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Chouker A.,Ludwig Maximilians University of Munich | Kaufmann I.,Ludwig Maximilians University of Munich | Kreth S.,Ludwig Maximilians University of Munich | Hauer D.,Ludwig Maximilians University of Munich | And 5 more authors.

Background: A substantial number of individuals are at risk for the development of motion sickness induced nausea and vomiting (N&V) during road, air or sea travel. Motion sickness can be extremely stressful but the neurobiologic mechanisms leading to motion sickness are not clear. The endocannabinoid system (ECS) represents an important neuromodulator of stress and N&V. Inhibitory effects of the ECS on N&V are mediated by endocannabinoid-receptor activation. Methodology/Principal Findings: We studied the activity of the ECS in human volunteers (n = 21) during parabolic flight maneuvers (PFs). During PFs, microgravity conditions (<10-2 g) are generated for approximately 22 s which results in a profound kinetic stimulus. Blood endocannabinoids (anandamide and 2-arachidonoylglycerol, 2-AG) were measured from blood samples taken in-flight before start of the parabolic maneuvers, after 10, 20, and 30 parabolas, in-flight after termination of PFs and 24 h later. Volunteers who developed acute motion sickness (n = 7) showed significantly higher stress scores but lower endocannabinoid levels during PFs. After 20 parabolas, blood anandamide levels had dropped significantly in volunteers with motion sickness (from 0.39±0.40 to 0.22±0.25 ng/ml) but increased in participants without the condition (from 0.43±0.23 to 0.60±0.38 ng/ml) resulting in significantly higher anandamide levels in participants without motion sickness (p = 0.02). 2-AG levels in individuals with motion sickness were low and almost unchanged throughout the experiment but showed a robust increase in participants without motion sickness. Cannabinoid-receptor 1 (CB1) but not cannabinoid-receptor 2 (CB2) mRNA expression in leucocytes 4 h after the experiment was significantly lower in volunteers with motion sickness than in participants without N&V. Conclusions/Significance: These findings demonstrate that stress and motion sickness in humans are associated with impaired endocannabinoid activity. Enhancing ECS signaling may represent an alternative therapeutic strategy for motion sickness in individuals who do not respond to currently available treatments. © 2010 Choukèr et al. Source

Auwarter V.,Albert Ludwigs University of Freiburg | Wohlfarth A.,Albert Ludwigs University of Freiburg | Traber J.,Albert Ludwigs University of Freiburg | Thieme D.,Institute of Doping Analysis and Sports Biochemistry | Weinmann W.,Albert Ludwigs University of Freiburg
Forensic Science International

Differentiation between external contamination and incorporation of drugs or their metabolites from inside the body via blood, sweat or sebum is a general issue in hair analysis and of high concern when interpreting analytical results. In hair analysis for cannabinoids the most common target is Δ9-tetrahydrocannabinol (THC), sometimes cannabidiol (CBD) and cannabinol (CBN) are determined additionally. After repeated external contamination by cannabis smoke these analytes are known to be found in hair even after performing multiple washing steps. A widely accepted strategy to unequivocally prove active cannabis consumption is the analysis of hair extracts for the oxidative metabolite 11-nor-9-carboxy-THC (THC-COOH). Although the acidic nature of this metabolite suggests a lower rate of incorporation into the hair matrix compared to THC, it is not fully understood up to now why hair concentrations of THC-COOH are generally found to be much lower (mostly <10 pg/mg) than the corresponding THC concentrations. Δ9-Tetrahydrocannabinolic acid A (THCA A) is the preliminary end product of the THC biosynthesis in the cannabis plant. Unlike THC it is non-psychoactive and can be regarded as a 'precursor' of THC being largely decarboxylated when heated or smoked. The presented work shows for the first time that THCA A is not only detectable in blood and urine of cannabis consumers but also in THC positive hair samples. A pilot experiment performed within this study showed that after oral intake of THCA A on a regular basis no relevant incorporation into hair occurred. It can be concluded that THCA A in hair almost exclusively derives from external contamination e.g. by side stream smoke. Elevated temperatures during the analytical procedure, particularly under alkaline conditions, can lead to decarboxylation of THCA A and accordingly increase THC concentrations in hair. Additionally, it has to be kept in mind that in hair samples tested positive for THCA A at least a part of the 'non-artefact' THC probably derives from external contamination as well, because in condensate of cannabis smoke both THC and THCA A are present in relevant amounts. External contamination by side stream smoke could therefore explain the great differences in THC and THC-COOH hair concentrations commonly found in cannabis users. © 2010 Elsevier Ireland Ltd. All rights reserved. Source

Krumbholz A.,Institute of Doping Analysis and Sports Biochemistry | Anielski P.,Institute of Doping Analysis and Sports Biochemistry | Reisch N.,Ludwig Maximilians University of Munich | Schelling G.,Ludwig Maximilians University of Munich | Thieme D.,Institute of Doping Analysis and Sports Biochemistry
Therapeutic Drug Monitoring

BACKGROUND:: Endogenous corticosteroids and endocannabinoids are both known to be involved in stress adaption and anti-inflammatory and immuneregulatory effects. The application of hair as retrospective specimen for long-term recording of corticosteroids and its association with stress-induced biochemical alterations was intensively examined. METHODS:: To evaluate the stability and correlation of various parameters of the endocannabinoid and corticosteroid systems, a prospective study was carried out. Hair samples were collected monthly over a pregnancy cycle (sixth week of pregnancy to 9 weeks postpartum). By comparison of hair concentrations in particular segments (ie, grown in the same time span but collected at different times), an examination of analyte stability in hair was achieved. Additionally, the comparison of proximal segments provided on biochemical information that is independent of alteration due to physical instability. The detection limits of a validated procedure using solid-phase extraction cleanup and liquid chromatography-mass spectrometry proved to be suitable to identify the endogenous levels of cortisol (limits of detection = 1.6 pg/mg), cortisone (2.1 pg/mg), anandamide (AEA, 0.3 pg/mg), and 2-arachidonoylglycerol (15 pg/mg). RESULTS:: Corticosteroid concentrations in corresponding hair segments were found to be reduced with increasing hair age; an average decline of cortisol and cortisone by 50% in 4 months was estimated. Independently, an increase of cortisol and cortisone in proximal segments collected during pregnancy was confirmed, which is assumed to be stress related. Endocannabinoids proved to be by far more stable, as demonstrated by subsequent monthly collection of corresponding segments and there was hardly any washout of AEA detectable. Elevated hair concentrations of AEA and 2- arachidonoylglycerol were detected in the first-second trimester of pregnancy, which corresponds to negative correlations between AEA, cortisol, and cortisone. Copyright © 2013 by Lippincott Williams and Wilkins. Source

Schonfelder M.,TU Munich | Hofmann H.,TU Munich | Anielski P.,Institute of Doping Analysis and Sports Biochemistry | Thieme D.,Institute of Doping Analysis and Sports Biochemistry | And 2 more authors.
Drug Testing and Analysis

Doping with anabolic agents is regulated within a number of sports. Testosterone and its functional analogs are popular compounds for increasing muscle mass, physical performance, recovery, and reducing body fat. While routine tests for anabolic drugs exist (e.g. hair, urine, and blood analysis), the aim of the present study is to determine specific gene expression profiles (induced by testosterone and exercise) which may be used as effective biomarkers to determine the use of anabolic drugs. In this study, whole blood samples of 19 male volunteers were analyzed by semi-quantitative real-time polymerase chain reaction (RT-PCR) for gene expression profiles in the context of exercise and transdermal testosterone application (1.5mg/kg body weight). The hormone application was monitored by urine and saliva analysis for testosterone. Both urinary and saliva levels indicate that transdermal testosterone application leads to an increase of testosterone, especially after exercise. RT-PCR results showed a clear variation in the expression of target genes as well as established housekeeping genes. Only one of the nine common housekeeping genes, cyclophilin b (PPIB), appears to be independent of both exercise and testosterone. Out of 14 candidate genes, five are unregulated; all others were more or less influenced by the mentioned variables. Only interleukin-6 appeared to be exclusively dependent on long-term testosterone application. This study indicates that many genes are not influenced by testosterone alone while exercise modulates gene expression in whole blood samples. As such, exercise must be considered when validating gene expression techniques for doping analysis. © 2011 John Wiley & Sons, Ltd. Source

Diepenbruck I.,University of Hamburg | Much C.C.,University of Hamburg | Krumbholz A.,Institute of Doping Analysis and Sports Biochemistry | Kolster M.,University of Hamburg | And 6 more authors.
Journal of Molecular Medicine

Prenatal steroids have an undisputed positive effect of decreasing neonatal morbidity and mortality by improving fetal lung maturation. Some concerns have been raised on long-term consequences on the hypothalamic-pituitary-adrenal axis and cognition, but there are no studies addressing effects on the immune system. The thymus is an essential organ for the development and selection of T cells, and thymocytes are extremely sensitive to steroids. Using a mouse model for prenatal steroid administration, we show here that betamethasone treatment to the mother has a profound effect on the thymus of the offspring. We find the thymus volume reduced, affecting mostly the developing CD4+ CD8+ double-positive thymocytes and a compensatory accelerated transition of the earlier stages to replenish the depleted compartment. This effect lasts for at least 3 days, which correspond to a very relevant period for the selection of the T cell repertoire. Moreover, we show that low doses of betamethasone have similar effects on human thymocytes in vitro. Therefore, further studies are needed to analyze possible long-term consequences of this treatment on the immune system of the offspring. Key message: Betamethasone administered to the mother before birth reaches the fetal thymus. Prenatal betamethasone results in massive loss of developing thymocytes. The effects of betamethasone on thymus development are visible for several days. Human thymocytes are also sensitive to low doses of betamethasone. Altered thymocyte development around birth may have an effect on the immune system. © 2013 Springer-Verlag Berlin Heidelberg. Source

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