A current overview of the pharmacological composition of "La Chimique" consumed in Mayotte: Preliminary results of the CHASSE-MAREE protocol.

Mayotte Island, a French department located in the Mozambique Channel, has for several years been faced with the consumption of "La Chimique" (LC), reputed (but extremely poorly documented) to be a mixture of tobacco and synthetic cannabinoid receptor agonists (SCRAs). One of the objectives of the CHASSE-MAREE protocol is to assess the composition and heterogeneity of LC products through successive LC sample collection campaigns among users. Currently underway, we present here the first analytical results (samples collected in 2022). Between September and December 2022, 80 samples were collected throughout the island over three periods: 70 in the usual form of LC (small folded papers containing a plant-like sample, mostly tobacco), 6 powders, and 4 cigarettes. Analysis was performed using liquid chromatography with high-resolution mass spectrometry. The detected substances (number of detections) included SCRAs (MDMB-4en-PINACA [35], ADB-FUBIATA [25], MDMB-INACA [16], ADB-BUTINACA [15], AFUBIATA [11], 4F-MDMD-BICA [7], CH-PIATA [14], 5C-APINACA [3], BZO-HEXOXIZID [2], and 4F-ABINACA [1]), nicotine (68), tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD) (2), medications (amantadine [11], cyamemazine [6], and acetaminophen [3]), and a designer benzodiazepine (bromazolam [4]). The SCRAs currently in use are varied, and the market for "cooks" (those who prepare LC) is dispersed according to where and when samples are collected. These preliminary results will be supplemented by analysis of samples collected in the first half of 2023 and by an improved description of the current panorama of consumption of LC in Mayotte (mapping, effects felt and dependence, etc.).

Metabolic ratios and SNPs implicated in tramadol-related deaths.

Tramadol (TR) metabolism is performed by polymorphic enzymes that are influenced by genetic polymorphisms. Within this scope, the study presented here aimed to describe 41 genetic variants within CYP2D6, CYP2B6, and CYP3A4 genes in 48 cases of TR-related death that may be involved in the response to TR and to assess whether there is a correlation between these genetic variants and metabolic ratios (MRs). Blood samples from 48 victims of a TR-related death were analyzed to determine the concentrations of TR and its metabolites [O-desmethyltramadol (M1) & N-desmethyltramadol (M2)] using a LC-MS/MS method. All the samples were also genotyped for 41 common CYP2D6, CYP2B6, and CYP3A4 single nucleotide polymorphisms (SNPs) using the HaloPlex Target Enrichment system. Cases with the T/- genotype (rs35742686 in CYP2D6) had significantly higher M2/M1 ratio than cases with T/T genotype and cases with the G/A genotype (rs35599367 in CYP3A4) had significantly higher MR2 (TR/M2) ratio than cases with G/G genotype. The frequency of tested SNPs which belong to CYP2D6, CYP2B6, and CYP3A4 revealed the over-presentation of 2 SNPs (rs1058172 in CYP2D6 and rs4803419 in CYP2B6) in TR overdose group, which could have toxicological implications. These results indicate these polymorphisms in CYP2D6, CYP2B6, and CYP3A4 might influence the function and could increase the risk of toxicity. However, these findings should be supported in future studies with larger groups of cases.

Interpretation of hair and nails findings in an infant death case related to maternal addiction to tramadol.

An 11-month-old boy was found dead. Autopsy findings (cyanosis and polyvisceral congestion) and blood tramadol (TR) concentration of 6240 µg/L were consistent with an acute TR intoxication. In this poisoning situation, owing to the mother's statements (TR addiction leading to daily TR-orange juice mixture preparation accidentally used for the baby bottle preparation by the mother's partner), and the question of possible previous TR administrations to the infant, hair and/or nails (infant, mother, partner, 6-year-old sister) analysis was performed. Hair (2-cm-long hair segments from proximal [S1] to distal [S3]) and nails concentrations (pg/mg; nd: not detected) were as follows: Infant (hair: TR 1420 [S1], 1622 [S2], 2736 [S3]; O-DMT 16-38; N-DMT 34-100 [TR in significant quantities in the hair decontamination bath]-toenails: TR 584; O-DMT 8; N-DMT 15), mother (hair: TR 2340 [S1], 2150 [S2], 2500 [S3]; O-DMT 704-1170; N-DMT 827-1360), mother's partner (fingernails: TR 72; O-DMT nd; N-DMT nd) and sister (hair: TR 261 [S1], 524 [S2]; O-DMT 15 [S1], 16 [S2]; N-DMT 20 [S1], 38 [S2]). Metabolite ratio (infant and sister hair) was comparable to those observed in hair of pharmaceutical industry employees manufacturing tramadol. TR in washing baths, low observed nail concentrations (infant and partner) confirm (i) TR-related mother's addiction and (ii) external contamination issues (TR in sweat of the child at the time of death and in living environment) to explain the infant's keratinized samples results. This case report illustrates the interest of analyzing keratinized matrices of the whole family in such a situation.

2-MeOPP positive hair result in case of urapidil treatment.

The metabolism of urapidil to 2-MeOPP induces the risk of detection of 2-MeOPP in biological samples (blood, urine and hair) in case of urapidil treatment. This is supported by two case reports and an in vitro study of urapidil metabolism.

Trends in the Pharmaceutical Design of New Psychoactive Substances Detected in Oral Fluid OF Drivers Around a Music Festival in South-West France: Comparison 2019/2017.

OBJECTIVE: New psychoactive substance use (NPS) is a reality in France, including among drivers. This work aims (i) to report the pharmaceutical design of NPS detected in oral fluid (OF) from drivers initially screened for drugs around a music festival in 2019 and (ii) to compare obtained results with those of a previous similar study carried out in 2017 in the same situation (and the same music festival) and according to the same methodology. METHODS: OF specimens were recovered from the user devices of the salivary immunochemical tests used by the police during the controls carried out at the entering and leaving the festival. These OF were analyzed using liquid chromatography coupled with tandem mass spectrometry and high-resolution mass spectrometry methods using mass spectra libraries of approximately 1700 substances, including (in 2020) more than 650 NPS and metabolites. RESULTS: NPS was detected in 14 out of the 265 collected OF specimens. Ten NPS were identified (number of identification): APINACA (1), AB-Chminaca (1), 5F-AMB (1), 5F-PB-22 (5), 2C-D (1), methoxetamine (2), ketamine (1), x-CMC (1), 4-MEC (2), ethylone (2). The prevalence of NPS detection in OF (5.2%) is in the same order as the observed one in 2017 (6.8%), but these results are marked by the majority and increasing proportion of synthetic cannabinoids (47% of identified NPS in 2019 vs. 25% in 2017), an increase also in the proportion of cathinone derivatives (29% in 2019 vs. 6% in 2017), and a decrease in cyclohexanones (17% in 2019 vs. 43% in 2017). CONCLUSION: These pharmaceutical design trends (2019 vs. 2017) observed in a population of drivers around a music festival seem to reflect those that can be seen in more general populations in France, with probably a rise in the consumption of synthetic cannabinoids.

Metabolite elucidation of 2-fluoro-deschloroketamine (2F-DCK) using molecular networking across three complementary in vitro and in vivo models.

This work first aims to investigate metabolites of 2-fluoro-deschloroketamine (2F-DCK), a new arylcyclohexylamine derivatives (a group of dissociative ketamine-based substances) using two in vitro experimental approaches, and to compare obtained results by means of molecular networking. Metabolites of 2F-DCK were investigated using both human liver microsomes (HLMs) and hepatic (HepaRG) cell line incubates using molecular networking approach: 2F-DCK pure substance was incubated with HLMs for up to 1 h at two concentrations (100 and 500 µM) and with HepaRG cells for two time periods (8 and 24 h) at one concentration (20 µM). In vitro obtained results were subsequently applied to a 2F-DCK-related fatality case. In vitro-produced metabolites were investigated using high-resolution accurate mass spectrometry using Orbitrap mass analyzer technology. Thirteen metabolites were in vitro produced and several metabolic pathways can be postulated. Seven additional metabolites were found in post-mortem samples (bile and urine) of the case, comprising three Phase II metabolites, which appear to be minor in vivo metabolites. HLMs and HepaRG cell models appear to be complementary and obtained data allowed the identification of several specific 2F-DCK metabolites in biological samples. In practical terms, observed metabolic ratios suggested that nor-2F-DCK (208.1137 m/z) and a hydrogenated metabolite (224.1443 m/z) could be proposed as reliable metabolites to be recorded in HRMS libraries in order to improve detection of 2F-DCK use.

At the Origins of Tobacco-Smoking and Tea Consumption in a Virgin Population (Yakutia, 1650-1900 A.D.): Comparison of Pharmacological, Histological, Economic and Cultural Data.

(1) Background: The way tobacco and tea spread among virgin populations is of major interest our understanding of how ancient economic and cultural practices could have influenced current habits. (2) Methods: hair concentrations of theobromine, theophylline, caffeine, nicotine, and cotinine were measured in hair samples from 47 frozen bodies of people from eastern Siberia, dated from the contact with Europeans to the assimilation of people into Russian society. (3) Results: hair concentration of theobromine, theophylline, and caffeine vary with the type of beverage consumed: green, black, or local herbal teas. Shortly after the first contacts, a few heavy consumers of tobacco were found among light or passive consumers. Tobacco-related co-morbidities began to be recorded one century after and heavy tea users were only found from the 19th century (4) Conclusions: Economic factors and social and family contacts seem to have played a decisive role in tobacco consumption very early on. Behavioral evolution governed the process of substance integration into Siberian culture and was a determinant for the continuity of its use across long periods of time. Analyzing the respective contributions of social and economic processes in the use of these substances opens avenues of investigation for today's public health.

Fatal intoxication related to two new arylcyclohexylamine derivatives (2F-DCK and 3-MeO-PCE).

Continuous development and rapid turnover of drug market of new psychoactive substances (NPS) make it difficult to obtain up-to-date analytical methods for efficient detection of intoxication cases with new substances: no analytical data and no previously published concentration values in biological samples are indeed available. In this context, we aim to report the first fatal case involving two newly emerging arylcyclohexylamine derivatives (a group of dissociative ketamine-based substances): 2-fluoro-deschloroketamine (2F-DCK) and 3-methoxyeticyclidine (3-MeO-PCE). A 42-year-old man was found dead at his home with three plastic bags of "research chemicals" powders near him. Comprehensive screenings of drugs and toxic compounds as well as more selective assays (performed using NMR, HS-GC-FID, LC-MS/MS and LC-HRMS methods) allowed (1) to identify the three unknown powders, 2F-DCK, 3-MeO-PCE, and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT, a hallucinogenic tryptamine-related NPS), with purity above 95%, and (2) to determine peripheral blood (1780, 90, and 52 µg/L), urine (6.1, 6.3, and 2.2 mg/L), bile (12, 3.5, and 1.7 mg/L), and vitreous humour (1500, 66 and 155 µg/L) concentrations of 2F-DCK, 3-MeO-PCE and 5-MeO-DMT, respectively. In addition, toxicological results also revealed recent use of cannabis, cocaine, and amphetamine by the victim, and hair analysis draw pathway of addiction (including experiments with various other NPS) for several months before death. This fatality was considered as the consequence of respiratory depression in a poly-drug user due to a "cocktail effect" of concurrent intakes of 2F-DCK (mainly), 3-MeO-PCE, 5-MeO-DMT, amphetamine, and cocaine. In addition, this case report provides analytical data that could support subsequent toxicological result interpretation in forensic cases involving such arylcyclohexylamine derivatives.

Exhumation of a Methamphetamine Body-Packer: Pitfalls of Hair Result Interpretation.

Carrying out toxicological investigations in biological samples (e.g. hair) collected from extensively decomposed bodies and even more interpretation of subsequently obtained results is challenging, even more in some particular circumstances of death. In order to illustrate these pitfalls, we report the case of the exhumation of a methamphetamine body-packer. Autopsy examination of a 41-year-old man, one year after his burial, revealed the presence of 44 green pellets (7 out of 44 were torn) along all the gastrointestinal tract. A 6-cm long dark hair strand and pellets were sampled for toxicological analyses. Large toxicological screenings were applied to hair and pellets using both LC-MS/MS and LC-HRMS. Intact pellets contained around 10 g of methamphetamine (MA) with a purity ranging from 29 to 35 %. Positive hair results were amiodarone (4.12 ng/mg), desethylamiodarone (5.29 ng/mg) and methamphetamine (7.63 ng/mg). Methamphetamine pellets in gastrointestinal tract were consistent with the autopsy conclusion, i.e. fatal intoxication due to in corpore pellet rupture in a body-packer (the victim was initially deemed to have died from heart failure). In the absence of available data in the literature, amiodarone and metabolite presence in hair could putatively be the consequence of a chronic treatment. Methamphetamine hair concentration was similar to those observed in regular consumers. However, interpreting this hair result is challenging due to (i) the possibility of contamination by sweat at the time of death, and (ii) the probable contamination by putrefaction fluids. This latter hypothesis (artifactual contamination during the post-mortem period) is highly supported by high concentration of methamphetamine in decontamination bath, and even more by the absence of the major methamphetamine metabolite (amphetamine) in hair. As a conclusion, in this particular situation, the hair analysis result (presence of MA and concomitant absence of amphetamine) is in agreement with the previously-established cause of death.

Involuntary 5F-ADB-related intoxication following e-cigarette use.

The detection of synthetic cannabinoid (SC) intoxication cases is challenging, even more when the involved SC identification is requested in a forensic context. This situation can be complicated by new modes of SC consumption, non-specific symptomatology, and analytical pitfalls. To illustrate these issues, we report the case of a 16-year-old man who presented symptoms evocating of a seizure disorder in the minutes following the use of a friend's e-cigarette. At admission in the emergency department, his electroencephalogram was interpreted as coherent with a recent seizure episode. 5F-ADB, a third generation SC, was detected in the e-liquid and in an early collected (H2 after the e-cigarette use) serum sample (0.50 µg/L), but not in urine samples (H18 and H38). One 5F-ADB metabolite, O-desmethyl-5F-ADB (M5), was detectable in urine up to at least 38 h after intoxication. Neither 5F-ADB nor its metabolites could be detected in victim's hair sampled 3 months after the intoxication. Although leading to a non-specific symptomatology, acute SC intoxication should be considered when the case history is related to e-cigarette or e-liquid use. Early biological samples are recommended, even if analytical screening can be positive for SC metabolites in urine sampled until 2 days after exposure. Accordingly, data from the literature and the present case underscore the relevance of adding both main 5F-ADB metabolites (M5 and 5-OH-pentyl-ADB) to mass spectrum databases used for toxicological screening in order to reduce the risk of false-negative results in intoxication cases involving 5F-ADB.

Testing for SGT-151 (CUMYL-PEGACLONE) and its Metabolites in Blood and Urine after Surreptitious Administration.

The authors aim to report a case of surreptitious administration of a synthetic cannabinoid (SC) and the subsequent toxicological investigations to be able to document accurately the case for submission at a hearing. A dealer gave surreptitiously a substance to two juvenile migrants who experienced shakings and faintness. The laboratory received a blood sample from each of the two victims, who, according to the investigators, were probably exposed to SGT-151, a SC, also known as CUMYL-PEGACLONE. Blood and urine specimens from the dealer, who claimed being a user of SGT-151 were received at the same time. To characterize the metabolites of SGT-151, the drug was incubated with a pool of human hepatic microsomes and the cofactors required to ensure the functioning of the main Phase I and Phase II enzymes. The incubation media were analyzed by liquid chromatography coupled to high-resolution mass spectrometry. The metabolites identified following transformation by hepatic microsomes were mostly N-dealkylated SGT-151, mono-hydroxylated SGT-151 and di-hydroxylated SGT-151. The presence of SGT-151 (5.4 ng/mL) and its metabolite, N-dealkyl SGT-151, was confirmed in the dealer's blood. Two metabolites of SGT-151 (OH-SGT-151, diOH-SGT-151) were detected in the dealer's urine. SGT-151 (~1 ng/mL) and its metabolite N-dealkyl SGT-151 were detected in the blood samples of the two victims.

Pyroglutamide-Based P2X7 Receptor Antagonists Targeting Inflammatory Bowel Disease.

This report deals with the design, the synthesis, and the pharmacological evaluation of pyroglutamide-based P2X7 antagonists. A dozen were shown to possess improved properties, among which inhibition of YO-PRO-1/TO-PRO-3 uptake and IL1ß release upon BzATP activation of the receptor and dampening signs of DSS-induced colitis on mice, in comparison with reference antagonist GSK1370319A. Docking study and biological evaluation of synthesized compounds has highlighted new SAR, and low toxicity profiles of pyroglutamides herein described are clues for the finding of a usable h-P2X7 antagonist drug. Such a drug would raise the hope for a cure to many P2X7-dependent pathologies, including inflammatory, neurological, and immune diseases.

The association between blood cadmium and glycated haemoglobin among never-, former, and current smokers: A cross-sectional study in France.

INTRODUCTION: The association between cadmium levels in the body and diabetes has been extensively studied, with sometimes contrasting results. Smoking is the primary non-occupational source of cadmium, and constitutes a risk factor for diabetes. One can therefore hypothesize that the putative association with cadmium is actually explained by tobacco. To fully control for this confounding factor, we studied the relationship between blood cadmium and glycated haemoglobin (HbA1c) levels separately in never-, former and current smokers. METHODS: We studied a sample of 2749 middle-aged adults from the cross-sectional ELISABET survey in and around the cities of Lille and Dunkirk; none had chronic kidney disease or a history of haematological disorders, and none were taking antidiabetic medication. The blood cadmium level-HbA1c associations in never-, former and current smokers were studied in separate multivariate models. The covariables included age, sex, city, educational level, tobacco consumption (or passive smoking, for the never-smokers), body mass index, estimated glomerular filtration rate, and (to take account of the within-batch effect) the cadmium batch number. RESULTS: In the multivariate analysis, a significant association between cadmium and HbA1c levels was found in all three smoking status subgroups. A 0.1 µg/L increment in blood cadmium was associated with an HbA1c increase [95% confidence interval] of 0.016% [0.003; 0.029] among never-smokers, 0.024% [0.010; 0.037] among former smokers, and 0.020% [0.012; 0.029] among current smokers. CONCLUSIONS: The observation of a significant association between the blood cadmium concentration and HbA1c levels in a group of never-smokers strengthens the hypothesis whereby diabetes is associated with cadmium per se and not solely with tobacco use. The small effect size observed in our population of never smokers with low levels of exposure to cadmium suggested that the risk attributable to this metal is not high. However, the impact of exposure to high cadmium levels (such as occupational exposure) on the risk of diabetes might be of concern.

New psychoactive substances in oral fluid of drivers around a music festival in south-west France in 2017.

Driving under the influence of drugs (DUID) is a worldwide problem with potentially major forensic and life-threatening consequences. Although it is obvious that new psychoactive substances (NPS) could lead to impaireddriving, the prevalence of NPS use in a DUID context is unknown as the applied roadside screening tests for drugs of abuse (DOA) are not adapted for NPS detection. This works aims to tested oral fluid (OF) specimens for NPS in French drivers circulating around two music festivals (Artsenik 2017 and Garorock 2017) in order to assess the prevalence of consumption and the kind of used NPS in this particular population. OF samples consisted in dried saliva spots obtained from used Drugwipe-5S® tests (after a positive or negative roadside screening test for DOA). These OF were analyzed using a liquid chromatography coupled with tandem mass spectrometry or high-resolution mass spectrometry method. NPS were detected in 17 out of the 229 OF collected specimens (7.4%). Eleven various NPS were identified (number of identification): 5F-AKB48 (2), MAM2201 (1), JWH122 (1), 4F-PVP (1), 3- or 4-MMC (2), fluoromethamphetamine (1), ketamine (3), MXE (3), methoxyketamine (1), 6-APB (2) and 25C-NBOMe (1). There is an apparent effect of the music festival proximity on the prevalence of NPS in OF from this controlled driver population compared to that of 140 controlled drivers from Northern France analyzed in the same period (7.4% versus 3%). The variety of used NPS appears to be increasing (e.g. large proportion of cyclohexanones). In addition, 5% of drivers initially roadside-tested negative for DOA were in fact driving after NPS use in this specific population. From a forensic perspective, these results confirm the reality of driving after NPS use in French drivers, notably in those driving to or from a music festival.