The undetected murder? Evaluation and validation of a practicable and rapid inductively coupled plasma-mass spectrometry method for the detection of arsenic, lead, and thallium intoxications in postmortem blood.

Homicide, suicide, or accident - elemental intoxication may be a cause in each of these types of deaths. Inductively coupled plasma mass spectrometry (ICP-MS) has emerged as the gold standard analytical method for toxic metal analysis in both clinical and forensic settings. An ICP-MS method was developed using a modified acidic workup for the quantitative determination of arsenic, lead, and thallium. Method validation focused on the assessment of linearity, between- and within-day precisions, limits of detection (LoD) and lower limits of quantification (LLoQ), and carryover. The method was applied to analysis of postmortem peripheral blood samples from 279 forensic cases for which orders for chemical-toxicological examination had been received from the public prosecutor's office. Using six-point and one-point calibrations (latter for rapid screening purposes), precisions and accuracies ranged from -4.8 to 5.8% and -6.4 to 7.5%. Analytical sensitivities for As, Pb, and Tl were 0.08, 0.18, and 0.01 µg/l (LoD) and 0.23, 0.66, and 0.03 µg/l (LLoQ), respectively. Observed postmortem peripheral blood concentrations were As, 1.31 ± 3.42 µg/L; Pb, 17.4 ± 13.1 µg/L; and Tl, 0.11 ± 0.07 µg/L (mean ± standard deviation [SD]). Elemental concentrations, determined in additional quality control samples, were in good agreement to those obtained with an external ICP-MS method based on alkaline sample processing. The current method is practicable and compatible with an ICP-MS system used for trace element analysis in an accredited medical laboratory. It allows for implementation of low-threshold investigations when metal intoxications are suspected in forensic routine.

Fatal intoxication with 1,4-butanediol: Case report and comprehensive review of the literature.

A fatal case of 1,4-butanediol (1,4-BD) oral ingestion is reported here, in which a 51-year-old man was found dead in his bed. According to the police report, the deceased was a known drug user. A glass bottle labeled (and later confirmed to be) "Butandiol 1,4" (1,4-BD) was found in the kitchen. Furthermore, the deceased's friend stated that he consumed 1,4-BD on a regular basis. The autopsy and histological examination of postmortem parenchymatous organ specimens did not revealed a clear cause of death. Chemical-toxicological investigations revealed gammahydroxybutyrat (GHB) in body fluids and tissues in the following quantities: femoral blood 390 mg/L, heart blood 420 mg/L, cerebrospinal fluid 420 mg/L, vitreous humor 640 mg/L, urine 1600 mg/L, and head hair 26.7 ng/mg. In addition, 1,4-BD was qualitatively detected in the head hair, urine, stomach contents, and the bottle. No other substances, including alcohol, were detected at pharmacologically relevant concentrations. 1,4-BD is known as precursor substance that is converted in vivo into GHB. In the synoptic assessment of toxicological findings, the police investigations and having excluded other causes of death, a lethal GHB-intoxication following ingestion of 1,4-BD, can be assumed in this case. Fatal intoxications with 1,4-BD have seldom been reported due to a very rapid conversion to GHB and, among other things, non-specific symptoms after ingestion. This case report aims to give an overview to the published of fatal 1,4-BD-intoxications and to discuss the problems associated with detection of 1,4-BD in (postmortem) specimens.

Characteristics and dose-effect relationship of clinical gamma-hydroxybutyrate intoxication: A case series.

Gamma-Hydroxybutyrate (GHB) overdoses cause respiratory depression, coma, or even death. Symptoms and severity of poisoning depend on blood-concentrations and individual factors such as tolerance. A retrospective case study was conducted, evaluating GHB intoxication cases. GHB-concentrations in blood and urine were determined by gas chromatography-mass spectrometry (GC-MS) along with, in part, via enzymatic assay. GHB-concentrations, demographic data, and additional drug use, as well as specific clinical information, were evaluated. The correlation between GHB-levels in blood and associated symptoms were examined. In total, 75 cases originating from the Emergency Departments (EDs) of Hamburg and surrounding hospitals were included. Fifty-four of the patients (72%) were male. The mean GHB-concentration in blood was 248 mg/L (range 21.5-1418 mg/L). Out of the group with detailed clinical information (n = 18), the comatose group (n = 10/18) showed a mean of 244 mg/L (range 136-403 mg/L), which was higher than that of the somnolent and awake patients. Of the comatose collective, 70% (n = 7) showed co-use of one or more substances, with the additional use of cocaine being the most frequently detected (n = 5). In conclusion, a moderate dose-effect relationship was observed, although, there was some overlap in dosage concentration levels of GHB in awake and comatose patients. In GHB-intoxication cases, co-use was common as were clinical effects such as acidosis, hypotension, and impact on the heart rate. Timely analytical determination of the GHB-concentration in blood could support correct diagnosis of the cause of unconsciousness.

Analytical findings in a non-fatal intoxication with the synthetic cannabinoid 5F-ADB (5F-MDMB-PINACA): a case report.

The case report centres on analytical findings from a spice sample (mixed with tobacco (as a cigarette) for consumption), and its corresponding plasma sample, smoked by a 31-year-old man who was attended by emergency services following collapse. The man was fully conscious and cooperative during initial medical treatment. Suddenly, he suffered a complete loss of self-control, whereupon the police was notified. The man encountered the police officers when exiting the apartment, at which point he threatened them with clenched fists and reached for a plant bucket in order to strike out in the direction of the officers. At the trial, he described himself as confused and as being completely overwhelmed, having lost self-control, suffered a panic attack and "just wanted to get out the situation". Furthermore, he stated that he had no recollection of the incident. He feared death due to palpitations, heart pain, dizziness and repetitive anxiety states. Routine systematic as well as extended toxicological analysis of the plasma sample, taken approximately 2 h after the incident, confirmed the use of cannabis and spice. Plasma concentrations of THC, OH-THC and THC-COOH were 8.0 µg/L, 4.0 µg/L and 147 µg/L, respectively. Furthermore, analysis confirmed uptake of 5F-ADB (5F-MDMB-PINACA) via detection of both 5F-ADB and the 5F-ADB N-(5-OH-pentyl) metabolite. The spice sample additionally contained 5F-MDMB-PICA, which was not detected in the plasma sample. A differentiation between a possible co-use and a recent use of cannabis was not possible. In summary, this case once more underlines the health risks of spice use.

Evidence for the transfer of methadone and EDDP by sweat to children's hair.

In cases where there is a question as to whether children have come into contact with drugs, examinations of their scalp hair are frequently carried out. Positive test results are often discussed in the forensic community due to the various possible modes via which drugs and their metabolites can be incorporated into the hair. These include drug uptake by the child (e.g. oral ingestion or inhalation), but also contamination of hair via contact with the sweat from drug users. In this study, the possibility of methadone and its metabolite EDDP being incorporated into children's hair by contact with sweat from persons undergoing opiate maintenance therapy (methadone) was examined. The transfer of methadone and EDDP via sweat from methadone patients (n = 15) to children's hair was simulated by close skin contact of drug-free children's hair, encased in mesh-pouches, for 5 days. Sweat-collecting patches (hereafter referred to as 'sweat patches') were applied to the test persons' skin. One strand of hair and one sweat patch were collected daily from each patient. Analyses were performed using GC-MS/MS (hair) and LC-MS/MS (serum, sweat patches). After 4 days of skin contact, methadone was detectable in the formerly drug-free hair strands in all 15 study participants. EDDP was detectable in 34 of 75 hair strands, with the maximum number of positive results (11 EDDP-positive hair strands) being detected after 5 days. These results show that transfer of methadone and EDDP to drug-free hair is possible through close skin contact with individuals taking part in methadone substitution programmes. A correlation between serum concentration, sweat concentration and substance concentration in hair strands could not be demonstrated, but a tendency towards higher concentrations due to longer contact time is clearly evident.

Quantification of direct-acting oral anticoagulants: Application of a clinically validated liquid chromatography-tandem mass spectrometry method to forensic cases.

In certain forensic cases, a quantification of direct-acting oral anticoagulants (DOACs) can be necessary. We evaluate the applicability of a previously described liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology for the determination of DOACs in plasma to postmortem specimen. Postmortem internal quality control (PIQC) samples were prepared in pooled blank postmortem heart blood, femoral blood, cerebrospinal fluid (CSF), and urine as well in plasma. To examine the application of the clinical method to forensic cases, the main validation parameters were reinvestigated using PIQC samples. Postmortem samples of 12 forensic cases with evidence of previous rivaroxaban intake and unknown bleeding disorders were analyzed. Interday variability remained within the acceptance criterion of ±15%. Matrix effects were comparable in blank plasma and postmortem matrix extracts. After 4 weeks of storage in the refrigerator, no relevant decrease of DOACs was evident. After 96 h of storage at room temperature, a slight decrease in edoxaban concentration was observed in CSF and urine, while plasma edoxaban decreased by about 50%. Median (range) rivaroxaban concentrations determined in specimen of forensic cases were as follows: heart blood (n = 6), 17.2 ng/ml (

Revisited: Therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics.

In order to assess the significance of drug/substance levels measured in intensive care medicine and clinical and forensic toxicology as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. We revisited and expanded our 2012 compilation of therapeutic and toxic plasma concentration ranges as well as half-lives of now more than 1100 drugs and other xenobiotics.Data have been abstracted from original papers, text books, and previous compilations and have been completed with data collected in our own forensic and clinical toxicology laboratories. We compiled the data presented in the table and the corresponding annotations over the past 30+ years. A previous compilation was completely double-checked, revised, and updated, if necessary. In addition, more than 200 substances, especially drugs who have been introduced since 2012 to the market as well as illegal drugs and other xenobiotics which became known to cause intoxications were added. We carefully referenced all data. Moreover, the annotations providing details were updated and revised, when necessary.For more than 1100 drugs and other xenobiotics, therapeutic ("normal") and, if data was available, toxic, and comatose-fatal plasma/blood concentrations as well as elimination half-lives were compiled in a table.In case of intoxications, the blood concentration of the substance and/or metabolite better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications as well as to support forensic and clinical expert opinions.

Mushroom Poisoning.

BACKGROUND: Poisonous mushrooms are eaten by mushroom hunters out of ignorance, after misidentification as edible mushrooms, or as a psychoactive drug. Mushroom poisoning commonly leads to consultation with a poison information center and to hospitalization. METHODS: This review is based on pertinent publications about the syndromes, toxins, and diagnostic modalities that are presented here, which were retrieved by a selective search in PubMed. It is additionally based on the authors' longstanding experience in the diagnosis and treatment of mushroom intoxication, expert consultation in suspected cases, macroscopic identification of wild mushrooms, and analytic techniques. RESULTS: A distinction is usually drawn between mushroom poisoning with a short latency of less than six hours, presenting with a gastrointestinal syndrome whose course is usually relatively harmless, and cases with a longer latency of six to 24 hours or more, whose course can be life-threatening (e.g., phalloides, gyromitra, orellanus, and rhabdomyolysis syndrome). The DRG diagnosis data for Germany over the period 2000-2018 include a total of 4412 hospitalizations and 22 deaths due to the toxic effects of mushroom consumption. 90% of the fatalities were due to the death cap mushroom (amatoxins). Gastrointestinal syndromes due to mushroom consumption can be caused not only by poisonous mushrooms, but also by the eating of microbially spoiled, raw, or inadequately cooked mushrooms, or by excessively copious or frequent mushroom consumption. CONCLUSION: There are few analytic techniques available other than the qualitative demonstration of amatoxins. Thus, the diagnosis is generally made on the basis of the clinical manifestations and their latency, along with meticulous history-taking, assisted by a mushroom expert, about the type(s) of mushroom that were consumed and the manner of their preparation.

[Poisonous plants-a new approach for assessing the risk of poisoning in small children]. / Risiko Pflanze ­ Ein neuer Ansatz zur Einschätzung des Vergiftungsrisikos für Kleinkinder.

BACKGROUND: Plant poisoning in small children (from 0.5 to <6 years of age) is the third most frequent cause for phone contact with a poison center. For prevention of poisonings, a list of poisonous plants that should not be planted close to playgrounds or other places frequently visited by children was published in 2000 by the Bundesanzeiger. This list has been reevaluated and updated by the "Toxicity of Plants" working group of the Committee of the Assessment of Intoxications at the Federal Institute of Risk Assessment (BfR). MATERIALS AND METHODS: Relevant plants were taken from a recent publication. A literature search was conducted in PubMed concerning all plant poisonings in children and the toxic ingredients of plants. Also, monographs and the database POISINDEX were integrated in the evaluation. A classification was made for plants that after oral, dermal, or ocular contact of small quantities could cause severe, moderate, mild, or no intoxications in small children. RESULTS: Based on data of exposure and potentially toxic ingredients of the involved plants, a risk assessment was executed, which diverges from other publications because it concerns the actual basic risk of an intoxication. In total, 251 plants were reevaluated. For 11 plants, there was a high risk, for 32 a moderate, for 115 a mild, and for 93 plants no risk of intoxication could be determined. CONCLUSION: The new assessment of evaluating a toxicity risk for small children on the basis of exposure data and including the toxicity of ingredients allows for a more realistic assessment of the risk of poisoning with outdoor plants. In this way, infant exposure carrying a high risk of intoxication can be identified.

[Poisoning by addictive substances, laboratory tests, and forensic medical death clarification in the case of poisoning]. / Vergiftungen durch Suchtstoffe, Laboruntersuchungen und rechtsmedizinische Todesfallaufklärung bei Vergiftungen.

Clinical-toxicological investigations are very helpful for the detection and assessment of the severity of questionable narcotics intoxications. In some cases, an initial case of clinical poisoning then progresses in the further course to a case of forensic relevance (for example after deliberate poisoning e.g, with knock-out drugs or with intend to commit murder, or in cases of intoxication in connection with a criminal offense).The specifics and problems of the analytical detection of these substances in clinical and forensic cases are explained with regard to the presented narcotic drugs. The information used comes from data from our own examination material and data from the literature.The spectrum of addictive substances has changed significantly in recent years. While established methods of detection are available for alcohol and classic drugs of abuse, new drugs with potential for abuse (such as methylphenidate, pregabalin) or NPS, GHB, GBL, and 4­BD cannot be detected by conventional methods of immunochemistry in combination with chromatographic methods such as GC-MS and HPLC-DAD.An improvement in the measurement equipment for specialised laboratories performing such investigations is therefore required in order to be able to adequately care for patients and to clarify criminal offenses. In the interests of legal certainty, it is important for offenders, in the case of a foreign substance being supplied to a victim, to assume that it can also be proven. In addition, with regard to the reliability of officially stated prevalence data for narcotic drugs in drug-related deaths, greater safety should be sought in the collection of all relevant substances.

Organ distribution of diclazepam, pyrazolam and 3-fluorophenmetrazine.

The organ distribution of 3-fluorophenmetrazine (3-FPM), pyrazolam, diclazepam as well as its main metabolites delorazepam, lormetazepam and lorazepam, was investigated. A solid phase extraction (SPE) and a QuEChERS (acronym for quick, easy, cheap, effective, rugged and safe) - approach were used for the extraction of the analytes from human tissues, body fluids and stomach contents. The detection was performed on a liquid chromatography-tandem mass spectrometry system (LCMS/MS). The analytes of interest were detected in all body fluids and tissues. Results showed femoral blood concentrations of 10 µg/L for 3-FPM, 28 µg/L for pyrazolam, 1 µg/L for diclazepam, 100 µg/L for delorazepam, 6 µg/L for lormetazepam, and 22 µg/L for lorazepam. Tissues (muscle, kidney and liver) and bile exhibited higher concentrations of the mentioned analytes than in blood. Additional positive findings in femoral blood were for 2-fluoroamphetamine (2-FA, approx. 89 µg/L), 2-flourometamphetamine (2-FMA, hint), methiopropamine (approx. 2.2 µg/L), amphetamine (approx. 21 µg/L) and caffeine (positive). Delorazepam showed the highest ratio of heart (C) and femoral blood (P) concentration (C/P ratio = 2.5), supported by the concentrations detected in psoas muscle (430 µg/kg) and stomach content (approx. 210 µg/L, absolute 84 µg). The C/P ratio indicates that delorazepam displays susceptibility for post-mortem redistribution (PMR), supported by the findings in muscle tissue. 3-FPM, pyrazolam, diclazepam, lorazepam and lormetazepam did apparently not exhibit any PMR. The cause of death, in conjunction with autopsy findings was concluded as a positional asphyxia promoted by poly-drug intoxication by arising from designer benzodiazepines and the presence of synthetic stimulants.

Death after misuse of anabolic substances (clenbuterol, stanozolol and metandienone).

A 34-year old male was found breathless and panting at home by his girlfriend three hours after a gym workout. Minutes later, he collapsed and died. Autopsy, histological and chemical analyses were conducted. The examination of the heart showed left ventricular hypertrophy, while the right coronary artery showed only a small vascular lumen (3 mm in diameter), due to its anatomical structure. In femoral blood concentrations of approx. 1 µg/L clenbuterol, approx. 56 µg/L stanozolol and approx. 8 µg/L metandienone, with trenbolone (

Fast increase of postmortem fentanyl blood concentrations after transdermal application: A call to careful interpretation.

BACKGROUND: Interpretation of postmortem fentanyl concentrations after transdermal application remains a challenge. There are indications that fentanyl shows relevant postmortem redistribution. The aim of this study was to investigate the time course of these changes and to develop recommendations for toxicological case work. MATERIAL AND METHOD: Blood specimens were collected from palliative care patients who were treated with fentanyl transdermal patches. Antemortem reference samples (ethylenediaminetetraacetic acid (EDTA) and serum specimens) were collected at stable dose rates. Postmortem femoral venous blood specimens were collected at four postmortem time-points: 2hpm (hours postmortem), 6-8hpm, 11-16hpm and approximately 24hpm. Liquid chromatography tandem mass spectrometry was applied to quantify fentanyl and norfentanyl. RESULTS: Ten patients were included in the study (8 men, 2 women). Fentanyl patches with delivery rates of 12-150µg/h were applied. Antemortem fentanyl levels in EDTA samples varied between 0.19 and 4.64µg/L. At 6 to 8hpm, blood concentrations of fentanyl were already significantly (p=0.05) higher in postmortem samples compared to the paired antemortem reference. On average, the antemortem concentration (range: 0.19-4.64µg/L) increased 3-fold within 6-8hpm (range: 0.4-14.9µg/L), and 5.5-fold within 24hpm (range: 0.39-21.88µg/L). Norfentanyl concentrations increased significantly (p=0.01) within 6-8hpm, too. In half of the patients, norfentanyl concentrations were below fentanyl concentrations, antemortem as well as postmortem. CONCLUSION: Postmortem fentanyl concentrations increased quickly. As early as 6-8h after death, postmortem concentrations differ significantly from antemortem ones. Our results strongly indicate that postmortem blood concentrations of fentanyl after transdermal application should be interpreted carefully.

Swollen Lips After a Night of Partying-An Allergic Reaction to Ecstasy?

Ecstasy (MDMA) is a mood-lifting drug with numerous somatic side effects, for example, dehydration or continuous chewing and biting. We describe the case of a young woman who underwent a forensic medical examination for suspected sexual assault. She claimed to have suffered from a memory lapse, and she had a painful swelling of her lips with a plaque-like coating on her lips and buccal mucosa. The attending physician suspected that these findings might have been caused by strong sucking pressure on her lips within the context of a sexual assault. A toxicological examination of a blood specimen verified that she had been under the influence of an extremely high dose of ecstasy (1.456 mg/L MDMA and 0.0213 mg/L MDA). Pursuant to the forensic medical assessment, the described findings on her lips, and buccal mucosa were interpreted as an allergic and mechanical reaction (through continuous chewing and biting) to ecstasy.

[Accidental intoxication by outdoor and garden plants : Data from two German poison centres]. / Akzidentelle Vergiftungen mit Gartenpflanzen und Pflanzen in der freien Natur : Daten aus zwei deutschen Giftinformationszentren.

BACKGROUND AND OBJECTIVES: Accidental exposure of children to plants occurs often and results in numerous calls to poison centres. The aim of this study was to identify outdoor plants that led to moderate or severe poisoning after accidental exposure and to identify patterns of paediatric plant exposures. MATERIALS AND METHODS: Human exposure data on accidental exposures provided by two German poison centres were retrospectively evaluated regarding the number and the routes of exposure. Special attention was turned to the kind and severity of symptoms. Based on these data a modified Litovitz factor was calculated. RESULTS: Out of 42,344 confirmed exposures to 227 plant species, 39,346 (93%) were asymptomatic, 2415 (5.7%) experienced minor, 580 (1.3%) moderate and 3 (0.007%) severe symptoms. Twenty-six plant genera were responsible for 70% of all exposures. Only eight of these plants (Arum spec., Laburnum anagyroides, Narcissus spec., Phaseolus vulgaris/coccineus, Prunus laurocerasus, Sambucus spec., Taxus baccata, Thuja spec.) led to at least moderate symptoms. Accidental exposure of children aged 0.5-5 years was mainly by oral ingestion (98%) and involved mostly fruits (60%). CONCLUSIONS: Exposure data collected by poison centres are very useful for hazard identification of outdoor plants. The data give a comprehensive overview of observed symptoms, which offers valuable instruments for use in clinical practice.

Simultaneous quantification of THC-COOH, OH-THC, and further cannabinoids in human hair by gas chromatography-tandem mass spectrometry with electron ionization applying automated sample preparation.

The detection of Δ9 -tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) in hair, for the purpose of identifying cannabis consumption, is conducted in many forensic laboratories. Since external contamination of hair with these cannabis components cannot be excluded, even after hair decontamination, only the detection of THC metabolites such as 11-nor-9-carboxy-Δ9 -tetrahydrocannabinol (THC-COOH) or 11-hydroxy-Δ9 -tetrahydrocannabinol (OH-THC), is considered to prove cannabis consumption. At present, testing for THC metabolites is not standard practice due to its analytical complexity. For these reasons, we developed a novel method for the detection of THC-COOH and OH-THC as well as THC, CBD, and CBN in one single analytical run using gas chromatography-tandem mass spectrometry (GC-MS/MS) with electron ionization. After manual hair washing and grinding, sample preparation was fully automated, by means of a robotic autosampler. The hair extraction took place by digestion with sodium hydroxide. A solid-phase extraction (SPE) was chosen for sample clean-up, using a mixed-mode anion exchange sorbent. Derivatization of all analytes was by silylation. The method has been fully validated according to guidelines of the Society of Toxicological and Forensic Chemistry (GTFCh), with a limit of detection (LOD) of 0.2 pg/mg for THC-COOH and OH-THC and 2 pg/mg for THC, CBD and CBN, respectively, thus fulfilling the Society of Hair Testing (SoHT) recommendations. The validated method has been successfully applied to our routine forensic case work and a summary of data from authentic hair samples is given, as well as data from proficiency tests.

Alcohol Biomarkers in Clinical and Forensic Contexts.

BACKGROUND: Biomarkers of alcohol consumption are important not only in forensic contexts, e.g., in child custody proceedings or as documentation of alcohol abstinence after temporary confiscation of a driver's license. They are increasingly being used in clinical medicine as well for verification of abstinence or to rule out the harmful use of alcohol. METHODS: This review is based on pertinent publications that were retrieved by a selective literature search in PubMed concerning the direct and indirect alcohol markers discussed here, as well as on the authors' experience in laboratory analysis and clinical medicine. RESULTS: Alongside the direct demonstration of ethanol, the available markers of alcohol consumption include the classic indirect markers carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (GGT), and mean corpuscular volume (MCV) as well as direct alcohol markers such as ethyl glucuronide (EtG) and ethyl sulfate (EtS) in serum and urine and EtG and fatty acid ethyl esters (FAEE) in hair. Phosphatidylethanol (PEth) is a promising parameter that com - plements the existing spectrum of tests with high specificity (48-89%) and sensi - tivity (88-100%). In routine clinical practice, the demonstration of positive alcohol markers often leads patients to admit previously denied alcohol use. This makes it possible to motivate the patient to undergo treatment for alcoholism. CONCLUSION: The available alcohol biomarkers vary in sensitivity and specificity with respect to the time period over which they indicate alcohol use and the minimum extent of alcohol use that they can detect. The appropriate marker or combination of markers should be chosen in each case according to the particular question that is to be answered by laboratory analysis.

Modafinil in Forensic and Clinical Toxicology-Case Reports, Analytics and Literature.

Modafinil is used because of its wakefulness-promoting properties for treatment of diseases associated with extreme sleepiness (i.e., narcolepsy). Additionally, it is misused as a "cognitive enhancer" to increase alertness and to improve concentration. We present modafinil concentrations in serum samples in five cases of our routine work measured by high-performance liquid chromatography coupled with a photo diode array detector after solid-phase extraction. One sample was analyzed for clinical toxicology purposes. The other four were investigated for the police: three cases of driving under the influence of drugs and one case of bodily harm. Sample preparation consisted of solid-phase extraction using Bond Elut® C18 columns. Papaverine was used as internal standard. Chromatographic separation was carried out using a Polaris C18-A column in an isocratic run. Wavelengths used for UV-detection were 220 nm for modafinil and 239 nm for the internal standard, respectively. The method was validated with a reduced validation design for rare analytes. A six-point-calibration from 0.5 to 5.0 mg/L, covering the therapeutic range (0.9-3.3 mg/L), was used for quantification. Concentrations in serum were in the range of 1.3 to ~34 mg/L (median: 3.6 mg/L; mean: 9.0 mg/L). To our knowledge, there are only few publications concerning the serum concentrations of modafinil in cases of (suspected) misuse, forensic cases or intoxications. In our discussion, the serum concentrations we determined are compared with the levels described in the literature so far.