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A 24-year-old man known to consume illegal drugs was found dead in his apartment. A reclosable plastic zipper bag containing several hundred milligrams of a brown powder was found close to the dead body and the first assumption of the investigators was death due to heroin intoxication. Therefore, a legal autopsy was ordered. The following toxicological analysis revealed ocfentanil in urine and in the brown powder. Four different approaches for the determination of the ocfentanil concentrations in peripheral whole blood are described. Enrichment of ocfentanil from the powder was realized. With this reference, it was possible to determine the ocfentanil concentration in the seized powder to be 0.91%. Concentrations of ocfentanil were also determined in the sampled body fluids using the standard addition procedure. In peripheral blood 9.1 µg/L, in heart blood 27.9 µg/L and in urine 480 µg/L were measured. In addition, the antidepressant citalopram, the neuroleptic quetiapine and cannabinoids were found in urine and subsequently quantified in peripheral blood.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Nasal application of midazolam has been studied for a variety of indications. Due to the limited application volume, highly concentrated formulations are required to reach clinically relevant concentrations in adult patients. No data on the pharmacokinetics and pharmacodynamics of nasal midazolam formulations based on cyclodextrin and chitosan are available. WHAT THIS STUDY ADDS• Clinically effective midazolam concentrations can be reached within less than 10 min after nasal administration of highly concentrated formulations containing an equimolar amount of the solubilizer randomly methylatedb-cyclodextrin combined with the absorption enhancer chitosan. Immediate non-invasive application of such formulations in emergency treatment of seizure patients by lay persons could offer clinical benefits in situations where intravenous access cannot be quickly established. AIMSTo investigate the pharmacokinetics and pharmacodynamics of nasal formulations containing midazolam (5-30 mg ml METHODSAn open-label sequential trial was conducted in eight healthy subjects receiving single doses of 1 mg and 3 mg intranasally and 1 mg midazolam intravenously. Pharmacokinetic parameters were obtained by non-compartmental and two-compartmental models. Pharmacodynamic effects of midazolam were assessed using VAS and a reaction time test. RESULTSMean bioavailability of midazolam after nasal administration ranged from 76 Ϯ 12% to 92 Ϯ 15%. With formulations delivering 1 mg midazolam, mean Cmax values between 28.1 Ϯ 9.1 and 30.1 Ϯ 6.6 ng ml -1 were reached after 9.4 Ϯ 3.2-11.3 Ϯ 4.4 min. With formulations delivering 3 mg midazolam, mean Cmax values were between 68.9 Ϯ 19.8 and 80.6 Ϯ 15.2 ng ml -1 after 7.2 Ϯ 0.7-13.0 Ϯ 4.3 min. Chitosan significantly increased Cmax and reduced tmax of midazolam in the high-dose formulation. Mean ratios of dose-adjusted AUC after intranasal and intravenous application for 1′-hydroxymidazolam were between 0.97 Ϯ 0.15 and 1.06 Ϯ 0.24, excluding relevant gastrointestinal absorption of intranasal midazolam. The pharmacodynamic effects after the low-dose nasal formulations were comparable with those after 1 mg intravenous midazolam. The maximum increase in reaction time by the chitosan-containing formulation delivering 3 mg midazolam was greater compared with 1 mg midazolam i.v. (95 Ϯ 78 ms and 19 Ϯ 22 ms, mean difference 75.5 ms, 95% CI 15.5, 135.5, P < 0.01). Intranasal midazolam was well tolerated but caused reversible irritation of the nasal mucosa. CONCLUSIONSEffective midazolam serum concentrations were reached within less than 10 min after nasal application of a highly concentrated midazolam formulation containing an equimolar amount of the solubilizer RMbCD combined with the absorption enhancer chitosan.

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A high-performance liquid chromatography method for the determination of benzodiazepines and their metabolites in whole blood and serum using mass spectrometry (MS) and photodiode array (PDA) detection is presented. The combination of both detection types can complement each other and provides extensive case relevant data. The limits of quantification (LOQ) with the MS detection lie between 2 and 3 microg/l for the following benzodiazepines or metabolites: 7-amino-flunitrazepam, alprazolam, desalkyl-flurazepam, desmethyl-flunitrazepam, diazepam, flunitrazepam, flurazepam, alpha-hydroxy-midazolam, lorazepam, midazolam, nitrazepam, nordazepam and oxazepam, respectively 5 microg/l for lormetazepam and 6 microg/l for bromazepam. The LOQ of clobazam determined with the PDA detector is 10 microg/l. A convenient approach for determining the measurement uncertainty of the presented method--applicable also for other methods in an accreditation process--is presented. At low concentrations (<10 microg/l), measurement uncertainty was estimated to be about 50%, and at concentrations >180 microg/l, it was estimated to be about 15%. One hundred and twenty-eight case data acquired over 1 year are summarised.

The distribution of analyte concentrations in hair across the scalp has not been thoroughly investigated. Differences in concentrations depending on sampling location are problematic, especially when measuring a second strand to confirm the result of the first measurement. Aiming at a better understanding of the concentration differences, the distribution of ethyl glucuronide (EtG) and caffeine concentrations in hair across the entire head of one test subject was investigated by dividing the scalp completely into regions of ca 2 cm × 2 cm area, yielding a total of 104 samples. For the quantification of EtG, a novel LC-MS /MRM method was developed and validated with a limit of detection and limit of quantification of 2 and 4 pg/mg, respectively. Large variations of the concentration across the head were found, with factors of ca 3.0 and 10.6 for EtG and caffeine, respectively. These differences could not be attributed to measurement error alone. The concentrations were projected onto the subject's head, and concentration patterns were identified for EtG and caffeine. When examining multiple strands from within one 2 cm × 2 cm sampling area, the strands showed similar concentrations. Segmental analysis of selected 3 cm strands showed decreasing concentrations of EtG and caffeine from proximal to distal end, possibly due to wash-out of the analytes. Copyright © 2017 John Wiley & Sons, Ltd.

When investigating someone's hair a single lock is cut, washed, extracted and analysed. The forensic institutes in Switzerland agreed to retain a second lock for a possible reassessment. We were interested in the reproducibility of the concentrations of analytes in hair locks taken from different areas of the head of the same person covering the same time period. Therefore we analysed ethyl glucuronide and caffeine as model substances in 10 hair locks from three individuals categorised as social drinkers. The individual coefficients of variation varied between 14% and 28% for ethyl glucuronide and between 13% and 62% for caffeine corresponding to factors of 1.6 to 4.2 for the highest to the lowest concentrations between the hair locks. This finding has a significant importance both when the second hair lock has to be analysed in a forensic case and if the interpretation of the result is depending on a cut-off value.