194 research outputs found
Effects of MDMA on body temperature in humans
Get PDFHyperthermia is a severe complication associated with the recreational use of 3,4-methylenedioxymethamphetamine(MDMA, Ecstasy). In this review, the clinical laboratory studies that tested the effects of MDMA on body temperature are summarized. The mechanisms that underlie the hyperthermic effects of MDMA in humans and treatment of severe hyperthermia are presented. The data show that MDMA produces an acute and dose-dependent rise in core body temperature in healthy subjects. The increase in body temperature is in the range of 0.2-0.8C and does not result in hyperpyrexia (>40C) in a controlled laboratory setting. However, moderately hyperthermic body temperatures >38.0C occur frequently at higher doses, even in the absence of physical activity and at room temperature. MDMA primarily releases serotonin and norepinephrine. Mechanistic clinical studies indicate that the MDMA-induced elevations in body temperature in humans partially depend on the MDMA-induced release of norepinephrine and involve enhanced metabolic heat generation and cutaneous vasoconstriction, resulting in impaired heat dissipation. The mediating role of serotonin is unclear. The management of sympathomimetic toxicity and associated hyperthermia mainly includes sedation with benzodiazepines and intravenous fluid replacement. Severe hyperthermia should primarily be treated with additional cooling and mechanical ventilation
Pharmacology of novel psychoactive substances
Get PDFThis PhD work consists of an in vitro and in vivo part. In the in vivo part, we investigated the role of dopamine in the acute clinical effects of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) in healthy human subjects. The role of dopamine in the addictive effects of drug of abuse is well established, but whether it contributes to the acute psychotropic effects of MDMA is unclear.
In this pharmacological interaction study, we used the dopamine and weak norepinephrine transporter inhibitor bupropion (Stahl et al. 2004) as a pharmacological tool to block the MDMA-induced dopamine release and to study the role of dopamine in the effects of MDMA. We hypothesized that bupropion would decrease the subjective effects of MDMA to the extent that they depend on MDMA-induced release of dopamine.
We included 16 healthy human subjects in this double-blind, placebo-controlled, crossover study. Bupropion pretreatment slightly increased MDMA plasma concentration and prolonged but not reduced the subjective effects contrary to our hypothesis. Additionally, bupropion reduced the MDMA-induced elevations in plasma norepinephrine concentrations and the heart rate response to MDMA.
These findings support a role for norepinephrine in the MDMA-induced cardiostimulant effects but no role for MDMA-induced transporter-mediated dopamine release in the elevated mood effects after MDMA administration. Possibly, most of the acute psychotropic effects of MDMA are mediated via transporter-mediated release of serotonin and norepinephrine as previously shown (Hysek et al. 2011, Hysek et al. 2012).
In the second and main part of this work we characterized the pharmacological profiles of novel psychoactive substances (NPS). Specifically, we studied whether and how potently NPS interacted with the human transporters for norepinephrine, dopamine, and serotonin, stably expressed in human embryonic kidney (HEK293) cells. Additionally, we assessed binding affinity to the serotonin 5-HT1A, 5-HT2A, 5-HT2C-receptors and the activation potency and activation efficacy at 5-HT2A and 5-HT2B receptors. Furthermore, binding to alpha1A/2A-adrenergic, dopamine D1-3, histamine H1 receptors, as well as trace amine-associated receptor 1 (TAAR1) was also assessed.
The NPS studied in this project included para-4-halogenated amphetamine derivatives, which were shown to be relatively more serotonergic than their non-4-halogenated counterparts and pyrovaleronering-substituted cathinones, which were highly potent dopamine transporter inhibitors with a high risk for abuse.
Para-halogenated drugs (4-fluoroephedrine, 4-fluoroamphetamine, 4-fluoromethamphetamine, 4-fluoromethcathinone, and 4-bromomethcathinone) also released monoamines, similar to MDMA, whereas pyrovalerones were found to be pure uptake inhibitors. Most benzofurans were similar to MDMA but slightly more serotoninergic than MDMA and additionally activated the serotonin 5-HT2B receptor.
The last big group of NPS studied in this project, were novel hallucinogens, which predominantly interacted with the 5-HT2A receptor. This serotonin receptor subtype mediates the hallucinogenic and hallucinogenic-like visual effects of classic serotonergic hallucinogens (Vollenweider et al. 1998, Nichols 2004, Halberstadt et al. 2013, Halberstadt et al. 2014, Halberstadt 2015).
Compounds tested in this project included the benzodifuran 8-Bromo-2,3,6,7-benzo-dihydro-difuran-ethylamine (2C-B-FLY), 2C-drugs with their highly potent N-(2-methoxy)benzyl (NBOMe)-derivatives, and lysergic acid diethylamide (LSD). Interestingly, NBOMe derivatives displayed higher affinities at the 5-HT2A receptor than LSD, together with a high selectivity for 5-HT2A over the 5-HT1A receptor, contrary to LSD. NBOMes were partial 5-HT2A receptor agonists, similar to LSD. These novel drugs likely carry a high hallucinogenic potential when used recreationally by humans and the high binding to α1A-receptor (Ki < 1µM) may result in additional vasocontrictive and cardiovascular stimulant effects.
Taken together, this PhD contributed to the understanding of the role of dopamine in the effects of MDMA, an important recreational substances. Additionally, we characterized the in vitro pharmacology of many novel designer drugs, which will be helpful in the prediction of the clinical toxicological effects of these newly used recreational drugs
The direct effects of tacrolimus and cyclosporin A on isolated human islets A functional, survival and gene expression study
No full textThe use of immunosuppressive drugs in transplanted patients is associated with the development of diabetes, possibly due to β-cell toxicity. To better understand the mechanisms leading to post-transplant diabetes, we investigated the actions of prolonged exposure of isolated human islets to therapeutical levels of tacrolimus (Tac) or cyclosporin A (CsA). Islets were isolated from the pancreas of multiorgan donors by enzymatic digestion and density gradient centrifugation. Functional, survival and molecular studies were then performed after 4 days of incubation with therapeutical concentrations of Tac or CsA. Glucose-induced insulin secretion was significantly decreased in Tac, but not in CsA exposed islets, which was associated with a reduction of the amount of insulin granules as shown by electron microscopy. The percentage of apoptotic β-cells was higher in Tac than CsA exposed islets. Microarray experiments followed by Gene Set Enrichment Analysis revealed that gene expression was more markedly affected upon Tac treatment. In conclusion, Tac and CsA affect features of beta-cell differently, with several changes occurring at the molecular leve
Avoiding the pitfalls of gene set enrichment analysis with SetRank
Get PDFThe purpose of gene set enrichment analysis (GSEA) is to find general trends in the huge lists of genes or proteins generated by many functional genomics techniques and bioinformatics analyses.
Here we present SetRank, an advanced GSEA algorithm which is able to eliminate many false positive hits. The key principle of the algorithm is that it discards gene sets that have initially been flagged as significant, if their significance is only due to the overlap with another gene set. The algorithm is explained in detail and its performance is compared to that of other methods using objective benchmarking criteria. Furthermore, we explore how sample source bias can affect the results of a GSEA analysis.
The benchmarking results show that SetRank is a highly specific tool for GSEA. Furthermore, we show that the reliability of results can be improved by taking sample source bias into account. SetRank is available as an R package and through an online web interface
Environmental Simulations for EOD Shaped Charges
Get PDFThis article describes the methodology and importance of environmental simulations and testing of shaped charges used for the disposal of explosive remnants of war and landmines. The author discusses a single sequence of tests conducted on a specific product as an example of the depth to which environmental factors should be investigated in order to address them before final production and manufacture
Don\u27t Take \u27No\u27 for an Answer
Get PDFTwo veterans, an retired Army officer and a World War II Women\u27s Army Corp veteran. find common ground in the bonds of shared military service.
Articles, stories, and other compositions in this archive were written by participants in the Mighty Pen Project. The program, developed by author David L. Robbins, and in partnership with Virginia Commonwealth University and the Virginia War Memorial in Richmond, Virginia, offers veterans and their family members a customized twelve-week writing class, free of charge. The program encourages, supports, and assists participants in sharing their stories and experiences of military experience so both writer and audience may benefit
Packers
Get PDFAn army officer reminisces about her past love, her military career, and a great pair of cowboy boots.
Articles, stories, and other compositions in this archive were written by participants in the Mighty Pen Project. The program, developed by author David L. Robbins, and in partnership with Virginia Commonwealth University and the Virginia War Memorial in Richmond, Virginia, offers veterans and their family members a customized twelve-week writing class, free of charge. The program encourages, supports, and assists participants in sharing their stories and experiences of military experience so both writer and audience may benefit
www.biogeosciences.net/9/1985/2012/ doi:10.5194/bg-9-1985-2012 © Author(s) 2012. CC Attribution 3.0 License.
No full textOrganic matter dynamics and stable isotope signature as tracers of the sources of suspended sedimen
Minimal stretch factors of orientation-reversing fully-punctured pseudo-Anosov maps
No full text27 pages, 6 figuresWe show that the stretch factor of an orientation-reversing fully-punctured pseudo-Anosov map on a finite-type orientable surface , with and having at least two puncture orbits, satisfies the inequality , where is the silver ratio. We provide examples showing that this bound is asymptotically sharp. This extends previous results of Hironaka and the third author to orientation-reversing maps
Pharmacokinetics and pharmacodynamics of γ-hydroxybutyrate in healthy subjects.
Get PDFAIMS
γ-Hydroxybutyrate (GHB) is used as a treatment for narcolepsy and alcohol withdrawal and as recreational substance. Nevertheless, there are limited data on the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of GHB in humans. We characterized the pharmacokinetic profile and exposure-psychotropic effect relationship of GHB in humans.
METHODS
Two oral doses of GHB (25 and 35 mg/kg) were administered to 32 healthy male subjects (16 for each dose) using a randomized, placebo-controlled, cross-over design.
RESULTS
Maximal concentrations of GHB were (geometric mean and 95%CI): 218 (176-270) nmol/ml and 453 (374-549) nmol/ml for the 25 and 35 mg/kg GHB doses, respectively. The elimination half-lives (mean ± SD) were 36 ± 9 and 39 ± 7 min and the AUC∞ values (geometric mean and 95%CI) were 15,747 (12,854-19,290) and 40,113 (33,093-48,622) nmol∙min/ml for the 20 and 35 mg/kg GHB doses, respectively. Thus, plasma GHB exposure (AUC0-∞ ) rose disproportionally (+40%) with the higher dose. γ-Hydroxybutyrate produced mixed stimulant-sedative effects, with a dose-dependent increase in sedation and dizziness. It did not alter heart rate or blood pressure. A close relationship between plasma GHB exposure and its psychotropic effects was found, with higher GHB concentrations associated with higher subjective stimulation, sedation, and dizziness. No clockwise hysteresis was observed in the GHB concentration effect plot over time (i.e., no acute pharmacological tolerance).
CONCLUSION
Evidence was found of a non-linear dose-exposure relationship (i.e., no dose proportionality) at moderate doses of GHB. The effects of GHB on consciousness were closely linked to its plasma exposure and exhibited no acute tolerance. This article is protected by copyright. All rights reserved
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