Abstracts

RATIONALE: Ganaxolone (3[alpha]-hydroxy-3[beta]-methyl-5[alpha]-pregnane-20-one), an orally active synthetic analog of the neurosteroid allopregnanolone, is a positive allosteric modulator of GABA-A receptors with anticonvulsant properties. It has enhanced potency in a rat model of catamenial epilepsy. We sought to determine if tolerance occurs to the anticonvulsant activity of ganaxolone in the pentylenetetrazol (PTZ) seizure test and if there is cross-tolerance with diazepam.
METHODS: Rats were treated with two daily injections of a 2 x ED50 dose of ganaxolone (7 mg/kg, s.c.), diazepam (4 mg/kg, i.p.) or vehicle for 3 or 7 days. On the day after the chronic treatment periods, the anticonvulsant potencies of ganaxolone and diazepam were determined. Plasma ganaxolone levels were determined by LC-MS technique.
RESULTS: The ED50 values for ganaxolone after 3 and 7 day treatment with ganaxolone were not significantly different from that in naive rats (ED50, 3.5 mg/kg). In contrast, in animals that were treated chronically with ganaxolone for 7 days, there was a significant reduction in the anticonvulsant potency of diazepam (ED50, 4.0 mg/kg vs. 1.9 mg/kg for naive controls). Chronic treatment with diazepam was not associated with a reduction in the potency of ganaxolone, but there was a reduction in the potency of diazepam (ED50, 3.7 mg/kg). Plasma ganaxolone determinations indicated that the pharmacokinetic properties of ganaxolone were unchanged after 7 day chronic ganaxolone treatment. The estimated plasma concentrations of ganaxolone associated with threshold (750-950 ng/ml) and 50% seizure protection (1215-1295 ng/ml) were similar in naive and chronically treated rats.
CONCLUSIONS: We conclude that there is no tolerance to the anticonvulsant activity of ganaxolone nor is there cross-tolerance to ganaxolone when tolerance develops to diazepam. However, chronic ganaxolone treatment induces cross-tolerance to anticonvulsant activity of diazepam.