title: A phase I trial of alfimeprase for peripheral arterial thrombolysis.
abstract: OBJECTIVE
  To evaluate the safety profile, pharmacokinetics, and thrombolytic activity of alfimeprase, a novel direct-acting thrombolytic agent, in patients with chronic peripheral arterial occlusion (PAO).
  
  
  METHODS
  In this multicenter, open-label, single-dose, dose-escalation study, 20 patients with worsening symptoms of lower extremity ischemia within 6 months of enrollment were treated with alfimeprase in five escalating dose cohorts (0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) by means of intraarterial and sometimes intrathrombic pulsed infusion. The primary endpoint was safety assessed by adverse event rates. Additional safety assessments included vital sign monitoring, serum chemistry testing, hematologic testing, and coagulation testing for 28 days after the procedure, as well as alpha2-macroglobulin and antialfimeprase antibody testing for as long as 3 months after treatment. Pharmacokinetic parameters were evaluated with use of an assay that measures free and alpha2-macroglobulin-bound (ie, total) alfimeprase.
  
  
  RESULTS
  No patient experienced a hemorrhagic adverse event. Mean plasminogen and fibrinogen concentrations were not substantially altered by treatment. Three transient treatment-related adverse events were reported in the same patient: one incidence each of increased blood fibrinogen level, skin rash, and headache. All three adverse events were graded as mild. The pharmacokinetic profile of alfimeprase suggested that the half-life for total alfimeprase ranges from 11 to 54 minutes (median, 25 min) in patients with PAO. The serum alpha2-macroglobulin concentrations decreased transiently in a dose response-like manner between 12 and 24 hours and returned to within normal limits approximately 14 days after alfimeprase exposure.
  
  
  CONCLUSIONS
  Alfimeprase in doses as high as 0.5 mg/kg was generally well-tolerated in patients with chronic PAO. No bleeding complications were noted. The stable fibrinogen concentrations suggest that the activity of alfimeprase may be limited to the target thrombus. Alfimeprase holds the potential to achieve dissolution of thrombus with a diminished risk of hemorrhage.
authors.affiliation: Department of Vascular Surgery, Desk S40, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. ourielk@ccf.org
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ouriel
authors.forename: Jacob
authors.initials: J
authors.lastname: Cynamon
authors.forename: Fred A
authors.initials: FA
authors.lastname: Weaver
authors.forename: Herbert
authors.initials: H
authors.lastname: Dardik
authors.forename: Donald
authors.initials: D
authors.lastname: Akers
authors.forename: John
authors.initials: J
authors.lastname: Blebea
authors.forename: Laura
authors.initials: L
authors.lastname: Gruneiro
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Toombs
authors.forename: Fong
authors.initials: F
authors.lastname: Wang-Clow
authors.forename: Margie
authors.initials: M
authors.lastname: Mohler
authors.forename: Luis
authors.initials: L
authors.lastname: Pena
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Wan
authors.forename: Steven R
authors.initials: SR
authors.lastname: Deitcher
mesh_terms: D000328:Adult; D000368:Aged; D000792:Angiography; D001779:Blood Coagulation Factors / Q000032:analysis; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007866:Leg / Q000098:blood supply*; D008297:Male; D008666:Metalloendopeptidases / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*; D000511:alpha-Macroglobulins / Q000032:analysis
chemical_list: D001779:Blood Coagulation Factors; D005343:Fibrinolytic Agents; D006454:Hemoglobins; D000511:alpha-Macroglobulins; D008666:Metalloendopeptidases; C436755:alfimeprase