Ganaxolone

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Jeffrey M. Witkin - One of the best experts on this subject based on the ideXlab platform.

  • Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice.
    European journal of pharmacology, 2003
    Co-Authors: Rafal M. Kaminski, Maciej Gasior, Richard B. Carter, Jeffrey M. Witkin
    Abstract:

    Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the gamma-aminobutyric acid (GABA(A)) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and Ganaxolone (a synthetic derivative of allopregnanolone 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABA(A) modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and Ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not Ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.

  • Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice.
    European Journal of Pharmacology, 2003
    Co-Authors: Rafal M. Kaminski, Maciej Gasior, Richard B. Carter, Jeffrey M. Witkin
    Abstract:

    Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the γ-aminobutyric acid (GABAA) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3α-hydroxy-5α-pregnan-20-one), pregnanolone (3α-hydroxy-5β-pregnan-20-one) and Ganaxolone (a synthetic derivative of allopregnanolone 3α-hydroxy-3β-methyl-5α-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABAA modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and Ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not Ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.

  • acute and chronic effects of the synthetic neuroactive steroid Ganaxolone against the convulsive and lethal effects of pentylenetetrazol in seizure kindled mice comparison with diazepam and valproate
    Neuropharmacology, 2000
    Co-Authors: Maciej Gasior, Jesse T. Ungard, Richard B. Carter, Marjolein Beekman, Jeffrey M. Witkin
    Abstract:

    Abstract A high-affinity positive modulator of the GABAA receptor complex, Ganaxolone, is a 3β-methylated analog of the naturally occurring neuroactive steroid allopregnanolone. In the present study, Ganaxolone was tested for its ability to (1) suppress seizures (clonic and tonic) and lethality induced by pentylenetetrazol (PTZ) in PTZ-kindled mice (anticonvulsive effect) and (2) to attenuate the development of sensitization to the convulsive and lethal effects of PTZ in kindled mice (anti-epileptogenic effect) when given as a pretreatment prior to each PTZ injection during kindling acquisition. Two classical antiepileptic drugs, diazepam and valproate, were tested for comparison. All three drugs dose-dependently suppressed tonic seizures and lethality induced by PTZ in kindled mice; only Ganaxolone was effective against clonic seizures. Ganaxolone showed anti-epileptogenic properties as it reduced the sensitivity of kindled mice to the convulsive (clonic and tonic seizures) and lethal effects of PTZ. Diazepam showed anti-epileptogenic effects against tonic seizures and lethality, but not clonic seizures; valproate was ineffective in preventing development of any of these effects. Sensitivity to PTZ-induced seizures and lethality was not affected in mice with a history of repeated treatment with Ganaxolone, diazepam, or valproate. The drugs had effects on ambulatory activity that ranged from no effect (Ganaxolone) through moderate impairment (diazepam) to marked disruption (valproate). Taken together, the results of the present study add to accumulating evidence of the unique anticonvulsive/behavioral profile of neuroactive steroids.

  • Modification of behavioral effects of drugs in mice by neuroactive steroids
    Psychopharmacology, 2000
    Co-Authors: Jesse T. Ungard, M Beekman, Maciej Gasior, Richard B. Carter, Durk Dijkstra, Jeffrey M. Witkin
    Abstract:

    Rationale: Neuroactive steroids represent a novel class of potential therapeutic agents (epilepsy, anxiety, migraine, drug dependence) thought to act through positive allosteric modulation of the GABAA receptor. A synthetically derived neuroactive steroid, Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), is in phase-II clinical trials for epilepsy. Unlike traditional anticonvulsants such as diazepam and phenobarbital, Ganaxolone shows equipotent suppression of both the seizure activity and the behavioral effects of pentylenetetrazol (PTZ) administration. Objectives: The present study explored possible reversal by Ganaxolone and related neuroactive steroids of some behavioral effects of additional pharmacological challenges. Methods: Direct behavioral observation and photocell-counted locomotor activity of male, Swiss-Webster mice were made with various compounds alone and in conjunction with Ganaxolone. Results: Ganaxolone both prevented and reversed PTZ-induced locomotor depression in mice. Further, Ganaxolone reversed the locomotor depression induced by other convulsant/anxiogenic stimuli: bicuculline, picrotoxin and, to a lesser extent, yohimbine. Ganaxolone failed to reverse the locomotor stimulation induced by cocaine, methamphetamine, dizocilpine, and phencyclidine. In addition to Ganaxolone, the endogenous neuroactive steroids allopregnanolone and pregnanolone and the synthetic neuroactive steroid Co 2-1068 also reversed observed behaviors and locomotor depression induced by PTZ. Conclusions: The present findings support the unique pharmacological effects of neuroactive steroids as a novel class of positive allosteric modulators of GABA.

  • Modification of behavioral effects of drugs in mice by neuroactive steroids
    2000
    Co-Authors: Jesse T. Ungard, Beekman M, Gasior M, Rb Carter, Dijkstra D, Jeffrey M. Witkin
    Abstract:

    Rationale: Neuroactive steroids represent a novel class of potential therapeutic agents (epilepsy, anxiety, migraine, drug dependence) thought to act through positive allosteric modulation of the GABA(A) receptor A synthetically derived neuroactive steroid, Ganaxolone (3 alpha-hydroxy-3 beta-methyl-5 alpha-pregnan-20-one), is in phase-II clinical trials for epilepsy. Unlike traditional anticonvulsants such as diazepam and phenobarbital, Ganaxolone shows equipotent suppression of both the seizure activity and the behavioral effects of pentylenetetrazol (PTZ) administration. Objectives: The present study explored possible reversal by Ganaxolone and related neuroactive steroids of some behavioral effects of additional pharmacological challenges. Methods: Direct behavioral observation and photocell-counted locomotor activity of male, Swiss-Webster mice were made with various compounds alone and in conjunction with Ganaxolone. Results: Ganaxolone both prevented and reversed PTZ-induced locomotor depression in mice. Further, Ganaxolone reversed the locomotor depression induced by other convulsant/anxiogenic stimuli: bituculline, picrotoxin and, to a lesser extent, yohimbine. Ganaxolone failed to reverse the locomotor stimulation induced by cocaine, methamphetamine, dizocilpine, and phencyclidine. In addition to Ganaxolone, the endogenous neuroactive steroids allopregnanolone and pregnanolone and the synthetic neuroactive steroid Co 2-1068 also reversed observed behaviors and locomotor depression induced by PTZ. Conclusions: The present findings support the unique pharmacological effects of neuroactive steroids as a novel class of positive allosteric modulators of GABA

Michael A. Rogawski - One of the best experts on this subject based on the ideXlab platform.

  • Intramuscular allopregnanolone and Ganaxolone in a mouse model of treatment-resistant status epilepticus.
    Epilepsia, 2018
    Co-Authors: Dorota Zolkowska, Michael A. Rogawski
    Abstract:

    Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, Ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA)A receptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The 2 neuroactive steroids are being investigated as treatments for SE, including as a treatment for SE induced by chemical threat agents. Intramuscular injection is the preferred route of administration in the prehospital treatment of SE. The objective of this study was to assess the efficacy of intramuscular allopregnanolone and Ganaxolone in the treatment of SE induced by the chemical threat agent tetramethylenedisulfotetramine (TETS). The test agents were administered 40 minutes after the onset of SE when mice are refractory to treatment. Allopregnanolone and Ganaxolone (each at 3 mg/kg) terminated SE in, respectively, 92% and 75% of animals, and prevented mortality in 85% and 50% of animals; the mean times to termination of behavioral seizures were, respectively, 172 ± 16 and 447 ± 52 seconds. In a separate series of experiments, mice were dosed with the neuroactive steroids by intramuscular injection, and plasma and brain levels were sampled at various time points following injection to estimate pharmacokinetic parameters. Plasma Cmax (maximum concentration) values for allopregnanolone and Ganaxolone were 645 and 550 ng/mL, respectively. Brain exposure of both steroids was approximately 3-fold the plasma exposure. Two-compartment pharmacokinetic analysis revealed that the central compartment Vd (volume of distribution), CL (clearance), t½ (terminal half-life), and F (intramuscular bioavailability) values for allopregnanolone and Ganaxolone were, respectively, 4.95 L/kg 12.88 L/kg/h,16 minutes, 97%, and 5.07 L/kg, 8.35 L/kg/h, 25 minutes, 95%. Allopregnanolone and Ganaxolone are effective in the treatment of TETS-induced SE when administered by the intramuscular route. Allopregnanolone is more rapidly acting and modestly more effective, possibly because it has greater potency on GABAA receptors.

  • Effects of the synthetic neurosteroid Ganaxolone on seizure activity and behavioral deficits in an Angelman syndrome mouse model.
    Neuropharmacology, 2016
    Co-Authors: Stephanie L. Ciarlone, Michael A. Rogawski, Xinming Wang, Edwin J. Weeber
    Abstract:

    Angelman syndrome (AS) is a rare neurogenetic disorder characterized by severe developmental delay, motor impairments, and epilepsy. GABAergic dysfunction is believed to contribute to many of the phenotypic deficits seen in AS. We hypothesized that restoration of inhibitory tone mediated by extrasynaptic GABAA receptors could provide therapeutic benefit. Here, we report that Ganaxolone, a synthetic neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, was anxiolytic, anticonvulsant, and improved motor deficits in the Ube3a-deficient mouse model of AS when administered by implanted mini-pump for 3 days or 4 weeks. Treatment for 4 weeks also led to recovery of spatial working memory and hippocampal synaptic plasticity deficits. This study demonstrates that Ganaxolone ameliorates many of the behavioral abnormalities in the adult AS mouse, and tolerance did not occur to the therapeutic effects of the drug. The results support clinical studies to investigate Ganaxolone as a symptomatic treatment for AS.

  • Evaluation of the neuroactive steroid Ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism
    Psychopharmacology, 2016
    Co-Authors: Tatiana M. Kazdoba, Michael A. Rogawski, Randi J. Hagerman, Dorota Zolkowska, Jacqueline N. Crawley
    Abstract:

    Rationale Abnormalities in excitatory/inhibitory neurotransmission are hypothesized to contribute to autism spectrum disorder (ASD) etiology. BTBR T ^+ Itpr3 ^ tf /J (BTBR), an inbred mouse strain, displays social deficits and repetitive self-grooming, offering face validity to ASD diagnostic symptoms. Reduced GABAergic neurotransmission in BTBR suggests that GABA_A receptor positive allosteric modulators (PAMs) could improve ASD-relevant BTBR phenotypes. The neuroactive steroid Ganaxolone acts as a PAM, displaying anticonvulsant properties in rodent epilepsy models and an anxiolytic-like profile in the elevated plus-maze. Objectives We evaluated Ganaxolone in BTBR and C57BL/6J mice in standardized assays for sociability and repetitive behaviors. Open field and anxiety-related behaviors were tested as internal controls and for comparison with the existing neuroactive steroid literature. Results Ganaxolone improved aspects of social approach and reciprocal social interactions in BTBR, with no effect on repetitive self-grooming, and no detrimental effects in C57BL/6J. Ganaxolone increased overall exploratory activity in BTBR and C57BL/6J in the open field, social approach, and elevated plus-maze, introducing a confound for the interpretation of social improvements. Allopregnanolone and diazepam similarly increased total entries in the elevated plus-maze, indicating that behavioral activation may be a general property of GABA_A receptor PAMs in these strains. Conclusions Ganaxolone shows promise for improving sociability. In addition, Ganaxolone, as well as other GABA_A receptor PAMs, enhanced overall BTBR activity. The translational implications of specific sociability improvements and nonspecific behavioral activation by Ganaxolone in the BTBR model remain to be determined. Future studies to explore whether PAMs provide a novel profile with unique benefits for ASD treatment will be worthwhile.

  • Evaluation of the neuroactive steroid Ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism.
    Psychopharmacology, 2015
    Co-Authors: Tatiana M. Kazdoba, Michael A. Rogawski, Randi J. Hagerman, Dorota Zolkowska, Jacqueline N. Crawley
    Abstract:

    Rationale Abnormalities in excitatory/inhibitory neurotransmission are hypothesized to contribute to autism spectrum disorder (ASD) etiology. BTBR T+Itpr3tf/J (BTBR), an inbred mouse strain, displays social deficits and repetitive self-grooming, offering face validity to ASD diagnostic symptoms. Reduced GABAergic neurotransmission in BTBR suggests that GABAA receptor positive allosteric modulators (PAMs) could improve ASD-relevant BTBR phenotypes. The neuroactive steroid Ganaxolone acts as a PAM, displaying anticonvulsant properties in rodent epilepsy models and an anxiolytic-like profile in the elevated plus-maze.

  • neurosteroids as endogenous regulators of seizure susceptibility and use in the treatment of epilepsy
    Epilepsia, 2010
    Co-Authors: Doodipala Samba Reddy, Michael A. Rogawski
    Abstract:

    Neurosteroids such as allopregnanolone are positive allosteric modulators of γ-aminobutyric acid (GABA) A receptors with powerful antiseizure activity in diverse animal models. Neurosteroids may be endogenous regulators of seizure susceptibility, for example, in catamenial epilepsy. Clinical trials with the synthetic neurosteroid analog Ganaxolone in the treatment of refractory partial seizures and infantile spasms have been encouraging. Neurosteroids and analogs such as Ganaxolone show promise in the treatment of diverse forms of epilepsy. For an expanded treatment of this topic see Jasper's basic mechanisms of the epilepsies. 4th ed. (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at www.ncbi.nlm.nih.gov/books).

Richard B. Carter - One of the best experts on this subject based on the ideXlab platform.

  • Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice.
    European journal of pharmacology, 2003
    Co-Authors: Rafal M. Kaminski, Maciej Gasior, Richard B. Carter, Jeffrey M. Witkin
    Abstract:

    Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the gamma-aminobutyric acid (GABA(A)) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and Ganaxolone (a synthetic derivative of allopregnanolone 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABA(A) modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and Ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not Ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.

  • Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice.
    European Journal of Pharmacology, 2003
    Co-Authors: Rafal M. Kaminski, Maciej Gasior, Richard B. Carter, Jeffrey M. Witkin
    Abstract:

    Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the γ-aminobutyric acid (GABAA) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3α-hydroxy-5α-pregnan-20-one), pregnanolone (3α-hydroxy-5β-pregnan-20-one) and Ganaxolone (a synthetic derivative of allopregnanolone 3α-hydroxy-3β-methyl-5α-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABAA modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and Ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not Ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.

  • acute and chronic effects of the synthetic neuroactive steroid Ganaxolone against the convulsive and lethal effects of pentylenetetrazol in seizure kindled mice comparison with diazepam and valproate
    Neuropharmacology, 2000
    Co-Authors: Maciej Gasior, Jesse T. Ungard, Richard B. Carter, Marjolein Beekman, Jeffrey M. Witkin
    Abstract:

    Abstract A high-affinity positive modulator of the GABAA receptor complex, Ganaxolone, is a 3β-methylated analog of the naturally occurring neuroactive steroid allopregnanolone. In the present study, Ganaxolone was tested for its ability to (1) suppress seizures (clonic and tonic) and lethality induced by pentylenetetrazol (PTZ) in PTZ-kindled mice (anticonvulsive effect) and (2) to attenuate the development of sensitization to the convulsive and lethal effects of PTZ in kindled mice (anti-epileptogenic effect) when given as a pretreatment prior to each PTZ injection during kindling acquisition. Two classical antiepileptic drugs, diazepam and valproate, were tested for comparison. All three drugs dose-dependently suppressed tonic seizures and lethality induced by PTZ in kindled mice; only Ganaxolone was effective against clonic seizures. Ganaxolone showed anti-epileptogenic properties as it reduced the sensitivity of kindled mice to the convulsive (clonic and tonic seizures) and lethal effects of PTZ. Diazepam showed anti-epileptogenic effects against tonic seizures and lethality, but not clonic seizures; valproate was ineffective in preventing development of any of these effects. Sensitivity to PTZ-induced seizures and lethality was not affected in mice with a history of repeated treatment with Ganaxolone, diazepam, or valproate. The drugs had effects on ambulatory activity that ranged from no effect (Ganaxolone) through moderate impairment (diazepam) to marked disruption (valproate). Taken together, the results of the present study add to accumulating evidence of the unique anticonvulsive/behavioral profile of neuroactive steroids.

  • Neuroactive steroids attenuate cocaine-induced sucrose intake in rats, but not cocaine-induced hyperactivity in mice.
    Psychopharmacology, 2000
    Co-Authors: Kimberly E. Vanover, Suruki M, Matthew Huber, Richard B. Carter
    Abstract:

    Rationale: Neuroactive steroids, including the potent anticonvulsants Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) and Co 2-1068 (3β-(4acetylphenyl)ethynyl-3α,21-dihydroxy-5β-20-one-21-hemisuccinate), have recently been shown to protect against cocaine-induced seizures. Objectives: The purpose of the present experiments was to determine whether Ganaxolone and Co 2-1068 attenuate acute behavioral effects of cocaine unrelated to seizures. Methods: In the first experiment, the locomotor effects of Co 2-1068 (10–100 mg/ kg), pentobarbital (10–100 mg/kg) and haloperidol (0.03–0.3 mg/kg), alone or in combination with cocaine (5.6–30 mg/kg), were determined in mice. In the second experiment, the effects on sucrose intake of Ganaxolone (4–16 mg/kg), Co 2-1068 (8–64 mg/kg), pentobarbital (4–32 mg/kg), and haloperidol (0.04–0.4 mg/kg), alone or in combination with cocaine (4–16 mg/kg), were determined in rats. Results: Cocaine caused a dose-related increase in locomotor activity in mice, whereas Co 2-1068, pentobarbital and haloperidol caused dose-related decreases. The dopamine antagonist haloperidol, at a dose that had no effect on activity by itself, but not Co 2-1068 or pentobarbital, attenuated the cocaine-induced increase in locomotor activity. Cocaine, Ganaxolone, Co 2-1068, and haloperidol produced dose-related decreases in sucrose intake in rats; the effects of pentobarbital on sucrose intake were variable. As with locomotor effects, haloperidol attenuated the cocaine-induced decrease in sucrose intake. In addition, cocaine-induced decreases in sucrose intake were attenuated by Ganaxolone and Co 2-1068. Pentobarbital had no statistically significant effect on the cocaine dose-response function. Conclusions: These results suggest that the interaction of neuroactive steroids with cocaine extends to pharmacologic actions beyond anticonvulsant efficacy, but that the blockade of behavioral effects of cocaine by neuroactive steroids does not apply to all acute behaviors.

  • Modification of behavioral effects of drugs in mice by neuroactive steroids
    Psychopharmacology, 2000
    Co-Authors: Jesse T. Ungard, M Beekman, Maciej Gasior, Richard B. Carter, Durk Dijkstra, Jeffrey M. Witkin
    Abstract:

    Rationale: Neuroactive steroids represent a novel class of potential therapeutic agents (epilepsy, anxiety, migraine, drug dependence) thought to act through positive allosteric modulation of the GABAA receptor. A synthetically derived neuroactive steroid, Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), is in phase-II clinical trials for epilepsy. Unlike traditional anticonvulsants such as diazepam and phenobarbital, Ganaxolone shows equipotent suppression of both the seizure activity and the behavioral effects of pentylenetetrazol (PTZ) administration. Objectives: The present study explored possible reversal by Ganaxolone and related neuroactive steroids of some behavioral effects of additional pharmacological challenges. Methods: Direct behavioral observation and photocell-counted locomotor activity of male, Swiss-Webster mice were made with various compounds alone and in conjunction with Ganaxolone. Results: Ganaxolone both prevented and reversed PTZ-induced locomotor depression in mice. Further, Ganaxolone reversed the locomotor depression induced by other convulsant/anxiogenic stimuli: bicuculline, picrotoxin and, to a lesser extent, yohimbine. Ganaxolone failed to reverse the locomotor stimulation induced by cocaine, methamphetamine, dizocilpine, and phencyclidine. In addition to Ganaxolone, the endogenous neuroactive steroids allopregnanolone and pregnanolone and the synthetic neuroactive steroid Co 2-1068 also reversed observed behaviors and locomotor depression induced by PTZ. Conclusions: The present findings support the unique pharmacological effects of neuroactive steroids as a novel class of positive allosteric modulators of GABA.

Julia Tsai - One of the best experts on this subject based on the ideXlab platform.

  • A randomized controlled trial of Ganaxolone in posttraumatic stress disorder
    Psychopharmacology, 2017
    Co-Authors: Ann M. Rasmusson, Christine E. Marx, Sonia Jain, Gail M. Farfel, Julia Tsai, Thomas D. Geracioti, Mark B. Hamner, James Lohr, Richard Rosse, Lanier Summerall
    Abstract:

    Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated Ganaxolone (a synthetic 3β-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants ( n  = 112) were randomized to Ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks. During an open-label 6-week extension phase, the initial Ganaxolone group continued Ganaxolone, while the placebo group crossed over to Ganaxolone. Eighty-six and 59 participants, respectively, completed the placebo-controlled and open-label phases. A modified intent-to-treat mixed model repeated measures analysis revealed no significant differences between the effects of Ganaxolone and placebo on Clinician Administered PTSD Symptom (CAPS) scores, global well-being, negative mood, or sleep. Dropout rates did not differ between groups, and Ganaxolone was generally well tolerated. Trough blood levels of Ganaxolone at the end of the double-blind phase were, however, lower than the anticipated therapeutic level of Ganaxolone in >35% of participants on active drug. Pharmacokinetic profiling of the Ganaxolone dose regimen used in the trial and adverse event sensitivity analyses suggest that under-dosing may have contributed to the failure of Ganaxolone to out-perform placebo. Future investigations of Ganaxolone may benefit from higher dosing, rigorous monitoring of dosing adherence, a longer length of placebo-controlled testing, and targeting of treatment to PTSD subpopulations with demonstrably dysregulated pre-treatment neuroactive steroid levels. Clinicaltrials.gov identifier: NCT01339689.

  • A randomized controlled trial of Ganaxolone in posttraumatic stress disorder
    Psychopharmacology, 2017
    Co-Authors: Ann M. Rasmusson, Christine E. Marx, Sonia Jain, Gail M. Farfel, Julia Tsai, Thomas D. Geracioti, Mark B. Hamner, Xiaoying Sun, James B. Lohr, Richard Rosse
    Abstract:

    Preclinical and clinical research supports a role for neuroactive steroids in the pathophysiology of posttraumatic stress disorder (PTSD). We investigated Ganaxolone (a synthetic 3β-methylated derivative of allopregnanolone, a GABAergic neuroactive steroid) for treatment of PTSD in a proof-of-concept, multisite, double-blind, placebo-controlled trial. Veteran and non-veteran participants (n = 112) were randomized to Ganaxolone or placebo at biweekly escalating doses of 200, 400, and 600 mg twice daily for 6 weeks. During an open-label 6-week extension phase, the initial Ganaxolone group continued Ganaxolone, while the placebo group crossed over to Ganaxolone. Eighty-six and 59 participants, respectively, completed the placebo-controlled and open-label phases. A modified intent-to-treat mixed model repeated measures analysis revealed no significant differences between the effects of Ganaxolone and placebo on Clinician Administered PTSD Symptom (CAPS) scores, global well-being, negative mood, or sleep. Dropout rates did not differ between groups, and Ganaxolone was generally well tolerated. Trough blood levels of Ganaxolone at the end of the double-blind phase were, however, lower than the anticipated therapeutic level of Ganaxolone in >35% of participants on active drug. Pharmacokinetic profiling of the Ganaxolone dose regimen used in the trial and adverse event sensitivity analyses suggest that under-dosing may have contributed to the failure of Ganaxolone to out-perform placebo. Future investigations of Ganaxolone may benefit from higher dosing, rigorous monitoring of dosing adherence, a longer length of placebo-controlled testing, and targeting of treatment to PTSD subpopulations with demonstrably dysregulated pre-treatment neuroactive steroid levels.

  • A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 3 Trial to Determine the Efficacy and Safety of Ganaxolone as Adjunctive Therapy for Adults with Drug-Resistant Focal-Onset Seizures (P5.237)
    Neurology, 2017
    Co-Authors: Jaakko Lappalainen, Julia Tsai, William Amerine, Albena Patroneva
    Abstract:

    Objective: To assess Ganaxolone as adjunctive therapy in drug-resistant focal-onset seizures Background: Ganaxolone is a synthetic analog of allopregnanolone and a positive allosteric modulator of GABAA receptors Design/Methods: This was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study conducted in the United States, Germany, Poland, Australia, Bulgaria, and Russia. Following a baseline period and randomization to receive Ganaxolone (1800 mg/day) or placebo, the subjects entered a 14-week double-blind treatment phase consisting of a 2-week titration phase and 12 weeks of maintenance treatment. The primary efficacy end-point was % change from baseline in 28-day focal onset seizure frequency Results: 359 patients were randomized (Ganaxolone 179, placebo 180). The median percent reduction in seizure frequency in the Ganaxolone group was 21.28% compared to 10.25% in the placebo group, which was not statistically significant (p=0.1537). The 50% responder rates were 28.7% vs 22.7% for the Ganaxolone and placebo groups (p=0.2052). In post hoc analyses a greater separation between placebo and Ganaxolone was seen in patients who were the most drug refractory. For example, in subjects treated with 3 concomitant AEDs, Ganaxolone showed a median seizure reduction of 23.8% as compared to 2.0% in the placebo group (p=0.018). Overall Ganaxolone was generally safe and well-tolerated. The most common adverse events reported in the Ganaxolone and placebo groups were somnolence (23.5% vs 4.5%), dizziness (19.6% vs 4.5%) and fatigue (11.7% vs 6.8%). There were 44 patients (25%) on Ganaxolone who discontinued the study compared to 26 (14%) patients on placebo. The most common reason for discontinuation was adverse event Conclusions: There was an 11% greater reduction in seizure rate in the Ganaxolone group as compared to placebo. However, this difference was not statistically significant. Post hoc analyses showed that Ganaxolone may be efficacious in the most drug refractory patient population. Ganaxolone was generally safe and well tolerated Study Supported by: Marinus Pharmaceuticals Disclosure: Dr. Lappalainen has received personal compensation for activities with Marinus Pharmaceuticals as an employee. Dr. Tsai has received personal compensation for activities with Marinus. Dr. Tsai has received research support from Marinus. Dr. Amerine has received personal compensation from Marinus Pharmaceuticals as an employee. Dr. Amerine has received research support from Marinus Pharmaceuticals. Dr. Patroneva has received personal compensation for activities with Marinus as the Chief Medical Officer and holds stock options with Marinus.

  • randomized double blind placebo controlled phase 2 study of Ganaxolone as add on therapy in adults with uncontrolled partial onset seizures
    Epilepsia, 2017
    Co-Authors: Michael R. Sperling, Pavel Klein, Julia Tsai
    Abstract:

    Objective To evaluate the efficacy and safety of Ganaxolone as adjunctive therapy in adults with uncontrolled partial-onset seizures despite taking up to three concomitant antiepileptic drugs (AEDs). Methods Adults aged 18-69 years and refractory to conventional AEDs were enrolled in a multicenter, double-blind, placebo-controlled trial. After an 8-week baseline period, patients were randomized 2:1 to Ganaxolone 1,500 mg/day or placebo for a 10-week treatment period (2-week forced titration and 8-week maintenance) followed by either tapering or entry into an open-label extension study. The primary endpoint was mean weekly seizure frequency. Secondary endpoints included the proportion of patients experiencing ≥50% reduction in seizure frequency (responder rate), percent change in mean weekly seizure frequency, seizure-free days, and quality of life. Safety and tolerability assessments included adverse events (AEs), treatment discontinuation, and clinical laboratory evaluations. Efficacy analyses were performed on the intent-to-treat population. Results Of 147 randomized patients (98 Ganaxolone, 49 placebo), 131 completed the study; 95% of participants titrated up to 1,500 mg/day and 78% maintained this dose. From baseline to endpoint, mean weekly seizure frequency decreased with Ganaxolone (6.5-5.2) versus placebo (9.2-10.8), representing an 11.4% decrease versus placebo (p = 0.0489, analysis of covariance [ANCOVA]). Mean percent change from baseline was -17.6% with Ganaxolone versus 2.0% with placebo (p = 0.0144, Kruskal-Wallis test). Responder rates were 24% with Ganaxolone versus 15% with placebo (p = 0.19). Discontinuation due to adverse events was similar with Ganaxolone (7.1%) and placebo (6.1%). Common adverse events were mild to moderate in severity and included dizziness (16.3% vs. 8.2%), fatigue (16.3% vs. 8.2%), and somnolence (13.3% vs. 2.0%). Significance Ganaxolone 1,500 mg/day reduced partial-onset seizure frequency and was generally safe and well tolerated in this phase 2 study. These results support continued development of Ganaxolone for adult patients with refractory partial-onset seizures.

  • Randomized, double‐blind, placebo‐controlled phase 2 study of Ganaxolone as add‐on therapy in adults with uncontrolled partial‐onset seizures
    Epilepsia, 2017
    Co-Authors: Michael R. Sperling, Pavel Klein, Julia Tsai
    Abstract:

    Objective To evaluate the efficacy and safety of Ganaxolone as adjunctive therapy in adults with uncontrolled partial-onset seizures despite taking up to three concomitant antiepileptic drugs (AEDs). Methods Adults aged 18-69 years and refractory to conventional AEDs were enrolled in a multicenter, double-blind, placebo-controlled trial. After an 8-week baseline period, patients were randomized 2:1 to Ganaxolone 1,500 mg/day or placebo for a 10-week treatment period (2-week forced titration and 8-week maintenance) followed by either tapering or entry into an open-label extension study. The primary endpoint was mean weekly seizure frequency. Secondary endpoints included the proportion of patients experiencing ≥50% reduction in seizure frequency (responder rate), percent change in mean weekly seizure frequency, seizure-free days, and quality of life. Safety and tolerability assessments included adverse events (AEs), treatment discontinuation, and clinical laboratory evaluations. Efficacy analyses were performed on the intent-to-treat population. Results Of 147 randomized patients (98 Ganaxolone, 49 placebo), 131 completed the study; 95% of participants titrated up to 1,500 mg/day and 78% maintained this dose. From baseline to endpoint, mean weekly seizure frequency decreased with Ganaxolone (6.5-5.2) versus placebo (9.2-10.8), representing an 11.4% decrease versus placebo (p = 0.0489, analysis of covariance [ANCOVA]). Mean percent change from baseline was -17.6% with Ganaxolone versus 2.0% with placebo (p = 0.0144, Kruskal-Wallis test). Responder rates were 24% with Ganaxolone versus 15% with placebo (p = 0.19). Discontinuation due to adverse events was similar with Ganaxolone (7.1%) and placebo (6.1%). Common adverse events were mild to moderate in severity and included dizziness (16.3% vs. 8.2%), fatigue (16.3% vs. 8.2%), and somnolence (13.3% vs. 2.0%). Significance Ganaxolone 1,500 mg/day reduced partial-onset seizure frequency and was generally safe and well tolerated in this phase 2 study. These results support continued development of Ganaxolone for adult patients with refractory partial-onset seizures.

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  • Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice.
    European journal of pharmacology, 2003
    Co-Authors: Rafal M. Kaminski, Maciej Gasior, Richard B. Carter, Jeffrey M. Witkin
    Abstract:

    Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the gamma-aminobutyric acid (GABA(A)) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and Ganaxolone (a synthetic derivative of allopregnanolone 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABA(A) modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and Ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not Ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.

  • Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice.
    European Journal of Pharmacology, 2003
    Co-Authors: Rafal M. Kaminski, Maciej Gasior, Richard B. Carter, Jeffrey M. Witkin
    Abstract:

    Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the γ-aminobutyric acid (GABAA) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3α-hydroxy-5α-pregnan-20-one), pregnanolone (3α-hydroxy-5β-pregnan-20-one) and Ganaxolone (a synthetic derivative of allopregnanolone 3α-hydroxy-3β-methyl-5α-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABAA modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and Ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not Ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.

  • acute and chronic effects of the synthetic neuroactive steroid Ganaxolone against the convulsive and lethal effects of pentylenetetrazol in seizure kindled mice comparison with diazepam and valproate
    Neuropharmacology, 2000
    Co-Authors: Maciej Gasior, Jesse T. Ungard, Richard B. Carter, Marjolein Beekman, Jeffrey M. Witkin
    Abstract:

    Abstract A high-affinity positive modulator of the GABAA receptor complex, Ganaxolone, is a 3β-methylated analog of the naturally occurring neuroactive steroid allopregnanolone. In the present study, Ganaxolone was tested for its ability to (1) suppress seizures (clonic and tonic) and lethality induced by pentylenetetrazol (PTZ) in PTZ-kindled mice (anticonvulsive effect) and (2) to attenuate the development of sensitization to the convulsive and lethal effects of PTZ in kindled mice (anti-epileptogenic effect) when given as a pretreatment prior to each PTZ injection during kindling acquisition. Two classical antiepileptic drugs, diazepam and valproate, were tested for comparison. All three drugs dose-dependently suppressed tonic seizures and lethality induced by PTZ in kindled mice; only Ganaxolone was effective against clonic seizures. Ganaxolone showed anti-epileptogenic properties as it reduced the sensitivity of kindled mice to the convulsive (clonic and tonic seizures) and lethal effects of PTZ. Diazepam showed anti-epileptogenic effects against tonic seizures and lethality, but not clonic seizures; valproate was ineffective in preventing development of any of these effects. Sensitivity to PTZ-induced seizures and lethality was not affected in mice with a history of repeated treatment with Ganaxolone, diazepam, or valproate. The drugs had effects on ambulatory activity that ranged from no effect (Ganaxolone) through moderate impairment (diazepam) to marked disruption (valproate). Taken together, the results of the present study add to accumulating evidence of the unique anticonvulsive/behavioral profile of neuroactive steroids.

  • Modification of behavioral effects of drugs in mice by neuroactive steroids
    Psychopharmacology, 2000
    Co-Authors: Jesse T. Ungard, M Beekman, Maciej Gasior, Richard B. Carter, Durk Dijkstra, Jeffrey M. Witkin
    Abstract:

    Rationale: Neuroactive steroids represent a novel class of potential therapeutic agents (epilepsy, anxiety, migraine, drug dependence) thought to act through positive allosteric modulation of the GABAA receptor. A synthetically derived neuroactive steroid, Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), is in phase-II clinical trials for epilepsy. Unlike traditional anticonvulsants such as diazepam and phenobarbital, Ganaxolone shows equipotent suppression of both the seizure activity and the behavioral effects of pentylenetetrazol (PTZ) administration. Objectives: The present study explored possible reversal by Ganaxolone and related neuroactive steroids of some behavioral effects of additional pharmacological challenges. Methods: Direct behavioral observation and photocell-counted locomotor activity of male, Swiss-Webster mice were made with various compounds alone and in conjunction with Ganaxolone. Results: Ganaxolone both prevented and reversed PTZ-induced locomotor depression in mice. Further, Ganaxolone reversed the locomotor depression induced by other convulsant/anxiogenic stimuli: bicuculline, picrotoxin and, to a lesser extent, yohimbine. Ganaxolone failed to reverse the locomotor stimulation induced by cocaine, methamphetamine, dizocilpine, and phencyclidine. In addition to Ganaxolone, the endogenous neuroactive steroids allopregnanolone and pregnanolone and the synthetic neuroactive steroid Co 2-1068 also reversed observed behaviors and locomotor depression induced by PTZ. Conclusions: The present findings support the unique pharmacological effects of neuroactive steroids as a novel class of positive allosteric modulators of GABA.

  • antiepileptogenic effects of the novel synthetic neuroactive steroid Ganaxolone against pentylenetetrazol induced kindled seizures comparison with diazepam and valproate
    Drug Development Research, 1998
    Co-Authors: Maciej Gasior, M Beekman, Richard B. Carter, Steven R Goldberg, Jeffrey M. Witkin
    Abstract:

    Pharmacological treatment of epilepsy is often unsatisfactory due to side effects and the lack of drugs that control the progressive epileptogenic process. Modulation of inhibitory gamma-aminobutyric acid (GABA)-ergic neurotransmission by synthetic agonists of the neuroactive steroid binding site on the GABAA receptor complex is one approach toward the identification of improved antiepileptic agents. In this study, antiepileptogenic and anticonvulsive effects of the novel synthetic neuroactive steroid, Ganaxolone (3 alpha-hydroxy-3 beta-methyl-5 alpha-piegnan-20-one) were evaluated in comparison with diazepam and valproate against pentylenetetrazol (PTZ)-induced kindled seizures in mice. Kindled seizures provide a model of the progressive epileptogenic process. Successive administration of 45 mg/kg PTZ on days 1, 3, 5, 8, and 10 resulted in the rapid development of kindled seizures and significant reductions in thresholds for clonic convulsions, tonic convulsions, and lethality induced by PTZ on day 10. Ganaxolone, diazepam, and valproate dose-dependently protected against clonic convulsions induced by acute submaximal dose of PTZ (70 mg/kg). The compounds also dose-dependently suppressed fully kindled seizures and blocked the expression of kindled seizures over successive treatments with PTZ (45 mg/kg). Relative to acute anticonvulsive potencies against 70 mg/kg PTZ, however, Ganaxolone was more potent than valproate or diazepam against fully kindled seizures and in blocking the expression of kindled seizures over successive treatments with PTZ. Importantly, only Ganaxolone demonstrated antiepileptogenic activity by blocking the development of kindling, as evidenced when PTZ was administered in the absence of anticonvulsant treatments. Both diazepam and valproate failed to prevent development of kindled seizures even at doses that fully suppressed motor expression of seizures during kindling acquisition.Unlike diazepam and valproate, Ganaxolone did not impair ambulatory activity within the dose range used in this study. These data, taken in conjunction with other findings on the unique pharmacological actions of Ganaxolone, predict an improvement in the pharmacological management of epilepsy with this synthetic neuroactive steroid. (C) 1998 Wiley-Liss, Inc.

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