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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 -
Journal of Clinical Research in... Nov 2023This study was designed to examine the effect of blue light exposure and exposure time on puberty in an animal model.
OBJECTIVE
This study was designed to examine the effect of blue light exposure and exposure time on puberty in an animal model.
METHODS
Eighteen 21-day-old female Sprague Dawley rats were divided into three equal groups which were: control group (CG); blue light-6 hours (BL-6); and blue light-12 hours (BL-12). CG rats were maintained with 12/12-hour light-dark cycles. The animals in BL-6 and BL-12 were exposed to blue light of wavelength 450-470 nm and intensity of 0.03 uW/cm for 6 and 12 hours, respectively. Exposure to blue light continued until the first signs of puberty. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, dehydroepiandrosterone sulfate (DHEA-S), leptin and melatonin were measured. Subsequently the ovaries and uterus were examined histomorphologically.
RESULTS
The median day of puberty start was 38, 32 and 30 for the CG, BL-6, and BL-12 groups, respectively (p=0.001). FSH, testosterone, DHEA-S, and leptin concentrations of all groups were similar. However, LH and estradiol concentrations in BL-6 were higher compared to CG (p=0.02). There was a negative correlation between blue light exposure, exposure time, and melatonin concentrations (r=-0.537, p=0.048). Ovarian tissue was compatible with puberty in all groups. As blue light exposure time increased, capillary dilatation and edema in the ovarian tissue increased. Prolonged exposure was associated with polycystic ovary-like (PCO) morphological changes and apoptosis in granulosa cells.
CONCLUSION
These results suggest that exposure to blue light and the duration of exposure induced earlier puberty in female rats. As the duration of blue light exposure increased, PCO-like inflammation, and apoptosis were detected in the ovaries.
Topics: Rats; Female; Humans; Animals; Leptin; Melatonin; Rats, Sprague-Dawley; Luteinizing Hormone; Follicle Stimulating Hormone; Estradiol; Puberty; Polycystic Ovary Syndrome; Testosterone; Dehydroepiandrosterone
PubMed: 37212628
DOI: 10.4274/jcrpe.galenos.2023.2022-12-1 -
The Journal of Clinical Endocrinology... Mar 2022Male sex is a major risk factor for abdominal aortic aneurysms (AAA) but few studies have addressed associations between sex hormone levels and AAA.
CONTEXT
Male sex is a major risk factor for abdominal aortic aneurysms (AAA) but few studies have addressed associations between sex hormone levels and AAA.
OBJECTIVE
We aimed to describe the associations between serum sex steroids and early, screening-detected AAA in men.
METHODS
We validated a high-sensitivity liquid chromatography-tandem mass spectrometry assay for comprehensive serum sex hormone profiling. This assay was then employed in a case-control study including 147 men with AAA (infrarenal aorta ≥ 30 mm) and 251 AAA-free controls recruited at the general population-based ultrasound screening for AAA in 65-year-old Swedish men.
OUTCOMES INCLUDED
associations between dehydroepiandrosterone, progesterone, 17α-hydroxyprogesterone, androstenedione, estrone, testosterone, dihydrotestosterone, and estradiol and AAA presence.
RESULTS
Dehydroepiandrosterone, progesterone, 17α-hydroxyprogesterone, testosterone, and estradiol, but not the other hormones, were lower in men with AAA. In models with adjustments for known AAA risk factors and comorbidity, only progesterone (odds ratio per SD decrease 1.62 [95% CI, 1.18-2.22]) and estradiol (1.40 [95% CI, 1.04-1.87]) remained inversely associated with the presence of AAA. Progesterone and estradiol contributed with independent additive information for prediction of AAA presence; compared with men with high (above median) levels, men with low (below median) levels of both hormones had a 4-fold increased odds ratio for AAA (4.06 [95% CI, 2.25-7.31]).
CONCLUSION
Measured by a high-performance sex steroid assay, progesterone and estradiol are inversely associated with AAA in men, independent of known risk factors. Future studies should explore whether progesterone and estradiol, which are important reproductive hormones in women, are protective in human AAA.
Topics: Aged; Aortic Aneurysm, Abdominal; Case-Control Studies; Dehydroepiandrosterone; Dihydrotestosterone; Estradiol; Female; Humans; Male; Progesterone; Testosterone
PubMed: 34865072
DOI: 10.1210/clinem/dgab867 -
Molecules (Basel, Switzerland) Sep 2020The biotransformation of steroid compounds is a promising, environmentally friendly route to new pharmaceuticals and hormones. One of the reaction types common in the...
The biotransformation of steroid compounds is a promising, environmentally friendly route to new pharmaceuticals and hormones. One of the reaction types common in the metabolic fate of steroids is Baeyer-Villiger oxidation, which in the case of cyclic ketones, such as steroids, leads to lactones. Fungal enzymes catalyzing this reaction, Baeyer-Villiger monooxygenases (BVMOs), have been shown to possess broad substrate scope, selectivity, and catalytic performance competitive to chemical oxidation, being far more environmentally green. This study covers the biotransformation of a series of androstane steroids (epiandrosterone and androsterone) and androstene steroids (progesterone, pregnenolone, dehydroepiandrosterone, androstenedione, 19-OH-androstenedione, testosterone, and 19-nortestosterone) by the cultures of filamentous fungus AM110. The transformation was monitored by GC and the resulting products were identified on the basis of chromatographic and spectral data. The investigated fungus carries out effective Baeyer-Villiger oxidation of the substrates. Interestingly, introduction of the 19-OH group into androstenedione skeleton has significant inhibitory effect on the BVMO activity, as the 10-day transformation leaves half of the 19-OH-androstenedione unreacted. The metabolic fate of epiandrosterone and androsterone, the only 5α-saturated substrates among the investigated compounds, is more complicated. The transformation of these two substrates combined with time course monitoring revealed that each substrate is converted into three products, corresponding to oxidation at C-3 and C-17, with different time profiles and yields.
Topics: Androstanes; Androstenedione; Androsterone; Biotransformation; Chromatography, Gas; Mixed Function Oxygenases; Nandrolone; Oxidation-Reduction; Penicillium; Substrate Specificity
PubMed: 32942593
DOI: 10.3390/molecules25184226 -
Translational Psychiatry Feb 2021Major depressive disorder (MDD) has a higher prevalence in women with supraphysiologic androgen levels. Whether there is also an association between depression and...
Major depressive disorder (MDD) has a higher prevalence in women with supraphysiologic androgen levels. Whether there is also an association between depression and androgen levels in the physiological range, is unknown. This study examined if women with current MDD have higher androgen levels compared to women who have never had MDD, and if androgen levels are associated with onset and remission of MDD. In 1659 women (513 current MDD, 754 remitted MDD, and 392 never MDD), baseline plasma levels of total testosterone, 5α-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulfate and sex hormone binding globulin (SHBG) with radioimmunoassays. Free testosterone was calculated. MDD status was assessed at baseline, and at 2 and 4 years follow-up. Women were aged between 18 and 65 years (mean age 41) with total testosterone levels in the physiological range (geometric mean 0.72 nmol/L [95% CI 0.27-1.93]). After adjusting for covariates and multiple testing, women with current MDD had a higher mean free testosterone than women who never had MDD (adjusted geometric mean 8.50 vs. 7.55 pmol/L, p = 0.0005), but this difference was not large enough to be considered clinically meaningful as it was consistent with statistical equivalence. Levels of other androgens and SHBG did not differ and were also statistically equivalent between the groups. None of the androgens or SHBG levels predicted onset or remission of MDD. Our findings support the idea that plasma androgens within the physiological range have no or only limited effects on depressive disorders in women.
Topics: Adolescent; Adult; Aged; Androgens; Androstenedione; Depression; Depressive Disorder, Major; Female; Humans; Middle Aged; Sex Hormone-Binding Globulin; Testosterone; Young Adult
PubMed: 33579903
DOI: 10.1038/s41398-021-01249-2 -
Urology Feb 2023Prescriptions for testosterone therapy (TT) to treat testosterone deficiency have increased in recent years. The purpose of this review was to evaluate the risks of... (Review)
Review
Prescriptions for testosterone therapy (TT) to treat testosterone deficiency have increased in recent years. The purpose of this review was to evaluate the risks of several treatment modalities to better counsel patients. Both short-acting and long-acting TT has been shown to restore normal serum testosterone levels and improve symptoms of testosterone deficiency. Short-acting pharmacology mimics normal physiology more closely than long-acting TT but requires multiple doses per day. Long-acting TT has a higher rate of patient adherence but is more likely to create supraphysiologic serum testosterone and pathologic sequelae.
Topics: Humans; Testosterone; Hormone Replacement Therapy
PubMed: 36455678
DOI: 10.1016/j.urology.2022.11.016 -
British Journal of Pharmacology Nov 2021Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung...
BACKGROUND AND PURPOSE
Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung target-site concentrations. We aimed to evaluate lung pharmacokinetics of commonly prescribed drugs by sampling different lung compartments after inhalation and oral administration.
EXPERIMENTAL APPROACH
Healthy volunteers received single, sequential doses of either inhaled salbutamol, salmeterol and fluticasone propionate (n = 12), or oral salbutamol and propranolol (n = 6). Each participant underwent bronchoscopies and gave breath samples for analysis of particles in exhaled air at two points after drug administration (1 and 6, 2 and 9, 3 and 12, or 4 and 18 h). Lung samples were taken via bronchosorption, bronchial brush, mucosal biopsy and bronchoalveolar lavage during each bronchoscopy. Blood samples were taken during the 24 h after administration. Pharmacokinetic profiles were generated by combining data from multiple individuals, covering all sample timings.
KEY RESULTS
Pharmacokinetic profiles were obtained for each drug in lung epithelial lining fluid, lung tissue and plasma. Inhalation of salbutamol resulted in approximately 100-fold higher concentrations in lung than in plasma. Salmeterol and fluticasone concentration ratios in lung versus plasma were higher still. Bronchosorption- and bronchoalveolar-lavage-generated profiles of inhaled drugs in epithelial lining fluid were comparable. For orally administered drugs, epithelial-lining-fluid concentrations were overestimated in bronchoalveolar-lavage-generated profiles.
CONCLUSION AND IMPLICATIONS
Combining pharmacokinetic data derived from several individuals and techniques sampling different lung compartments enabled generation of pharmacokinetic profiles for evaluation of lung targeting after inhaled and oral drug delivery.
Topics: Albuterol; Fluticasone; Humans; Lung; Pharmaceutical Preparations; Salmeterol Xinafoate
PubMed: 34250588
DOI: 10.1111/bph.15621 -
PloS One 2022To better understand how health risk processes are linked to adrenarche, measures of adrenarcheal timing and tempo are needed. Our objective was to describe and classify...
To better understand how health risk processes are linked to adrenarche, measures of adrenarcheal timing and tempo are needed. Our objective was to describe and classify adrenal trajectories, in terms of timing and tempo, in a population of children transitioning to adolescence with repeated measurements of salivary dehydroepiandrosterone (DHEA), DHEA-sulphate, and testosterone. We analysed data from the Childhood to Adolescence Transition Study (CATS), a longitudinal study of 1239 participants, recruited at 8-9 years old and followed up annually. Saliva samples were assayed for adrenal hormones. Linear mixed-effect models with subject-specific random intercepts and slopes were used to model longitudinal hormone trajectories by sex and derive measures of adrenarcheal timing and tempo. The median values for all hormones were higher at each consecutive study wave for both sexes, and higher for females than males. For all hormones, between-individual variation in hormone levels at age 9 (timing) was moderately large and similar for females and males. Between-individual variation in hormone progression over time (tempo) was of moderate magnitude compared with the population average age-slope, which itself was small compared with overall hormone level at each age. This suggests that between-individual variation in tempo was less important for modelling hormone trajectories. Between-individual variation in timing was more important for determining relative adrenal hormonal level in childhood than tempo. This finding suggests that adrenal hormonal levels at age 8-9 years can be used to predict relative levels in early adolescence (up to 13 years).
Topics: Male; Female; Animals; Adrenarche; Dehydroepiandrosterone; Longitudinal Studies; Prospective Studies; Dehydroepiandrosterone Sulfate
PubMed: 36520840
DOI: 10.1371/journal.pone.0278948 -
Journal of Obstetrics and Gynaecology :... Dec 2023Total testosterone (TT), sex hormone-binding globulin (SHBG), dehydroepiandrosterone (DHEA) levels, and cervical length (CL) were investigated in pregnant Egyptian women...
Testosterone, sex hormone-binding globulin and dehydroepiandrosterone levels and cervical length of Egyptian women with a history of recurrent miscarriages, polycystic ovary syndrome and without the conditions at three stages of pregnancy.
Total testosterone (TT), sex hormone-binding globulin (SHBG), dehydroepiandrosterone (DHEA) levels, and cervical length (CL) were investigated in pregnant Egyptian women with polycystic ovary syndrome (PCOS, = 38), history of miscarriages (RM, = 40) and without the conditions (HC, = 40). At week 8, the RM had lower levels of TT ( 0.000) and free androgen index (FAI) ( = 0.000) and higher SHBG ( = 0.000) and DHEA ( < 0.05) than the PCOS. Compared with the HC, they had elevated SHBG ( < 0.05) and DHEA ( = 0.001) and reduced CL ( = 0.000). TT ( = 0.001) and FAI ( = 0.000) were higher and SHBG ( = 0.000) and CL ( = 0.001) lower in the PCOS than in the HC group. At week 16, TT ( = 0.000) and FAI ( = 0.000) were higher, and SHBG ( = 0.000) and CL ( < 0.05) lower in PCOS than in RM and HC. The PCOS had elevated FAI than the RM ( = 0.000) and HC ( = 0.001) at week 20. The DHEA, SHBG and CL abnormalities in PCOS and RM may compromise pregnancy outcomes.IMPACT STATEMENT Hyperandrogenaemia, low sex hormone-binding globulin (SHBG), shortened cervical length (CL) and polycystic ovary syndrome (PCOS) are the most cited risk factors for recurrent miscarriages (RM). However, the published data are inconsistent, perhaps because of the confounding effects of ethnicity and nutritional milieu. The study's findings comprising ethnically and socially homogenous women demonstrate that PCOS and RM are characterised by elevated dehydroepiandrosterone (DHEA) and shortened CL, and PCOS by reduced SHBG. These abnormalities would be expected to have an adverse impact on pregnancy outcomes. Twenty-weeks DHEA and CL values have the potential to predict outcome risk in women with a history of RM and PCOS. Further research on other population groups is required to validate the current study's findings.
Topics: Pregnancy; Female; Humans; Testosterone; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Egypt; Dehydroepiandrosterone; Abortion, Habitual
PubMed: 36689253
DOI: 10.1080/01443615.2022.2163625 -
The Journal of Clinical Endocrinology... Apr 2022Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol.
CONTEXT
Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol.
OBJECTIVE
To determine the relative contributions of each hormone to the observed effects of testosterone treatment in older men with hypogonadism.
METHODS
Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and DHT levels over 12 months of testosterone treatment with hemoglobin, high-density lipoprotein (HDL) cholesterol, volumetric bone mineral density (vBMD) of lumbar spine, sexual desire, and prostate-specific antigen (PSA). We used random forests to model the associations of predicted mean changes in outcomes with change in each hormone at low, mean, or high change in the other 2 hormones. Stepwise regression models were run to confirm the findings of random forests.
RESULT
Predicted increases in hemoglobin and sexual desire were greater with larger increases in estradiol and were larger with high change in DHT compared with low change in DHT. Greater increases in estradiol were associated with larger decreases in HDL cholesterol; this association did not vary according to changes in DHT or testosterone. Change in vBMD was most robustly associated with change in estradiol and was greater with high change in testosterone and DHT. There was no consistent relation between change in PSA and change in any hormone.
CONCLUSION
Change in estradiol level was the best predictor not only of the change in vBMD and sexual desire but also of the changes in hemoglobin and HDL cholesterol. Consideration of testosterone, estradiol, and DHT together offers a superior prediction of treatment response in older hypogonadal men than testosterone alone.
Topics: Aged; Cholesterol, HDL; Dihydrotestosterone; Estradiol; Humans; Male; Prostate-Specific Antigen; Testosterone
PubMed: 35041751
DOI: 10.1210/clinem/dgac028