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Respiratory Medicine Sep 1995Fluticasone propionate (FP) is a novel androstane glucocorticoid with potent anti-inflammatory activity which has been effectively used, intranasally, as therapy for... (Review)
Review
Fluticasone propionate (FP) is a novel androstane glucocorticoid with potent anti-inflammatory activity which has been effectively used, intranasally, as therapy for seasonal and allergic perennial rhinitis. When taken by the inhaled route, FP has shown significant therapeutic efficacy in the management of asthma. Fluticasone propionate is a highly lipophilic molecule with good uptake, binding and retention characteristics in human lung tissue. Fluticasone propionate has high glucocorticoid receptor selectivity and affinity, demonstrating rapid receptor association and slow receptor dissociation. In vitro, FP has been shown to potently inhibit T lymphocyte proliferation, cytokine generation, tumour necrosis factor alpha (TNF-alpha)-induced adhesion molecule expression, interleukin-5-induced eosinophilia, mucosal oedema and toluene 2,4-diisocyanate-induced mast cell proliferation, while promoting secretory leucocyte protease inhibitor production and eosinophil apoptosis. In human studies, FP has demonstrated marked vasoconstrictor potency in normal subjects and inhibited antigen-induced mucosal platelet activating factor/eicosanoid production, T lymphocytes and CD25+ cells in patients with rhinitis. Biopsy data from mild asthmatics demonstrate FP-associated reduction in CD3, CD4, CD8 and CD25 cells, with an accompanying reduction in eosinophil and mast cell markers. Clinical studies have evaluated lung function, bronchial reactivity, exacerbation rates and oral corticosteroid-sparing effect. Results show that FP has at least twice the clinical potency of beclomethasone dipropionate and budesonide. This appears to be achieved without an accompanying increase in systemic effects, suggesting a therapeutic index which may be higher than other currently available inhaled corticosteroids.
Topics: Androstadienes; Animals; Anti-Inflammatory Agents; Asthma; Clinical Trials as Topic; Dose-Response Relationship, Drug; Fluticasone; Humans; Lung; Rhinitis
PubMed: 7569173
DOI: 10.1016/0954-6111(95)90259-7 -
International Journal of Andrology Jun 2012Previous studies suggest that male testosterone concentrations have declined over time. To explore this in a large US population, we examined testosterone and free...
Previous studies suggest that male testosterone concentrations have declined over time. To explore this in a large US population, we examined testosterone and free testosterone concentrations in National Health and Nutrition Examination Surveys (NHANES) from 1988-1991 and 1999-2004. We also examined sex hormone-binding globulin (SHBG), estradiol, and androstanediol glucuronide (3α-diol-G) over the same period. Non-Hispanic white, non-Hispanic black, and Mexican-American men from 1988-1991 and 1999-2004 NHANES surveys who were ≥20 years old and had serum from morning blood draws were included in this analysis (1988-1991: N = 1,413; 1999-2004: N = 902). Testosterone, estradiol and SHBG were measured by competitive electrochemiluminescence immunoassays and 3α-diol-G was measured by enzyme immunoassay. Free testosterone was calculated using testosterone and SHBG values. Adjusted mean hormone concentrations were estimated using linear regression, accounting for NHANES sampling weights and design, age, race/ethnicity, body mass index, waist circumference, alcohol use and smoking. Differences in adjusted mean concentrations (Δ) and two-sided p-values were calculated; p < 0.05 was statistically significant. Overall, 3α-diol-G and estradiol declined between 1988-1991 and 1999-2004, but there was little change in testosterone, free testosterone, or SHBG (Δ: 3α-diol-G = -1.83 ng/mL, p < 0.01; estradiol = -6.07 pg/mL, p < 0.01; testosterone = -0.03 ng/mL, p = 0.75; free testosterone = -0.001 ng/mL, p = 0.67; SHBG = -1.17 nmol/L, p = 0.19). Stratification by age and race revealed that SHBG and 3α-diol-G declined among whites 20-44 years old (Δ: SHBG = -5.14 nmol/L, p < 0.01; 3α-diol-G = -2.89 ng/mL, p < 0.01) and free testosterone increased among blacks 20-44 years old (Δ: 0.014 ng/mL, p = 0.03). Estradiol declined among all ages of whites and Mexican-Americans. In conclusion, there was no evidence for testosterone decline between 1988-1991 and 1999-2004 in the US general population. Subgroup analyses suggest that SHBG and 3α-diol-G declined in young white men, estradiol declined in white and Mexican-American men, and free testosterone increased in young black men. These changes may be related to the increasing prevalence of reproductive disorders in young men.
Topics: Adult; Aged; Androstane-3,17-diol; Black People; Estradiol; Gonadal Steroid Hormones; Humans; Male; Mexican Americans; Middle Aged; Nutrition Surveys; Sex Hormone-Binding Globulin; Testosterone; White People
PubMed: 22150314
DOI: 10.1111/j.1365-2605.2011.01230.x -
Steroids Dec 2021Vecuronium bromide (Piperidinium, 1-[(2β,3α,5α,16β,17β)-3,17-bis(acetyloxy)-2-(1-piperidinyl)androstan-16-yl]-1-methyl-, bromide; Norcuron®) has been extensively...
Vecuronium bromide (Piperidinium, 1-[(2β,3α,5α,16β,17β)-3,17-bis(acetyloxy)-2-(1-piperidinyl)androstan-16-yl]-1-methyl-, bromide; Norcuron®) has been extensively used in anesthesiology practice as neuromuscular blocking agent since its launch on the market in 1982. However, a detailed crystallographic and NMR analysis of its advanced synthetic intermediates is still lacking. Hence, with the aim of filling this literature gap, vecuronium bromide was prepared starting from the commercially available 3β-hydroxy-5α-androstan-17-one (epiandrosterone), implementing some modifications to a traditional synthetic procedure. A careful NMR study allowed the complete assignment of the H, C, and N NMR signals of vecuronium bromide and its synthetic intermediates. The structural and stereochemical characterization of 2β,16β-bispiperidino-5α-androstane-3α,17β-diol, the first advanced synthetic intermediate carrying all the stereocenters in the final configuration, was described by means of single-crystal X-ray diffraction and Hirshfeld surface analysis, allowing a detailed conformational investigation.
Topics: Crystallography, X-Ray; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Neuromuscular Blocking Agents; Vecuronium Bromide
PubMed: 34655596
DOI: 10.1016/j.steroids.2021.108928 -
Future Oncology (London, England) Nov 2011
Review
Topics: 3-Hydroxysteroid Dehydrogenases; Abiraterone Acetate; Androstadienes; Androstenediol; Antineoplastic Agents; Dehydroepiandrosterone; Etiocholanolone; Humans; Male; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Testosterone
PubMed: 22044197
DOI: 10.2217/fon.11.98 -
The Journal of Clinical Endocrinology... Jan 2023Initiating feminizing gender-affirming hormone therapy (GAHT) in transgender women causes a steep decline in serum testosterone. It is unknown if testosterone...
BACKGROUND
Initiating feminizing gender-affirming hormone therapy (GAHT) in transgender women causes a steep decline in serum testosterone. It is unknown if testosterone concentrations change further and whether adrenal androgen levels change during feminizing GAHT and after gonadectomy. This limits clinical decision making in transgender women with symptoms attributed to GAHT or gonadectomy.
METHODS
Transgender women (n = 275) initiating estradiol and cyproterone acetate (CPA) were included at baseline, and had follow-up visits after 3 months, 12 months, and 2 to 4 years. During follow-up, 49.5% of transgender women underwent a gonadectomy. Total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione (A4) were measured using liquid chromatography tandem mass spectrometry.
RESULTS
After 3 months of GAHT, mean TT, calculated free testosterone (cFT), and A4 decreased by 18.4 nmol/L (95% CI, -19.4 to -17.4, P < 0.001 [ie, -97.1%]), 383 pmol/L (95% CI, -405 to -362, P < 0.001 [ie, -98.3%]), and 1.2 nmol/L (95% CI, -1.4 to -1.0, P < 0.001 [ie, -36.5%]), respectively, and remained stable thereafter. DHEA and DHEAS decreased by 7.4 nmol/L (95% CI, -9.7 to -5.1 [ie, -28.0%]) and 1.8 µmol/L (95% CI, -2.2 to -1.4 [ie, -20.1%]), respectively, after 1 year and did not change thereafter. After gonadectomy, CPA therapy is stopped, which induced no further change in TT, cFT, DHEA, DHEAS, and A4 compared with those who did not undergo gonadectomy.
CONCLUSIONS
Our findings confirm that after an initial drop, testosterone levels in transgender women remain stable. Adrenal androgens decrease in the first year of CPA and estrogen supplementation and remain unchanged after gonadectomy. Androgens did not change after gonadectomy and cessation of CPA. Correlates with clinical symptoms remain to be elucidated.
Topics: Female; Humans; Androgens; Transgender Persons; Testosterone; Androstenedione; Cyproterone Acetate; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate
PubMed: 36201493
DOI: 10.1210/clinem/dgac576 -
Environment International Nov 2023Indoor pollutants change over time and place. Exposure to hazardous organics is associated with adverse health effects. This work sampled gaseous organics by Tenax TA...
Indoor pollutants change over time and place. Exposure to hazardous organics is associated with adverse health effects. This work sampled gaseous organics by Tenax TA tubes in two indoor rooms, i.e., an office set as samples, and the room of chassis dynamometer (RCD) set as backgrounds. Compounds are analyzed by a thermal desorption comprehensive two-dimensional gas chromatography-quadrupole mass spectrometer (TD-GC × GC-qMS). Four new chemicals of emerging concern (CECs) are screened in 469 organics quantified. We proposed a three-step pipeline for CECs screening utilizing GC × GC including 1) non-target scanning of organics with convincing molecular structures and quantification results, 2) statistical analysis between samples and backgrounds to extract useful information, and 3) pixel-based property estimation to evaluate the contamination potential of addressed chemicals. New CECs spotted in this work are all intermediate volatility organic compounds (IVOCs), containing mintketone, isolongifolene, β-funebrene, and (5α)-androstane. Mintketone and sesquiterpenes may be derived from the use of volatile chemical products (VCPs), while (5α)-androstane is probably human-emitted. The occurrence and contamination potential of the addressed new CECs are reported for the first time. Non-target scanning and the measurement of IVOCs are of vital importance to get a full glimpse of indoor organics.
Topics: Humans; Gas Chromatography-Mass Spectrometry; Mass Spectrometry; Gases; Androstanes
PubMed: 37839268
DOI: 10.1016/j.envint.2023.108259 -
Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions.Comprehensive Physiology Oct 2014The human adrenal produces more 19 carbon (C19) steroids, by mass, than either glucocorticoids or mineralocorticoids. However, the mechanisms regulating adrenal C19... (Review)
Review
The human adrenal produces more 19 carbon (C19) steroids, by mass, than either glucocorticoids or mineralocorticoids. However, the mechanisms regulating adrenal C19 steroid biosynthesis continue to represent one of the most intriguing mysteries of endocrine physiology. This review will discuss the C19 steroids synthesized by the human adrenal and the features within the adrenal that allow production of these steroids. Finally, we consider the effects of these steroids in normal physiology and disorders of adrenal C19 steroid excess.
Topics: Adrenal Glands; Androgens; Androstanes; Animals; Humans
PubMed: 25428847
DOI: 10.1002/cphy.c140006 -
Anesthesiology Feb 2023The clinical actions of sugammadex have been well studied, but the detailed molecular mechanism of the drug encapsulation process has not been systematically documented....
BACKGROUND
The clinical actions of sugammadex have been well studied, but the detailed molecular mechanism of the drug encapsulation process has not been systematically documented. The hypothesis was that sugammadex would attract rocuronium and vecuronium via interaction with the sugammadex side-chain "tentacles," as previously suggested.
METHODS
Computational molecular dynamics simulations were done to investigate docking of sugammadex with rocuronium and vecuronium. To validate these methods, strength of binding was assessed between sugammadex and a heterogeneous group of nine other drugs, the binding affinities of which have been experimentally determined. These observations hinted that high concentrations of unbound sugammadex could bind to propofol, potentially altering its pharmacokinetic profile. This was tested experimentally in in vitro cortical slices.
RESULTS
Sugammadex encapsulation of rocuronium involved a sequential progression down a series of metastable states. After initially binding beside the sugammadex molecule (mean ± SD center-of-mass distance = 1.17 ± 0.13 nm), rocuronium then moved to the opposite side to that hypothesized, where it optimally aligned with the 16 hydroxyl groups (distance, 0.82 ± 0.04 nm) before entering the sugammadex cavity to achieve energetically stable encapsulation by approximately 120 ns (distance, 0.35 ± 0.12 nm). Vecuronium formed fewer hydrogen bonds with sugammadex than did rocuronium; hence, it was less avidly bound. For the other molecules, the computational results showed good agreement with the available experimental data, showing a clear bilogarithmic relation between the relative binding free energy and the association constant (R2 = 0.98). Weaker binding was manifest by periodic unbinding. The brain slice results confirmed the presence of a weak propofol-sugammadex interaction.
CONCLUSIONS
Computational simulations demonstrate the dynamics of neuromuscular blocking drug encapsulation by sugammadex occurring from the opposite direction to that hypothesized and also how high concentrations of unbound sugammadex can potentially weakly bind to other drugs given during general anesthesia.
Topics: Sugammadex; Vecuronium Bromide; Rocuronium; gamma-Cyclodextrins; Neuromuscular Nondepolarizing Agents; Androstanols; Propofol; Dose-Response Relationship, Drug; Neuromuscular Blockade
PubMed: 36512718
DOI: 10.1097/ALN.0000000000004442 -
BMJ Case Reports Nov 2014A 30-year-old male body builder and androgenic-anabolic steroid and insulin abuser was admitted for day case elective tonsillectomy (bipolar). He returned with primary... (Review)
Review
A 30-year-old male body builder and androgenic-anabolic steroid and insulin abuser was admitted for day case elective tonsillectomy (bipolar). He returned with primary post-tonsillectomy haemorrhage 18 h after the operation and required bipolar cautery to the multiple small bleeding points in the right and left tonsillar fossa. Thorough coagulation screen was normal. Recurrent primary haemorrhage occurred 3 h post-operatively requiring immediate surgical intervention, removal of the inferior poles, precautionary throat packs, intubation and observation on the intensive treatment unit (ITU). Re-examination in theatre revealed a bleeding left superior pole that was under-run to achieve haemostasis and the patient returned to ITU. Hypertensive episodes were noted in the emergency department and intraoperatively including one recording >200 mm Hg. Haemostasis was eventually achieved once the blood pressure was adequately controlled. A slow wean of steroids was also instigated and the patient was managed on a surgical ward for 2 weeks post-tonsillectomy.
Topics: Adult; Ambulatory Surgical Procedures; Androstanes; Doping in Sports; Follow-Up Studies; Hemostasis, Surgical; Humans; Insulin; Male; Performance-Enhancing Substances; Postoperative Hemorrhage; Rare Diseases; Recurrence; Reoperation; Risk Assessment; Tonsillectomy; Treatment Outcome
PubMed: 25398921
DOI: 10.1136/bcr-2014-207111 -
Journal of Neuroendocrinology Mar 2009Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a basic response of animals to environmental perturbations that threaten homeostasis. These responses are... (Review)
Review
Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a basic response of animals to environmental perturbations that threaten homeostasis. These responses are regulated by neurones in the paraventricular nucleus of the hypothalamus (PVN) that synthesise and secrete corticotrophin-releasing hormone (CRH). Other PVN neuropeptides, such as arginine vasopressin and oxytocin, can also modulate activity of CRH neurones in the PVN and enhance CRH secretagogue activity of the anterior pituitary gland. In rodents, sex differences in HPA reactivity are well established; females exhibit a more robust activation of the HPA axis after stress than do males. These sex differences primarily result from opposing actions of sex steroids, testosterone and oestrogen, on HPA function. Ostreogen enhances stress activated adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) secretion, whereas testosterone decreases the gain of the HPA axis and inhibits ACTH and CORT responses to stress. Data show that androgens can act directly on PVN neurones in the male rat through a novel pathway involving oestrogen receptor (ER)beta, whereas oestrogen acts predominantly through ERalpha. Thus, we examined the hypothesis that, in males, testosterone suppresses HPA function via an androgen metabolite that binds ERbeta. Clues to the neurobiological mechanisms underlying such a novel action can be gleaned from studies showing extensive colocalisation of ERbeta in oxytocin-containing cells of the PVN. Hence, in this review, we address the possibility that testosterone inhibits HPA reactivity by metabolising to 5alpha-androstane-3beta,17beta-diol, a compound that binds ERbeta and regulates oxytocin containing neurones of the PVN. These findings suggest a re-evaluation of studies examining pathways for androgen receptor signalling.
Topics: Androgens; Androstane-3,17-diol; Animals; Estrogen Receptor beta; Female; Hypothalamo-Hypophyseal System; Male; Neurons; Oxytocin; Pituitary-Adrenal System; Sex Characteristics; Stress, Psychological; Testosterone
PubMed: 19207807
DOI: 10.1111/j.1365-2826.2009.01840.x