Metabolism study for CUMYL-4CN-BINACA in human hepatocytes and authentic urine specimens: Free cyanide is formed during the main metabolic pathway.

To further elucidate the metabolism of CUMYL-4CN-BINACA, a new synthetic cannabinoid with a cyano group, and to evaluate biomarkers, we incubated the substance in human hepatocytes and analysed 9 authentic urine specimens. We also quantified CUMYL-4CN-BINACA and cyanide in blood and provide comprehensive data on the 7 autopsy cases, 5 of them determined CUMYL-4CN-BINACA intoxications. For metabolite elucidation, CUMYL-4CN-BINACA was incubated with pooled human hepatocytes for up to 5 hours, urine samples were analysed with and without enzymatic hydrolysis. Data was acquired in data-dependent mode by ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) with an Agilent 6550 QTOF. For quantitative analysis of CUMYL-4CN-BINACA, blood samples were precipitated and analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cyanide was determined by gas chromatography-headspace-nitrogen phosphorus detection (GC-headspace-NPD). CUMYL-4CN-BINACA was metabolised via CYP450-mediated hydroxylation at 4-butyl position generating a cyanohydrin (M12), which releases free cyanide to form an aldehyde intermediate and eventually generates 4-hydroxybutyl CUMYL-BINACA (M11) and CUMYL-BINACA butanoic acid (M10). Other minor metabolites were produced by hydroxylation, dihydroxylation, N-dealkylation, and dihydrodiol formation; glucuronidation was observed. One urine sample showed high intensities of M10 and a wide variety of metabolites; the other samples contained fewer metabolites in low abundance and 1 sample showed no metabolites. CUMYL-4CN-BINACA blood concentrations ranged from 0.1 to 8.3 ng/g showing an overlap between fatal and non-fatal concentrations. One blood sample contained 0.36 µg/g cyanide. Release of free cyanide during metabolism is worrying as it might induce liver toxicity. As suggested earlier, CUMYL-BINACA butanoic acid is the most abundant biomarker in urine, but monitoring of additional metabolites or, even better, analysis for the parent in blood is recommended.

A non-fatal intoxication and seven deaths involving the dissociative drug 3-MeO-PCP.

INTRODUCTION: 3-methoxyphencyclidine (3-MeO-PCP) appeared on the illicit drug market in 2011 and is an analogue of phencyclidine, which exhibits anesthetic, analgesic and hallucinogenic properties. In this paper, we report data from a non-fatal intoxication and seven deaths involving 3-MeO-PCP in Sweden during the period March 2014 until June 2016. CASE DESCRIPTIONS: The non-fatal intoxication case, a 19-year-old male with drug problems and a medical history of depression, was found awake but tachycardic, hypertensive, tachypnoeic and catatonic at home. After being hospitalized, his condition worsened as he developed a fever and lactic acidosis concomitant with psychomotor agitation and hallucinations. After 22h of intensive care, the patient had made a complete recovery. During his hospitalization, a total of four blood samples were collected at different time points. The seven autopsy cases, six males and one female, were all in their twenties to thirties with psychiatric problems and/or an ongoing drug abuse. METHODS: 3-MeO-PCP was identified with liquid chromatography (LC)/time-of-flight technology and quantified using LC-tandem mass spectrometry. RESULTS: In the clinical case, the concentration of 3-MeO-PCP was 0.14µg/g at admission, 0.08µg/g 2.5h after admission, 0.06µg/g 5h after admission and 0.04µg/g 17h after admission. The half-life of 3-MeO-PCP was estimated to 11h. In the autopsy cases, femoral blood concentrations ranged from 0.05µg/g to 0.38µg/g. 3-MeO-PCP was the sole finding in the case with the highest concentration and the cause of death was established as intoxication with 3-MeO-PCP. In the remaining six autopsy cases, other medications and drugs of abuse were present as well. CONCLUSION: Despite being scheduled in January 2015, 3-MeO-PCP continues to be abused in Sweden. Exposure to 3-MeO-PCP may cause severe adverse events and even death, especially if the user does not receive life-supporting treatment.

Wafer scale imprint uniformity evaluated by LSPR spectroscopy: a high volume characterization method for nanometer scale structures.

We exploit the localized surface-plasmon resonance (LSPR) of terahertz gold gammadion structures for wafer scale critical dimension metrology of nanostructures. The proposed characterization method, LSPR spectroscopy, is based on optical transmission measurements and is benchmarked against numerical simulations of imprinted structures characterized by atomic force microscopy. There is a fair agreement between the two methods and the simulations enable the translation of optical spectra to critical dimensions of the physical structures, a concept known from scatterometry. The results demonstrate the potential of LSPR spectroscopy as an alternative characterization method to scanning electron microscopy, atomic force microscopy and scatterometry.