title: Successful microbubble sonothrombolysis without tissue-type plasminogen activator in a rabbit model of acute ischemic stroke.
abstract: OBJECTIVE
  Microbubbles (MB) combined with ultrasound (US) have been shown to lyse clots without tissue-type plasminogen activator (tPA) both in vitro and in vivo. We evaluated sonothrombolysis with 3 types of MB using a rabbit embolic stroke model.
  
  
  METHODS
  New Zealand White rabbits (n=74) received internal carotid angiographic embolization of single 3-day-old cylindrical clots (0.6 × 4.0 mm). Groups included: (1) control (n=11) embolized without treatment; (2) tPA (n=20); (3) tPA+US (n=10); (4) perflutren lipid MB+US (n=16); (5) albumin 3 μm MB+US (n=8); and (6) tagged albumin 3 μm MB+US (n=9). Treatment began 1 hour postembolization. Ultrasound was pulsed-wave (1 MHz; 0.8 W/cm²) for 1 hour; rabbits with tPA received intravenous tPA (0.9 mg/kg) over 1 hour. Lipid MB dose was intravenous (0.16 mg/kg) over 30 minutes. Dosage of 3 μm MB was 5 × 10⁹ MB intravenously alone or tagged with eptifibatide and fibrin antibody over 30 minutes. Rabbits were euthanized at 24 hours. Infarct volume was determined using vital stains on brain sections. Hemorrhage was evaluated on hematoxylin and eosin sections.
  
  
  RESULTS
  Infarct volume percent was lower for rabbits treated with lipid MB+US (1.0%± 0.6%; P=0.013), 3 μm MB+US (0.7% ± 0.9%; P=0.018), and tagged 3 μm MB+US (0.8% ± 0.8%; P=0.019) compared with controls (3.5%± 0.8%). The 3 MB types collectively had lower infarct volumes (P=0.0043) than controls. Infarct volume averaged 2.2% ± 0.6% and 1.7%± 0.8% for rabbits treated with tPA alone and tPA+US, respectively (P=nonsignificant).
  
  
  CONCLUSIONS
  Sonothrombolysis without tPA using these MB is effective in decreasing infarct volumes. Study of human application and further MB technique development are justified.
authors.affiliation: Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA. culpwilliamc@uams.edu
authors.forename: William C
authors.initials: WC
authors.lastname: Culp
authors.forename: Rene
authors.initials: R
authors.lastname: Flores
authors.forename: Aliza T
authors.initials: AT
authors.lastname: Brown
authors.forename: John D
authors.initials: JD
authors.lastname: Lowery
authors.forename: Paula K
authors.initials: PK
authors.lastname: Roberson
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Hennings
authors.forename: Sean D
authors.initials: SD
authors.lastname: Woods
authors.forename: Jeff H
authors.initials: JH
authors.lastname: Hatton
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Culp
authors.forename: Robert D
authors.initials: RD
authors.lastname: Skinner
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borrelli
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000628:therapy*; D002533:Cerebral Angiography; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D045423:Microbubbles / Q000627:therapeutic use*; D011817:Rabbits; D020521:Stroke / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000628:therapy*; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D016896:Treatment Outcome; D014464:Ultrasonic Therapy / Q000379:methods*; D014463:Ultrasonography
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator