Effect of BQ-123 and Tissue Plasminogen Activator on Vasospasm After Subarachnoid Hemorrhage in Monkeys

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Abstract
Background and Purpose We aimed to determine the effect of intracisternal administration of an endothelin-A receptor antagonist (BQ-123) against vasospasm in a monkey model and to determine whether this drug would have adverse interactions with intracisternal tissue plasminogen activator (TPA). Methods Thirty-three monkeys were randomly allocated to undergo baseline cerebral angiography, creation of right subarachnoid hemorrhage (SAH), and intracisternal delivery of (1) placebo (n=10); (2) low-dose BQ-123 (5 mg/kg per day, n=7); (3) high-dose BQ-123 (10 mg/kg per day, n=9); or (4) BQ-123 10 mg/kg per day plus TPA 1 mg every 12 hours for three doses (n=7). Angiography was repeated after 7 days, and animals were killed. Vasospasm was assessed by comparisons of angiograms within groups across time by paired t test and by comparisons across groups at each time by ANOVA. Results Significant clot remained in the basal cisterns in all groups except those receiving TPA, in whom complete clot clearance was noted. Comparisons of angiograms at baseline and after 7 days showed significant vasospasm of the right middle cerebral artery in animals receiving placebo (mean±SEM reduction in diameter, 36±7%; P <.05) and low- and high-dose BQ-123 (16±4% and 18±7%, respectively). Animals that received TPA did not develop significant right cerebral artery vasospasm. Comparisons of arterial diameters at day 7 revealed significant variance in right middle cerebral artery diameter, with animals in the placebo group having significantly more and animals in the TPA group having significantly less vasospasm than the BQ-123 groups. Histopathological examination of the brains did not show inflammation or pathological change in animals that received BQ-123 or BQ-123 plus TPA. Conclusions Intracisternal TPA was efficacious against vasospasm in monkeys. Combination therapy with TPA and BQ-123 was not associated with reduction in efficacy of either drug or with evidence of toxicity.