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Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands
Published in Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen, Handbook of Depression and Anxiety, 2003
Since allopregnanolone has a poor oral availability, a new synthetic neuroactive steroid ganaxolone (3α-hydroxy-3β -methyl-5α-pregnan-20-one) has been developed and is currently under clinical trials. It is a potent and efficacious anticonvulsant agent for the management of generalized absence and partial seizures [82] as well as for convulsions due to cocaine poisoning [83]. Recently, it was reported that ganaxolone is superior to valproate, ethosuximide, clonazepam, diazepam, and phenobarbital in preventing the pen- tylenetetrazole-induced convulsions and the behavioral effects of pentylenetetrazole including its depressant effects on locomotor activity and rearing in mice, thereby suggesting that ganaxolone may provide additional benefits in the treatment of epilepsy by controlling anxiety, mood changes, and other behavioral alterations associated with preseizure activity [84].
Current and future pharmacotherapy options for drug-resistant epilepsy
Published in Expert Opinion on Pharmacotherapy, 2022
Ganaxolone is a synthetic derivative of the endogenous neuro-steroid allopregnanolone, which is a metabolite of progesterone, and has been approved by the FDA in 2022 for the treatment of seizures in Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder. It is a positive allosteric modulator of GABA-A receptors. Ganaxolone is also under development for focal epilepsies and has been trialed in status epilepticus and infantile spasms [62] which are not discussed in this review. A 10-week randomized, double-blind, placebo-controlled Phase II study of ganaxolone 1500 mg/ day in 147 patients with drug-refractory focal epilepsy demonstrated a 17.6% reduction in mean weekly seizure frequency [63]. Pooled data showed that most adverse effects were mild to moderate in severity and reversible on drug reduction/discontinuation. Common adverse events included dizziness, fatigue, somnolence in 13–16% of patients with discontinuation due to adverse events in 7%. A Phase III trial of 359 patients with focal epilepsy was underway but has been discontinued by Marinus Pharmaceuticals due to ganaxolone missing its primary endpoint of demonstrating a statistically significant difference from placebo in percentage change in 28-day seizure frequency from baseline (NCT02519439).
A review of the pharmacotherapeutic considerations for managing epilepsy in people with autism
Published in Expert Opinion on Pharmacotherapy, 2022
Lance V Watkins, Maire O’Dwyer, Rohit Shankar
The onset of PCDH19-related epilepsy is usually in the first few years of life (age <3 years) presenting with febrile and afebrile seizures of a generalized and/or focal onset. The seizures are treatment resistant in the early years, but control tends to improve through adolescence. Seizures are characteristically focal, occurring in clusters, and associated with fever between the ages of 2 and 10 years. PCDH19 is also associated with cognitive and behavioral changes including psychiatric disorders and autism [71]. At present, no one anti-seizure drug demonstrates good efficacy in PCDH19 and most people require a polytherapy regime. On a cellular level, PCDH19 likely plays a role in GABA-A receptor function [72]. Ganaxolone is a molecule trialed in a number of severe seizure disorders and plays a role in GABA-A modulation. There is some positive evidence that this may be a useful treatment adjunct for at least a part of the PCDH19 spectrum. However, a role as a precision treatment encompassing the disorder’s neuropsychiatric symptoms remains unproven [71].
GABA(A) receptor-targeted drug development -New perspectives in perioperative anesthesia
Published in Expert Opinion on Drug Discovery, 2019
Bernd Antkowiak, Gerhard Rammes
Ganaxolone is a 3-methylated analogue of 3α,5α-THPROG [191] and, at nanomolar concentrations, acts as a PAM whereas at higher concentrations directly activates GABAA receptors [191]. Currently, ganaxolone is undergoing clinical evaluation as adjunctive therapy in female children with PCDH19 mutations suffering from infantile spasms (ClinicalTrials.gov Identifier: NCT02358538). In adults with uncontrolled partial-onset seizures [192] ganaxolone as an adjunctive therapy reduced seizure frequency [193]. In 2015 Marinus Pharmaceuticals conducted a randomized, placebo-controlled, phase 2 clinical trial evaluating the effect of ganaxolone on behaviours associated with Fragile X syndrome children (ClinicalTrials.gov Identifier: NCT01725152). However, no significant improvements in the outcome measures were reported [194]. Although the most striking adverse effect in non-clinical and clinical studies was reported to be a dose-dependent but reversible sedation, somnolence, dizziness and fatigue [191], no further studies followed up to test ganaxolone as an anaesthetic.