Chiral Serum Pharmacokinetics of 4-Fluoroamphetamine after Controlled Oral Administration: Can (R)/(S)-Concentration Ratios Help in Interpreting Forensic Cases?

2020 ◽  
Author(s):  
Moritz Losacker ◽  
Stefan W Toennes ◽  
Elizabeth B de Sousa Fernandes Perna ◽  
Johannes G Ramaekers ◽  
Joerg Roehrich ◽  
...  
Keyword(s):  
Drug Effects ◽  
Serum Samples ◽  
Blood Samples ◽  
Chromatography Tandem Mass Spectrometry ◽  
Elimination Half ◽  
Liquid Chromatography Tandem Mass ◽  
Precision And Accuracy ◽  
Enantioselective Pharmacokinetics ◽  
Over Time ◽  
Concentration Ratios

Abstract Over the last two decades, misuse of 4-fluoroamphetamine (4-FA) became an emerging issue in many European countries. Stimulating effects last for 4–6 hours and can impact psychomotor performance. The metabolism of amphetamine-type stimulants is stereoselective and quantification of (R)- and (S)-enantiomers has been suggested for assessing time of use. To date, no data on enantioselective pharmacokinetics is available for 4-FA in serum samples. An enantioselective liquid chromatography−tandem mass spectrometry (LC–MS-MS) method was developed using a chiral Phenomenex® Lux 3 μm AMP column. Validation of the method showed satisfactory selectivity, sensitivity, linearity (0.5–250 ng/mL), precision and accuracy. Recreational stimulant users orally ingested two doses (100 mg, n = 12; 150 mg, n = 5) of 4-FA. Blood samples were drawn prior to application and over a period of 12 hours after ingestion and analyzed for 4-FA enantiomers. Peak concentrations and corresponding times did not differ significantly between the enantiomers (mean (R)/(S)-ratio at tmax 1.05, 0.85–1.16). With mean 12.9 (8.3–16.1) hours, apparent elimination half-lives (t1/2) were significantly (P < 0.01) longer for (R)-4-FA than for (S)-4-FA (6.0 hours; range 4.4–10.2 hours) and independent of the dose given. Over time, (R)/(S)-concentration-ratios were linearly increasing in all subjects to maximum ratios of 2.00 (1.08–2.77) in the last samples (after 12 hours). The slopes of the (R)/(S)-ratio exhibited marked interindividual differences (0.023–0.157 h−1, mean 0.095 h−1). Ratios higher than 1.60 only appeared earliest after a minimum of 6 hours and therefore suggest the absence of acute drug effects. Different elimination half-lives of enantiomers lead to constantly increasing (R)/(S)-concentration-ratios. Consequently, ratios of 4-FA enantiomers in serum are a promising indicator for assessment of the time of drug consumption.

scholarly journals Enantioselective Quantification of Amphetamine and Metabolites in Serum Samples: Forensic Evaluation and Estimation of Consumption Time

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 521
Author(s):  
Moritz Losacker ◽  
Michael Kraemer ◽  
Alexandra Philipsen ◽  
Kristina Duecker ◽  
Nadine Dreimueller ◽  
...  
Keyword(s):  
Simultaneous Detection ◽  
Forensic Toxicology ◽  
Psychiatric Inpatients ◽  
Forensic Evaluation ◽  
Tandem Mass ◽  
Serum Samples ◽  
Time Intervals ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Precision And Accuracy

In forensic toxicology, amphetamine intoxications represent one of the most common case groups and present difficult questions for toxicologists. Estimating the time of consumption and the current influence of the stimulant is particularly difficult when only total amphetamine concentrations are considered. Stereoselective analysis and the consideration of metabolites can provide valuable information to facilitate interpretation. An enantioselective liquid chromatography−tandem mass spectrometry (LC-MS/MS) method for detection of amphetamine, norephedrine and 4-hydroxyamphetamine was developed. Validation showed satisfactory selectivity, sensitivity, linearity (0.5–250 ng/mL), precision and accuracy for all enantiomers. The method was applied to a collective of 425 forensic serum samples and 30 serum samples from psychiatric inpatients stating their last time of amphetamine consumption. Norephedrine and 4-hydroxyamphetamine were detected more frequently at higher amphetamine concentrations and at lower amphetamine (R)/(S) concentration ratios, possibly indicating recent consumption. Mean (R)/(S) ratio of amphetamine was 1.14, whereas higher ratios (mean 1.36) were found for amphetamine concentrations below 100 ng/mL. The (R)/(S) ratios of psychiatric inpatients significantly correlated with the reported time intervals to last consumption. The use of amphetamine (R)/(S) ratios and the simultaneous detection of metabolites are promising factors that can facilitate estimation of consumption time and current impairment.

scholarly journals Apixaban concentration variability and relation to clinical outcomes in real-life patients with atrial fibrillation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alenka Mavri ◽  
Nina Vene ◽  
Mojca Božič-Mijovski ◽  
Marko Miklič ◽  
Lisbeth Söderblom ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Outcomes ◽  
Thromboembolic Event ◽  
Real Life ◽  
Individual Variability ◽  
Blood Samples ◽  
Chromatography Tandem Mass Spectrometry ◽  
Significant Difference ◽  
Liquid Chromatography Tandem Mass ◽  
Peak Blood

AbstractIn some clinical situations, measurements of anticoagulant effect of apixaban may be needed. We investigated the inter- and intra-individual apixaban variability in patients with atrial fibrillation and correlated these results with clinical outcome. We included 62 patients receiving either 5 mg (A5, n = 32) or 2.5 mg (A2.5, n = 30) apixaban twice-daily. We collected three trough and three peak blood samples 6–8 weeks apart. Apixaban concentration was measured by liquid chromatography-tandem mass-spectrometry (LC–MS/MS) and by anti-Xa. Patients on A2.5 were older, had lower creatinine clearance, higher CHA2DS2VASc (4.7 ± 1.0 vs. 3.4 ± 1.7) and lower trough (85 ± 39 vs. 117 ± 53 ng/mL) and peak (170 ± 56 vs. 256 ± 91 ng/mL) apixaban concentrations than patients on A5 (all p < 0.01). In patients on A5, LC–MS/MS showed a significant difference between through levels and between peak levels (p < 0.01). During apixaban treatment, 21 patients suffered bleeding (2 major). There was no association between bleeding and apixaban concentrations or variability. Four patients who suffered thromboembolic event had lower peak apixaban concentrations than patients without it (159 ± 13 vs. 238 ± 88 ng/mL, p = 0.05). We concluded, that there was a significant intra- and inter-individual variability in apixaban trough and peak concentrations. Neither variability nor apixaban concentrations were associated with clinical outcomes.

scholarly journals Sex differences in serum levels of 5α-androstane-3β, 17β-diol, and androstenediol in the young adults: A liquid chromatography–tandem mass spectrometry study

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261440
Author(s):  
Haruka Tanabe ◽  
Hitoshi Mutai ◽  
Daimei Sasayama ◽  
Hidehiko Sasamoto ◽  
Yoshimichi Miyashiro ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Sex Differences ◽  
Menstrual Cycle ◽  
Rating Scale ◽  
Serum Levels ◽  
Tandem Mass ◽  
Blood Samples ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Hamilton Rating Scale

Animal experiments have consistently shown that estrogen receptor β (ERβ)-selective ligands have antidepressant and anxiolytic effects. In humans, endogenous ligands for ERβ include 5α-androstane-3β, 17β-diol (3βAdiol) and androstenediol (Δ5-diol). We determined, for the first time, the exact serum levels of 3βAdiol and Δ5-diol in young healthy volunteers using liquid chromatography–tandem mass spectrometry (LC–MS/MS). We investigated the effect of the menstrual cycle on the levels of these steroids in women; then, we performed a gender comparison. Blood samples were collected from 48 subjects: 23 women (mean age = 28.4±7.8 years) and 25 men (mean age = 31.4±7.8 years). We collected the blood samples of women at three time-points in the menstrual cycle: the early follicular phase, ovulatory or mid-cycle phase, and mid-luteal phase. A total of 92 blood samples were analyzed using LC–MS/MS. The levels of two well-studied steroids, namely dehydroepiandrosterone (DHEA) and 17β-estradiol (E2), were simultaneously measured. Depression rating scale (Hamilton Rating Scale for Depression, Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology) scores were also recorded at the time of blood sampling. Significant differences in the levels of 3βAdiol and E2 and in the depression rating scale scores were observed over the duration of the menstrual cycle of the women. The levels of 3βAdiol and Δ5-diol were significantly lower in women than in men. E2 levels were higher in women than in men, and DHEA levels did not differ significantly between men and women. Further, women had higher scores than men on the Hamilton Rating Scale for Depression. Sex differences in depressive symptoms can be explained by 3βAdiol and Δ5-diol levels, and the effect of the menstrual cycle on mood can be explained by 3βAdiol and E2 levels, not by Δ5-diol level.

scholarly journals Blood Concentrations of Designer Benzodiazepines: Relation to Impairment and Findings in Forensic Cases

2020 ◽  
Vol 44 (8) ◽  
pp. 905-914 ◽  
Author(s):  
Gunhild Heide ◽  
Gudrun Høiseth ◽  
Gerrit Middelkoop ◽  
Åse Marit Leere Øiestad
Keyword(s):  
High Performance ◽  
Clinical Test ◽  
Concentration Data ◽  
Criminal Offenders ◽  
Blood Concentrations ◽  
Blood Samples ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
The Relationship ◽  
Designer Benzodiazepines

Abstract The use of designer benzodiazepines appears to be increasing in many countries, but data concerning blood concentrations are scarce, making interpretation of concentrations difficult. The aim of this study was to report blood concentrations of clonazolam, diclazepam, etizolam, flualprazolam, flubromazepam, flubromazolam and phenazepam and to investigate the relationship between blood concentrations and impairment. The concentration data are from blood samples collected from living cases (apprehended drivers and other drug offences) and medico-legal autopsies. The blood samples were analysed for the seven designer benzodiazepines mentioned above by ultra high performance liquid chromatography–tandem mass spectrometry. Positive cases from between 1 June 2016 and 30 September 2019 were included. Blood concentrations and the conclusion from a clinical test of impairment (when available) are reported. The presented seven benzodiazepines were detected in a total of 575 cases, where 554 of these cases concerned apprehended drivers or other criminal offenders. The number of findings and the median (range) concentrations were as follows: clonazolam, n = 22, 0.0041 mg/L (0.0017–0.053 mg/L); diclazepam, n = 334, 0.0096 mg/L (0.0016–0.25 mg/L); etizolam, n = 40, 0.054 mg/L (0.015–0.30 mg/L); flualprazolam, n = 10, 0.0080 mg/L (0.0033–0.056 mg/L); flubromazepam, n = 5, 0.037 mg/L (0.0070–0.70 mg/L); flubromazolam, n = 20, 0.0056 mg/L (0.0004–0.036 mg/L); and phenazepam, n = 138, 0.022 mg/L (0.0018–0.85 mg/L). A designer benzodiazepine was the only drug detected with relevance for impairment in 25 of the 554 living cases. The physician concluded with impairment in 19 of the 25 cases. Most of the concentrations in these cases were relatively similar to or higher than the median reported concentrations. The most frequent other drugs detected were amphetamine, tetrahydrocannabinol, clonazepam and methamphetamine. The presented blood concentrations can be helpful with the interpretation of cases involving one or more of these seven benzodiazepines. The results indicate that concentrations commonly observed in forensic cases are associated with impairment.

scholarly journals Measuring sucrose in blood after oral administration to detect abomasal ulcers in calves

2019 ◽  
Vol 31 (5) ◽  
pp. 737-741
Author(s):  
Alexandra Hund ◽  
Armin Schaffer ◽  
Marlies Dolezal ◽  
Hermann Mascher ◽  
Thomas Wittek
Keyword(s):  
Mass Spectrometry ◽  
Oral Administration ◽  
Mixed Models ◽  
Sucrose Solution ◽  
Terminally Ill ◽  
Liquid Chromatography Mass Spectrometry ◽  
Serum Samples ◽  
Blood Samples ◽  
Highperformance Liquid Chromatography ◽  
Over Time

Abomasal ulcers are common in cattle, especially in calves, and to date, there is no reliable antemortem method for diagnosis, to our knowledge. We assessed if measuring sucrose in blood after oral administration in calves could be used to identify animals with abomasal ulcers. Terminally ill calves ( n = 12; part A) and calves designated for slaughter ( n = 123; part B) were given a sucrose solution per os, and blood samples were taken 15, 30, 60, 90, and 120 min (part A) or 30 and 60 min (part B) after administration. The calves were then euthanized or slaughtered, and their abomasa were examined. Serum samples were analyzed using highperformance liquid chromatography-mass spectrometry, and data were analyzed using general linear mixed models. Calves both with and without affected abomasa had increasing sucrose values over time without significant differences. Also, there was no relationship between the size of the mucosal lesion and sucrose values.

scholarly journals Stability Evaluation of DMT and Harmala Alkaloids in Ayahuasca Tea Samples

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2072 ◽  
Author(s):  
Gabriela de Oliveira Silveira ◽  
Rafael Guimarães dos Santos ◽  
Felipe Rebello Lourenço ◽  
Giordano Novak Rossi ◽  
Jaime Hallak ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Stability Evaluation ◽  
Glass Containers ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Harmala Alkaloids ◽  
Health Disorders ◽  
The Stability ◽  
Over Time

Ayahuasca tea is a hallucinogenic beverage used for religious purposes in Brazil and many other countries that has therapeutic potential in the treatment of some mental health disorders. In the context of psychedelic research, quantification of the tea’s main alkaloids prior to its administration in animal or human studies is essential. For this reason, this study aims to provide information regarding the stability of the main ayahuasca alkaloids (dimethyltryptamine, DMT; harmine, HRM; tetrahydroharmine, THH; harmaline, HRL) in three different conditions: (1) A year stored in a refrigerator either in plastic or glass containers, (2) seven days at 37 °C to reproduce usual mail transportation, and (3) after three freeze–thaw cycles. Samples were quantified after a dilute-and-shoot procedure using liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS). There was no significant degradation of DMT concentration over time in all tested conditions. Harmala alkaloids (THH, HRL, and HRM) showed important variations after long-term and high-temperature storages. Although DMT has proven to be stable in all studied conditions, the harmala alkaloids revealed intense degradation and even concentration increment. This may be caused by degradation, alkaloid inter-conversion, and leaching from tea precipitate material. Therefore, ayahuasca quantification before administration in controlled sets is mandatory.

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