Concentrations of para-Fluorofuranylfentanyl (FFF) in Paired Central and Peripheral Blood Collected During Postmortem Death Investigations

2021 ◽  
Author(s):  
Judith Rodriguez Salas ◽  
Alex J Krotulski ◽  
Reta Newman ◽  
Jon R Thogmartin ◽  
Amanda L A Mohr ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Peripheral Blood ◽  
The United States ◽  
Blood Concentrations ◽  
Pinellas County ◽  
Flight Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Death Investigation ◽  
Medicolegal Death Investigation

Abstract The opioid epidemic in the United States (U.S.) has been associated with an increasing mortality rate in large part due to the emergence and proliferation of synthetic opioids over the last fifteen years. Fentanyl and its analogues have played a large part in these statistics due to their potency and toxicity. Fluorofuranylfentanyl (FFF) is a fentanyl analogue that emerged in the U.S. in 2018 and was associated with numerous adverse events and deaths. During this study, a liquid chromatography tandem mass spectrometry (LC-MS/MS) workflow was developed to accurately identify the isomer of FFF present (ortho- vs. meta- vs. para-) in medicolegal death investigation cases from Pinellas County, Florida. FFF was quantified in central and peripheral blood samples collected at autopsy. In addition, the metabolism of FFF was studied using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). para-FFF was quantitatively confirmed in 29 postmortem cases; no other isomer of FFF was detected. Central blood concentrations ranged between 0.66 and 73 ng/mL (mean = 11±14 ng/mL, median = 10 ng/mL) and peripheral blood concentrations ranged between 0.53 and 23 ng/mL (mean = 5.7±6.4 ng/mL, median = 2.7 ng/mL). Comparison of central to peripheral blood concentrations were evaluated to determine the possibility of postmortem redistribution (PMR). The metabolism of ortho-FFF was studied and found to undergo metabolic processes similar to fentanyl, producing ortho-fluorofuranyl-norfentanyl, fluoro-4-ANPP, and hydroxylated species. The results of this study demonstrate the toxicity of FFF and its implication in medicolegal death investigations. Laboratories must remain aware of new or re-emerging fentanyl analogues, as they pose significant risks to public health and public safety.

Flualprazolam Blood Concentrations in 197 Forensic Investigation Cases

2020 ◽  
Author(s):  
Donna M Papsun ◽  
Alex J Krotulski ◽  
Joseph Homan ◽  
Keith D H Temporal ◽  
Barry K Logan
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Drug Testing ◽  
Human Performance ◽  
Standard Addition ◽  
Blood Concentrations ◽  
Median Concentration ◽  
Flight Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
The Mean

Abstract Flualprazolam is a designer benzodiazepine and novel psychoactive substance that is increasing in prevalence and appearing in forensic investigations. Flualprazolam was quantitatively confirmed in 197 blood samples from medicolegal death investigations and human performance cases reported between August 2019 and February 2020. Drug screening was performed using liquid chromatography–time-of-flight mass spectrometry and quantitative confirmation was performed using liquid chromatography–tandem mass spectrometry. A three-point standard addition protocol was implemented for quantitation in the absence of an available traditionally validated assay. In postmortem cases with quantitative results (n = 167), the mean (±standard deviation [SD]) flualprazolam concentration was 20 (±63) ng/mL, the median concentration was 8.2 ng/mL and the range of concentrations was 2.0–620 ng/mL. Four additional postmortem cases were reported positive (<2.0 ng/mL). In drug impaired driving cases (n = 22), the mean (±SD) flualprazolam concentration was 22 (±18) ng/mL, the median concentration was 14 ng/mL and the range of concentrations was 4.4 to 68 ng/mL. The four remaining cases were of unknown circumstances. This report details the most extensive dataset of flualprazolam intoxication cases reported to date. There was significant overlap in concentrations of flualprazolam between postmortem and DUID cases. Flualprazolam was commonly (83% of the time) found in combination with opioids (e.g. fentanyl). Toxicologists should consider quantitative flualprazolam results in the context of case history, observations, and/or other toxicological findings. Addition of flualprazolam to the scope of drug testing should be considered by all laboratories.

A Case Series of Etizolam in Opioid-Related Deaths

2020 ◽  
Author(s):  
Jirair Gevorkyan ◽  
Juliet Kinyua ◽  
Sue Pearring ◽  
Luke N Rodda
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Drug Toxicity ◽  
Case Series ◽  
Gastric Fluid ◽  
Multiple Drug ◽  
Flight Mass Spectrometry ◽  
Nonmedical Use ◽  
Liquid Chromatography Tandem Mass ◽  
Death Investigation

Abstract Etizolam is a novel psychoactive substance and novel benzodiazepine of the thienotriazolodiazepine class, which has recently seen an increasing trend in use worldwide. We report a case series of 10 decedents with etizolam and opioids in their systems. Death investigation, expanded toxicology and medical investigation information were included for contextualization of etizolam in death. Etizolam was detected and confirmed within peripheral and cardiac blood, urine, vitreous humor and, in one case, gastric fluid, by liquid chromatography–tandem mass spectrometry and liquid chromatography–quadrupole time of flight mass spectrometry methodologies. Death investigation indicated nonmedical use of most drugs. Medical investigation commonly noted pulmonary edema, cardiomegaly and cerebral swelling. The majority of the decedents appeared to be unaware of the presence of etizolam and succumbed to the mixed drug toxicity of their routine depressant and narcotic analgesic drug of abuse in combination with etizolam. Etizolam use continues to be observed and poses as a potentially lethal contribution to multiple drug toxicity, especially in the age of the opioid crisis. Assessment of analytes like etizolam requires up-to-date methodologies and vigilance in testing to better characterize the toxicology and interpret the contribution to death.

scholarly journals Determination of Tissue Distribution of Alisol G, a CB1R Antagonist, in Rats by Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry

2021 ◽  
Author(s):  
Chen-Yu Gao ◽  
Jian-Qiang Xi ◽  
Ding-Zhong Song ◽  
Jie Yuan ◽  
Wu-Si Hao ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Tandem Mass Spectrometry ◽  
High Performance ◽  
Tandem Mass ◽  
Blood Concentrations ◽  
Therapeutic Benefits ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass

AbstractPeripheral CB1R blockers without crossing the blood–brain barrier (BBB) have demonstrated therapeutic benefits in metabolic syndromes, including obesity. Among them is Alisol G, a tetracyclic triterpene from Alismatis rhizoma (zexie), which can effectively reduce the weight of obese mice. Results from CP55940-induced [35S] GTPγS cannabinoid-type 1 receptor (CB1R) binding assay show an IC50 of 34.8 μmol/L for Alisol G, implicating its role as a CB1R antagonist. The purpose of our study is to assess whether Alisol G could serve as a peripheral CB1R antagonist for obesity treatment. In this study, we build a simple, reliable, and sensitive method to detect the concentration of Alisol G in rat tissue by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The results showed that Alisol G was mainly distributed in intestinal midgut, mucosa and small intestine, with little brain exposure. We suggested that intestine may be the main acting sites of Alisol G. Through comparison of brain and blood concentrations of Alisol G, our data showed that Alisol G cannot penetrate the BBB easily. In conclusion, Alisol G may represent a peripheral CB1R antagonist for the further treatment of obesity.

scholarly journals Qualitative analysis of 7- and 8-hydroxyzolpidem and discovery of novel zolpidem metabolites in postmortem urine using liquid chromatography–tandem mass spectrometry

2022 ◽  
Author(s):  
Koji Yamaguchi ◽  
Hajime Miyaguchi ◽  
Youkichi Ohno ◽  
Yoshimasa Kanawaku
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Pyridine Ring ◽  
Multiple Reaction Monitoring ◽  
Fragmentation Pattern ◽  
The Novel ◽  
Flight Mass Spectrometry ◽  
Urine Extract ◽  
Liquid Chromatography Tandem Mass ◽  
Characteristic Fragmentation

Abstract Purpose Zolpidem (ZOL) is a hypnotic sometimes used in drug-facilitated crimes. Understanding ZOL metabolism is important for proving ZOL intake. In this study, we synthesized standards of hydroxyzolpidems with a hydroxy group attached to the pyridine ring and analyzed them to prove their presence in postmortem urine. We also searched for novel ZOL metabolites in the urine sample using liquid chromatography–triple quadrupole mass spectrometry (LC-QqQMS) and liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QqTOFMS). Methods 7- and 8-Hydroxyzolpidem (7OHZ and 8OHZ, respectively) were synthesized and analyzed using LC-QqQMS. Retention times were compared between the synthetic standards and extracts of postmortem urine. To search for novel ZOL metabolites, first, the urine extract was analyzed with data-dependent acquisition, and the peaks showing the characteristic fragmentation pattern of ZOL were selected. Second, product ion spectra of these peaks at various collision energies were acquired and fragments that could be used for multiple reaction monitoring (MRM) were chosen. Finally, MRM parameters were optimized using the urine extract. These peaks were also analyzed using LC-QqTOFMS. Results The presence of 7OHZ and 8OHZ in urine was confirmed. The highest peak among hydroxyzolpidems was assigned to 7OHZ. The novel metabolites found were zolpidem dihydrodiol and its glucuronides, cysteine adducts of ZOL and dihydro(hydroxy)zolpidem, and glucuronides of hydroxyzolpidems. Conclusions The presence of novel metabolites revealed new metabolic pathways, which involve formation of an epoxide on the pyridine ring as an intermediate.

Sensitive, specific quantitative analysis of tacrolimus (FK506) in blood by liquid chromatography-electrospray tandem mass spectrometry

1996 ◽  
Vol 42 (2) ◽  
pp. 279-285 ◽  
Author(s):  
P J Taylor ◽  
A Jones ◽  
G A Balderson ◽  
S V Lynch ◽  
R L Norris ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Tandem Mass Spectrometry ◽  
Complex Mixture ◽  
Turnaround Time ◽  
Pharmacokinetic Studies ◽  
Tandem Mass ◽  
Blood Concentrations ◽  
Liquid Chromatography Tandem Mass ◽  
The Difference

Abstract The capacity of liquid chromatography-tandem mass spectrometry (LC-MS2) to detect and define individual components in a complex mixture has been utilized to develop a quantitative assay of the potent immunosuppressant drug, tacrolimus. Trough blood concentrations were measured in 175 samples obtained over several weeks after liver transplantation from seven patients. The assay was linear over the range of 0.2 to 100 micrograms/L. Imprecision was <8%, and accuracy was 99-101%. The turnaround time for a batch of 20 samples was 2.5 h. No interference from any of the other drugs being administered to the patients was evident. An ELISA also performed on the same samples overestimated the concentrations substantially, as indicated by a plot of the difference between the results for the two methods vs their mean. The favorable characteristics of the LC-MS2 assay, especially its sensitivity and specificity, will facilitate detailed pharmacokinetic studies of tacrolimus, particularly under circumstances in which metabolism is perturbed by either hepatic dysfunction or drug interactions.

Emerging Synthetic Cannabinoids: Development and Validation of a Novel Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry Assay for Real-Time Detection

2019 ◽  
Vol 44 (3) ◽  
pp. 207-217 ◽  
Author(s):  
Alex J Krotulski ◽  
Amanda L A Mohr ◽  
Barry K Logan
Keyword(s):  
United States ◽  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Real Time ◽  
Synthetic Cannabinoids ◽  
Time Of Flight ◽  
Forensic Toxicology ◽  
The United States ◽  
Synthetic Cannabinoid ◽  
Flight Mass Spectrometry

Abstract Synthetic cannabinoids pose significant threats to public health and safety, as their implications in overdose and adverse events continue to arise in United States and around the world. Synthetic cannabinoids have seen several generations of chemically diverse structural elements, impacting potency and effects. These factors create new analytical challenges for forensic laboratories. This report describes an efficient liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) assay for the identification of synthetic cannabinoid parent compounds and metabolites, including real-time identification of emergent compounds, using a SCIEX TripleTOF® 5600+ with non-targeted SWATH® acquisition. Method validation evaluated precision/accuracy, limits of detection, interferences, processed sample stability and carryover, for which 19 parent compounds and 19 metabolites were tested. To demonstrate feasibility, de-identified blood sample extracts were acquired from a large forensic toxicology laboratory and analyzed using the validated LC-QTOF-MS assay. In mid-2018, 200 blood extracts were analyzed, demonstrating a 19% positivity rate with > 94% agreement rate with original testing. In addition, three newly discovered synthetic cannabinoids were identified, including 5F-MDMB-PICA, 4-cyano CUMYL-BUTINACA and 5F-EDMB-PINACA. These synthetic cannabinoids were previously unreported in forensic toxicology casework in the United States. 5F-MDMB-PICA has become the most prevalent synthetic cannabinoid in United States, as of early 2019. These results demonstrate the effectiveness of this assay and workflow in the identification and characterization of synthetic cannabinoids, as well as the usefulness of sample-mining using non-targeted mass acquisition by LC-QTOF-MS for the discovery of NPS. High resolution mass spectrometry should be considered when developing new or novel assays for synthetic cannabinoids.

Method Validation of Seven Synthetic Cathinones by LC–MS-MS Analysis and the Prevalence of N-Ethylpentylone in Postmortem Casework

2020 ◽  
Author(s):  
Alexander D Giachetti ◽  
Joseph H Kahl ◽  
M Elizabeth Zaney ◽  
George W Hime ◽  
Diane M Boland
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Tandem Mass Spectrometry ◽  
Solid Phase ◽  
Synthetic Cathinones ◽  
Medical Examiner ◽  
Tandem Mass ◽  
Blood Concentrations ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass

Abstract N-ethylpentylone (NEP, ephylone, bk-EBDP) was the most prevalent synthetic cathinone detected by the Miami-Dade Medical Examiner Toxicology Laboratory from 2016 to 2018. There is limited information regarding the toxicity of NEP; however, the few published reports suggest that NEP can cause serious toxic effects and sudden death. The purpose of this publication is to describe a validated liquid chromatography-tandem mass spectrometry (LC–MS-MS) method for seven synthetic cathinones (methylone, ethylone, butylone, dibutylone, alpha-Pyrrolidinopentiophenone (α-PVP), pentylone and NEP) and to present a detailed summary regarding the presence of NEP in postmortem casework at the Miami-Dade Medical Examiner Department. Postmortem iliac blood, serum, liver and brain specimens were prepared by solid-phase extraction with analysis by ultra-high-performance liquid chromatography-tandem mass spectrometry. Analyte linearity was established from 0.01 to 0.5 mg/L on a six-point calibration curve. A total of 101 NEP quantitations were performed using this method. Concentrations in postmortem case samples ranged from 0.01 to 2.7 mg/L. Iliac blood concentrations averaged 0.312 mg/L with a median of 0.137 mg/L (n = 72) across all causes and manners of death. Approximately half of the cases were homicides in which the decedent was the victim of gunshot wounds or stabbing. Two of the three highest concentration cases of NEP (2.7 and 1.7 mg/L) involved 38-year-old white males who were tasered by police prior to death. The psychostimulant effect of NEP may result in an excited delirium and/or hallucinogenic state. The concentration of NEP detected in accidental intoxication and polydrug cases overlapped with those attributed to other causes, including homicides and police-involved deaths.

scholarly journals Case Series of Novel Illicit Opioid-Related Deaths

2017 ◽  
Vol 7 (3) ◽  
pp. 477-486 ◽  
Author(s):  
Donna Papsun ◽  
Amy Hawes ◽  
Amanda L.A. Mohr ◽  
Melissa Friscia ◽  
Barry K. Logan
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Whole Blood ◽  
High Performance ◽  
Case Series ◽  
Forensic Toxicology ◽  
Smoke Inhalation ◽  
Manner Of Death ◽  
Flight Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass

Novel illicit opioids, such as furanyl fentanyl and U-47700, are being encountered with increasing frequency in street heroin samples and have been confirmed in a series of overdose deaths in Tennessee. In this paper, we report the pathology and toxicology from 11 deaths involving furanyl fentanyl and U-47700. Routine toxicology was performed on postmortem femoral or antemortem hospital blood samples with targeted broad spectrum drug screening using liquid chromatography-time-of-flight mass spectrometry (LC-TOF/MS). Confirmation and quantitation of the opioid agonists U-47700 and furanyl fentanyl was performed by ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) using a novel method. Two cases were identified as containing U-47700 in whole blood (189 and 547 ng/mL), and nine cases contained furanyl fentanyl in whole blood, with concentrations ranging from 2.0 – 42.9 ng/mL. In all 11 cases, the manner of death was deemed accident, with drug intoxication being the primary cause of death; one case was complicated by smoke inhalation. All of the decedents were males ranging from 18-62 years, with the median age being 36 years old. The successful identification and confirmation of these novel illicit opioids in this case series relied on the comprehensive investigation and collaboration of scene investigation, forensic pathology, and forensic toxicology.

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