Postmortem fatal and non-fatal concentrations of amlodipine

International audienceAmlodipine is a dihydropyridine calcium channel blocker widely used in the treatment of high blood pressure and coronary heart disease. Intoxication can lead to reflex tachycardia following massive hypotension and death. The objective of this work was to study the post-mortem concentrations of amlodipine in 62 patients in order to determine whether the use of the reference concentrations from the living patients was applicable in postmortem setting, and to define more precisely the fatal and non-fatal postmortem concentrations of amlodipine. The amlodipine concentrations were measured in femoral whole blood by LC–MS/MS validated method. When sufficient information was available, the data were classified into 2 different groups, based on the conclusions of the autopsy and toxicological results: G1: non-toxic death and G2: fatal poisoning involving amlodipine alone or as part of a multidrug poisoning. The median concentration of amlodipine [1st quartile - 3rd quartile] of the whole population (n = 62) was 81 [42–134] ng/mL. Twenty-two cases were classified as G1 and thirteen as G2. The observed median [1st quartile - 3rd quartile] concentration of amlodipine was 66 [40.5–79.5] ng/mL in G1 and 240 [170–404] ng/mL in G2. The median concentrations observed in “non-toxic” deaths (66 ng/mL) were three times higher than those usually observed in living patients. Amlodipine distribution ratio between plasma and whole blood concentrations seems insufficient to explain this difference and postmortem redistribution from organs should be considered, and could suggest the same redistribution pattern for other drugs belonging to the same family

Fatal intoxication with ivabradine: First case report

International audienceIvabradine is a bradycardic drug used worldwide in the treatment of chronic stable angina and chronic heart failure. We presented here a case of a 61-year-old woman who was admitted to emergency department for overdose. She presented with drowsiness, bradycardia (45bpm) and a low blood pressure (116/21mmHg). She died ten hours after admission from multiple organ failure. Ivabradine was quantified in different matrices sampled during autopsy using a method on LC-MS/MS (TSQ Vantage Thermo Fisher Scientific®), after a double liquid-liquid extraction with a mixture of hexane/ethyl acetate (1/1; v/v) and then chloroform/isopropanol (80/20; v/v). Chromatographic separation was achieved using a Hypersyl gold PFP column (200×2.1mm, 1.9μm) and an acetonitrile/formiate 2mM, 0.1% formic acid buffer gradient. Method was fully validated on whole blood. The mean overall recovery was 90%. Linearity was validated in the 5-500ng/mL range, with intra and inter-day precision lower than 14.3%. The ivabradine concentration found in patient post-mortem blood was 1210ng/mL. Ivabradine was also quantified in different viscera like lung (2910ng/g), kidney (1510ng/g), liver (1050ng/g), heart (900ng/g), and brain (110ng/g). The vitreous humor concentration was 760ng/mL. Pregabalin and zopiclone were also found in blood at 50μg/mL and 206ng/mL, respectively. This case seems to be the first report of a fatal intoxication involving ivabradine and the first published concentrations in organs

Autopsy, histological and toxicological findings in deaths associated with new psychoactive substances (NPS): a study with 12 autopsies

International audienceBackground: “New psychoactive substances” (NPS), has been described as a “growing global epidemic”. The aim of our study was to document acute and chronic lesions that can be induced by NPS from autopsy cases for which complete toxicological analyses (including hair analysis) have been performed, in order to better define the role of NPS in the mechanisms of death. Material and methods: A retrospective study was performed at the Department of Forensic Medicine and Pathology, jointly with the Department of Pharmacology and Toxicology. All records for forensic autopsy case within a 6-year period, from January 2016 to January 2021, were reviewed for the diagnosis “death associated with NPS”. Results and discussion: Twelve young male adults complied with the inclusion criteria. Lifestyles were dominated by drug addiction and homosexual context which could be anchored in a practice of ChemSex or even of “slamming”. In regard to autopsy findings, previous pathological state was dominated by cardiovascular and hepatic lesions possibly of toxic etiology. Causes and manners of death were, on the whole, quite heterogeneous; however, an accident as a manner of death was the most frequently observed. In terms of histological findings, the most notable lesions were: (1) cardiovascular (sequelae of myocardial infarction probably secondary to a vasospasm, accelerated atherosclerosis); (2) hepatic (steatohepatitis); (3) neurological (peri mortem convulsions); (4) renal (granular cylinders that may indicate rhabdomyolysis); (5) pulmonary (chronic instertitial inflammation); all of them may have had a toxic origin. In regard to toxicological findings, our case series was mostly subject to chronic consumption of synthetic cathinones, in particular 3-MMC; their involvement in the fatal determinism was retained in 7 cases. Tissue distribution was highlighted as increased in brain, explaining at least partially psychoactive effects of these NPS. Average cardio-femoral ratio of 3.78 suggested a cardiac tropism. A lethal concentration of mexedrone, measured at 640 ng/mL, was described for the first time. Conclusion: We provide autopsy data on NPS consumption habits in Ile-de-France, namely men who have sex with men in ChemSex. Macroscopic and microscopic lesions observed were cardiovascular, hepatic, neurological, renal and pulmonary. From a toxicological point of view, we collect additional data on toxic, even lethal concentrations of NPS. Concerning 3-MMC, calculated cardio-femoral ratio is positive; moreover, it is to our knowledge the first study that demonstrates its pharmacokinetic tissue distribution

Dangers of Chemsex: an autopsy case report

Background: ''Chemsex'' is an emerging practice all over the world, sometimes fatal for its users. The victim, a 36-year-old martial arts athlete, was found lifeless lying on his back on the ground in the woods, with a rope tied around the neck, passing over the branch of a tree 2 m from the ground, the other end of the ligature being held in the dead body’s right hand. A third party (a male prostitute) was present at the time of death. Material and methods: A forensic autopsy was performed 48 h after death, including a complete histologic examination of most organs and toxicological analyses. Blood, hair, and organs were analysed for drugs and narcotics (LC-MS/MS and GC-MS), and alcohol was determined by GC-FID. Results and discussion: Autopsy findings showed moderate asphyxia syndrome without clear skin ligature marks, but there were deep cervical contusions. Other contusions were found including deep bruises in the dorsal area and superficial hemorrhagic infiltration of the medial surface of both wrists. Focal bruising of the tongue was found. Organs showed no significant pathology. There was a residual thymus, suggesting chronic drug addiction. Histological examination showed frank signs of hemodynamic shock. Foci of contusions found during autopsy were confirmed, showing no inflammatory reaction. Foci of granular cylinders were present in renal tubules. Heart showed focal non-specific endocardial fibrosis. Toxicological findings were the following ones: (1) peripheral blood: THC at 0.1 ng/mL, THC-COOH at 1 ng/mL, with no 11-OH-THC, indicating last use more than 12 h before death; 3-MMC, NPS-type cathinone at 960 ng/mL, a high, potentially lethal concentration; GHB (gamma-hydroxybutyric acid) at 24 mg/L, a medium concentration, but consistent with last use in the hours before death; ethanol at 0.73 g/L, a relatively low concentration, but which potentiates the toxic effects of the associated molecules. (2) Hair: 3-MMC at 1986 pg/mg, consistent with chronic use in the last few months. (3) Viscera: 3-MMC at 700 ng/mg in the brain, suggesting a cerebral distribution of this molecule. The cardio-femoral ratio of 7.6 was consistent with post mortem release from the heart and/or diffusion from the stomach and/or reservoir organs. Conclusion: We present a case of lethal mechanical asphyxia by atypical hanging, which occurred after recent consumption of 3-MMC and GHB, which contributed to the death in a context of chemsex, which is sometimes associated with sadomasochistic practices such as strangulation. As there was a third-party present at the time of death, according to the police investigation, manner of death was undetermined, as homicide possibly by strangulation was not formally ruled out. This autopsy case illustrates the need to carefully confront police investigations with complete forensic investigations, including exhaustive toxicological analyses

Graines de pavot présentes sur du pain anormalement contaminées aux alcaloïdes de l’opium en France

International audienceFollowing positive opiate urine testing in employees working in risk positions in a transport company while these subjects claimed to consume nothing other than poppy seed sandwiches, a study was carried out to evaluate the opiates content of poppy seed baguettes and sandwiches as well as the urine, saliva and plasmatic concentrations observed after consumption of these products. Eleven people took part in this study, 6 ingested a whole poppy seed baguette and 9 ate a sandwich. Urinary concentrations for opioids were measured for 48 hours, saliva was analyzed for 10 hours, and plasma levels were measured up to 3.5 hours in one subject. Analyses were performed using liquid chromatography – tandem mass spectrometry. In order to highlight biomarkers of exposure to poppy seeds, urine samples were also analyzed in high resolution mass spectrometry with a metabolomic approach. The concentrations found in poppy seeds for morphine, codeine, thebaine and laudanosine are 530 mg/kg, 80 mg/kg, 300 mg/kg and 10 mg/kg, respectively. Urine concentrations observed after ingestion of the baguette were all positive until 18 h with maximal average concentrations observed at H4 around 2800 ng/mL for total morphine and 700 ng/mL for total codeine. After ingestion of a sandwich, all urines tested positive for morphine until 18 h, with a maximal average at H4 around 1800 ng/mL and 360 ng/mL for total codeine. Some were still positive after 48 h. In plasma, the morphine concentrations were between 18 and 19 ng/mL, corresponding to pharmacologically active concentrations. Noscapine and 6-acetylmorphine are biomarkers for heroin intake, while thebaine and for the first time here, 6-O-desmethylthebaine-glucuronide and O-desmethyl-laudanosine-glucuronide are identified as biomarkers for poppy seeds ingestion. This study showed the presence of morphine and codeine in very large quantities in some commercially available breads. These concentrations, far superior from the European Food Safety Authority's (EFSA) recommendations, can have major consequences particularly from a forensic point of view or in the context of occupational medicine, but also for the health of the most vulnerable populations. The detection of thebaine should be systematically performed when looking for opiates in blood, urine and saliva to facilitate interpretation of the results.Suite à des dépistages urinaires positifs en opiacés chez certains employés travaillant sur des postes à risque dans une société de transport alors que ces sujets prétendaient ne rien consommer d’autres que des sandwichs aux graines de pavot, une étude a été menée afin d’évaluer la teneur en opiacés des baguettes et sandwichs aux graines de pavot commercialisés dans certaines boulangeries ainsi que les concentrations urinaires, salivaires et plasmatiques observées après consommation de ces produits. Onze personnes ont participé à cette étude, parmi elles 6 ont ingéré une baguette entière aux graines de pavot, et 9 un sandwich avec ces graines provenant de 2 boulangeries situées à Paris et à Versailles. Les concentrations urinaires des différents opiacés ont été mesurées durant les 18 h qui ont suivi l’ingestion des baguettes et les 48 h suivant l’ingestion des sandwichs, une recherche salivaire a été effectuée durant 10 h et les concentrations plasmatiques ont été mesurées jusqu’à 3,5 h chez un des sujets après ingestion du sandwich. Les analyses ont été réalisées en chromatographie liquide couplée à la spectrométrie de masse en tandem. Afin de mettre en évidence d’éventuels biomarqueurs spécifiques d’exposition au graines de pavot et discriminant d’une prise d’héroïne, les échantillons d’urine ont également été analysés en spectrométrie de masse haute résolution avec une approche métabolomique. Les concentrations retrouvées dans les graines de pavot sont pour la morphine, la codéine, la thébaïne et la laudanosine de 530 mg/kg, 80 mg/kg, 300 mg/kg et 10 mg/kg, respectivement. Après ingestion d’une baguette, toutes les urines sont positives pendant au moins 18 heures, durée du recueil, avec des concentrations moyennes maximales à H4 atteignant pratiquement 2800 ng/mL pour la morphine totale et 700 ng/mL pour la codéine totale. Après ingestion d’un sandwich, les urines sont toutes positives en morphine totale jusqu’à 18 heures avec des concentrations moyennes maximales à H4 de l’ordre de 1800 ng/mL et 360 ng/mL pour la codéine totale. Certaines sont toujours positives 48 h après ingestion. Dans le plasma, les concentrations de morphine retrouvées sont comprises entre 18 et 19 ng/mL, soit des concentrations actives pharmacologiquement. La noscapine et la 6-acetylmorphine ne sont retrouvées qu’après prise d’héroïne, alors que la thébaïne et pour la première fois décrit ici, la 6-O-desmethylthébaïne-glucuronide et la O-desmethyl-laudanosine-glucuronide ne sont présents qu’après absorption de graines de pavot. Cette étude a montré la présence de morphine et de codéine en quantité très importante dans certains pains aux graines de pavot disponibles dans le commerce. Ces concentrations, bien supérieures aux recommandations de l’Autorité Européenne de Sécurité des aliments (EFSA), peuvent avoir des conséquences importantes dans un cadre médicolégal ou dans un cadre de médecine du travail, mais également présenter des risques pour la santé sur les populations les plus fragiles. La recherche de thébaine devrait être réalisée systématiquement lors de la recherche d’opiacés dans le sang, les urines et la salive afin de discriminer une prise de graines de pavot d’une prise d’héroïne