DELAYED ADJUVANT THERAPY WITH THE 21-AMINOSTEROID U74006F AND THE ANION CHANNEL BLOCKER L644-711 DOES NOT IMPROVE OUTCOME FOLLOWING THROMBOLYTIC THERAPY IN A RABBIT MODEL OF THROMBOEMBOLIC STROKE

BACKGROUND Both the 21-aminosteroid U74006F, a potent inhibitor of lip id peroxidation, and L644-711, an anion channel blocker that inhibits both neutrophil and astrocyte function, have been previously shown to reduce brain injury in pretreatment paradigms of cerebral ischemia. It was therefore of interest to examine the effect of these agents in co mbination, when given on a delayed basis as adjuvants to thrombolytic therapy in a rabbit model of thromboembolic stroke. METHODS Animals we re mechanically ventilated and arterial blood gases controlled. Core a nd brain temperature, intracranial pressure, and mean arterial pressur e were continuously monitored. Regional cerebral blood flow and hemato crit were measured hourly. Blood samples were taken to measure neutrop hil (aggregation and chemiluminescence) and platelet (aggregation) act ivity. Following delivery of an autologous clot via the carotid artery , all experiments were continued for an 8-hour period. U74006F (3 mg/k g I.V.) and L644,711 (12 mg/kg I.V.) or their vehicle control (n = 8, each group) were given 3.5 hours following autologous clot embolizatio n. Both groups received tissue-type plasminogen activator (t-PA) (6.3 mg/kg I.V.), beginning 4 hours following thromboembolic stroke and con tinuing over a 2-hour infusion period. Infarct size was determined fol lowing staining and image analysis. RESULTS In the L644,711/U74006F gr oup, neutrophil chemiluminescence was reduced following drug therapy; however, there were no significant differences between groups regardin g infarct size (50.3 +/- 8.7 vs. 49.9 +/- 10.6, treatment vs. t-PA con trol, mean +/- SEM), or in regional cerebral blood flow or intracrania l pressure over time. CONCLUSIONS It is concluded that prolonged (3.5 hours) delay of the initiation of therapy with the anion channel block er L644,711 and the 21-aminosteroid U74006F fails to further reduce br ain injury when given in combination with tissue plasminogen activator in a rabbit model of thromboembolic stroke. (C) 1997 by Elsevier Scie nce Inc.