Effect of early treatment with tirilazad (U74006F) combined with delayed thrombolytic therapy in rat embolic stroke

Sixty-eight rats were embolized in the right carotid territory with a 200-mu l suspension of white clots made from autologous blood. The purpose was to investigate the effect of early treatment with tirilazad mesylate alone and in combination with thrombolytic therapy delayed 2 h. Twenty-six rats died spontaneously before the second postoperative day, and 42 animals were killed after 48 h of survival. The brains were removed, and the infarct volumes were measured in percent of the affected hemisphere. The animals that had died spontaneously were used for an estimation of an overall treatment effect in an analysis combining infarct size and mortality. Spontaneous death occurred in: 45% of the animals in the control group, 41% in the group treated with tirilazad alone, 38% of the animals treaetd with recombinant tissue plasminogen activator (rt-PA) and 25% of the animals receiving combined treatment. Among the surviving animals, the median infarct volume was 47% in the control group (n = 12). Tirilazad treatment (7.5 mg/kg over 5 h) initiated 10 min after embolization (n = 10) reduced median infarct volume to 15% (p = 0.003). Human rt-PA, 20 mg/kg, was infused intravenously during 1 h starting 2 h after embolization (n = 8). This treatment reduced median infarct volume to 31% (p = 0.22). When the two treatment regimens were combined (n = 12), the median infarct volume was reduced to 17% (p = 0.007). In the analysis combining infarct size and mortality, the infarct size among the spontaneously dead rats was set to 68%, which was the largest infarct found in these animals. Following this procedure, the median infarct volume was 63% in the control group, 38% in the group treated with tirilazad alone, 44% in the rats treated with rt-PA alone and 22% in the combined treatment group (p = 0.01, compared to the control group). In conclusion, the primary data analysis of the surviving animals showed that early treatment with tirilazad significantly reduced infarct size in this stroke model, whereas the analysis combining mortality rates and infarct volume indicated that the combination of rt-PA and tirilazad was superior to either therapy alone.