-
JAMA Psychiatry Sep 2021Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child.
OBJECTIVE
To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor-positive allosteric modulator, in PPD.
DESIGN, SETTING, AND PARTICIPANTS
This phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or ≤4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019.
INTERVENTIONS
Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks.
MAIN OUTCOMES AND MEASURES
Primary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥50% score reduction) and remission (score ≤7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments.
RESULTS
Of 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (-17.8 vs -13.6; difference, -4.2; 95% CI, -6.9 to -1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, -2.7; 95% CI, -5.1 to -0.3; P = .03) through day 45 (difference, -4.1; 95% CI, -6.7 to -1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, -4.6; 95% CI, -8.3 to -0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, -3.9; 95% CI, -6.7 to -1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02978326.
Topics: Adolescent; Adult; Depression, Postpartum; Depressive Disorder, Major; Double-Blind Method; Female; GABA Modulators; Humans; Middle Aged; Outcome Assessment, Health Care; Postpartum Period; Pregnancy; Pregnancy Trimester, Third; Pregnanes; Pyrazoles; Young Adult
PubMed: 34190962
DOI: 10.1001/jamapsychiatry.2021.1559 -
CNS Drugs Mar 2019Postpartum depression is one of the most common complications of childbirth. Untreated postpartum depression can have substantial adverse effects on the well-being of... (Review)
Review
Postpartum depression is one of the most common complications of childbirth. Untreated postpartum depression can have substantial adverse effects on the well-being of the mother and child, negatively impacting child cognitive, behavioral, and emotional development with lasting consequences. There are a number of therapeutic interventions for postpartum depression including pharmacotherapy, psychotherapy, neuromodulation, and hormonal therapy among others, most of which have been adapted from the treatment of major depressive disorder outside of the peripartum period. Current evidence of antidepressant treatment for postpartum depression is limited by the small number of randomized clinical trials, underpowered samples, and the lack of long-term follow-up. The peripartum period is characterized by rapid and significant physiological change in plasma levels of endocrine hormones, peptides, and neuroactive steroids. Evidence supporting the role of neuroactive steroids and γ-aminobutyric acid (GABA) in the pathophysiology of postpartum depression led to the investigation of synthetic neuroactive steroids and their analogs as potential treatment for postpartum depression. Brexanolone, a soluble proprietary intravenous preparation of synthetic allopregnanolone, has been developed. A recent series of open-label and placebo-controlled randomized clinical trials of brexanolone in postpartum depression demonstrated a rapid reduction in depressive symptoms, and has led to the submission for regulatory approval to the US Food and Drug Administration (decision due in March 2019). SAGE-217, an allopregnanolone analog, with oral bioavailability, was recently tested in a randomized, double-blind, placebo-controlled phase III study in severe postpartum depression, with reportedly positive results. Finally, a 3β-methylated synthetic analog of allopregnanolone, ganaxolone, is being tested in both intravenous and oral forms, in randomized, double-blind, placebo-controlled phase II studies in severe postpartum depression.
Topics: Animals; Depression, Postpartum; Drug Combinations; Drug Development; Female; GABA Modulators; Humans; Neurosteroids; Pregnanes; Pregnanolone; Pyrazoles; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration; beta-Cyclodextrins
PubMed: 30790145
DOI: 10.1007/s40263-019-00605-7 -
Neuropharmacology Dec 2020Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABA receptor positive allosteric modulator designed with the pharmacokinetic properties...
Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABA receptor positive allosteric modulator designed with the pharmacokinetic properties to support oral daily dosing. In vitro, zuranolone enhanced GABA receptor current at nine unique human recombinant receptor subtypes, including representative receptors for both synaptic (γ subunit-containing) and extrasynaptic (δ subunit-containing) configurations. At a representative synaptic subunit configuration, αβγ, zuranolone potentiated GABA currents synergistically with the benzodiazepine diazepam, consistent with the non-competitive activity and distinct binding sites of the two classes of compounds at synaptic receptors. In a brain slice preparation, zuranolone produced a sustained increase in GABA currents consistent with metabotropic trafficking of GABA receptors to the cell surface. In vivo, zuranolone exhibited potent activity, indicating its ability to modulate GABA receptors in the central nervous system after oral dosing by protecting against chemo-convulsant seizures in a mouse model and enhancing electroencephalogram β-frequency power in rats. Together, these data establish zuranolone as a potent and efficacious neuroactive steroid GABA receptor positive allosteric modulator with drug-like properties and CNS exposure in preclinical models. Recent clinical data support the therapeutic promise of neuroactive steroid GABA receptor positive modulators for treating mood disorders; brexanolone is the first therapeutic approved specifically for the treatment of postpartum depression. Zuranolone is currently under clinical investigation for the treatment of major depressive episodes in major depressive disorder, postpartum depression, and bipolar depression.
Topics: Animals; Anticonvulsants; Antidepressive Agents; Binding Sites; Brain; Diazepam; Drug Synergism; Electroencephalography; GABA Modulators; GABA-A Receptor Agonists; Hippocampus; Humans; Male; Mice; Pregnanes; Pyrazoles; Rats, Sprague-Dawley; Receptors, GABA; Seizures; Steroids; gamma-Aminobutyric Acid
PubMed: 32976892
DOI: 10.1016/j.neuropharm.2020.108333 -
International Journal of Molecular... Dec 2022Allopregnanolone (3α-THP) has been one of the most studied progesterone metabolites for decades. 3α-THP and its synthetic analogs have been evaluated as therapeutic... (Review)
Review
Allopregnanolone (3α-THP) has been one of the most studied progesterone metabolites for decades. 3α-THP and its synthetic analogs have been evaluated as therapeutic agents for pathologies such as anxiety and depression. Enzymes involved in the metabolism of 3α-THP are expressed in classical and nonclassical steroidogenic tissues. Additionally, due to its chemical structure, 3α-THP presents high affinity and agonist activity for nuclear and membrane receptors of neuroactive steroids and neurotransmitters, such as the Pregnane X Receptor (PXR), membrane progesterone receptors (mPR) and the ionotropic GABA receptor, among others. 3α-THP has immunomodulator and antiapoptotic properties. It also induces cell proliferation and migration, all of which are critical processes involved in cancer progression. Recently the study of 3α-THP has indicated that low physiological concentrations of this metabolite induce the progression of several types of cancer, such as breast, ovarian, and glioblastoma, while high concentrations inhibit it. In this review, we explore current knowledge on the metabolism and mechanisms of action of 3α-THP in normal and tumor cells.
Topics: Humans; Gonadal Steroid Hormones; Pregnanolone; Progesterone; Receptors, Progesterone; Neoplasms
PubMed: 36614002
DOI: 10.3390/ijms24010560 -
Neurotherapeutics : the Journal of the... Jan 2007Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) (GNX) is the 3beta-methylated synthetic analog of allopregnanolone; it belongs to a class of compounds... (Review)
Review
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
PubMed: 17199022
DOI: 10.1016/j.nurt.2006.11.003 -
Journal of Neuroendocrinology Feb 2022Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the... (Review)
Review
Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and pathological conditions. In addition, its physiological and neuroprotective effects are also reported. Interestingly, the levels of this neuroactive steroid, as well as its effects, are sex-dimorphic, suggesting a possible gender medicine based on this neuroactive steroid for neurological disorders. However, allopregnanolone presents low bioavailability and extensive hepatic metabolism, limiting its use as a drug. Therefore, synthetic analogues or a different therapeutic strategy able to increase allopregnanolone levels have been proposed to overcome any pharmacokinetic issues.
Topics: Neurosteroids; Pregnanolone; Progesterone
PubMed: 34189791
DOI: 10.1111/jne.12996 -
British Journal of Anaesthesia Apr 1981
Topics: Alfaxalone Alfadolone Mixture; Humans; Pregnanes; Pregnanolone
PubMed: 7225264
DOI: 10.1093/bja/53.4.323 -
Molecules (Basel, Switzerland) Sep 2022Lindl. is an important genus of the Apocynaceae family, not only as ornamental plants but also for its medicinal uses. In Brazil, species are indicated to treat asthma...
Lindl. is an important genus of the Apocynaceae family, not only as ornamental plants but also for its medicinal uses. In Brazil, species are indicated to treat asthma and skin infections, their anti-inflammatory potential and wound healing properties are also reported in the literature. Concerning their chemical composition, this group of plants is a conspicuous producer of pregnane glycosides. is an endemic species from the Brazilian semiarid region not studied by any phytochemical methods. In view of the medicinal potential of species, this study aimed to isolate new pregnane glycosides from . To achieve this main goal, modern chromatography techniques were employed. Five new pregnane glycosides, dardanols A-E, were isolated from the roots of by HPLC. Their structures were determined using extensive 1D and 2D-NMR and mass spectrometry (MS and HRESIMS) data. The cytotoxicity and the anti-inflammatory potential of these compounds were evaluated. The first was evaluated by measuring proinflammatory cytokines and nitric oxide production by stimulated macrophages. Dardanols were able to inhibit the production of nitric oxide and reduce IL-1β and TNF-α. The current work demonstrates the chemodiversity of Brazilian semiarid species and contributes to amplifying knowledge about the biological potential of the genus.
Topics: Anti-Inflammatory Agents; Apocynaceae; Glycosides; Nitric Oxide; Plant Extracts; Plants; Pregnanes; Tumor Necrosis Factor-alpha
PubMed: 36144723
DOI: 10.3390/molecules27185992 -
Molecules (Basel, Switzerland) Aug 2022For our interest in the potential biologically active and structurally unique steroidal glycosides, continued phytochemical investigation of was carried out; twelve new...
For our interest in the potential biologically active and structurally unique steroidal glycosides, continued phytochemical investigation of was carried out; twelve new seco-pregnane glycosides, cynataihosides I-L (-), M-T (-), and two known glycosides, glaucoside A () and atratcynoside F (), were isolated from the 95% ethanol extract of . Two new aglycones were found among compounds , , , and . The structures of the glycosides were elucidated based on 1D and 2D NMR spectroscopic data, HR-ESI-MS analysis, and chemical evidence. The cytotoxicity of compounds against three human tumor cell lines (HL60, THP-1, and PC-3) were evaluated by MTT assay. Compound displayed significant cytotoxicity against THP-1 and PC-3 cell line with IC values of 5.08 and 22.75 μm, respectively. Compounds and exhibited moderate and selective cytotoxicity on HL60 and THP-1 with IC values of 17.78 and 16.02 μm, respectively.
Topics: Cynanchum; Glycosides; Humans; Molecular Structure; Plant Roots; Pregnanes
PubMed: 36080268
DOI: 10.3390/molecules27175500 -
Nature Reviews. Endocrinology Apr 2013Regenerative therapeutics hold the promise of self-renewal and repair. Ageing and age-associated neurodegenerative diseases are marked by a decline in self-renewal and... (Review)
Review
Regenerative therapeutics hold the promise of self-renewal and repair. Ageing and age-associated neurodegenerative diseases are marked by a decline in self-renewal and repair, but a capacity for regeneration is retained. The challenge faced by researchers developing molecular therapeutics to promote self-renewal in the nervous system is to activate regenerative and repair pathways often in the context of progressive degeneration. Neurosteroids regulate both regeneration and repair systems in the brain, and among this class of molecules, allopregnanolone has been broadly investigated for its role to promote regeneration in both the central and peripheral nervous systems. In the brain, allopregnanolone induced generation and survival of new neurons in the hippocampus of both aged mice and mice with Alzheimer disease, accompanied by restoration of associative learning and memory function. In the brain of mice with Alzheimer disease, allopregnanolone increased liver X receptor and pregnane X receptor expression, reduced amyloid-β and microglial activation, and increased markers of myelin and white matter generation. Therapeutic windows for efficacy of allopregnanolone were evident in the brains of mice with both normal ageing and Alzheimer disease. Allopregnanolone dose and a regenerative treatment regimen of intermittent allopregnanolone exposure were determining factors regulating therapeutic efficacy. Allopregnanolone serves as proof of concept for therapeutics that target endogenous regeneration, windows of therapeutic opportunity for regeneration, and critical system biology factors that will determine the efficacy of regeneration.
Topics: Alzheimer Disease; Animals; Brain; Humans; Neurotransmitter Agents; Pregnanolone
PubMed: 23438839
DOI: 10.1038/nrendo.2013.31