Ganaxolone: a prospective overview
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abstract
Ganaxolone is a synthetic analogue of the endogenous neurosteroid allopregnanolone, a metabolite of progesterone. Like allopregnanolone, ganaxolone is a potent positive allosteric modulator of -aminobutyric acid type A (GABAA) receptors. Ganaxolone has robust anticonvulsant effects in a variety of animal models of epilepsy, is orally active and lacks hormonal side effects. Unlike diazepam, anticonvulsant tolerance does not develop to ganaxolone following chronic therapy. Recent preclinical studies suggest that ganaxolone is a particularly promising treatment for catamenial epilepsy, a menstrual cycle-related seizure disorder characterized by an increase in seizures at the time of menstruation. Preliminary evidence of the efficacy of ganaxolone in the treatment of epilepsy is encouraging. In general, ganaxolone has a favorable safety profile. The most frequently reported side effect is somnolence, which occurs with an acceptable therapeutic index. Ganaxolone has demonstrated significant clinical efficacy in suppressing complex partial seizures. Two open-label trials of ganaxolone in infantile spasms have been reported with indications of efficacy in both cases. Ganaxolone has enhanced potency in an animal model of catamenial epilepsy, and there is promising preliminary evidence for the efficacy of ganaxolone 'pulse therapy' for catamenial seizures in women. In addition, since premenstrual syndrome (PMS) is associated with allopregnanolone deficiency, ganaxolone may also have utility in the management of PMS. As a novel GABAA receptor modulator with unique, broad-spectrum protective efficacy, ganaxolone may have additional therapeutic potential in alcohol and cocaine withdrawal seizures, as well as in the treatment of anxiety and other mood disorders.
