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Respiratory Research Aug 2023Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic...
BACKGROUND
Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients.
METHODS
We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA- (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts.
RESULTS
Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4, PDE4D, MMP8, CRISP3, and BCL2L15. Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay (pre-DEXA: 42 [29-49] vs. 18 [13-27] days, p < 0.001; DEXA: 42 [28-57] vs. 13 [7-24] days, p < 0.001) and mortality (pre-DEXA: 47% vs. 15%, p = 0.009; DEXA: 61% vs. 19%, p < 0.001) were higher in the PF-groups compared to the no-PF-groups within both cohorts. Early dexamethasone therapy did not influence these outcomes.
CONCLUSIONS
ICU patients with COVID-19 who develop PF exhibit upregulated coagulation, inflammation, and neutrophil extracellular trap-related pathways as well as prolonged ICU length-of-stay and mortality. This study indicates that early dexamethasone treatment neither influences the incidence or clinical course of PF, nor clinical outcomes.
Topics: Humans; COVID-19; SARS-CoV-2; Prednisone; Respiration, Artificial; Idiopathic Pulmonary Fibrosis; Dexamethasone; Disease Progression
PubMed: 37559053
DOI: 10.1186/s12931-023-02496-1 -
Lakartidningen Jan 2021
Topics: Betamethasone; Dexamethasone; Glucocorticoids; Humans; Research
PubMed: 33417235
DOI: No ID Found -
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 -
Hormone Molecular Biology and Clinical... Jun 2023Major Depressive Disorder (MDD) is a mood disorder classified as a persistent depressive mood and loss of interest lasting for more than two weeks and accompanied by a... (Review)
Review
Major Depressive Disorder (MDD) is a mood disorder classified as a persistent depressive mood and loss of interest lasting for more than two weeks and accompanied by a list of symptoms outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria. MDD affects approximately 264 million people worldwide and is the most prevailing form of neuropsychiatric disorder. Owing to the probable hypothesized pathophysiology of MDD being an outcome of abnormalities in the amino acid neurotransmitter system, including glutamate (the primary excitatory neurotransmitter) and -aminobutyric acid (GABA), SAGE-217 (Zuranolone) is being evaluated as a possible therapeutic treatment for MDD. Zuranolone is a synthetic, neuroactive steroid (NAS) and positive allosteric modulator (PMA) of GABAA receptors, regulating both synaptic and extra-synaptic release of GABA. It is administered as a once-daily oral dose for 2 weeks due to its low-moderate clearance. A change in total HAM-D score from baseline was the primary end-point of all the trials. A phase II trial conducted to evaluate the efficacy and safety of Zuranolone (30 mg, once-daily dose), described a significant reduction in total HAM-D score at day 14 and reported the drug to be well tolerated with headache, dizziness, nausea, and somnolence as the most common adverse events (AE). Additional phase III trials were also conducted to evaluate similar outcomes, the interim topline results of which have been released. Consequently, this article attempts to briefly analyze the pharmacology of Zuranolone, review the available clinical data and outcomes regarding its use, and evaluate its place as a prospective novel therapy in the effective management of MDD.
Topics: Humans; Depressive Disorder, Major; Prospective Studies; Pregnanes; gamma-Aminobutyric Acid; Double-Blind Method
PubMed: 36848317
DOI: 10.1515/hmbci-2022-0042 -
Frontiers in Endocrinology 2022The best approach to patients with adrenal incidentaloma (AI) and possible autonomous cortisol secretion (PACS) is debated. The aim of this study was to assess the... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The best approach to patients with adrenal incidentaloma (AI) and possible autonomous cortisol secretion (PACS) is debated. The aim of this study was to assess the metabolic effect of adrenalectomy in AI patients with PACS in relation to cortisol secretion parameters, peripheral activation, and glucocorticoid sensitivity.
DESIGN
This is a multicenter randomized study (NCT number: NCT04860180).
METHODS
Sixty-two AI outpatients (40-75 years) with AI >1 cm and cortisol after overnight dexamethasone suppression test (F-1mgDST) between 50 and 138 nmol/L were randomized to adrenalectomy (Arm A) or a conservative approach (Arm B). Fifty-five patients completed the 6-month follow-up, 25 patients in Arm A (17 female patients, aged 62.5 ± 10.4 years) and 30 patients in Arm B (24 female patients, 66.1 ± 9.1 years). Plasma adrenocorticotroph hormone (ACTH), 24-h urinary free cortisol, 24-h urinary free cortisone, F-1mgDST, glucose, lipids, glycated hemoglobin (HbA1c) levels, blood pressure (BP), body weight, and treatment variations were assessed. The 24-h urinary free cortisol/cortisone ratio (an 11-beta hydroxysteroid dehydrogenase type 2 activity marker), BclI, and the N363S variants of glucocorticoid receptor (GR) polymorphisms were also evaluated.
RESULTS
BP control improved in 68% and 13% of the subjects in Arm A and Arm B, respectively ( = 0.001), and the glycometabolic control improved in 28% and 3.3% of the subjects in Arm A and Arm B patients, respectively ( = 0.02). Arm A subjects more rarely showed the BP and/or glycometabolic control worsening than Arm B patients (12% and 40%, respectively, = 0.03). The surgical approach was independently associated with BP amelioration (OR 3.0, 95% CI 3.8-108.3, < 0.001) but not with age, F-1mgDST levels, BMI, and hypertension and diabetes mellitus presence at baseline. The 24-h urinary free cortisol/cortisone ratio and the presence of sensitizing GR polymorphisms were not associated with the surgical outcome. The receiver operating characteristic (ROC) curve analysis showed that the BP control amelioration was associated with F-1mgDST [area under the curve (AUC), 0.82 ± 0.09 = 0.012]. The F-1mgDST cutoff with the best compromise in predicting the BP amelioration was set at 75 nmol/L (sensitivity 77%, specificity 75%).
CONCLUSIONS
AI patients with PACS benefit from surgery in terms of BP and glycometabolic control.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Blood Pressure; Cortisone; Female; Humans; Hydrocortisone
PubMed: 35721734
DOI: 10.3389/fendo.2022.898084 -
Steroids Jan 2022Beclomethasone dipropionate (1) is a synthetic corticosteroid with anti-inflammatory, antipruritic, and anti-allergy properties. It is widely used to treat asthma,...
Beclomethasone dipropionate (1) is a synthetic corticosteroid with anti-inflammatory, antipruritic, and anti-allergy properties. It is widely used to treat asthma, allergic rhinitis, and dermatoses. However, existing synthetic routes to this active pharmaceutical ingredient (API) contain steps resulting in low and/or inconsistent yields, and use obsolete reagents. Such inconsistencies coupled with a lack of reliable experimental data makes laboratory-scale and large-scale synthesis of this API difficult and time-consuming. In this paper, we report a practical and scalable approach to synthesize 1 from the readily available steroidal intermediate, 16β-methyl epoxide (3, DB-11). A gram-scale to kilogram-scale synthesis of 1 was achieved with 82% yield, using a cost-effective and scalable methodology. Selective propionylation of the hydroxyl groups at C and C demonstrate the fact that this approach can be conveniently implemented in fine chemical industries.
Topics: Beclomethasone; Molecular Conformation; Stereoisomerism
PubMed: 34871605
DOI: 10.1016/j.steroids.2021.108948 -
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 -
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 -
The New England Journal of Medicine Sep 2019Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown.
METHODS
In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse).
RESULTS
A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence.
CONCLUSIONS
Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.).
Topics: Administration, Oral; Adult; Allosteric Regulation; Antidepressive Agents; Depressive Disorder, Major; Dizziness; Double-Blind Method; Female; GABA Modulators; Humans; Least-Squares Analysis; Male; Middle Aged; Nausea; Pregnanes; Psychiatric Status Rating Scales; Pyrazoles; Receptors, GABA-A
PubMed: 31483961
DOI: 10.1056/NEJMoa1815981 -
Psychoneuroendocrinology Oct 2023Anxiety disorders are the most common psychiatric disorder during the perinatal period and one of the major risk factors for postpartum depression, yet we know little...
BACKGROUND
Anxiety disorders are the most common psychiatric disorder during the perinatal period and one of the major risk factors for postpartum depression, yet we know little about biological factors in the etiology of perinatal anxiety. A growing literature points to neuroactive steroid (NAS) dysregulation in perinatal mental illness, but directionality has not been clearly demonstrated, results are not consistent, and no studies have investigated NAS in a population with pure anxiety without comorbid depression. We aimed to add to the limited literature by examining the association between anxiety without comorbid depression and metabolic pathways of NAS longitudinally across the peripartum.
METHODS
We measured anxiety symptoms by psychological scales and NAS levels using Gas Chromatography-Mass Spectrometry (GC-MS) at the second and third trimester (T2 and T3) and week 6 postpartum (W6) in n = 36 women with anxiety and n = 38 healthy controls. The anxiety group was determined by a data-driven approach, and cross-sectional and longitudinal statistical methods were used to examine the relationship between the study population and NAS.
RESULTS
We found that anxiety had a significant moderating effect on the relationship between progesterone and allopregnanolone, with no such effect for the relationships between progesterone and the intermediate (5α-DHP) or isomeric (isoallopregnanolone) compounds in this pathway, and no effects on the corresponding pathway converting progesterone to pregnanolone and epipregnanolone. We also found a less precipitous decline in the ratio of allopregnanolone to progesterone between T3 and W6 in the anxiety group compared to the non-anxiety group. A genotype analysis of a single-nucleotide polymorphism in the AKR1C2 gene demonstrated that the relationship of allopregnanolone to the intermediate metabolite, 5α-DHP, differed by genotype.
CONCLUSION
Our exploratory findings indicate that, for pregnant people with anxiety, metabolism is shunted more aggressively toward the endpoint of the progesterone to allopregnanolone metabolic pathway than it is for those without anxiety.
Topics: Pregnancy; Humans; Female; Progesterone; 5-alpha-Dihydroprogesterone; Pregnanolone; Cross-Sectional Studies; Anxiety Disorders; Neurosteroids
PubMed: 37423029
DOI: 10.1016/j.psyneuen.2023.106327