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PloS One 20232,4-dinitrophenol (DNP) is a mitochondrial toxin sometimes used as a weight loss agent. Reports of fatalities from DNP have been increasing since 2000, suggesting an...
INTRODUCTION
2,4-dinitrophenol (DNP) is a mitochondrial toxin sometimes used as a weight loss agent. Reports of fatalities from DNP have been increasing since 2000, suggesting an increase in use. Our understanding of DNP toxicity in humans comes from reports to Poison Control and postmortem analyses, sources that are biased to more extreme presentations. This leads to a gap in our knowledge about the adverse effects of DNP at nonlethal doses. Here we investigate the doses and effects of DNP as reported online.
METHODS
We analyzed publicly available Internet posts that we collected from 2017-2019. The posts came from anonymous users or users who voluntarily self-identified. We collected data from websites whose terms of use allow for the secondary analysis of data that their users agree to make public. We used natural language processing techniques that we had previously developed to extract doses, effects, and substances mentioned in each post.
RESULTS
We collected 1,630 posts across 5 online forums and the Reddit forum r/DNP. The posts were from 1,234 unique usernames. The most commonly reported doses were between 150 to 300 mg each day followed by 300 to 450 mg each day. At those doses, the most reported adverse effects were profuse sweating and fatigue. Reports of thermoregulatory (sweating, feeling hot flashes or flushed), fatigue-related, and neurologically related symptoms were statistically significantly more frequent at reported daily doses greater than 150 mg than doses below 150 mg (post-hoc χ2-test with Bonferroni correction). The effects were judged as plausible by two board-certified medical toxicologists. Triiodothyronine, clenbuterol, testosterone, and trenbolone, an androgenic anabolic steroid were the most significantly co-mentioned substances.
CONCLUSIONS
Fatigue, increased body temperature, and paresthesias from DNP are reported more frequently at doses greater than 150 mg each day than at doses less than 150 mg each day. Online discussions of DNP frequently mention androgenic anabolic steroids and other weight loss agents.
Topics: Humans; Self Report; 2,4-Dinitrophenol; Androstanes; Anti-Obesity Agents; Dinitrophenols; Drug-Related Side Effects and Adverse Reactions; Fatigue
PubMed: 37703241
DOI: 10.1371/journal.pone.0290630 -
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 -
Hormones and Behavior May 2008The complexity of gonadal steroid hormone actions is reflected in their broad and diverse effects on a host of integrated systems including reproductive physiology,... (Review)
Review
An alternate pathway for androgen regulation of brain function: activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5alpha-androstane-3beta,17beta-diol.
The complexity of gonadal steroid hormone actions is reflected in their broad and diverse effects on a host of integrated systems including reproductive physiology, sexual behavior, stress responses, immune function, cognition, and neural protection. Understanding the specific contributions of androgens and estrogens in neurons that mediate these important biological processes is central to the study of neuroendocrinology. Of particular interest in recent years has been the biological role of androgen metabolites. The goal of this review is to highlight recent data delineating the specific brain targets for the dihydrotestosterone metabolite, 5alpha-androstane, 3beta,17beta-diol (3beta-Diol). Studies using both in vitro and in vivo approaches provide compelling evidence that 3beta-Diol is an important modulator of the stress response mediated by the hypothalmo-pituitary-adrenal axis. Furthermore, the actions of 3beta-Diol are mediated by estrogen receptors, and not androgen receptors, often through a canonical estrogen response element in the promoter of a given target gene. These novel findings compel us to re-evaluate the interpretation of past studies and the design of future experiments aimed at elucidating the specific effects of androgen receptor signaling pathways.
Topics: Androgens; Androstane-3,17-diol; Animals; Behavior; Behavior, Animal; Brain; Dihydrotestosterone; Estrogen Receptor beta; Humans; Hypothalamo-Hypophyseal System; Mental Disorders; Pituitary-Adrenal System; Promoter Regions, Genetic; Sex Characteristics; Signal Transduction; Stress, Psychological
PubMed: 18067894
DOI: 10.1016/j.yhbeh.2007.09.012 -
The Journal of Clinical Investigation Sep 1974Kinetics of 5alpha-androstane-3alpha, 17beta-diol (3alpha-diol) were studied in man. Clearance rates were determined by both the constant infusion and single injection...
Kinetics of 5alpha-androstane-3alpha, 17beta-diol (3alpha-diol) were studied in man. Clearance rates were determined by both the constant infusion and single injection techniques. Production rates were calculated as the product of clearance rate data and plasma values in the a.m. obtained by a radioimmunoassay specific for 3alpha-diol. Mean metabolic clearance rates were 1,776+/-492 (SD) liters/day in males and 1,297+/-219 (SD) liters/day in females. Metabolic clearance rates by single injection were similar. Calculated production rates are 208+/-26 (SD) mug/day in males and 35+/-11 mug/day in females, which are significantly different. Hepatic extraction of 3alpha-diol determined by hepatic vein catheterization during constant infusion was 76% which was greater than expected from information on in vitro binding in plasma. The kinetic data is of interest since 3alpha-diol has a calculated inner pool (V(1)) volume of 12-14 liters, similar to 17beta-hydroxyandrost-4-en-3-one (testosterone) and 5alpha-androstan-17beta-ol-3-one (dihydrotestosterone), but the calculated outer pool (V(2)) of 33.5 liters is very large as are the metabolic rate and transfer constant. In contrast to testosterone and dihydrotestosterone, 3alpha-diol, although bound to sex hormone binding globulin, has a high metabolic clearance of which a large fraction represents extrahepatic (splanchnic) metabolism. A production rate of 3alpha-diol similar to dihydrotestosterone together with rather unique kinetic characteristics encourages further investigation of the biological role of this potent androgen.
Topics: Abdomen; Androstanes; Carbon Radioisotopes; Female; Hepatic Veins; Humans; Infusions, Parenteral; Injections, Intravenous; Kinetics; Liver; Liver Circulation; Male; Radioimmunoassay; Testosterone; Time Factors; Tritium
PubMed: 4855449
DOI: 10.1172/JCI107802 -
Journal of Natural Products Apr 201717β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active...
17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature. In total, 36 hit molecules were selected for biological evaluation. Of these compounds, 12 inhibited 17β-HSD2 with nanomolar to low micromolar IC values. The most potent compounds, nordihydroguaiaretic acid (1), IC 0.38 ± 0.04 μM, (-)-dihydroguaiaretic acid (4), IC 0.94 ± 0.02 μM, isoliquiritigenin (6), IC 0.36 ± 0.08 μM, and ethyl vanillate (12), IC 1.28 ± 0.26 μM, showed 8-fold or higher selectivity over 17β-HSD1. As some of the identified compounds belong to the same structural class, structure-activity relationships were derived for these molecules. Thus, this study describes new 17β-HSD2 inhibitors from nature and provides insights into the binding pocket of 17β-HSD2, offering a promising starting point for further research in this area.
Topics: 17-Hydroxysteroid Dehydrogenases; Biological Products; Enzyme Inhibitors; Etiocholanolone; Humans; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Testosterone
PubMed: 28319389
DOI: 10.1021/acs.jnatprod.6b00950 -
Biochemical Pharmacology Oct 2021Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate...
Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate acetylcholine binding and function. Using radioligand binding experiments we investigated their binding mode. We show that neuroactive steroids bind to two binding sites on muscarinic receptors. Their affinity for the high-affinity binding site is about 100 nM. Their affinity for the low-affinity binding site is about 10 µM. The high-affinity binding occurs at the same site as binding of steroid-based WIN-compounds that is different from the common allosteric binding site for alcuronium or gallamine that is located between the second and third extracellular loop of the receptor. This binding site is also different from the allosteric binding site for the structurally related aminosteroid-based myorelaxants pancuronium and rapacuronium. Membrane cholesterol competes with neurosteroids/neuroactive steroids binding to both high- and low-affinity binding site, indicating that both sites are oriented towards the cell membrane..
Topics: Allosteric Regulation; Androstanes; Androstenes; Animals; Benzimidazoles; Binding Sites; CHO Cells; Cholesterol; Cricetinae; Cricetulus; Gallamine Triethiodide; Humans; Neuromuscular Nondepolarizing Agents; Neurosteroids; Receptors, Muscarinic; Vecuronium Bromide
PubMed: 34324870
DOI: 10.1016/j.bcp.2021.114699 -
PLoS Genetics Mar 2016Methadone maintenance treatment (MMT) is commonly used for controlling opioid dependence, preventing withdrawal symptoms, and improving the quality of life of...
Genome-Wide Pharmacogenomic Study on Methadone Maintenance Treatment Identifies SNP rs17180299 and Multiple Haplotypes on CYP2B6, SPON1, and GSG1L Associated with Plasma Concentrations of Methadone R- and S-enantiomers in Heroin-Dependent Patients.
Methadone maintenance treatment (MMT) is commonly used for controlling opioid dependence, preventing withdrawal symptoms, and improving the quality of life of heroin-dependent patients. A steady-state plasma concentration of methadone enantiomers, a measure of methadone metabolism, is an index of treatment response and efficacy of MMT. Although the methadone metabolism pathway has been partially revealed, no genome-wide pharmacogenomic study has been performed to identify genetic determinants and characterize genetic mechanisms for the plasma concentrations of methadone R- and S-enantiomers. This study was the first genome-wide pharmacogenomic study to identify genes associated with the plasma concentrations of methadone R- and S-enantiomers and their respective metabolites in a methadone maintenance cohort. After data quality control was ensured, a dataset of 344 heroin-dependent patients in the Han Chinese population of Taiwan who underwent MMT was analyzed. Genome-wide single-locus and haplotype-based association tests were performed to analyze four quantitative traits: the plasma concentrations of methadone R- and S-enantiomers and their respective metabolites. A significant single nucleotide polymorphism (SNP), rs17180299 (raw p = 2.24 × 10(-8)), was identified, accounting for 9.541% of the variation in the plasma concentration of the methadone R-enantiomer. In addition, 17 haplotypes were identified on SPON1, GSG1L, and CYP450 genes associated with the plasma concentration of methadone S-enantiomer. These haplotypes accounted for approximately one-fourth of the variation of the overall S-methadone plasma concentration. The association between the S-methadone plasma concentration and CYP2B6, SPON1, and GSG1L were replicated in another independent study. A gene expression experiment revealed that CYP2B6, SPON1, and GSG1L can be activated concomitantly through a constitutive androstane receptor (CAR) activation pathway. In conclusion, this study revealed new genes associated with the plasma concentration of methadone, providing insight into the genetic foundation of methadone metabolism. The results can be applied to predict treatment responses and methadone-related deaths for individualized MMTs.
Topics: Adult; Androstanes; Cytochrome P-450 CYP2B6; Extracellular Matrix Proteins; Female; Genome-Wide Association Study; Haplotypes; Heroin; Heroin Dependence; Humans; Male; Methadone; Middle Aged; Opiate Substitution Treatment; Pharmacogenetics; Polymorphism, Single Nucleotide; Stereoisomerism
PubMed: 27010727
DOI: 10.1371/journal.pgen.1005910 -
Endocrinology Jul 2022Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women. A common symptom of PCOS is hyperandrogenism (AE); however, the source of these androgens...
Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women. A common symptom of PCOS is hyperandrogenism (AE); however, the source of these androgens is uncertain. Aldo-keto reductase family 1 member C3 (AKR1C3) catalyzes the formation of testosterone (T) and 5α-dihydrotestosterone (DHT) in peripheral tissues, which activate the androgen receptor (AR). AKR1C3 is induced by insulin in adipocytes and may be central in driving the AE in PCOS. We elucidated the conversion of both classical and 11-oxygenated androgens to potent androgens in a model of PCOS adipocytes. Using high-performance liquid chromatography (HPLC) discontinuous kinetic assays to measure product formation by recombinant AKR1C3, we found that the conversion of 11-keto-Δ4-androstene-3,17-dione (11K-4AD) to 11-ketotestosterone (11K-T) and 11-keto-5α-androstane-3,17-dione (11K-5AD) to 11-keto-5α-dihydrotestosterone (11K-DHT) were superior to the formation of T and DHT. We utilized a stable isotope dilution liquid chromatography high resolution mass spectrometric (SID-LC-HRMS) assay for the quantification of both classical and 11-oxygenated androgens in differentiated Simpson-Golabi-Behmel syndrome adipocytes in which AKR1C3 was induced by insulin. Adipocytes were treated with adrenal derived 11β-hydroxy-Δ4-androstene-3,17-dione (11β-OH-4AD), 11K-4AD, or Δ4-androstene-3,17-dione (4AD). The conversion of 11β-OH-4AD and 11K-4AD to 11K-T required AKR1C3. We also found that once 11K-T is formed, it is inactivated to 11β-hydroxy-testosterone (11β-OH-T) by 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1). Our data reveal a unique role for HSD11B1 in protecting the AR from AE. We conclude that the 11-oxygenated androgens formed in adipocytes may contribute to the hyperandrogenic profile of PCOS women and that AKR1C3 is a potential therapeutic target to mitigate the AE of PCOS.
Topics: Adipocytes; Aldo-Keto Reductase Family 1 Member C3; Androgens; Androstenes; Dihydrotestosterone; Female; Humans; Insulin; Polycystic Ovary Syndrome; Testosterone
PubMed: 35560164
DOI: 10.1210/endocr/bqac068 -
Journal of Aerosol Medicine and... Jun 2022Wixela Inhub (trademarks of Viatris, Inc.) is a dry powder inhaler (DPI) that delivers a fixed-dose combination of fluticasone propionate and salmeterol and is approved...
Wixela Inhub (trademarks of Viatris, Inc.) is a dry powder inhaler (DPI) that delivers a fixed-dose combination of fluticasone propionate and salmeterol and is approved as a generic equivalent to Advair Diskus (trademarks of GlaxoSmithKline plc) for the treatment of asthma and chronic obstructive pulmonary disease (COPD). The dosing performance of DPIs is dependent on the patient's inspiratory capability, which may be impacted in disease populations such as those with severe COPD. The objective of this study was to evaluate the dose delivery of fluticasone propionate and salmeterol from the Inhub inhaler with inhalation profiles of severe COPD patients, using two types of breathing simulator with different modes of operation. Two breathing simulators (Si-Plan and Copley BRS3100) were used with United States Pharmacopoeia (USP) <601> apparatus 5 (Next Generation Impactor and accessories) to measure the total emitted dose and fine particle mass of fluticasone propionate and salmeterol for Wixela Inhub (250/50 mcg) using 13 severe COPD patient inhalation profiles. Wixela Inhub demonstrated low flow dependency across the range of COPD patient profiles tested (peak inspiratory flow rate 60.8-84.9 L minute), when assessed by total emitted dose and fine particle mass. The results were similar to literature results reported for fluticasone propionate from the Diskus inhaler, tested using a proprietary breathing simulator and Andersen Cascade Impactor. Comparison between the breathing simulators showed no significant difference in fluticasone propionate results, but a small difference was observed between the breathing simulators for salmeterol total emitted dose and fine particle mass. This study demonstrates that severe COPD patients are likely to achieve a consistent inhaled dose from Wixela Inhub, with low flow dependency observed within this patient population. In addition, both breathing simulators, which differ significantly in design, produced similar results for fluticasone propionate, but yielded slightly (but statistically significant) different results for salmeterol.
Topics: Administration, Inhalation; Androstadienes; Bronchodilator Agents; Dry Powder Inhalers; Fluticasone; Fluticasone-Salmeterol Drug Combination; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate
PubMed: 34726509
DOI: 10.1089/jamp.2021.0017 -
British Journal of Anaesthesia Oct 1983
Topics: Atracurium; Humans; Isoquinolines; Neuromuscular Blocking Agents; Pancuronium; Vecuronium Bromide
PubMed: 6138052
DOI: 10.1093/bja/55.10.1042