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

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

Weed or wheel! FMRI, behavioural, and toxicological investigations of how cannabis smoking affects skills necessary for driving.

Marijuana is the most widely used illicit drug, however its effects on cognitive functions underling safe driving remain mostly unexplored. Our goal was to evaluate the impact of cannabis on the driving ability of occasional smokers, by investigating changes in the brain network involved in a tracking task. The subject characteristics, the percentage of Δ(9)-Tetrahydrocannabinol in the joint, and the inhaled dose were in accordance with real-life conditions. Thirty-one male volunteers were enrolled in this study that includes clinical and toxicological aspects together with functional magnetic resonance imaging of the brain and measurements of psychomotor skills. The fMRI paradigm was based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. We show that cannabis smoking, even at low Δ(9)-Tetrahydrocannabinol blood concentrations, decreases psychomotor skills and alters the activity of the brain networks involved in cognition. The relative decrease of Blood Oxygen Level Dependent response (BOLD) after cannabis smoking in the anterior insula, dorsomedial thalamus, and striatum compared to placebo smoking suggests an alteration of the network involved in saliency detection. In addition, the decrease of BOLD response in the right superior parietal cortex and in the dorsolateral prefrontal cortex indicates the involvement of the Control Executive network known to operate once the saliencies are identified. Furthermore, cannabis increases activity in the rostral anterior cingulate cortex and ventromedial prefrontal cortices, suggesting an increase in self-oriented mental activity. Subjects are more attracted by intrapersonal stimuli ("self") and fail to attend to task performance, leading to an insufficient allocation of task-oriented resources and to sub-optimal performance. These effects correlate with the subjective feeling of confusion rather than with the blood level of Δ(9)-Tetrahydrocannabinol. These findings bolster the zero-tolerance policy adopted in several countries that prohibits the presence of any amount of drugs in blood while driving