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1.
Sci Rep ; 14(1): 6402, 2024 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-38493224

RESUMO

Allopregnanolone (ALLO) is a known neurosteroid and a progesterone metabolite synthesized in the ovary, CNS, PNS, adrenals and placenta. Its role in the neuroendocrine control of ovarian physiology has been studied, but its in situ ovarian effects are still largely unknown. The aims of this work were to characterize the effects of intrabursal ALLO administration on different ovarian parameters, and the probable mechanism of action. ALLO administration increased serum progesterone concentration and ovarian 3ß-HSD2 while decreasing 20α-HSD mRNA expression. ALLO increased the number of atretic follicles and the number of positive TUNEL granulosa and theca cells, while decreasing positive PCNA immunostaining. On the other hand, there was an increase in corpora lutea diameter and PCNA immunostaining, whereas the count of TUNEL-positive luteal cells decreased. Ovarian angiogenesis and the immunohistochemical expression of GABAA receptor increased after ALLO treatment. To evaluate if the ovarian GABAA receptor was involved in these effects, we conducted a functional experiment with a specific antagonist, bicuculline. The administration of bicuculline restored the number of atretic follicles and the diameter of corpora lutea to normal values. These results show the actions of ALLO on the ovarian physiology of the female rat during the follicular phase, some of them through the GABAA receptor. Intrabursal ALLO administration alters several processes of the ovarian morpho-physiology of the female rat, related to fertility and oocyte quality.


Assuntos
Pregnanolona , Progesterona , Gravidez , Feminino , Ratos , Animais , Pregnanolona/farmacologia , Progesterona/farmacologia , Antígeno Nuclear de Célula em Proliferação , Bicuculina/farmacologia , Receptores de GABA-A , Corpo Lúteo
2.
J Affect Disord ; 351: 904-914, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38325605

RESUMO

BACKGROUND: Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact of zuranolone-a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid under investigation for adults with MDD and approved as an oral, once-daily, 14-day treatment course for adults with PPD in the US-on health-related quality of life, including functioning and well-being, as assessed using the 36-item Short Form Health Survey V2 (SF-36). METHODS: Integrated data from 3 MDD (201B, MOUNTAIN, WATERFALL) and 1 PPD trial (ROBIN) for individual SF-36 domains were compared for zuranolone (30- and 50-mg) vs placebo at Day (D)15 and D42. Comparisons between zuranolone responders (≥50 % reduction from baseline in 17-item Hamilton Depression Rating Scale total score) and nonresponders were assessed. RESULTS: Overall, 1003 patients were included (zuranolone, n = 504; placebo, n = 499). Significant differences in change from baseline (CFB) to D15 for patients in zuranolone vs placebo groups were observed in 6/8 domains; changes were sustained or improved at D42, with significant CFB differences for all 8 domains. Zuranolone responders had significantly higher CFB scores vs nonresponders for all domains at D15 and D42 (p < 0.001). LIMITATIONS: Two zuranolone doses were integrated across populations of 2 disease states with potential differences in functioning, comorbidities, and patient demographics. All p-values presented are nominal. CONCLUSIONS: Integrated data across 4 zuranolone clinical trials showed improvements in functioning and well-being across all SF-36 domains. Benefits persisted after completion of treatment course at D42.


Assuntos
Transtorno Depressivo Maior , Pirazóis , Adulto , Feminino , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Pregnanolona/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
3.
Arch Toxicol ; 98(4): 1177-1189, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38305864

RESUMO

Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by acute organophosphate (OP) intoxication. However, there are concerns that combined midazolam and allopregnanolone increases risk of adverse cardiovascular events. To address this, we used telemetry devices to record cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with diisopropylfluorophosphate (DFP). Animals were administered DFP (4 mg/kg, sc), followed immediately by atropine (2 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m.). At 40 min post-exposure, a subset of animals received midazolam (0.65 mg/kg, im); at 50 min, these rats received a second dose of midazolam or allopregnanolone (12 mg/kg, im). DFP significantly increased blood pressure by ~ 80 mmHg and pulse pressure by ~ 34 mmHg that peaked within 12 min. DFP also increased core temperature by ~ 3.5 °C and heart rate by ~ 250 bpm that peaked at ~ 2 h. Heart rate variability (HRV), an index of autonomic function, was reduced by ~ 80%. All acute (within 15 min of exposure) and two-thirds of delayed (hours after exposure) mortalities were associated with non-ventricular cardiac events within 10 min of cardiovascular collapse, suggesting that non-ventricular events should be closely monitored in OP-poisoned patients. Compared to rats that survived DFP intoxication without treatment, midazolam significantly improved recovery of cardiovascular parameters and HRV, an effect enhanced by allopregnanolone. These data demonstrate that midazolam improved recovery of cardiovascular and autonomic function and that the combination of midazolam and allopregnanolone may be a better therapeutic strategy than midazolam alone.


Assuntos
Midazolam , Intoxicação por Organofosfatos , Humanos , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Midazolam/farmacologia , Midazolam/uso terapêutico , Pregnanolona/farmacologia , Isoflurofato/farmacologia , Organofosfatos , Encéfalo , Intoxicação por Organofosfatos/tratamento farmacológico
4.
Expert Opin Pharmacother ; 25(1): 5-14, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38164653

RESUMO

INTRODUCTION: Major depressive disorder (MDD) is a common and debilitating mental illness. Postpartum depression (PPD) impacts women globally and is one of the most common complications of childbirth that is underdiagnosed and undertreated, adversely impacting the mental health of women, children, and partners.Available antidepressant medications require weeks to months before showing effect. In this setting, zuranolone, an oral neuroactive steroid and a positive allosteric modulator of GABAA receptors, is an attractive alternative as a rapid-acting antidepressant treatment. AREAS COVERED: This article reviews zuranolone (SAGE217), focusing on available clinical studies in individuals with PPD and MDD. This paper adds to the extant literature by presenting the efficacy data as Number Needed to Treat (NNT) to facilitate indirect comparisons with other antidepressants. EXPERT OPINION: Zuranolone is a novel rapid-acting (i.e. two week course) oral antidepressant for the treatment of adults with PPD with ongoing clinical trials evaluating its efficacy in adults with MDD. Zuranolone is well tolerated with no significant safety concerns in any clinical trials completed to date. Zuranolone will be scheduled by the Drug Enforcement Agency (DEA).


Assuntos
Depressão Pós-Parto , Transtorno Depressivo Maior , Pirazóis , Adulto , Criança , Feminino , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Depressão Pós-Parto/tratamento farmacológico , Antidepressivos/efeitos adversos , Pregnanolona/efeitos adversos
5.
Neurosci Biobehav Rev ; 158: 105558, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38244954

RESUMO

This mini-review presents emerging evidence that endogenous neurosteroids modulate both pro- and anti-inflammatory signaling by immune cells and brain cells that contribute to depression, alcohol use disorders, and other inflammatory conditions. We first review the literature on pregnenolone and allopregnanolone inhibition of proinflammatory neuroimmune pathways in the periphery and the brain - effects that are independent of GABAergic mechanisms. We follow with evidence for neurosteroid enhancement of anti-inflammatory and protective pathways in brain and immune cells. These studies draw clinical relevance from a large body of evidence that pro-inflammatory immune signaling is dysregulated in many brain disorders and the fact that neurosteroids inhibit the same inflammatory pathways that are activated in depression, alcohol use disorders and other inflammatory conditions. Thus, we describe evidence that neurosteroid levels are decreased and neurosteroid supplementation has therapeutic efficacy in these neuropsychiatric conditions. We conclude with a perspective that endogenous regulation of immune balance between pro- and anti-inflammatory pathways by neurosteroid signaling is essential to prevent the onset of disease. Deficits in neurosteroids may unleash excessive pro-inflammatory activation which progresses in a feed-forward manner to disrupt brain networks that regulate stress, emotion and motivation. Neurosteroids can block various inflammatory pathways in mouse and human macrophages, rat brain and human blood and therefore provide new hope for treatment of intractable conditions that involve excessive inflammatory signaling.


Assuntos
Alcoolismo , Neuroesteroides , Ratos , Humanos , Camundongos , Animais , Neuroesteroides/metabolismo , Alcoolismo/metabolismo , Encéfalo/metabolismo , Pregnanolona/farmacologia , Pregnanolona/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico
6.
Epilepsia ; 65(3): e41-e46, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38243753

RESUMO

Trilostane is a 3ß-hydroxysteroid dehydrogenase/Δ5-4 isomerase inhibitor able to produce a manyfold increase in brain levels of various neurosteroids, including allopregnanolone. We previously found that treatment with trilostane can slow down epileptogenesis in the kainic acid (KA) model of temporal lobe epilepsy. It is unknown whether trilostane may have a similar effect on the progression of epilepsy severity, as observed in KA-treated rats. Consequently, we investigated the effects of trilostane (50 mg/kg/day, 1 week) in epileptic rats, given 64 days after KA administration. Seizures were monitored by video-electrocorticographic recordings before and during the treatment with trilostane or vehicle (sesame oil), and neurosteroid levels were measured in serum and cerebral tissue using liquid chromatography-electrospray tandem mass spectrometry after treatment. Pregnenolone sulfate, pregnenolone, progesterone, 5α-dihydroprogesterone, and allopregnanolone peripheral levels were massively increased by trilostane. With the only exception of hippocampal pregnenolone sulfate, the other neurosteroids augmented in both the neocortex and hippocampus. Only pregnanolone levels were not upregulated by trilostane. As expected, a significant increase in the seizure occurrence was observed in rats receiving the vehicle, but not in the trilostane group. This suggests that the increased availability of neurosteroids produced a disease-modifying effect in the brain of epileptic rats.


Assuntos
Epilepsia , Neuroesteroides , Ratos , Animais , Neuroesteroides/farmacologia , Pregnanolona/farmacologia , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Encéfalo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
7.
J Anesth ; 38(2): 261-274, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38252143

RESUMO

Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and they play important biological roles in brain development, brain function and as mediators of mood. One class of NS, 3α-hydroxy-pregnane steroids such as allopregnanolone (AlloP) or pregnanolone (Preg), inhibits neuronal excitability; these endogenous NS and their analogues have been therapeutically applied as anti-depressants, anti-epileptics and general anesthetics. While NS have many favorable properties as anesthetics (e.g. rapid onset, rapid recovery, minimal cardiorespiratory depression, neuroprotection), they are not currently in clinical use, largely due to problems with formulation. Recent advances in understanding NS mechanisms of action and improved formulations have rekindled interest in development of NS as sedatives and anesthetics. In this review, the synthesis of NS, and their mechanism of action will be reviewed with specific emphasis on their binding sites and actions on γ-aminobutyric acid type A (GABAA) receptors. The potential advantages of NS analogues as sedative and anesthetic agents will be discussed.


Assuntos
Anestésicos Gerais , Anestésicos , Neuroesteroides , Anestésicos Gerais/efeitos adversos , Anestésicos/efeitos adversos , Pregnanolona/farmacologia , Ácido gama-Aminobutírico , Receptores de GABA-A
8.
Clin Pharmacol Drug Dev ; 13(3): 248-258, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38231434

RESUMO

Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA ) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20 mg) or 5 minutes (10 or 30 mg), ganaxolone was detected in plasma with a median Tmax of 5 minutes, whereas a 60-minute infusion (10 or 30 mg) or a bolus (6 mg over 5 minutes) followed by infusion (20 mg/h) for 4 hours achieved a median Tmax of approximately 1 and 3 hours, respectively. Cmax was dose and administration-time dependent, ranging from 73.8 ng/mL (10 mg over 5 minutes) to 1240 ng/mL (30 mg over 5 minutes). Bolus doses above 10 mg of ganaxolone markedly influenced the bispectral index score with a rapid decline; smaller changes occurred on the Modified Observer's Assessment of Alertness/Sedation scale and in quantitative electroencephalogram. Most adverse events were of mild severity, with 2 events of moderate severity; none were reported as serious. No effects on systemic hemodynamics or respiratory functions were reported. Overall, ganaxolone was generally well tolerated at the doses studied and demonstrated pharmacokinetic and pharmacodynamic properties suitable to treat SE.


Assuntos
Síndromes Epilépticas , Pregnanolona/análogos & derivados , Convulsões , Adulto , Humanos , Pré-Escolar , Convulsões/tratamento farmacológico , Administração Intravenosa , Anticonvulsivantes/efeitos adversos , Receptores de GABA-A
10.
J Pharmacol Exp Ther ; 388(2): 273-300, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-37977814

RESUMO

This article describes recent advances in the use of neurosteroids as novel anticonvulsants for refractory status epilepticus (RSE) and as medical countermeasures (MCs) for organophosphates and chemical nerve agents (OPNAs). We highlight a comprehensive 15-year journey to bring the synthetic neurosteroid ganaxolone (GX) from bench to clinic. RSE, including when caused by nerve agents, is associated with devastating morbidity and permanent long-term neurologic dysfunction. Although recent approval of benzodiazepines such as intranasal midazolam and intranasal midazolam offers improved control of acute seizures, novel anticonvulsants are needed to suppress RSE and improve neurologic function outcomes. Currently, few anticonvulsant MCs exist for victims of OPNA exposure and RSE. Standard-of-care MCs for postexposure treatment include benzodiazepines, which do not effectively prevent or mitigate seizures resulting from nerve agent intoxication, leaving an urgent unmet medical need for new anticonvulsants for RSE. Recently, we pioneered neurosteroids as next-generation anticonvulsants that are superior to benzodiazepines for treatment of OPNA intoxication and RSE. Because GX and related neurosteroids that activate extrasynaptic GABA-A receptors rapidly control seizures and offer robust neuroprotection by reducing neuronal damage and neuroinflammation, they effectively improve neurologic outcomes after acute OPNA exposure and RSE. GX has been selected for advanced, Biomedical Advanced Research and Development Authority-supported phase 3 trials of RSE and nerve agent seizures. In addition, in mechanistic studies of neurosteroids at extrasynaptic receptors, we identified novel synthetic analogs with features that are superior to GX for current medical needs. Development of new MCs for RSE is complex, tedious, and uncertain due to scientific and regulatory challenges. Thus, further research will be critical to fill key gaps in evaluating RSE and anticonvulsants in vulnerable (pediatric and geriatric) populations and military persons. SIGNIFICANCE STATEMENT: Following organophosphate and nerve agent intoxication, refractory status epilepticus (RSE) occurs despite benzodiazepine treatment. RSE occurs in 40% of status epilepticus patients, with a 35% mortality rate and significant neurological morbidity in survivors. To treat RSE, neurosteroids are better anticonvulsants than benzodiazepines. Our pioneering use of neurosteroids for RSE and nerve agents led us to develop ganaxolone as a novel anticonvulsant and neuroprotectant with significantly improved neurological outcomes. This article describes the bench-to-bedside journey of bringing neurosteroid therapy to patients, with ganaxolone leading the way.


Assuntos
Contramedidas Médicas , Agentes Neurotóxicos , Neuroesteroides , Pregnanolona/análogos & derivados , Estado Epiléptico , Humanos , Criança , Idoso , Anticonvulsivantes/uso terapêutico , Neuroesteroides/uso terapêutico , Midazolam , Estado Epiléptico/tratamento farmacológico , Convulsões/tratamento farmacológico , Benzodiazepinas , Organofosfatos
11.
Psychiatry Res ; 331: 115640, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38029628

RESUMO

Major depressive disorder (MDD) and postpartum depression (PPD) are common and burdensome conditions. This study aims to evaluate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid type A receptors-positive allosteric modulator, in treating MDD and PPD. A comprehensive literature search was conducted until September 2023, identifying seven randomized controlled trials (RCTs). The results demonstrated that zuranolone significantly decreased Hamilton Rating Scale for Depression (HAM-D) scores in patients with PPD or MDD at day 15 (concluding the 14-day course) and day 42-45 (4 weeks after treatment cessation) compared with the placebo, albeit exhibiting a diminishing trend. Moreover, a higher percentage of patients with PPD or MDD achieved HAM-D response and remission with zuranolone treatment compared with placebo at day 15. However, zuranolone did not significantly increase the proportion of MDD patients achieving HAM-D remission at 42/43 days. Adverse events (AEs) such as somnolence, dizziness, and sedation were linked to zuranolone, with a higher but not statistically significant rate of discontinuation due to AEs in the zuranolone group. Overall, our findings support the rapid antidepressant effects of zuranolone in MDD and PPD, along with a relatively favorable safety and tolerability. Large-scale longitudinal RCTs are needed to evaluate the long-term efficacy of zuranolone.


Assuntos
Depressão , Transtorno Depressivo Maior , Feminino , Humanos , Antidepressivos/uso terapêutico , Pregnanolona/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/induzido quimicamente , Resultado do Tratamento , Método Duplo-Cego
12.
Epilepsia ; 65(1): 37-45, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37950390

RESUMO

OBJECTIVE: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold. METHODS: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. RESULTS: Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3). SIGNIFICANCE: Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.


Assuntos
Anticonvulsivantes , Epilepsia Tônico-Clônica , Síndromes Epilépticas , Pregnanolona/análogos & derivados , Espasmos Infantis , Humanos , Feminino , Pré-Escolar , Masculino , Anticonvulsivantes/efeitos adversos , Seguimentos , Resultado do Tratamento , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Epilepsia Tônico-Clônica/tratamento farmacológico , Método Duplo-Cego , Quinases Ciclina-Dependentes/uso terapêutico
13.
J Pharmacol Exp Ther ; 388(2): 376-385, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-37770198

RESUMO

Status epilepticus (SE) is a life-threatening development of self-sustaining seizures that becomes resistant to benzodiazepines when treatment is delayed. Benzodiazepine pharmacoresistance is thought in part to result from internalization of synaptic GABAA receptors, which are the main target of the drug. The naturally occurring neurosteroid allopregnanolone is a therapy of interest against SE for its ability to modulate all isoforms of GABAA receptors. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been partially effective in combination with benzodiazepines in mitigating SE-associated neurotoxicity. In this study, allopregnanolone as an adjunct to midazolam or midazolam-ketamine combination therapy was evaluated for efficacy against cholinergic-induced SE. Adult male rats implanted with electroencephalographic (EEG) telemetry devices were exposed to the organophosphorus chemical (OP) soman (GD) and treated with an admix of atropine sulfate and HI-6 at 1 minute after exposure followed by midazolam, midazolam-allopregnanolone, or midazolam-ketamine-allopregnanolone 40 minutes after seizure onset. Neurodegeneration, neuronal loss, and neuroinflammation were assessed 2 weeks after GD exposure. Seizure activity, EEG power integral, and epileptogenesis were also compared among groups. Overall, midazolam-ketamine-allopregnanolone combination therapy was effective in reducing cholinergic-induced toxic signs and neuropathology, particularly in the thalamus and hippocampus. Higher dosage of allopregnanolone administered in combination with midazolam and ketamine was also effective in reducing EEG power integral and epileptogenesis. The current study reports that there is a promising potential of neurosteroids in combination with benzodiazepine and ketamine treatments in a GD model of SE. SIGNIFICANCE STATEMENT: Allopregnanolone, a naturally occurring neurosteroid, reduced pathologies associated with soman (GD) exposure such as epileptogenesis, neurodegeneration, and neuroinflammation, and suppressed GD-induced toxic signs when used as an adjunct to midazolam and ketamine in a delayed treatment model of soman-induced status epilepticus (SE) in rats. However, protection was incomplete, suggesting that further studies are needed to identify optimal combinations of antiseizure medications and routes of administration for maximal efficacy against cholinergic-induced SE.


Assuntos
Ketamina , Neuroesteroides , Soman , Estado Epiléptico , Ratos , Masculino , Animais , Midazolam/farmacologia , Midazolam/uso terapêutico , Ketamina/farmacologia , Ketamina/uso terapêutico , Pregnanolona/efeitos adversos , Soman/toxicidade , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Doenças Neuroinflamatórias , Neuroesteroides/uso terapêutico , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Convulsões/tratamento farmacológico , Benzodiazepinas , Colinérgicos/efeitos adversos , Receptores de GABA-A , Ácido gama-Aminobutírico
14.
Arch Womens Ment Health ; 27(1): 35-44, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37831172

RESUMO

OBJECTIVE: Brexanolone (Zulresso®) that was approved for the USA in March 2019 is indicated for the treatment of postpartum depression (PPD), but information on adverse drug reactions (ADRs) associated with its use is limited. The main aim of this study was to explore the postmarketing safety profile of brexanolone. METHODS: In our case/non-case pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS), the reporting odds ratio and information component with 95% confidence intervals were estimated as measures of disproportionate reporting. Primary disproportionality analyses were performed by comparing brexanolone with all other drugs or selective serotonin reuptake inhibitors (SSRIs). Sensitivity analyses were performed on a subset of perinatal depression. RESULTS: We identified 267 cases using brexanolone. Brexanolone was reported as a primary or secondary suspect drug in most cases (n = 260, 97.38%). Of the total brexanolone cases, positive dechallenge and discontinuation accounted for 12.36% (n = 33) and 26.22% (n = 70), respectively. Serious outcomes were reported in 11.61% (n = 31) patients. Compared to all the other drugs or SSRIs within the same time window, the reporting risks of brexanolone were mainly from psychiatric and nervous systems. Sensitivity analyses indicated that these significant disproportionalities were mostly retained. CONCLUSION: Our pharmacovigilance analysis showed a high reporting frequency of psychiatric and nervous system ADRs associated with the use of brexanolone. In additional prospective research, these signals urgently need to be clarified.


Assuntos
Farmacovigilância , Inibidores Seletivos de Recaptação de Serotonina , beta-Ciclodextrinas , Feminino , Gravidez , Humanos , Estados Unidos , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Estudos Prospectivos , Pregnanolona/efeitos adversos , United States Food and Drug Administration , Combinação de Medicamentos
15.
Psychoneuroendocrinology ; 160: 106684, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38091917

RESUMO

RATIONALE: Premenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD's pathophysiology and treatment mechanisms are poorly characterized, but may involve altered neuroactive steroid function in the brain. Selective serotonin reuptake inhibitors (SSRIs), a first-line PMDD treatment, reportedly alter gamma-aminobutyric acid (GABA)ergic neuroactive steroid levels in PMDD. AIMS: The aims of this study were to determine whether the SSRI sertraline increased serum levels of neuroactive steroids that modulate the effect of GABA at GABA-A receptors (GABAAR) and if so, whether an increase was associated with improvement in PMDD symptoms. METHODS: Participants included controls and individuals with PMDD. Serum levels of 9 neuroactive steroids were measured (3α,5α-THP; 3α5ß-THP; pregnenolone; 3α,5α-androsterone; 3α,5ß-androsterone; 3α,5α-A-diol; 3α5ß-A-diol; 3α,5α-THDOC; 3α5ß-THDOC) in the follicular and luteal phases. In the subsequent luteal phase, neuroactive steroids were measured during sertraline treatment (50 mg sertraline from approximate ovulation to menses onset) in the PMDD group. Mixed models assessed associations among diagnostic group, menstrual cycle phase, and sertraline treatment. RESULTS: Participants included 38 controls and 32 women with PMDD. There were no significant differences in neuroactive steroid levels between controls and participants with PMDD in the luteal phase (p > 0.05). Within the PMDD group, sertraline treatment significantly increased serum pregnanolone levels and the pregnanolone:progesterone ratio, and decreased 3α,5α-androsterone. CONCLUSIONS: This was the first study to assess the impact of SSRI treatment on peripheral levels of GABAergic neuroactive steroids in PMDD. Within the PMDD group, sertraline treatment was associated with a significant increase in luteal phase serum pregnanolone levels and a significantly increased pregnanolone:progesterone ratio, a novel finding. Future research should examine alterations in the metabolic pathways among GABAergic neuroactive steroids in individuals with PMDD, in a placebo-controlled design.


Assuntos
Neuroesteroides , Transtorno Disfórico Pré-Menstrual , Síndrome Pré-Menstrual , Humanos , Feminino , Transtorno Disfórico Pré-Menstrual/tratamento farmacológico , Sertralina/farmacologia , Sertralina/uso terapêutico , Progesterona , Pregnanolona , Androsterona , Ácido gama-Aminobutírico , Síndrome Pré-Menstrual/tratamento farmacológico
18.
Drug Des Devel Ther ; 17: 3397-3408, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38024537

RESUMO

Background: Allopregnanolone is a kind of neuroactive steroid or neurosteroid in the central nervous system that acts as an endogenenous GABAA receptor positive modulator. However, at present, no comprehensive bibliometric analysis regarding allopregnanolone research is available. In our study, we intend to analyze the research trends and hot spots related to allopregnanolone in the past 20 years. Methods: We searched for allopregnanolone related articles and reviews between 2004 and 2023 from the Web of Science Core Collection database. Then, the bibliometric analysis was conducted using VOSviewer, CiteSpace, Microsoft Excel 2019, as well as the online bibliometric analysis platform (http://bibliometric.com/). Results: A total of 1841 eligible publications were identified. The number of annual publications and citations was generally on the rise. Among countries, the United States ranked first in overall publications, citations, international cooperation, and the number of research institutions. The University of North Carolina was the most active institution, conducting numerous preclinical and clinical work that focusing on allopregnanolone treatment for diverse psychiatric or neurologic disorders. As for authors, Dr. Frye CA, Morrow AL, and Pinna G were identified as the top three prolific scholars due to their great publications and citations. Based on the publication clusters and citation bursts analysis, the keyword co-occurrence network, the strongest citation bursts, and co-cited references analysis, the hot spots in recent years included "depression", "postpartum depression", "GABAA receptor", and so on. Conclusion: Allopregnanolone is still a popular area of research, and the United States leads the way in this area. Dr. Frye CA, Morrow AL, Pinna G, and their teams contributed greatly to the mechanism study and translation study of allopregnanolone. The use of allopregnanolone for the treatment of psychiatric or neurologic disorders, especially postpartum depression, is the current hot spot. However, the underlying mechanisms of anti-depression are still not clear, deserving more in-depth research.


Assuntos
Depressão Pós-Parto , Doenças do Sistema Nervoso , Feminino , Humanos , Pregnanolona , Bibliometria , Sistema Nervoso Central , Bases de Dados Factuais
19.
Biomolecules ; 13(10)2023 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-37892178

RESUMO

Objectives In Vitro: To study the effects of GR3027 (golexanolone) on neurosteroid-induced GABA-mediated current responses under physiological GABAergic conditions with recombinant human α5ß3γ2L and α1ß2γ2L GABAA receptors expressed in human embryonic kidney cells, using the response patch clamp technique combined with the Dynaflow™ application system. With α5ß3γ2L receptors, 0.01-3 µM GR3027, in a concentration-dependent manner, reduced the current response induced by 200 nM THDOC + 0.3 µM GABA, as well as the THDOC-induced direct gated effect. GR3027 (1 µM) alone had no effect on the GABA-mediated current response or current in the absence of GABA. With α1ß2γ2L receptors, GR3027 alone had no effect on the GABA-mediated current response or did not affect the receptor by itself. Meanwhile, 1-3 µM GR3027 reduced the current response induced by 200 nM THDOC + 30 µM GABA and 3 µM GR3027 that induced by 200 nM THDOC when GABA was not present. Objectives In Vivo: GR3027 reduces allopregnanolone (AP)-induced decreased learning and anesthesia in male Wistar rats. Rats treated i.v. with AP (2.2 mg/kg) or vehicle were given GR3027 in ratios of 1:0.5 to 1:5 dissolved in 10% 2-hydroxypropyl-beta-cyclodextrin. A dose ratio of AP:GR3027 of at least 1:2.5 antagonized the AP-induced decreased learning in the Morris Water Mase (MWM) and 1:7.5 antagonized the loss of righting reflex (LoR). GR3027 treatment did not change other functions in the rat compared to the vehicle group. Conclusions: GR3027 functions in vitro as an inhibitor of GABAA receptors holding α5ß3γ2L and α1ß2γ2L, in vivo, in the rat, as a dose-dependent inhibitor toward AP's negative effects on LoR and learning in the MWM.


Assuntos
Neuroesteroides , Receptores de GABA-A , Masculino , Ratos , Humanos , Animais , Antagonistas GABAérgicos , Ratos Wistar , Pregnanolona/farmacologia , Ácido gama-Aminobutírico/farmacologia
20.
Asian J Psychiatr ; 90: 103800, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37898099

RESUMO

To reveal the exact changes of allopregnanolone-mediated γ-aminobutyric acid A receptor pathways and its specific therapeutic targets by Shuyu Capsule treating premenstrual depression, female Wistar rat models of premenstrual depression was established by Forced swimming test (FST). Behavioral tests, enzyme-linked immunosorbent assay (ELISA), interference knockdown adenovirus, and overexpressed vector adenovirus of GABAARδ, RT-qPCR, Western-Blot, and immunohistochemical detecting expressions were applied to identify the therapeutic targets. FST-based rat model indicated that Shuyu capsules alleviated typical premenstrual depression and may regulate alternations of 5α-reductase and 3α-steroid dehydrogenase, enhancing the metabolic pathway of progesterone to allopregnanolone, as well as targeting the GABAARδ subunit, thereby alleviating premenstrual depression of PMDD rat models.


Assuntos
Pregnanolona , Receptores de GABA-A , Ratos , Feminino , Animais , Ratos Wistar , Pregnanolona/metabolismo , Pregnanolona/uso terapêutico , Hipocampo/metabolismo , Ácido gama-Aminobutírico , Redes e Vias Metabólicas
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