Synthèse d'inhibiteurs mixtes des enzymes impliquées dans la dégradation des enképhalines

PARIS-BIUP (751062107) / SudocSudocFranceF

Is the use of tandem mass spectrometry to determine 0.5 µg/L of Δ9-tetrahydrocannabinol in whole blood really necessary?

Aims: Since the decree of September 5th 2001, French toxicologists have had to confirm drug screening in drivers by gas-chromatography (GC) and mass-spectrometry (MS). Furthermore, the French Society of Analytical Toxicology (SFTA) has advocated the determination of Δ9-tetrahydrocannabinol (THC) at 0.5 µg/L in whole blood, since its Cannabis Consensus past on June 13th, 2013. Because of this new analytical target, we had to develop a new method. Our first choice was to use our GC/tandem-MS however we decided to analyse the samples on this instrument alongside our GC/single quadrupole-MS, and validated on both without difficulties. Methods: The extraction method consisted of those from the SFTA’s recommendations with some modifications: a smaller blood volume, another derivatisation reagent. The calibration was composed of a blank blood sample and six blood samples, spiked with cannabinoid standards from 0.3 to 100 µg/L (THC and its two main metabolites). Extracts were analysed with a SHIMADZU QP-2010SE GC-single quadrupole-MS equipped with J&W Ultra 1 column (12 m x 0.20 mm x 0.33 μm) after splitless injection and in SIM mode. Validation was performed with ARLENDA ENOVAL software. Results: For THC, the lower limit of quantification (LLQ) was 0.5 µg/L and the detection limits were 0.2 µg/L, with the ion pair 386/389 m/z. Conclusion: Determining the most appropriate method parameters were the key to this success. Using a calibrator lower than LLQ can be considered as unusual but without it, mathematical model and LLQ were of a lower quality. After this validation, we decided to establish the method as a routine method. After one year of using this method, the Shewhart chart for THC is still good. This method is robust, satisfies the requirements (for THC metabolites too) and costs less. This finding allows us to focus our most sensitive equipment on more demanding analyses

The development of new psychoactive substances in France

If our European neighbours have been involved in the fight against new psychoactive substances (NPS) for several years, the seizures from our police forces have been rare. Only the laboratories of French customs analysed large amounts of NPS. Nevertheless, in the last three years, an increased number of French toxicologists have reported detection of NPS use. On the ground, because of the posed problems, police officers attempt to make it part of their jurisdiction and seize the substances. Thus, from our laboratories, the seizures could bring much information about the NPS phenomenon. From seizures submitted to our laboratory, all were analysed according to standard analytical strategy defined in our quality plan. Between 2013 and 2014, 62 seizures of NPS were analysed in our laboratory: 4 seizures in 2013 and 58 seizures in 2014, showing a sudden increase. Synthetic cannabinoids were the main substances identified (15 different compounds detected), five different phenylethylamines, four different cathinones, two tryptamines, two new benzodiazepines, methoxetamine, methiopropamine, mCPP and dimethylaminoethanol were also found. If the proportion of NPS seizures remains low in comparison with the more “classical” drugs of abuse in our laboratory, the dramatic increase in requests from investigators expresses the expansion of NPS throughout France in all likelihood

The development of new psychoactive substances in France

Our European neighbours have been involved in the fight against new psychoactive substances (NPS) for several years but the seizures from our police forces had been rare. Only the laboratories of French customs analysed large amounts of NPS. Nevertheless, in the last three years, an increased number of French toxicologists have reported detection of NPS use. On the ground, there is limited possibility of prosecutions because most of the NPS are not scheduled in France at this time. However, because of the problems posed, police officers attempt to make it part of their jurisdiction and seize the substances. We have monitored the recent NPS seizures to characterise their use in France and to participate in raising the awareness of the increase in seizures of these substances in France which may have an impact on other areas of Europe. All seizures were analysed according to standard analytical strategy defined in our quality plan. The analysis consisted of screening by ion mobility spectrometry (Ionscan™ 400B, Smiths Detection) and by gas-chromatography/mass-spectrometry (MSD 5975 GC/MSD, Agilent Technologies) after dilution or decoction in an organic solvent: (i) methanol or (ii) acetonitrile or after (iii) derivatisation by Sil-Prep™. Observed mass spectra were compared to the spectral libraries from the ENFSI-DWG and the SWGDRUG. All results relating to NPS were evaluated and substances and their origins were classified. Between 2013 and 2014, 56 seizures of NPS were analysed in our laboratory: 4 seizures in 2013 and 52 seizures in 2014, showing a dramatic increase in the last year. If synthetic cannabinoids (SC) were the main substances identified (15 different compounds), we also found five different phenylethylamines (ethylphenidate, MDAI, DCMP, camfetamine, fencamfamine), two tryptamines (5-MeO-DALT and αMT), two benzodiazepines (etizolam and diclazepam), a thiophenic analogue of methamphetamine (methiopropamine), a piperazine (mCPP) and dimethylaminoethanol. These seizures came from different areas of France. All results were registered in our national database from which some government bodies are informed. If all of the substances identified in the analysed seizures were already known, the increasing number of cases objectivises a geographical extension and a supply diversification which may be representative in other parts of Europe. France has not been spared from NPS and seems to be catching up, unfortunately. In France, we are observing a new kind of market with legal and illegal aspects and an evolution of use previously described in some countries. For example, suppliers now often sell pure powdered substance; packagings are simpler than the previous coloured bags and they clearly provide the name and formula of the substance(s). As in many other countries, there are too few tools to prevent this expansion, however, the French government has begun to register the NPS. Ethylphenidate has been registered since March 17th and some synthetic cannabinoid families should follow. Consequently we monitor NPS seizures with the additional aim of monitoring the consequences of these registrations on composition of seized powders and we continue to make magistrates and police-officers aware of the NPS development

Trends in Fatal Poisoning Among Drug Users in France From 2011 to 2021

Importance The DRAMES (Décès en Relation avec l’Abus de Médicaments Et de Substances) register is a database of drug-related deaths with the aim of identifying the psychoactive substances associated with and estimating the trends in these deaths. Our novel approach is based on the collection of data on all deaths for which toxicology experts have performed analyses. Objective To describe drug-related deaths in France and report trends over an 11-year period. Design, Setting, and Participants This case series used a national register to assess 4460 drug-related deaths that occurred from 2011 to 2021 in France. Data analyses were performed from January 1, 2012, to December 31, 2022. Main Outcomes and Measures Demographic characteristics; medical and substance abuse history; forensic autopsy findings; and toxicology reports. Results Among the 4460 deceased individuals (mean [SD] age, 37.8 [10.5] years), the mortality rate was highest among men (sex ratio, 4.4:1). Of the deaths involving a single or predominant drug, the legal substitution product, methadone, was the leading cause of death during the entire study period, ahead of heroin—44.7% and 35.9% for methadone vs 15.8% and 21.8% for heroin in 2011 and 2021, respectively. Between 2011 and 2021, most of the drug-related deaths shifted from licit to illicit drugs, and statistically significant variations were found for buprenorphine, cocaine, heroin, methadone, and other licit opioids. Deaths related to polydrug use increased from 23.2% in 2011 to 30.6% in 2021. In this context, opioids remained associated with most deaths, with at least 1 opioid being involved in approximately 9 of 10 cases (85.9%) in 2021. However, the main trend was the dramatic increase in drug combinations with cocaine, from less than one-third of cases in 2011 (30.8%) to more than half in 2021 (57.8%). Conclusions and Relevance This case series assessment of 4460 drug-related deaths found that opioids used alone or in combination were the main contributor to drug-related deaths, despite having a lower prevalence than other drugs. This finding is similar to that of other countries; however, in France licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. Deaths associated with use of cannabis, new psychoactive substances, and stimulants (including amphetamine-type stimulants and cocaine, especially in combination) have increased and should be closely monitored