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1.
Clin Chem ; 66(4): 579-586, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32232452

RESUMO

BACKGROUND: Insulin-like growth factor-I (IGF-1) is measured mainly by immunoassay for the diagnosis and treatment of growth hormone (GH) disorders, and to detect misuse of GH in sport. Immunoassays often have insufficient inter-laboratory agreement, especially between commercial kits. Over the expected range of IGF-1 in blood (∼50-500 ng/mL), in an inter-laboratory study we previously established a measurement imprecision of 11% (%CV) for the digested protein analyzed by LC-MS. Measuring intact IGF-1 by LC-MS should be simpler. However, no inter-laboratory agreement has been published. METHODS: Intact and trypsin-digested IGF-1 in 32 serum samples from healthy volunteers and human growth hormone administration studies were analyzed by LC-MS using different instruments in five laboratories, as well as by immunoassay in a single laboratory. Another 100 samples were analyzed for IGF-1, both intact and after trypsin-digestion, in each laboratory by LC-MS. The statistical relationship between measurements and the imprecision of each assay group was assessed. RESULTS: An intra-laboratory variability of 2-4% CV was obtained. Inter-laboratory variability was greater at 14.5% CV. Orthogonal regression of intact versus trypsin-digestion methods (n = 646) gave a slope of 1.01 and intercept of 2.05 ng/mL. CONCLUSIONS: LC-MS measurements of IGF-1 by intact and trypsin-digestion methods are not statistically different and each is similar to immunoassay. The two LC-MS approaches may be used interchangeably or together to eliminate concerns regarding an immunoassay IGF-1 measurement. Because intact and digested IGF-1 measurements generally agreed within 20% of each other, we propose this as a criterion of assay acceptability.

2.
Drug Test Anal ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32180361

RESUMO

Dried blood spots (DBS) have been considered as complementary matrix in sports drug testing for many years. Especially concerning substances prohibited in-competition only, the added value of DBS collected concomitantly with routine doping control urine samples has been debated, and an increasing potential of DBS has been discussed in the scientific literature. To which extent and under which prerequisites DBS can contribute to enhanced anti-doping efforts is currently evaluated. As a proof-of-principle, two analytical applications, one targeting cocaine/benzoyl ecgonine and the other prednisone/prednisolone, are presented in this perspective to indicate potential added value but also presently existing limitations of the DBS approach.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32143236

RESUMO

RATIONALE: The misuse of 7-oxo-DHEA (3ß-hydroxyandrost-5-ene-7,17-dione) is prohibited according to the World Anti-Doping Agency (WADA) code. Nevertheless, it is easily available as a dietary supplement and from black market sources. In two recent doping control samples, significant amounts of its main metabolite 7ß-OH-DHEA were identified, necessitating further investigations. METHODS: As both 7-oxo-DHEA and 7ß-OH-DHEA are endogenously produced steroids and no concentration thresholds, applicable to routine doping controls, exist, the development and validation of a carbon isotope ratio (CIR) mass spectrometry method has been desirable. Excretion studies encompassing 7-oxo-DHEA, 7-oxo-DHEA-acetate, and in-house deuterated 7-oxo-DHEA were conducted and evaluated with regard to urinary CIR and potential new metabolites of 7-oxo-DHEA. RESULTS: Numerous urinary metabolites were identified, some of which have not been reported before while others corroborate earlier findings on the metabolism of 7-oxo-DHEA. The CIRs of both 7-oxo-DHEA and 7ß-OH-DHEA were significantly influenced for more than 50 h after a single oral dose of 100 mg, and a novel metabolite (5α-androstane-3ß,7ß-diol-17-one) was found to prolong this detection time window by approximately 25 h. Applying the validated method to routine doping control specimens presenting atypically high urinary 7ß-OH-DHEA levels clearly demonstrated the exogenous origin of 7-oxo-DHEA and 7ß-OH-DHEA. CONCLUSION: As established for other endogenously produced steroids such as testosterone, the CIR allows for a clear differentiation between endo- and exogenous sources of 7-oxo-DHEA and 7ß-OH-DHEA. The novel metabolites detected after administration may help to improve the detection of 7-oxo-DHEA misuse and simplifies its detection in doping control specimens.

4.
Exerc Immunol Rev ; 26: 24-42, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32139353

RESUMO

INTRODUCTION: The essential amino acid tryptophan (TRP) is primarily degraded through the kynurenine (KYN) pathway, which is dysregulated in several chronic diseases. KYN pathway metabolites have immune- and neuro-modulatory properties and are involved in th de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Currently, little evidence exists demonstrating that physical exercise may influence this pathway. However, differences between acute and chronic stimuli as well as the influence of exercise modalities remain to be investigated. Here, we provide an overview of existing studies and present results of a randomized cross-over trial on acute effects of a single-bout of resistance and endurance exercise. METHODS: 24 healthy male adults conducted both an acute endurance exercise (EE) and resistance exercise (RE) session. Blood samples were collected before, immediately after and one hour after cessation of each exercise session. Outcomes comprised serum levels of TRP, KYN, kynurenic acid (KA), quinolinic acid (QA) and calculated ratios. Gene expression of the enzymes indoleamine 2,3 dioxygenase (IDO) 1 and kynurenine aminotransferase (KAT) 4 was measured in peripheral blood mononuclear cells (PBMCs). Moreover, serum concentrations of the potential KYN pathway mediators interleukin (IL)-6 and cortisol were determined. Finally, we investigated baseline correlations between immune cell subsets, potential mediators and initial KYN pathway activation outcomes. RESULTS: The KYN/TRP ratio correlated positively with IL-6 and CD56bright NK-cells and negatively with CD56dim NKcells. Expression of IDO1 in PBMCs correlated positively with IL-6, regulatory T-cells and CD56bright NK-cells, whereas negative correlations to cytotoxic T-cells and CD56dim NKcells were revealed. A significant time effect on KYN/TRP ratio was detected for RE. Regarding KA and KA/KYN ratio, an increase after exercise followed by a decrease at the follow- up measurement was revealed in EE. KAT4 expression also increased after exercise in EE. Moreover, elevated QA levels were observed after the EE session. CONCLUSIONS: In contrast to chronic exercise interventions, single-bouts of endurance exercise provoke acute alterations on KYN pathway outcomes in humans. Our results indicate that EE induces stronger alterations than RE. Enhanced conversion of KYN to both, KA and QA suggest a peripheral KYN clearance, thereby preventing pathological accumulation within the CNS. Future acute and chronic exercise studies are needed to examine the role of NAD+ synthesis starting with TRP and the interplay between KYN pathway activation and mid- to long-term immunological modulations.


Assuntos
Treino Aeróbico , Cinurenina/sangue , Leucócitos Mononucleares/imunologia , Treinamento de Resistência , Adulto , Estudos Cross-Over , Exercício , Humanos , Hidrocortisona/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Interleucina-6/imunologia , Ácido Cinurênico/sangue , Leucócitos Mononucleares/enzimologia , Masculino , Ácido Quinolínico/sangue , Transaminases/imunologia , Triptofano/sangue
6.
Drug Test Anal ; 12(3): 382-390, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31930697

RESUMO

The quantification of peptide hormones by means of liquid chromatography (LC) coupled to mass spectrometry (MS) or other techniques (e.g. immunoassays) has been a challenging task in modern analytical chemistry. Especially for insulin, its synthetic analogs, and C-peptide, reliable determinations are urgently needed due to their diagnostic value in the management of diabetes and insulin resistance and because of the illicit use of insulin as a performance-enhancing agent in professional sports or as an effective toxin in forensic toxicology. The concomitant measurement of C-peptide and insulin offers an established tool for the diagnostic workup of hypoglycemia (endogenous vs. exogenous hyperinsulinemia), characterizing hepatic insulin clearance, and the assessment of beta-cell function (insulin secretion). Thus, the present approach offers the possibility to determine human insulin and its synthetic analogs (lispro, glulisine, aspart, glargine metabolite, degludec, detemir, porcine, and bovine) and C-peptide simultaneously after sample preparation utilizing protein precipitation and a mixed-mode cation-exchange solid-phase extraction, and subsequent detection by LC-high resolution MS. The method was fully validated regarding the following parameters: specificity, limit of detection (0.2 ng/mL), limit of quantification (0.6 ng/mL), recovery (40-90%), accuracy (78-128%), linearity, precision (< 21%), carry over, robustness, and matrix effects. The proof-of-concept was shown by analyzing authentic plasma samples from adults with class II obesity and prediabetes collected in the course of an oral glucose tolerance test. All sample preparation steps were controlled by two stable isotope-labeled internal standards, namely [[2 H10 ] Leu B6, B11, B15, B17 ]-insulin, and [[13 C6 ] Leu 26, 30 ] C-peptide.

7.
Drug Test Anal ; 12(1): 7-26, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31724288

RESUMO

Within the complex construct of today's antidoping work, continuously updated routine doping controls, as well as advancements in sampling and analysis have been of particular relevance and importance. New analytes of existing classes of prohibited substances are frequently included into sports drug testing assays, analytical approaches are optimized to allow for better sensitivities, selectivity, and/or faster turnaround times, and research dedicated to addressing analytical issues concerning scenarios of both (potentially) inadvertent doping and new emerging doping agents is constantly conducted. By way of reviewing and summarizing, this annual banned-substance review evaluates the literature published between October 2018 and September 2019 offering an in-depth evaluation of developments in these arenas and their potential application to substances reported in WADA's 2019 Prohibited List.

8.
Int J Legal Med ; 134(1): 229-241, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31735981

RESUMO

This study centres on the prevalence of new psychoactive substances (NPS) stimulant use, and its relevance as a cause of death amongst individuals between the ages of 12 and 35 in the greater Cologne area. An automated solid-phase extraction-liquid chromatography-tandem mass spectrometry method was developed for the determination of 97 stimulants in urine (including conventional stimulants, e.g. amphetamine and MDMA), of which 68 analytes were fully validated for quantification. Samples of urine or kidney tissue (in cases where urine was unavailable) of 268 deceased were collected, during autopsy, between January 2011 and May 2017 and analyzed. Blood (if available) was also investigated in cases where urine/kidney samples were tested positive for NPS. An intake of stimulants (including NPS stimulants) was proven in 50 cases. In 33 cases, only conventional stimulants were detected. A total of 17 cases were tested positive for NPS. Of the 17 NPS-positive cases, 13 were also tested positive for other conventional drugs of abuse (mostly amphetamine and MDMA). In six NPS-positive cases, at least three different NPS were proven to be ingested. Due to the determined blood concentrations, NPS was assigned as the leading cause of death, or of toxicological relevance, in the cause of death in only 5 cases. In two of the cases, NPS was judged to be a component of a multidrug poisoning, but of minor relevance.

10.
Drug Test Anal ; 12(1): 27-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31412168

RESUMO

This article comprises the development and validation of a protocol for the qualitative analysis of 61 phase I synthetic cannabinoid metabolites in urine originating from 29 synthetic cannabinoids, combining solid-phase extraction (SPE) utilizing a reversed phase silica-based sorbent (phenyl) with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Validation was performed according to the guidelines of the German Society of Toxicological and Forensic Chemistry. Sufficient chromatographic separation was achieved within a total runtime of 12.3 minutes. Validation included specificity and selectivity, limit of detection (LOD), recovery and matrix effects, as well as auto-sampler stability of processed urine samples. LOD ranged between 0.025 ng/mL and 0.5 ng/mL in urine. Recovery ranged between 43% and 97%, with only two analytes exhibiting recoveries below 50%. However, for those two analytes, the LODs were 0.05 ng/mL in urine. In addition, matrix effects between 81% and 185% were determined, whereby matrix effects over 125% were observed for 10 non-first-generation synthetic cannabinoid metabolites. The developed method enables the rapid and sensitive detection of synthetic cannabinoid metabolites in urine, complementing the spectrum of existing analytical tools in forensic case work. Finally, application to 61 urine samples from both routine and autopsy case work yielded one urine sample that tested positive for ADB-PINACA N-pentanoic acid.

11.
Clin Chem Lab Med ; 58(5): 690-700, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31860462

RESUMO

Background Peptide-derived drugs represent an emerging class of prohibited substances in professional sports and, thus, in modern doping controls. After parental administration (e.g. subcutaneous, intravenous), these drugs undergo various metabolic processes, which degrade them to biologically active or inactive peptides. Knowledge about these metabolic processes and the hereby produced metabolites plays a key role in successful doping controls due to the effective design of analytical assays under consideration of optimal analytical targets. Unfortunately, the complexity of biological matrix (e.g. blood or urine) complicates the immediate identification of relevant metabolites due to the enormous excess of naturally occurring peptides and their degradation products. Methods In this study, a strategy employing in-vitro metabolism of stable isotope-labeled peptides producing characteristic reporter ions derived from labeled immonium ions is shown. The in-vitro experiments were performed with human skin tissue microsomes (S9), and model drugs representing prohibited peptide hormones were synacthen, insulin, and corticorelin (respectively, their stable isotope-labeled analogs). After generic sample preparation, the metabolites were identified by means of liquid chromatography (LC) coupled to high-resolution mass spectrometry (MS) in an untargeted approach. Results and conclusions For all three model peptides, several metabolic products were readily identified. While insulin and corticorelin were found to be comparably stable, synacthen was fully degraded, yielding a plethora of metabolic products. A proof of concept concerning the transferability of the obtained data was accomplished by analyzing plasma samples collected post-administration of recombinant human insulin, corroborating the presence of a skin protease-indicative insulin metabolite in vivo.

12.
Drug Test Anal ; 11(11-12): 1755-1760, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31670462

RESUMO

According to class M2.1 of the World Anti-Doping Agency (WADA) Prohibited List, the manipulation of doping control urine samples to alter their integrity and validity is prohibited both in- and out-of-competition. However, some paraplegic athletes with an overactive bladder need to be regularly treated with anti-cholinergic and anti-spasmodic drugs such as oxybutynin, which are often administered intravesically to reduce the substantial side effects observed after oral application. So far, it remains unclear whether such bladder instillations have a negative impact on analytical procedures and thus represent an anti-doping rule violation. Within this pilot study, urine samples were collected from five paraplegic athletes before and after an intravesical oxybutynin hydrochloride instillation. The samples were routinely tested for the presence of performance-enhancing drugs and afterwards fortified with 25 model compounds representing different classes of doping agents (anabolic agents, cannabinoids, diuretics, glucocorticoids, hormone and metabolic modulators, and stimulants) at low and medium concentrations. Additionally, the pH value and specific gravity were measured and the presence of oxybutynin was qualitatively determined by gas chromatography-mass spectrometry (GC-MS). In initial testing procedures, all samples were tested negative. Oxybutynin was present in most of the samples but found to have no significant effect on the detectability of the 25 model compounds subsequently added to each urine specimen. Therefore, it can be concluded that intravesical instillations with oxybutynin hydrochloride do not alter the integrity and validity of doping control urine samples.

14.
Drug Test Anal ; 11(11-12): 1587-1588, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31742912
15.
Drug Test Anal ; 11(11-12): 1644-1655, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31733090

RESUMO

The anabolic-androgenic steroid methylstenbolone (MSTEN; 2α,17α-dimethyl-17ß-hydroxy-5α-androst-1-en-3-one) is available as a so-called designer steroid or nutritional supplement. It is occasionally detected in doping control samples, predominantly tested and confirmed as the glucuronic acid conjugate of methylstenbolone. The absence of other meaningful metabolites reported as target analytes for sports drug testing purposes can be explained by the advertised metabolic stability of methylstenbolone. In 2013, a first investigation into the human metabolism of methylstenbolone was published, and two hydroxylated metabolites were identified as potential targets for initial testing procedures in doping controls. These metabolites were not observed in recent doping control samples that yielded adverse analytical findings for methylstenbolone, and in the light of additional data originating from a recent publication on the in vivo metabolism of methylstenbolone in the horse, revisiting the metabolic reactions in humans appeared warranted. Therefore, deuterated methylstenbolone together with hydrogen isotope ratio mass spectrometry (IRMS) in combination with high accuracy/high resolution mass spectrometry were employed. After oral administration of a single dose of 10 mg of doubly labeled methylstenbolone, urine samples were collected for 29 days. Up to 40 different deuterated methylstenbolone metabolites were detected in post-administration samples, predominantly as glucuronic acid conjugates, and all were investigated regarding their potential to prolong the detection window for doping controls. Besides methylstenbolone excreted glucuronidated, three additional metabolites were still detectable at the end of the study on day 29. The most promising candidates for inclusion into routine sports drug testing methods (2α,17α-dimethyl-5α-androst-1-ene-3ß,17ß-diol and 2α,17α-dimethyl-5α-androst-1-ene-3α,17ß-diol) were synthesized and characterized by NMR.

16.
Drug Test Anal ; 11(11-12): 1675-1697, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31758732

RESUMO

Follistatin, a myostatin-inhibiting protein, is prohibited according to chapter S4 of the "WADA 2019 List of Prohibited Substances and Methods". While currently no approved pharmaceutical formulations of follistatin are available, follistatin can be bought on the black market. Most of the products are labeled "follistatin 344" (FS344), a few "follistatin 315". A study on FS344 black market products was performed and an electrophoretic detection method for serum and urine developed. While only nine of the 17 tested products actually contained follistatin, in some of the others growth promoting peptides were found (e.g. MGF, GHRP-2). Surprisingly, all nine products contained His-tagged FS344 and a high degree of its oligomers. The detection method is based on immunomagnetic purification followed by SDS-PAGE and Western blotting with a monoclonal anti-His antibody. Alternatively, a monoclonal anti-follistatin antibody can be used. For immunoprecipitation (IP), a polyclonal anti-follistatin antibody is applied. An evaluation of suitable antibodies for IP and immunoblotting is also presented. Furthermore, practically all currently available follistatin standards were investigated. The detection limit of the method for black market FS344 in urine is ca 0.1 ng/mL for 10 mL. For a sample volume of 100 µL, an LOD of 5 ng/mL could be achieved for serum. Due to the presence of His-tags an unambiguous differentiation from endogenous follistatin is possible.

17.
Drug Test Anal ; 11(11-12): 1714-1723, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31692253

RESUMO

The TGF-ß cytokine myostatin is considered to be one of the key regulators of skeletal muscle mass. Consequently, specific inhibitors of the growth factor and its signaling pathways are promising therapeutics for the treatment of muscle wasting disorders as well as potential performance-enhancing agents in sports. Domagrozumab is a humanized monoclonal antibody that neutralizes the circulating cytokine, thus preventing receptor activation. Within this study, two complementary detection assays for Domagrozumab from serum were developed by using ammonium sulfate precipitation and immunoaffinity purification either in combination with tryptic digestion and LC-HRMS or Western blotting. While the LC-HRMS assay is highly specific for diagnostic peptides originating from both the heavy and the light chain of the antibody, the second assay is capable of generically detecting intact therapeutic proteins comprising a human Fc domain and exhibiting high specificity for dimeric myostatin/GDF-11. Following optimization, both assays were comprehensively characterized. They can readily be modified to include further protein drugs and will expand the range of available tests for emerging myostatin inhibitors.

18.
Adv Clin Chem ; 93: 115-167, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31655729

RESUMO

The qualitative and quantitative determination of insulin and its related substances (e. g., C-peptide) is of great importance in many different areas of analytical chemistry. In particular, due to the steadily increasing prevalence of metabolic disorders such as diabetes mellitus, an adequate control of the circulating amount of insulin is desirable. In addition, also in forensics and doping control analysis, the determination of insulin in blood, urine or other biological matrices plays a major role. However, in order to establish general reference values for insulin and C-peptide for diabetology, the comparability of measured concentrations is indispensable. This has not yet been fully implemented, although enormous progress has been made in recent years, and the search for a "gold standard" method is still ongoing. In addition to established ligand-binding assays, an increasing number of mass-spectrometric methods have been developed and employed as the to-date available systems (for example, high-resolution/high accuracy mass spectrometers) provide the sensitivity required to determine analyte concentrations in the sub-ng/mL (sub-100pmol/L) level. Meanwhile, also high-throughput measurements have been realized to meet the requirement of testing a high number of samples in a short period of time. Further developments aim at enabling the online measurement of insulin in the blood with the help of an insulin sensor and, in the following, in addition to a brief review, today's state of the art testing developments are summarized.


Assuntos
Líquidos Corporais/metabolismo , Insulina/metabolismo , Sequência de Aminoácidos , Peptídeo C/metabolismo , Medicina Legal , Humanos , Insulina/sangue , Insulina/normas , Insulina/urina , Limite de Detecção , Espectrometria de Massas
19.
Anal Bioanal Chem ; 411(28): 7563-7571, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31641821

RESUMO

Detecting the administration of naturally occurring but synthetically derived steroids (e.g., testosterone) in routine doping controls is particularly laborious and time-consuming. Carbon isotope signatures determined by isotope ratio mass spectrometry (IRMS) have been established as the method of choice to generate confirmatory evidence in case of suspicious or atypical findings in steroid profile analyses; however, IRMS measurements require sophisticated sample preparation methods employing up to two high-performance liquid chromatography (HPLC) purification steps. Here, an alternative sample preparation approach is presented. Immunoaffinity chromatography (IAC) was employed to reduce the batch analysis time by omitting the time-consuming HPLC purification steps, while pre- and post-IAC sample handling followed published protocols. IAC exploits specific antibody-immunogen interactions, and the option of combining three immunoaffinity gels containing specific antibodies for testosterone, pregnanediol, and 11-ketoetiocholanolone into a multi-immunoaffinity sample preparation approach was assessed. Due to cross reactivities, also etiocholanolone, androsterone, 5ß-androstanediol, and 5α-androstanediol were co-extracted and included in the testing protocol. The method was validated by determining precision, recovery, and carry over, and performing linear mixing models. IAC was found to be applicable to the determination of carbon isotope ratios in doping controls and the approach allowed for an accelerated sample preparation. Graphical abstract.


Assuntos
Cromatografia de Afinidade/métodos , Doping nos Esportes , Cromatografia Gasosa-Espectrometria de Massas/métodos , Detecção do Abuso de Substâncias/métodos , Congêneres da Testosterona/urina , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Isótopos , Reprodutibilidade dos Testes
20.
Forensic Sci Int ; 303: 109959, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31546164

RESUMO

The organ distribution of 3-fluorophenmetrazine (3-FPM), pyrazolam, diclazepam as well as its main metabolites delorazepam, lormetazepam and lorazepam, was investigated. A solid phase extraction (SPE) and a QuEChERS (acronym for quick, easy, cheap, effective, rugged and safe) - approach were used for the extraction of the analytes from human tissues, body fluids and stomach contents. The detection was performed on a liquid chromatography-tandem mass spectrometry system (LCMS/MS). The analytes of interest were detected in all body fluids and tissues. Results showed femoral blood concentrations of 10 µg/L for 3-FPM, 28 µg/L for pyrazolam, 1 µg/L for diclazepam, 100 µg/L for delorazepam, 6 µg/L for lormetazepam, and 22 µg/L for lorazepam. Tissues (muscle, kidney and liver) and bile exhibited higher concentrations of the mentioned analytes than in blood. Additional positive findings in femoral blood were for 2-fluoroamphetamine (2-FA, approx. 89 µg/L), 2-flourometamphetamine (2-FMA, hint), methiopropamine (approx. 2.2 µg/L), amphetamine (approx. 21 µg/L) and caffeine (positive). Delorazepam showed the highest ratio of heart (C) and femoral blood (P) concentration (C/P ratio = 2.5), supported by the concentrations detected in psoas muscle (430 µg/kg) and stomach content (approx. 210 µg/L, absolute 84 µg). The C/P ratio indicates that delorazepam displays susceptibility for post-mortem redistribution (PMR), supported by the findings in muscle tissue. 3-FPM, pyrazolam, diclazepam, lorazepam and lormetazepam did apparently not exhibit any PMR. The cause of death, in conjunction with autopsy findings was concluded as a positional asphyxia promoted by poly-drug intoxication by arising from designer benzodiazepines and the presence of synthetic stimulants.


Assuntos
Benzodiazepinas/farmacocinética , Drogas Desenhadas/farmacocinética , Diazepam/análogos & derivados , Fenmetrazina/análogos & derivados , Mudanças Depois da Morte , Adulto , Benzodiazepinas/análise , Bile/química , Líquidos Corporais/química , Química Encefálica , Drogas Desenhadas/análise , Diazepam/análise , Diazepam/farmacocinética , Toxicologia Forense , Conteúdo Gastrointestinal/química , Humanos , Rim/química , Fígado/química , Lorazepam/análogos & derivados , Lorazepam/análise , Lorazepam/farmacocinética , Pulmão/química , Masculino , Nordazepam/análogos & derivados , Nordazepam/análise , Nordazepam/farmacocinética , Líquido Pericárdico/química , Fenmetrazina/análise , Fenmetrazina/farmacocinética , Músculos Psoas/química , Espectrometria de Massas em Tandem
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