title: Intra-arterial administration of recombinant tissue-type plasminogen activator (rt-PA) causes more intracranial bleeding than does intravenous rt-PA in a transient rat middle cerebral artery occlusion model.
abstract: BACKGROUND
  Intra-arterial (IA) administration of rt-PA for ischemic stroke has the potential for greater thrombolytic efficacy, especially for a large thrombus in the M1 or M2 segment of the middle cerebral artery (MCA). Intracranial hemorrhage (ICH) is a concern with IA or intravenous (IV) administration especially as the therapeutic window is extended. However, because IA administration delivers a higher local concentration of agent, the incidence and severity of ICH may be greater than with similar doses IV. We investigated the safety of rt-PA administration by IA compared to IV infusion following 6 hours of MCA occlusion (MCAo) with reflow in the spontaneously hypertensive rat (SHR).
  
  
  METHODS
  Male SHRs were subjected to 6 hours MCAo with 18 hours reflow using a snare ligature model. They were treated with IA saline, IA rt-PA (1, 5, 10, 30 mg/kg), or IV rt-PA (10 and 30 mg/kg) by a 10 to 60 minute infusion beginning approximately 1 minute before reflow. The rats were recovered for 24 hours after MCAo onset at which time Bleeding Score, infarct volume, and Modified Bederson Score were measured.
  
  
  RESULTS
  Greater hemorrhagic transformation occurred with 10 and 30 mg/kg rt-PA administered IA than IV. The IV 10 mg/kg rt-PA dosage induced significantly less bleeding than did the 1 or 5 mg/kg IA groups. No significant increase in infarct volume was observed after IA or IV treatment. Rats treated with 30 mg/kg rt-PA by either the IA or IV route had greater neurological dysfunction compared to all other groups.
  
  
  CONCLUSIONS
  Administration of rt-PA by the IA route following 6 hours of MCAo results in greater ICH and worse functional recovery than comparable dosages IV. Significantly greater bleeding was observed when the IA dose was a tenth of the IV dose. The increased bleeding did not translate in larger infarct volumes.
authors.affiliation: Research and Pre-clinical Development, Grifols Therapeutics, Inc,, Research Triangle Park, North Carolina, USA. chris.crumrine@talecris.com.
authors.forename: R Christian
authors.initials: RC
authors.lastname: Crumrine
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Marder
authors.forename: G McLeod
authors.initials: GM
authors.lastname: Taylor
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Lamanna
authors.forename: Constantinos P
authors.initials: CP
authors.lastname: Tsipis
authors.forename: Philip
authors.initials: P
authors.lastname: Scuderi
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Petteway
authors.forename: Vikram
authors.initials: V
authors.lastname: Arora