Phase III
subarachnoid hemorrhage clinical trials have shown a beneficial effect of
tirilazad only in men. One explanation for the decreased efficacy in women is that women metabolize the
drug up to 60% faster than men. However, it is also possible that other more subtle differences between the sexes alter the pharmacodynamic response of women to
tirilazad. The purpose of the present study was to compare the efficacy of
tirilazad in attenuating early post-
subarachnoid hemorrhage-induced blood-brain barrier damage in the rat, a species in which single-dose metabolism of the
drug is comparable between males and females. Male and female rats were treated with 0.1, 0.3, 1.0, or 3.0 mg/kg
tirilazad (intravenous) 10 minutes before and 2 hours after
subarachnoid hemorrhage. At 3 hours posthemorrhage, the extent of blood-brain barrier damage, as measured by
Evan's blue extravasation, did not differ between male and female vehicle-treated rats. In addition, treatment with
tirilazad produced a similar effect in both males and females at all doses tested. At 0.3 mg/kg, blood-brain barrier damage was reduced 43.4% in males and 48.0% in females (P</=.01 vs vehicle), at 1.0 mg/kg, 33.1% in males and 29.1% in females (P</=.05), and at 3.0 mg/kg, 28.0% in males and 23.8% in females (P=NS). The lowest dose, 0.1 mg/kg, failed to protect the blood-brain barrier in both genders. These results suggest that gender differences do not significantly effect the blood-brain barrier protective efficacy of
tirilazad following
subarachnoid hemorrhage in the rat.