Pharmacobezoar-Related Fatalities: A Case Report and a Review of the Literature.

ABSTRACT: Pharmacobezoars develop after an acute overdose or during routine drug administration. Here, the authors present a case of fatal multidrug overdose involving a 62-year-old woman. Her usual treatment included tramadol extended-release, citalopram, and mirtazapine. Furthermore, she self-medicated and misused her husband's medications. The autopsy revealed the presence of a voluminous medication bezoar in the stomach. No mechanical complication was noted. Toxicologic analyses were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection, gas chromatography with mass spectrometry detection, and liquid chromatography coupled to tandem mass spectrometry. Tramadol (34,000 mcg/L), O-desmethyltramadol (2200 mcg/L), propranolol (6000 mcg/L), bromazepam (2500 mcg/L), zopiclone (1200 mcg/L), and citalopram (700 mcg/L) were identified in femoral blood at toxic concentrations. Interestingly, the femoral blood and vitreous humor concentration ratio was approximately 0.7. Furthermore, an English exhaustive literature search was performed using several different electronic databases without any limiting period to identify published pharmacobezoar-related fatalities. Seventeen publications were identified reporting a total of 19 cases. Decedents' mean age was 47.6 years [0.8-79] and a clear female predominance emerged. Several drugs were involved in pharmacobezoar formation. Death was attributed to drug toxicity in 13 cases, and to mechanical complications and/or sepsis in 4 cases. A mixed cause of death was reported in 2 cases. Although rare, pharmacobezoars remain potentially lethal and raise challenges in therapeutic management.

Acute Sodium Oxybate Intoxication: A Case Report and Review of the Literature.

PURPOSE: Despite a better safety profile than illicit γ-hydroxybutyric acid (GHB) and other GHB analogs, sodium oxybate continues to raise serious concerns regarding clinical safety. In this study, the authors report the case of near-fatal intoxication involving sodium oxybate-alcohol combination in a 40-year-old woman. In addition, a review of the literature on published cases of intoxication involving this pharmaceutical form of GHB was conducted. A 40-year-old woman was admitted to the intensive care unit in a coma after voluntary ingestion of 18 g of sodium oxybate and alcohol. METHODS: The GHB plasma concentration was quantified to be 146 mg/L using liquid chromatography coupled with tandem mass spectrometry. An English literature search was performed using PubMed without any limiting period to identify all available scientific publications involving cases of sodium oxybate intoxication. RESULTS: Six cases were identified. Five involved fatal intoxication cases, with GHB postmortem blood concentrations ranging from 11.5 to 3500 mg/L. One involved a nonfatal intoxication case with a GHB serum concentration of 569 mg/L 7 hours postingestion. CONCLUSIONS: In the present case, the estimated elimination half-life was 154 minutes. The risk of acute poisoning seems to be high considering the pharmacokinetic properties of sodium oxybate. Physicians and toxicologists must take such properties into account.

3-Methylmethcathinone Intoxication: Discrepancies Between Blood Concentrations and Clinical Outcomes-A Short Communication.

BACKGROUND: The absence of a correlation between the blood concentration of 3-methylmethcathinone (3-MMC) and clinical outcomes in intoxication cases has been attributed to stability issues. Indeed, a loss of more than 50%, 70%, and even 95% of 3-MMC in whole blood after 2 weeks of storage at 20°C, 4°C, and room temperature, respectively, has been reported in the past. Here, the authors report the case of a 43-year-old man who was hospitalized with generalized convulsive status epilepticus related to 3-MMC use with a plasma concentration of 9600 ng/mL (delay between sampling and analysis <72 hours). The stability of 3-MMC was evaluated in several biological specimens. METHODS: Three quality control samples (human plasma, whole blood, and postmortem blood) spiked with 3-MMC were stored at -20°C and 4°C for 14 days. The initial analysis was performed on day 1 to establish the initial concentration of 3-MMC in each specimen type, and the samples were divided into 2 aliquots for storage under both conditions. Further analyses were performed on days 7 and 14 for each specimen, and the results were compared with those obtained on day 1. RESULTS: 3-MMC appeared relatively stable in whole and postmortem blood when stored at -20°C for 1 week, with losses of <3% in both matrices (0% and 2.5%, respectively). At +4°C, 3-MMC losses ranged from 25% to 53%. CONCLUSIONS: These results differ from others reported in the literature. Hence, it may be hypothesized that other elements should be considered to explain the discrepancy between the concentration and toxicity pointed out by the Toxicology community, especially the development of tolerance.

Preliminary Metabolomic Profiling of the Vitreous Humor from Hypothermia Fatalities.

The postmortem diagnosis of hypothermia fatalities is often complex due to the absence of pathognomonic lesions and biomarkers. In this study, potential novel biomarkers of hypothermia fatalities were searched in the vitreous humor of known cases of hypothermia fatalities (n = 20) compared to control cases (n = 16), using a targeted metabolomics approach allowing quantitative detection of 188 metabolites. A robust discriminant model with good predictivity was obtained with the supervised OPLS-DA multivariate analysis, showing a distinct separation between the hypothermia and control groups. This signature was characterized by the decreased concentrations of five metabolites (methionine sulfoxide, tryptophan, phenylalanine, alanine, and ornithine) and the increased concentration of 28 metabolites (21 phosphatidylcholines, 3 sphingomyelins, spermine, citrulline, acetylcarnitine, and hydroxybutyrylcarnitine) in hypothermia fatalities compared to controls. The signature shows similarities with already identified features in serum such as the altered concentrations of tryptophan, acylcarnitines, and unsaturated phosphatidylcholines, revealing a highly significant increased activity of methionine sulfoxide reductase, attested by a low methionine sulfoxide-to-methionine ratio. Our results show a preliminary metabolomics signature of hypothermia fatalities in the vitreous humor, highlighting an increased methionine sulfoxide reductase activity.

A fatal case after an intravenous injection of levamisole.

Levamisole is a drug originally prescribed as an antihelmintic. Because of the occurrence of severe cases of agranulocytosis and leukoencephalitis it was removed from the French market in 1998 for human use, while it remains available for veterinary use. Nowadays in France its only use in humans is regulated by authorization for temporary use for its immunomodulatory properties in the treatment of nephritic syndrome.A 52-year-old man was found dead at his farm. Injection points were observed on his arm and a syringe containing a dark orange-brown liquid was found near the body. At his home, the discovery of a letter highlighted suicidal intent. Analysis of the aforementioned liquid, peripheral blood and urine confirmed the unique presence of levamisole. The femoral blood concentration of levamisole was of 25 mg/L whereas the femoral blood concentrations reported in cases of fatalities after cocaine use do not exceed 0.0056 mg/L. In humans, levamisole can be detected in biological samples after cocaine use as this drug is also an adulterant and one of its metabolites (aminorex) seems to have amphetamine-like properties. In this case, the man consumed levamisole from time to time for its stimulant and strengthening effects.Cases of fatal poisoning using levamisole are very rare and poorly documented, which makes the interpretation of postmortem blood levamisole concentration difficult.

Pitfalls of toxicological investigations in hair, bones, and nails in extensively decomposed bodies: illustration with two cases.

It is difficult to carry out toxicological investigations in biological samples collected from extensively decomposed bodies and to interpret obtained results as several pitfalls should be considered: redistribution phenomena, degradation of xenobiotics during the postmortem period, contamination by putrefaction fluids, and external contamination. This work aims to present two cases in order to illustrate and discuss these difficulties in this tricky situation. Case#1: the body of a 30-year-old woman was found in a wooded area (1 month after she has been reported missing by her family): hair and a femur section were sampled. Case#2: the decomposed corpse of a 52-year-old man was found in a ditch: hair and nails were sampled. After decontamination steps, toxicological investigations were performed using liquid chromatography with high-resolution mass spectrometry and tandem mass spectrometry detection methods. In case#1, the same drugs or metabolites (benzodiazepines, propranolol, tramadol, acetaminophen, paroxetine, and oxetorone) were detected in hair and in bone specimens. This result combination strongly suggests intakes close to the time of death for three of them (oxazepam, lormetazepam, and propranolol). In case#2, results of toxicological investigations in hair and nails [(hair/nail concentration in ng/mg) nordiazepam (1.12/1.06), oxazepam (0.113/0.042), zolpidem (0.211/< 0.01), hydroxyzine (0.362/< 0.01), and cetirizine (0.872/1.110)] were both consistent with several drug intakes but were not contributory to cause of death determination. In case of positive toxicological results in biological samples collected from extensively decomposed bodies (such as hair, bones, or nails), it is challenging to determine the time, and even more, the level of the dose of exposure(s).

Tramadol intoxication in children: An emerging issue.

BACKGROUND: Prescribing tramadol in children raises safety concerns. In Europe, tramadol is still approved and licensed for use in children over 1-3 years of age, depending on the country. In this context, the authors report a case of a tramadol overdose in a 5-year-old-child with a medical history of homozygous sickle cell disease. METHODS: Tramadol and M1 were quantified using liquid chromatography with a diode array detection method. CYP2D6 genotype was determined using a next generation sequencing platform (MISeq, Illumina). RESULTS: Tramadol and M1 were quantified in blood respectively at 5.48 and 1.32µg/mL at admission, at 0.77 and 0.35µg/mL 12hours later, and at 0.32 and 0.18µg/mL 20hours later. The patient was predicted as a CYP2D6 normal metabolizer (*35/*29). CONCLUSION: One of the most important difficulties with the use of tramadol in children relates to its pharmacokinetic (PK) properties. Indeed, tramadol's PK is characterized by a great variability related to: (i) anatomical/physiological factors that impact the volume of distribution (Vd); (ii) CYP2D6 genetic polymorphisms. Considering such an issue is particularly relevant to prevent poisoning. In the reported case, the plasma elimination half-life was estimated at 6.3h, significantly more than those reported in 2-8 year-old children (about 3h). This discrepancy does not seem related to genetic polymorphisms but rather to the Vd. Indeed, the patient was predicted to be a CYP2D6 normal metabolizer (*35/*29). The case presented here highlights the risk associated with the tramadol use in children and emphasizes the importance of considering PK variability among this population. Such variability necessitates greater caution in prescribing tramadol in children and highlights the importance of therapeutic education for families of children treated with this painkiller.

The interest of using vitreous humor for γ-hydroxybutyrate (GHB) quantification in related fatalities: Stability evaluation, case report and literature review.

Analysis and interpretation of the findings for γ-hydroxybutyrate (GHB) in related fatalities remains problematic. Indeed, GHB is a naturally occurring compound present in both the mammalian central nervous system and peripheral tissue. Moreover, a postmortem increase in endogenous GHB concentration has been observed, especially in blood. Facing this issue, the use of an alternative matrix such as vitreous humor (VH) can thus be particularly interesting for GHB testing and quantification. VH is considered to be less prone to postmortem redistribution, is easy to collect, and has relatively few interfering compounds for the analytical process. In this context, the authors report the case of a GHB-related fatality involving 22-year-old male. In this case, GHB femoral blood (FB) (790 mg/L) and vitreous (750 mg/L) concentrations appeared similar with a FB to VH (FB/VH) ratio of 1.05. In addition, other similar cases with both GHB blood and vitreous concentrations were reviewed. Five cases were identified. The blood to VH ratios ranging from 0.13 to 2.58. Finally, GHB stability was documented in postmortem blood and VH, in order to address the reliability of VH as an alternative matrix for GHB quantitation at postmortem. GHB appeared relatively stable in postmortem blood specimens (at 50 mg/L) over a period of 28 days when stored at +4 °C or -20 °C. The same results were observed in VH specimens.

Synthetic cathinones in drug-facilitated sexual assault: A case report involving the novel generation substituted cathinone N-ethylpentedrone and a review of the literature.

The use of 3,4-methylenedioxymethamphetamine (MDMA) in drug-facilitated sexual assault (DFSA) is not uncommon. Indeed, the effects associated with the use of this substance may lead to disinhibition. Several synthetic cathinones, such as mephedrone or methylone, also possess marked entactogenic properties. This manuscript aims to (i) report a DFSA case involving a novel cathinone derivative, namely N-ethyl-pentedrone (NEPD) and (ii) review previously reported DFSA cases involving synthetic cathinones. Using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), NEPD was detected in both plasma and urine collected from a 36-year-old male who had been victim of DFSA. Furthermore, an exhaustive, non-period-specific English-language literature search was performed using several different electronic databases to identify DFSA cases involving synthetic cathinones. Overall, five synthetic cathinones have been associated with DFSA:methylenedioxypyrovalerone, 4-methylethcathinone, α -pyrrolidinopentiophenone, mephedrone, α -pyrrolidinohexiophenone, and methylone, which appears to be the most frequently reported. Methylone is the ß-keto analog of MDMA, with which it shares substantial pharmacological similarities. Indeed, the pharmacological effects of methylone are similar to those associated with MDMA. By contrast, little is known regarding NEPD's pharmacological effects in humans. Based on subjective reports, NEPD can produce both positive and negative effects in human. Unlike what is reported in the case of methylone or mephedrone, only a small minority of NEPD users report slightly entactogenics effects. Such properties theoretically make NEPD more suitable for use in a chemsex context than in DFSA context; even though, the boundary between these two specific forms of sexualized drug use can sometimes appear tenuous.

Toxicity of designer benzodiazepines: A case of etizolam and cocaine intoxication.

During the last decade, only few cases of acute etizolam intoxication have been detailed. Little is known about the toxic effects of etizolam overdose. Here, the authors report the case of a 42-year-old man who was admitted to the emergency department for intense agitation following etizolam and cocaine consumption. Detection and determination of etizolam and cocaine (including metabolites) were achieved using liquid chromatography tandem mass spectrometry. Etizolam and benzoylecgonine (BZE) were detected in plasma at 64 and 10 ng/mL, respectively. The level of cocaine was below the limit of quantification (< 5 ng/mL). To the authors' knowledge, the only report detailing an etizolam overdose was provided by O'Connell et al. and was characterized by the presence of central nervous system (CNS) depression signs. Interestingly, here, there were no signs of CNS depression but only signs of CNS excitation. With regard to cocaine and BZE plasma concentrations, the clinical presentation cannot be only explained by the co-consumption of cocaine. It may be hypothesized that the clinical presentation was related to a paradoxical reaction to etizolam overdose. To date, no case of paradoxical excitation related to etizolam use has been reported in adults. The case presented here appears particularly interesting, given the limited data relating to high-dose etizolam toxicity.

Molybdenum Occupational Study in a French Cohort of Workers.

OBJECTIVES: Occupational exposure to molybdenum has been poorly documented to date. Here, we present a retrospective study evaluating urinary molybdenum concentration before and after shift over a period of 2 years in exposed workers. METHODS: This retrospective study was conducted across eight industrial sites in France and included all workers undergoing medical follow-up for occupational molybdenum exposure. A mean of six sequential samples (before and after shift) was performed for each worker. The urinary molybdenum concentration was determined using a validated method of inductively coupled plasma-mass spectrometry. A mixed linear model was built and linear regression was used to verify the extent to which the urinary molybdenum concentration depends on the age of the workers and the sampling period. Additionally, an analysis based on individual trajectory was also performed. RESULTS: Seventy-seven workers were included in the present study. Post-shift urinary molybdenum concentrations were significantly higher than pre-shift values [median (95th percentile) 37.9 (91.1), versus 60.6 (190.0) µg g-1 creatinine, respectively, P < 0.009]. No accumulation of molybdenum over time was observed. The urinary molybdenum concentrations were not influenced by age. Four workers presented high post-shift values as a result of not adhering to protection measures (maxima of 529.8, 359.7, 386.3, and 1459.7 µg g-1 creatinine, respectively). CONCLUSIONS: To our knowledge, this is the first study of occupational molybdenum exposure in France to include an individual trajectory analysis. No accumulation of molybdenum was seen but high post-shift molybdenum urinary concentrations were observed for some workers. The study emphasizes the importance of molybdenum monitoring in exposed workers.

Lethal self-administration of propofol and atracurium.

Acute propofol intoxications appear rare and remain primarily related to the acquisition of the material from the hospital. In this study, two cases of suicide following self-administration of a propofol-atracurium combination are presented as well as other propofol-related fatalities, in order to investigate propofol postmortem blood concentrations and circumstances surrounding death. The two case studies involved a 48-years-old male and a 61-year-old female, both anesthesiologists, who were found unresponsive with drugs (propofol, atracurium for both, and cisatracurium for one of them) discovered at the scene. Toxicological analyses were performed using validated chromatographic methods and highlighted the presence of propofol (1.0 µg/ml), laudanosine (0.2 µg/ml), paroxetine (3.4 µg/ml), and ethanol (12 mg/dl) for the first case and propofol (1.9 µg/ml), laudanosine (1.2 µg/ml), and hydroxyzine (0.03 µg/ml) for the second case. In the literature, 14 publications describing 27 cases of propofol-related lethal intoxications were identified. Except for two cases, all these fatalities involved healthcare professionals. Accidental overdose was the most frequently reported manner of death and the reported propofol blood concentrations ranged from 0.026 to 223.8 µg/ml. These cases, in agreement with other reported cases, highlight the concerns related to the misuse of hospital-based medicines, especially by health-care professionals, and so, the need for a much more stringent internal control of such drugs.

Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial.

Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optimal population PK study design. Fourteen patients were enrolled in the PK ancillary study of the BIG-1 trial and 6-8 samples were taken up to 24 h after administration of the first dose of daunorubicin (90 mg/m2/day). Daunorubicin and daunorubicinol quantifications were assessed using a validated liquid chromatography technique coupled with a fluorescence detector method. Data were analysed using a non-compartmental approach and non-linear mixed effects modelling. Optimal sampling strategy was proposed using the R function PFIM. The median daunorubicin and daunorubicinol AUC0-tlast were 577 ng/mL·hr (Range: 375-1167) and 2200 ng/mL·hr (range: 933-4683), respectively. The median metabolic ratio was 0.32 (range: 0.1-0.44). Daunorubicin PK was best described by a three-compartment parent, two-compartment metabolite model, with a double first-order transformation of daunorubicin to metabolite. Body surface area and plasma creatinine had a significant impact on the daunorubicin and daunorubicinol PK. A practical optimal population design has been derived from this model with five sampling times per subject (0.5, 0.75, 2, 9, 24 h) and this can be used for a future population PK study.

Chemsex/slamsex-related intoxications: A case report involving gamma-hydroxybutyrate (GHB) and 3-methylmethcathinone (3-MMC) and a review of the literature.

Chemsex and slamsex represent a serious public health concern that has to be considered by both clinical and forensic toxicologists. Indeed, such practices appear to carry a significant degree of risk, including acute intoxication. Here we report the case of the intoxication of a 31-year-old male involving 3-methylmethcathinone (3-MMC) and gamma-hydroxybutyrate (GHB) during a slamsex session. In addition, we conducted a review of further cases. The 31-year-old man was admitted to the emergency department for severe impaired consciousness following the administration of psychoactive substances during a chemsex party. The detection and determination of 3-MMC and GHB concentrations were achieved using liquid chromatography-tandem mass spectrometry. 3-MMC and GHB blood concentrations were 177 ng/mL and 131 mg/L, respectively. Further, an English and French exhaustive literature search was performed using several different electronic databases without any limiting period in order to identify all published case reports detailing chemsex/slamsex-related (fatal and nonfatal) intoxications. Nine publications detailing chemsex/slamsex-related intoxication cases have been published (between 2016 and 2020). These articles reported an overall of 13 cases, all involving men with a mean age of 39.1±9.8 years. The outcome was fatal in only 6 cases. 4-MEC and GHB were the two predominant drugs identified. However, given the rapid emergence of novel NPSs in the global market as well as the ease with which they can be accessed through the Internet, toxicological laboratories have to be ready to face new patterns of intoxications resulting from chemsex/slamsex.

Slower degradation rate of cytarabine in blood samples from acute myeloid leukemia by comparison with control samples.

PURPOSE: Cytarabine, a key chemotherapy agent for acute myeloid leukemia (AML) treatment, is deaminated into inactive uracil-arabinoside by cytidine deaminase. This deamination leads to samples stability issues with respect to clinical pharmacokinetic trials. The aim of our study was to study in vitro cytarabine stability in blood samples obtained from AML patients. METHODS: Cytarabine quantification was performed using a fully validated LC/MS/MS method. In vitro cytarabine stability was assessed at room temperature over 24 h in samples coming from 14 AML patients and 7 control patients (CTRL) with no hematological malignancy. In vitro concentrations versus time data were analyzed using a noncompartmental approach. RESULTS: Cytarabine in vitro area under the curve (AUCIVlast) was 22-fold higher in AML samples as compared to CTRL samples (AML mean (standard deviation (SD)), 51,829 (27,004) h ng/mL; CTRL mean (SD), 2356 (1250) h ng/mL, p = 0.00019). This increase was associated with a prolonged in vitro degradation half-life (t1/2IVdeg AML mean (SD), 15 (11.8) h; CTRL mean (SD), 0.36 (0.37) h, p = 0.0033). Multiple linear regression analysis showed that AML diagnosis significantly influenced t1/2IVdeg and AUCIVlas relationship. CONCLUSION: Cytarabine stability is higher in AML than in CTRL samples. The absence of correlation between t1/2IVdeg and AUCIVlast in AML samples suggests that in vitro cytarabine degradation in AML is complex. These results open perspectives including the evaluation of the clinical relevance and the involved molecular mechanisms.

[Thanatobiochemistry: its contribution to the diagnosis of hypothermia fatalities]. / Biochimie thanatologique : ses apports au diagnostic de décès par hypothermie.

Hypothermia is a potentially lethal pathology whose in vivo diagnosis is relatively easy, based on the observation of a body temperature below 35̊C. However, its post mortem diagnosis is much more complex because of a thermal decrease occurring systematically after the death, which renders most often uninterpretable the body temperature as a diagnostic argument for hypothermia. Moreover, none of the macroscopic or microscopic autopsy elements described as suspicious of hypothermia are pathognomonic of a hypothermic death. Currently, this diagnosis arises in the light of an association of concordant arguments including these autopsic and histological elements but also some biomarkers. The aim of this article is to illustrate by a practical case the diagnostic complexity of a death by hypothermia through the evocative elements currently described, by emphasizing the reflection on some biomarkers confirmed or under study.

[Thanatobiochemistry: post mortem study of the vitreous humor for the diagnosis of diabetic ketoacidosis death]. / Biochimie thanatologique : intérêt de l'étude post mortem de l'humeur vitrée pour le diagnostic de décès par acidocétose diabétique.

Thanatobiochemistry refers to a post mortem study of biochemical parameters enabling to shed light on a cause of death. This discipline shines when suspected lethal pathology doesn't have any noticeable macroscopic or microscopic features such as diabetic ketoacidosis. We relate the case of fourty-five years old patient followed-up for type I diabetes mellitus, discovered dead at home, for which only post mortem biochemical exploration of vitreous humor allowed to determine the cause of death by diabetic ketoacidosis.

Clinical and biological specificity of beta-thalassemia intermedia: a case report.

We report the case of a nine-year-old girl, of Moroccan origin, hospitalised for fever and stomach ache. The clinical and biological investigations showed merely a moderate enlargement of the spleen associated with discrete regenerative hemolytic anemia. The etiologic analysis of the hemolysis was completed by the electrophoresis of hemoglobin (Hb) that revealed total absence of HbA, with the presence of 98.7% of HbF and 1.3% of HbA2. These results led to a diagnosis of ß0 thalassemia associated with an intermediate phenotype, i.e. beta thalassemia intermedia (BTI). The molecular study of the ß-globin gene evidenced a homozygous mutation at codon 35 of the exon 2 TAC>TAA (HBB: c.108C>A) leading to the premature stop codon. The study of several polymorphisms involved in the regulation of the expression of HbF concords with the intermediate phenotype found in the patient. This observation offers an opportunity to redefine BTI and further explore its clinical and genetic specificity.