPA demonstrates partial fibrin selectivity in comparison to SK in that tPA generates greater plasmin and fibrinolytic activity locally, in the neighborhood of thrombus, than systemically. The result is relatively less plasminemia, fib-rinogenolysis, and general (systemic) proteolysis than SK. tPA is subject to inhibition by a circulating plasminogen activator inhibitor (PAI-1), and its activity is rapidly cleared from the circulation with a half-life of <5 min (71). tPA is nonantigenic and, unlike SK, may be reutilized without concern about interference with activity by neutralizing antibodies (72). tPA is manufactured for clinical application using recombinant technology as alteplase (rtPA).

Recombinant Plasminogen Activator

Reteplase (recombinant plasminogen activator, or rPA) became the first clinically available mutant (modified) form of native plasminogen activator (73-75). rPA is a deletion mutant of alteplase (rtPA) in which the finger, epidermal growth factor, and kringle-1 domains have been deleted. As a result of structural and biosynthetic modifications, rPA, compared to tPA, is nonglycosylated, smaller, and less fibrin-specific (with lower fibrin affinity and more readily reversible binding), but it has an extended half-life (13-18 min). The slower clearance allows rPA to be given in a double-bolus regimen (two boluses separated by 30 min) compared with the 90-min infusion for rtPA. Following the demonstration of a favorable (at least "equivalent") effect on clinical events in AMI compared to SK (73), rPA received market approval in the U.S. in 1997. An apparent advantage in establishment of early patency compared with tPA in a relatively small study (74) was not associated with a superior mortality outcome in a large (15,000 patients), randomized AMI trial, Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) III (75).

Tenecteplase

Tenecteplase (TNK-tPA) is a genetically engineered, triple-site substitution variant of tPA (76). At amino acid 103, threonine is replaced by asparagine, adding a glycosylation site; at site 117, asparagine is replaced by glutamine, removing a glycosylation site; and at a third site (296-299), four amino acids (lysine, histidine, arginine, and arginine) are replaced by four alanines. The first two changes decrease clearance rate (half-life of 20 min), allowing for single bolus dosing (77-79). The third change confers greater fibrin

100"!—■—■—I—r—"—I—1—■—I—■—■—I—■—'—i—1'—■—I

0 30 60 90 120 150 180 Time (minutes)

Fig. 2. Similar pharmacologic properties are demonstrated with bolus doses of TNK compared to the standard 90-min infusion of tPA. Adapted with permission from ref. 83.

100"!—■—■—I—r—"—I—1—■—I—■—■—I—■—'—i—1'—■—I

0 30 60 90 120 150 180 Time (minutes)

Fig. 2. Similar pharmacologic properties are demonstrated with bolus doses of TNK compared to the standard 90-min infusion of tPA. Adapted with permission from ref. 83.

specificity (77) and resistance to PAI-1 (77,80,81). Given these favorable properties, clinical testing of TNK-tPA was undertaken in the Thrombolysis in Myocardial Infarction (TIMI) 10A trial (77). Doses tested ranged from 5 to 50 mg. TNK-tPA showed a slower plasma clearance rate, approximately one-third or less of that previously observed with tPA. The corresponding plasma half-life of elimination of TNK-tPA ranged from 11 to 20 min, compared to 3.5 min for tPA (82). These results were replicated in the TIMI 10B trial (78,83). After bolus TNK-tPA, plasma levels are maintained over time, so that the curve approximates that of the tPA bolus-infusion regimen (Fig. 2).

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