title: TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A dose-ranging trial.
abstract: BACKGROUND
  TNK-tissue plasminogen activator (TNK-TPA) is a genetically engineered variant of TPA, which in experimental models has a slower plasma clearance and greater fibrin specificity and is 80-fold more resistant to plasminogen activator inhibitor-1 than alteplase TPA.
  
  
  RESULTS
  The thrombolysis in Myocardial Infarction (TIMI) 10A trial was a Phase 1, dose-ranging pilot trial designed to evaluate the pharmacokinetics, safety, and efficacy of TNK-TPA in patients with acute myocardial infarction. One hundred thirteen patients with acute ST-segment elevation myocardial infarction presenting within 12 hours and without contraindications to thrombolysis were enrolled and treated with a single bolus of TNK-TPA over 5 to 10 seconds with doses ranging from 5 to 50 mg. TNK-TPA demonstrated a plasma clearance of 151 +/- 55 mL/min and a half-life of 17 +/- 7 minutes. Comparable values for wild-type TPA are 572 +/- 132 mL/min and 3.5 +/- 1.4 minutes, respectively. Systemic fibrinogen and plasminogen levels fell by only 3% and 13%, respectively, at 1 hour after TNK-TPA administration. TIMI grade 3 flow at 90 minutes was achieved in 57% to 64% of patients at the 30- to 50-mg doses. Seven patients (6.2%) experienced a major hemorrhage, which occurred at a vascular access site in six patients.
  
  
  CONCLUSIONS
  TNK-TPA has a prolonged half-life so it can be administered as a single bolus. TNK-TPA appears to be very fibrin specific, and the initial patency and safety profiles are encouraging. Further study of this new thrombolytic agent is ongoing.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Cannon
authors.forename: C H
authors.initials: CH
authors.lastname: McCabe
authors.forename: C M
authors.initials: CM
authors.lastname: Gibson
authors.forename: M
authors.initials: M
authors.lastname: Ghali
authors.forename: R F
authors.initials: RF
authors.lastname: Sequeira
authors.forename: G R
authors.initials: GR
authors.lastname: McKendall
authors.forename: J
authors.initials: J
authors.lastname: Breed
authors.forename: N B
authors.initials: NB
authors.lastname: Modi
authors.forename: N L
authors.initials: NL
authors.lastname: Fox
authors.forename: R P
authors.initials: RP
authors.lastname: Tracy
authors.forename: T W
authors.initials: TW
authors.lastname: Love
authors.forename: E
authors.initials: E
authors.lastname: Braunwald
mesh_terms: D000328:Adult; D000368:Aged; D001779:Blood Coagulation Factors / Q000032:analysis; D017023:Coronary Angiography; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D010865:Pilot Projects; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D001779:Blood Coagulation Factors; C104096:TNK-tissue plasminogen activator; D010959:Tissue Plasminogen Activator