ganaxolone and Epilepsy

Epilepsy is one of the most common and refractory neurological disorders globally. Ganaxolone, a neuroactive steroid that enhances GABAergic inhibition, has been tested in many trials for the resolution of refractory epilepsy. Based on these, our study implemented a meta-analysis to evaluate the general benefit of ganaxolone for refractory epilepsy.. EMBASE, Medline, Scopus, Cochrane Library, and Clinicaltrials.gov were searched for relevant randomized controlled trials (RCTs) up to June 20, 2022. The risk ratio (RR) and standard mean difference (SMD) were analyzed using dichotomous and continuous outcomes, respectively with a random effect model. Trial sequential analysis (TSA) was also performed to judge the reliability of results.. We totally collected 659 patients from four RCTs to evaluate the efficacy and safety of ganaxolone. As results showed, ≥50% reduction in mean seizure frequency has improved significantly compared with placebo (RR = 1.60, 95%CI: 1.02-2.49, p = 0.04, I. Based on our research, we have observed that ganaxolone is safe and has potential efficacy in the treatment of refractory epilepsy, waiting for further studies.

Topics: Anticonvulsants; Drug Resistant Epilepsy; Epilepsy; Humans; Randomized Controlled Trials as Topic

Multiple medications have recently been approved or are nearing US Food and Drug Administration approval for treatment of pediatric epilepsy, while a number of other compounds are in development. Many of these therapies are seeking indications in rare epilepsy syndromes and present novel mechanisms of action for the treatment of epilepsy.. Data related to drugs in development or under study were accessed following literature search via PubMed or author knowledge of publically available data.. Several new compounds are recently approved or under study for epilepsy in children.. The following is a brief overview of the new and emerging medications for the treatment of pediatric epilepsy.

Topics: Anticonvulsants; Cannabidiol; Child; Dioxolanes; Epilepsy; Fenfluramine; Humans; Piperidines; Pregnanolone; Pyridines

Topics: Anesthetics; Animals; Apoptosis; Cell Membrane; Epilepsy; Humans; Neurons; Neurosteroids; Pregnanolone; Receptors, Progesterone

Epilepsy is a neurological disorder that significantly impacts the quality of life of affected persons. Despite advances in research, nearly a third of patients have refractory or pharmacoresistant epilepsy. Even though numerous antiepileptic drugs (AEDs) have been approved over the past decade, there are no agents that halt the development of epilepsy. Thus, new and improved AEDs to prevent these conditions are necessary.. We highlight recent advances in new and innovative drugs for epilepsy disorders. We review three small molecule drugs in phase II clinical trials: Cannabidivarin, BGG492 (Selurampanel) and Ganaloxone.. The full potential of Cannabidivarin will be realized by testing in other types of treatment-resistant seizures; if they are beneficial, larger phase III clinical trials would probably be undertaken in the same patient population. About BGG492, the challenge will be to find 'superselective' AMPAR antagonists targeting only calcium-permeable receptors, with specific mechanisms, that may be attractive partners for drugs in polytherapy. Moreover, there is anew interest surrounding Ganaloxone because of a new submicron formulation that improves its absorption and pharmacokinetic profile, but new studies are necessary before progressing. Further clinical innovations will define the future for these small molecule-type drugs in epilepsy therapeutics.

Topics: Animals; Anticonvulsants; Cannabinoids; Clinical Trials, Phase II as Topic; Drug Design; Drug Resistant Epilepsy; Drugs, Investigational; Epilepsy; Humans; Pregnanolone; Quality of Life; Quinazolinones

Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) (GNX) is the 3beta-methylated synthetic analog of allopregnanolone; it belongs to a class of compounds referred to as neurosteroids. GNX is an allosteric modulator of GABA(A) receptors acting through binding sites which are distinct from the benzodiazepine binding site. It has activity in a broad range of animal models of epilepsy. GNX has been shown to be well tolerated in adults and children. In early phase II studies, GNX has been shown to have activity in adult patients with partial-onset seizures and epileptic children with history of infantile spasms. It is currently undergoing further development in infants with newly diagnosed infantile spasms, in women with catamenial epilepsy, and in adults with refractory partial-onset seizures.

Topics: Animals; Anticonvulsants; Brain; Clinical Trials as Topic; Epilepsy; Humans; Pregnanolone

Catamenial epilepsy is a menstrual cycle-related seizure disorder characterized by an increase in seizures at the time of menstruation. Catamenial epilepsy affects up to 70% of women with epilepsy. Catamenial seizures are common among women with focal or generalized epilepsy, which affects an estimated 1 million women in the United States. Presently, there is no specific, FDA-approved drug treatment for catamenial epilepsy. Despite the increased use of wide-ranging antiepileptic and hormonal drugs, catamenial seizures are often refractory to many treatments. Recent studies have provided an improved understanding of the pathophysiology of catamenial epilepsy. Cyclical changes of ovarian hormones estrogens and progesterone are now widely believed to be essential for the genesis of catamenial seizures. Generally, progesterone has antiseizure effects, while estrogens facilitate seizure susceptibility. The progesterone metabolite allopregnanolone has been identified as a key endogenous neurosteroid with powerful antiseizure activity. Allopregnanolone is a potent, positive allosteric modulator of GABA(A) receptors. Progesterone and allopregnanolone exposure and withdrawal affects GABA(A) receptor plasticity. In animal models, withdrawal from chronic progesterone and, consequently, of allopregnanolone levels in brain, has been shown to increase seizure susceptibility. Natural progesterone therapy is proven to be effective in women with epilepsy. Consequently, synthetic neurosteroids that are devoid of hormonal side effects represent a novel class of antiepileptic drugs for women with catamenial epilepsy. Our studies suggest that ganaxolone, a GABA(A) receptor-modulating synthetic neuroactive steroid, is a particularly promising treatment for catamenial epilepsy. Future studies are clearly warranted to determine the molecular pathophysiology and an effective treatment of catamenial epilepsy.

Topics: Animals; Anticonvulsants; Area Under Curve; Epilepsy; Estrogens; Female; Half-Life; Humans; Incidence; Menstrual Cycle; Mice; Pregnanolone; Progesterone; Receptors, GABA-A

Catamenial epilepsy is a menstrual cycle-related seizure disorder that affects up to 70% of women with epilepsy. Catamenial epilepsy is characterized by an increase in seizures during particular phases of the menstrual cycle. Three distinct patterns of catamenial epilepsy - perimenstrual, periovulatory, and inadequate luteal phase - have been described. Currently, there is no specific treatment for catamenial epilepsy. The molecular mechanisms involved in the pathophysiology of catamenial epilepsy are not well understood. Recent studies suggest that cyclical changes of ovarian hormones estrogens (proconvulsant) and progesterone (anticonvulsant) appear to play a key role in the genesis of catamenial seizures. Progesterone reduces seizure susceptibility partly through conversion to neurosteroids such as allopregnanolone, which enhances GABA(A) receptor function and thereby inhibits neuronal excitability. In animal models, withdrawal from chronic progesterone and, consequently, of allopregnanolone levels in brain, has been shown to increase seizure susceptibility. Natural progesterone therapy has proven effective in women with epilepsy. Moreover, neurosteroids have been shown to be very effective inhibitors of catamenial seizures in animal models. Thus, synthetic neuroactive steroids, such as ganaxolone, which are orally active and devoid of hormonal side effects, represent a novel treatment strategy for catamenial epilepsy. However, their clinical efficacy in catamenial epilepsy has yet to be explored. A greater understanding of the molecular mechanisms is clearly needed for designing effective treatment and prevention strategies of catamenial epilepsy in women at risk.

Topics: Animals; Anticonvulsants; Brain Chemistry; Disease Models, Animal; Epilepsy; Female; Humans; Menstruation Disturbances; Models, Molecular; Pregnanolone; Progesterone; Receptors, GABA-A; Steroids

In women with epilepsy, seizures can be influenced by variations in sex hormone secretion during the menstrual cycle. The proconvulsant effects of estrogen have been demonstrated in both animals and humans, whereas progesterone has been found to have anticonvulsant properties. Catamenial epilepsy affects approximately one-third of women with epilepsy. This type of epilepsy has generally been defined as an increase in seizure frequency beginning immediately before or during menses. However, three distinct patterns of catamenial epilepsy have been described: perimenstrual, periovulatory, and luteal. The diagnosis of catamenial epilepsy can be made through careful assessment of menstrual and seizure diaries and characterization of cycle type and duration. A variety of therapies for catamenial epilepsy have been proposed, including acetazolamide, cyclical use of benzodiazepines or conventional antiepileptic drugs (AEDs), and hormonal therapy. However, evidence for the effectiveness of these treatment approaches comes from small, unblinded series or anecdotal reports. Larger multicenter trials, as well as further investigation of the pathophysiology of the disorder, are needed to identify the most effective treatment for women with catamenial epilepsy.

Topics: Acetazolamide; Adolescent; Adult; Animals; Anticonvulsants; Brain Edema; Bromides; Contraceptives, Oral, Hormonal; Convulsants; Epilepsy; Estradiol; Estrogen Receptor Modulators; Female; Gonadal Steroid Hormones; Humans; Incidence; Menstrual Cycle; Middle Aged; Models, Biological; Periodicity; Potassium Compounds; Pregnanolone; Progesterone; Pyramidal Cells; Rats; Seizures

A pilot study of the safety, tolerability, dose range and potential efficacy of ganaxolone for the treatment of refractory epilepsy in pediatric and adolescent subjects.. We report the results of a nonrandomized, nonblinded, open-label, dose-escalation trial of ganaxolone in pediatric subjects (5-15 years) suffering from refractory epilepsy. Subjects received an oral suspension of ganaxolone in a 1:1 complex with beta-cyclodextrin in a dose escalation (1 mg/kg, b.i.d. to 12 mg/kg t.i.d.) schedule over 16 days. This was followed by a maintenance period for 8 weeks. Subjects that showed significant response were eligible for a compassionate use extension period.. Fifteen subjects enrolled, eight completed the trial and three continued in the open-label compassionate-use extension period. All subject exhibited refractory partial or generalized epilepsy. In an intent-to-treat analysis, four (25%) were considered substantial responders (>or=50% reduction in seizure frequency), two (13%) were considered moderate responders (between 25 and 50% reduction in seizure frequency) and the remainder were considered nonresponders (<24% reduction). Three subjects entered the extension phase, one remained essentially seizure-free for over 3.5 years of ganaxolone administration. Ganaxolone was tolerated well. A total of 17 adverse events were reported in 10 patients, all were considered mild to moderate in severity. Somnolence was the most frequently (nine) reported adverse event.. This pilot study is consistent with other clinical studies indicating that ganaxolone has anticonvulsant activity in humans. The results of this study encourage the further study of ganaxolone as an antiepileptic therapy.

Topics: Adolescent; Age Factors; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsy; Female; Humans; Male; Pilot Projects; Pregnanolone; Treatment Outcome

Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective in approximately 50% of babies, but may contribute to neuronal injury. Here, we assessed the efficacy of phenobarbital versus the synthetic neurosteroid, ganaxolone, to moderate seizure activity and neuropathology in neonatal lambs exposed to perinatal asphyxia.. Asphyxia was induced via umbilical cord occlusion in term lambs at birth. Lambs were treated with ganaxolone (5mg/kg/bolus then 5mg/kg/day for 2 days) or phenobarbital (20mg/kg/bolus then 5mg/kg/day for 2 days) at 6 hours. Abnormal brain activity was classified as stereotypic evolving (SE) seizures, epileptiform discharges (EDs), and epileptiform transients (ETs) using continuous amplitude-integrated electroencephalographic recordings. At 48 hours, lambs were euthanized for brain pathology.. Asphyxia caused abnormal brain activity, including SE seizures that peaked at 18 to 20 hours, EDs, and ETs, and induced neuronal degeneration and neuroinflammation. Ganaxolone treatment was associated with an 86.4% reduction in the number of seizures compared to the asphyxia group. The total seizure duration in the asphyxia+ganaxolone group was less than the untreated asphyxia group. There was no difference in the number of SE seizures between the asphyxia and asphyxia+phenobarbital groups or duration of SE seizures. Ganaxolone treatment, but not phenobarbital, reduced neuronal degeneration within hippocampal CA1 and CA3 regions, and cortical neurons, and ganaxolone reduced neuroinflammation within the thalamus.. Ganaxolone provided better seizure control than phenobarbital in this perinatal asphyxia model and was neuroprotective for the newborn brain, affording a new therapeutic opportunity for treatment of neonatal seizures. ANN NEUROL 2022;92:1066-1079.

Topics: Animals; Animals, Newborn; Anticonvulsants; Asphyxia Neonatorum; Disease Models, Animal; Epilepsy; Humans; Infant, Newborn; Phenobarbital; Pregnanolone; Seizures; Sheep

Topics: Anticonvulsants; Child; Epilepsy; Humans; Pregnanolone; Status Epilepticus

Cicer arietinum (Chickpea) is one of the most important harvests in the world with high nutritional value. Lack of essential oils in the seeds of Chickpea is an advantage in search for drug-like molecules with less toxicity. We evaluated anticonvulsant effect of C. arietinum in common animal models of epilepsy.. Dichloromethane extract was obtained from C. arietinum seeds by percolation. Acute toxicity of the extract was assessed in mice. Protective effect of the extract was examined against tonic seizures induced by maximal electroshock (MES; 50 mA, 50 Hz, 1 s) in mice, clonic seizures induced by pentylenetetrazole (PTZ; 60 mg/kg, i.p.) in mice, and electrical kindling model of complex partial seizures in rats. The extract was fractionated by n-hexane to f1 and f2 fractions. The extract and fractions underwent phytochemical analysis by thin layer chromatography. The active anticonvulsant fraction, f1, was subjected to matrix assisted laser desorption/ionization (MALDI) mass analysis.. The crude extract had neither toxicity up to 7 g/kg nor protective activity in MES and kindling models. However, it significantly inhibited clonic seizures induced by PTZ. f1 fraction mimicked protective effect of the extract. Phytochemical screening revealed the presence of considerable amount of alkaloids in the extract and fractions. Moreover, a novel structural class was detected in f1 fraction.. Finding an anticonvulsant molecule pertaining to a new structural class in the seeds of C. arietinum promises an effective and inexpensive source of antiepileptic medication. Further studies are needed to identify its mechanism of action and more clues into its structure-activity relationship.

Topics: Animals; Anticonvulsants; Cicer; Disease Models, Animal; Electroshock; Epilepsy; Male; Mice; Pentylenetetrazole; Plant Extracts; Pregnanolone; Rats; Rats, Wistar; Seeds; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Neuroactive steroids that function as positive modulators of GABA-A receptors are potential anticonvulsant drugs. We previously demonstrated that ganaxolone is effective against pentetrazol-induced motor seizures in immature rats. In the present study, we examined the effects of ganaxolone in another model, cortical epileptic afterdischarges (ADs). The possible side effects of ganaxolone were studied in rats 12, 18, and 25 days of age following the implantation of epidural electrodes. Low-frequency stimulation of the sensorimotor cortical area elicited ADs characterized by a spike-and-wave rhythm and clonic seizures. Ganaxolone (5, 10, 20, or 40 mg/kg) was administered intraperitoneally after the first AD and stimulation was repeated five more times. The highest dose of ganaxolone (40 mg/kg) suppressed progressive prolongation of ADs in 25-day-old rats and postponed it in 12-day-old rats. No significant effect was observed in 18-day-old animals. Movements during stimulation and clonic seizures accompanying ADs were not affected by ganaxolone. Ganaxolone at doses of 20 and 40 mg/kg had no significant effect on motor function, such as surface righting, negative geotaxis, wire mesh ascending, and bar holding. After administration of 40 mg/kg ganaxolone to 18- and 25-day-old rats, spontaneous locomotion in the open field tended to decrease. Doses of ganaxolone with a moderate anticonvulsant effect in the present model did not seriously compromise motor performance.

Topics: Aging; Animals; Anticonvulsants; Brain; Disease Models, Animal; Electric Stimulation; Epilepsy; Male; Motor Activity; Neuropsychological Tests; Pregnanolone; Rats; Rats, Wistar; Seizures; Time Factors

Perimenstrual catamenial epilepsy, the exacerbation of seizures in association with menstruation, may in part be due to withdrawal of the progesterone metabolite allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), an endogenous anticonvulsant neurosteroid that is a positive allosteric modulator of gamma-aminobutyric acid(A) receptors. Neurosteroid replacement is a potential approach to therapy, but natural neurosteroids have poor bioavailability and may be converted to metabolites with undesired progestational activity. The synthetic neuroactive steroid ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnane-20-one) is an orally active analog of allopregnanolone that is not converted to the hormonally active 3-keto form. To assess the potential of ganaxolone in the treatment of catamenial seizure exacerbations, a state of persistently high serum progesterone (pseudopregnancy) was induced in 26-day-old female rats with gonadotropins, and neurosteroids were withdrawn on postnatal day 39 with finasteride, a 5alpha-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone. Finasteride treatment during pseudopregnancy results in a reduction in the threshold for pentylenetetrazol seizures. During this state of enhanced seizure susceptibility, there was a 3-fold increase in the anticonvulsant potency of ganaxolone (control ED(50) = 3.5 mg/kg; withdrawn = 1.2 mg/kg) without a change in the potency for induction of motor toxicity in the rotarod test. The plasma concentrations of ganaxolone did not differ significantly in control and withdrawn animals; the estimated plasma concentrations of ganaxolone producing 50% seizure protection were approximately 500 and approximately 225 ng/ml in control and withdrawn rats, respectively. Unlike ganaxolone, neurosteroid withdrawal was associated with a decrease in the anticonvulsant potency of diazepam (control ED(50) = 1.9 mg/kg; withdrawn = 4.1 mg/kg) and valproate (control ED(50) = 279 mg/kg; withdrawn = 460 mg/kg). The enhanced anticonvulsant potency of ganaxolone after neurosteroid withdrawal supports the use of ganaxolone as a specific treatment for perimenstrual catamenial epilepsy.

Topics: Animals; Anticonvulsants; Convulsants; Diazepam; Disease Models, Animal; Enzyme Inhibitors; Epilepsy; Female; Finasteride; Menstruation; Oxidoreductases; Pentylenetetrazole; Pregnanolone; Pseudopregnancy; Rats; Rats, Sprague-Dawley; Seizures; Steroids; Valproic Acid

Topics: Animals; Anticonvulsants; Clinical Trials as Topic; Epilepsy; GABA-A Receptor Agonists; Humans; Pregnanolone; Receptors, GABA-A; Seizures