Methoxpropamine (MXPr) in powder, urine and hair samples: Analytical characterization and metabolite identification of a new threat.

Methoxpropamine (MXPr) is an arylcyclohexylamine dissociative drug with structural similarities with 3-MeO-PCE, ketamine and deschloroketamine. MXPr was identified for the first time in Europe in October 2019 in Denmark and is considered a new psychoactive substance. We undertook the molecular identification and characterization of MXPr in urine, hair and powder samples. We used a combination of several analytical methods: liquid-state nuclear magnetic resonance (NMR), infra-red spectroscopy (IR) and liquid chromatography high-resolution mass spectrometry (LC-HRMS). The second objective was to explore the metabolism of MXPr in silico and in vitro. To detect characteristic metabolites that prove MXPr consumption by urine analysis, pooled human liver microsome (pHLM) assays were performed and evaluated using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS). A software algorithm (Unifi®) was used to predict in silico biotransformations of MXPr. Three metabolites were identified in the in vitro studies including N-despropyl(nor)MXPr, O-desmethyl MXPr and dihydroMXPr. Most of these phase II metabolites were confirmed to be present in urine and hair samples collected from an MXPr consumer. This is the first report of the identification of MXPr in France with analytical findings. This study highlights the challenge of identifying new psychoactive substances (NPS) when they are missing from compound libraries and if a standard is not available. The use of various complementary analytical methods combined with HRMS offers a promising approach for the molecular characterization of NPS.

Suitability of infrared spectroscopy for drug checking in harm reduction centres.

Drug checking is a service for people who use drugs that includes product analysis and an individual interview including results feedback and harm reduction counselling. It uses different analytical methods but few studies demonstrate their value in current practice. The main objective of this work is to compare the analytical performance of IR spectroscopy to laboratory reference method in the context of drug checking in a harm reduction centre. The secondary objectives are to carry out a description of the people who use drugs requesting a product analysis, and to compare the assumed compositions of products purchased with their real compositions. During 2018, all requests for drug testing analysis were included for on-site analysis by IR spectrometry in a harm reduction center and verified by the reference method (UPLC-HRMS) at Bordeaux University Hospital Center. Socioeconomic and product data were also collected. One hundred and thirty-six samples were collected. The results obtained with IR and UPLC-HRMS were compared. IR spectrometry results did not match with reference method in 8 % (n=11) of cases, corresponding to blotters, cannabis and some psychoactive substances present in mixture or in small quantities. Among the products collected, only 5.1 % (n=7) did not correspond to the declared product, either alone or with adulterants. The IR spectrometer allows a simple and rapid detection of at least one molecule, most often the one of interest. However, it is limited to powder and tablet type matrices and is not suitable for blotters, cannabis, mixed or low content substances for which high resolution mass spectrometry remains the reference method.

Death related to nicotine replacement therapy: A case report.

Transdermal nicotine patches and nicotine tablets are widely used for substitution therapies after cessation of smoking. Toxic concentrations of nicotine and cotinine, its main metabolite, are rarely reported, either in cases of misuse or in a fatal context. We report here a rare fatal case due to massive exposure to nicotine replacement therapy. A 41-year-old man was found dead by his cellmate with 7 nicotine patches on the body. There were 14 nicotine patches (21 mg) and 5 empty blisters of nicotine tablets (Nicopass® 1.5 mg) in the bin. External, internal, and histological examinations revealed asphyxia syndrome. Toxicological analyses indicated lethal concentrations of nicotine and cotinine in femoral (2239 and 1230 ng/mL) and cardiac blood (1344 and 1090 ng/mL). Screening for ethanol, drugs, and illicit drugs revealed therapeutic concentrations of cyamemazine, lormetazepam, nordiazepam, oxazepam, and buprenorphine and its metabolite. THC and its metabolites were also detected, reflecting use of cannabis. The findings highlight the risk of nicotine poisoning in persons using nicotine patches. This case emphasises the importance of carrying out complete toxicological analyses to prevent other instances of nicotine poisoning from being overlooked.

Acute Methiopropamine Intoxication After "Synthacaine" Consumption.

Use of methiopropamine (MPA), a synthetic metamfetamine analog, has been detected since 2011 in Europe, but there is limited information on its acute toxicity. A 30-year-old man was admitted to the emergency department in a confused state, with paranoid delusion, auditory and visual hallucinatory experiences, and incoherent speech following the use of "synthacaine" (a slang term derived from "synthetic" and "cocaine"). Toxicological screening for pharmaceuticals and drugs of abuse by liquid chromatography-diode-array detector, gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry (LC-MS-MS) detected MPA, which was subsequently quantified by a specific LC-MS-MS method. Of note, 13 h after presentation to the emergency department, the plasma concentration of MPA was 14 ng/mL. This case report confirms the toxicity of MPA and the need for toxicological analysis to confirm the substance actually ingested by users of new psychoactive substances.

High-performance liquid chromatographic method with diode array detection to identify and quantify atypical antipsychotics and haloperidol in plasma after overdose.

For toxicological purposes, an HPLC assay was developed for the simultaneous determination of haloperidol and atypical antipsychotics (risperidone, 9-hydroxyrisperidone, olanzapine, clozapine) in human plasma. After a double-step liquid-liquid extraction, compounds were separated on a C(8) column eluted with a gradient of acetonitrile and phosphate buffer 50 mM pH 3.8. A sequential ultraviolet detection was used (260, 280 and 240 nm). Calibration curves were linear in the range 10-1000 ng/ml. The limits of quantification were 5 ng/ml for all drugs. Average accuracy at four concentrations ranged from 93 to 109%. Both inter- and intra-day variation coefficients were lower than 11% for all drugs. This simple and rapid method (run time<15 min) is currently used for poison management.

[Plasmatic dosage of antiretroviral drugs by high performance liquid chromathography ]. / Dosage plasmatique des antirétroviraux par chromatographie liquide haute performance.

A high-performance liquid chromatographic method has been developed for the determination of eight antiretroviral drugs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, efavirenz and nevirapine) in a single run. After a liquid-liquid extraction with diethylether, the antiretroviral drugs are separated on a Stability RP18 column eluted with a gradient of acetonitrile and phosphate buffer (50 mM pH 5.65). A sequential ultraviolet detection allowed for simultaneous quantitation of antiretroviral drugs (240, 215, 260 nm). Calibration curves were linear in the range 100-10,000 ng/ml. The limit of quantitation was 50 ng/ml for all drugs except for nevirapine (100 ng/ml). The accuracies ranged from 88.2% to 110.9% and both inter- and intra-day coefficients of variation were lower than 11%. The extraction recoveries were higher than 62%. This method is simple and shows good specificity with respect to commonly coprescribed drugs.

Simplified high-performance liquid chromatographic method for determination of risperidone and 9-hydroxyrisperidone in plasma after overdose.

For toxicological purposes, a HPLC assay was developed for the simultaneous determination of risperidone and 9-hydroxyrisperidone in human plasma. After a single-step liquid-liquid extraction, both compounds were separated on a C(18) column and measured at 280 nm. A good inter-assay accuracy (<116%) was achieved with inter-assay precision less than 12%. Quantification limits were 10 ng/ml. This rapid method (run time <5 min) is currently used for poison management.

Rapid high-performance liquid chromatographic measurement of venlafaxine and O-desmethylvenlafaxine in human plasma. Application to management of acute intoxications.

Venlafaxine, a second-generation antidepressant, acts by inhibition of the reuptake of presynaptic noradrenaline and serotonin. The main metabolite, O-desmethylvenlafaxine was found biologically active. For toxicological purpose, a rapid specific and accurate RP-HPLC assay was developed for the simultaneous determination of venlafaxine and O-desmethylvenlafaxine in human plasma. A linear response was observed over the concentration range 0.2-4 microg/ml. A good accuracy (<8%) was achieved for all quality controls, with intra-day and inter-day variation coefficient less than 10%. Finally, no interference was observed with other psychotic drugs encountered in acute poisoning. This rapid method (run time <10 min) was used to manage four voluntary intoxications involving venlafaxine.

Toxicological management of chlorophacinone poisoning.

A 33-year-old man was admitted 8 hours after voluntary ingestion of 1875 mg of chlorophacinone (C'Operat 750 mL). The examination revealed excitation and nausea, with a normal prothrombin index (PI). Comprehensive testing for abused and therapeutic drugs in blood confirmed chlorophacinone (maximum plasma level: 27.6 mg/L), an antivitamin K (AVK) rodenticide. In a search for easy toxicological management of chlorophacinone poisoning treated by phytomenadione and a cytochrome P450 inducer (phenobarbital), PI and chlorophacinone plasma levels were monitored concomitantly during 17 days. A simple HPLC procedure for the determination of chlorophacinone in human plasma is reported for that purpose. Under phenobarbital 200 mg/day, chlorophacinone exhibited an apparent elimination half-life (3.27 days) shorter than in previously reported cases. If PI is useful for planning phytomenadione treatment and used for therapeutic monitoring of AVK, the chlorophacinone concentrations follow-up may provide a better estimation of the duration of hospitalisation. Chlorophacinone accumulation in target cells or existence of an unidentified metabolite may explain persistence of the hypocoagulability syndrome at low plasmatic concentrations of chlorophacinone. This case illustrates how toxicological management may facilitate toxicokinetics and therapeutic data acquisition.