A comparison of the effects of tirilazad on subarachnoid hemorrhage-induced blood-brain barrier permeability in male and female rats

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.