Morphine concentrations in fatalities after palliative treatment of acute burn injury.

The evaluation of a morphine concentration in postmortem blood is routine for a forensic toxicologist. We here report three fatal cases where we found high morphine concentrations with 7.96, 4.30, and 5.82 mg/l in femoral blood that have to be estimated as unusually high. All these individuals died due to severe burn injuries and obtained morphine in the context of their palliative care in the last hours of their lives. According to the autopsy results, the cause of death in case 1 was burn disease with burns of about 90% of the body surface area (BSA), case 2 burn trauma, and case 3 burn shock. Besides morphine, propofol, fentanyl, sufentanil, midazolam, diazepam, lorazepam, cefazolin, and rocuronium were detected in femoral blood. The findings fitted well with the detailed clinical documentation. Further evidence of therapeutic concentrations of quetiapine, duloxetine, and melperone could be matched to preexisting medication of the individuals. Physiologically based pharmacokinetic modelling (PBPK) was applied, developed for the intravenous administration of morphine, to find an explanation for the high morphine concentrations in femoral blood. Quantification of morphine in body fluids and tissue was performed to calculate morphine tissue concentration ratios to the morphine concentration in femoral blood. The presented cases show that pharmacokinetic simulations can reflect decreased renal clearance and decreased hepatic metabolism in general. However, this prediction is not sufficient to explain the high morphine concentrations in femoral blood measured here. It can be assumed that burn shock in particular leads to altered pharmacokinetics, namely decreased distribution of morphine.

Indomethacin has no effect on trigeminally provoked parasympathetic output.

BACKGROUND: Unlike other non-steroidal anti-inflammatory drugs, indomethacin has been shown to be highly effective in two forms of trigeminal autonomic cephalalgias, hemicrania continua and paroxysmal hemicrania and in some forms of idiopathic stabbing headaches. This specificity is unique in the headache field. Previous findings suggest the involvement of the trigeminal autonomic reflex to play an important role in the pathophysiology of these diseases. METHODS: 22 healthy participants were enrolled in a double-blind, three-day within-subject design. The participants received indomethacin, ibuprofen or placebo in a randomized order. After an incubation period of 65 min the baseline lacrimation and the lacrimation during intranasal stimulation evoked by kinetic oscillation stimulation were assessed using Schirmer II lacrimation tests. The lacrimation difference in mm was calculated and compared in a repeated measures ANOVA. RESULTS: No significant differences were found between the three conditions. CONCLUSION: In our study, neither indomethacin nor ibuprofen had an inhibitory effect on the trigeminal autonomic reflex. We suggest that blocking this reflex may not be the treatment mechanism of indomethacin.

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.

[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.

Ethyl Glucuronide in Alcoholic Beverages.

AIMS: This study examines the biomarker ethyl glucuronide (EtG) in various alcoholic beverages. SHORT SUMMARY: The biomarker EtG was consistently found to be a natural compound of wine, whereas it was not detected in any of the other tested alcoholic beverages, which included various distilled spirits, liqueurs and beer of different types and geographical origins. METHODS: Alcoholic beverages (n = 114) were analyzed by a validated liquid chromatography/tandem mass spectrometry assay. Beverages included samples from beer, wine, liqueurs and spirits from different manufacturers and geographical origins. RESULTS: EtG was not detected in any kind of distilled alcoholic beverages, regardless of the type of spirit (rum, gin, vodka, whiskey, fruit brandy, corn brandy, cordial) or liqueur (n = 52). EtG was also not detected in any of the analyzed samples of beer, which included pilsener, weissbier, lager beer and ale from different origins (n = 20). In contrast, EtG was detected in every of the analyzed samples of wine (n = 42) without exception. Highest amounts were found in red wine and ranged from 1425 to 3720 µg/l (n = 16). Significantly, lower concentrations of EtG were observed for white wine (347-1685 µg/l, n = 14) and sparkling wine (281-1447 µg/l, n = 10). CONCLUSIONS: Wine is an external source of EtG. It has been shown that milligram amounts of the biomarker can be contained in a bottle of wine. This should be considered in biomarker testing, especially in EtG hair analysis, which is susceptible to external contamination.

[Accidental ingestion of methadone by children and suggestions for better prevention]. / Akzidentelle Methadoneinnahme durch Kinder - Gedanken zur Verbesserung der Prävention.

Despite the medial attention attracted by the presented case in January 2012 and the determined measures taken to minimize the risk of accidental poisoning for children in the direct surroundings of substituted persons, we recently faced two more cases of methadone-intoxicated children in Hamburg. We believe that the most important step to increase awareness of the dangerous effects of methadone for children might be the storage of methadone in lockable boxes, which would make it safe from access by children and third parties. Moreover this way of storing reminds the patients of the risks resulting from their medication. Repeated and comprehensive instruction appears to be the best protection against cases like this to counteract careless handling of the substitution medication.

Intravenous methadone application as a serious risk factor for an overdose death: methadone-related fatalities in Hamburg from 2007 to 2012.

Methadone plays an increasing role in drug-related deaths in Hamburg. To find out whether intravenous application of methadone plays a relevant role in methadone-related deaths, body fluids of all methadone-positive cases (n=130) and three buprenorphine-positive cases where a urine sample was available (n=58+3) were investigated for disaccharides (sucrose and lactose as markers for intravenous methadone abuse). Sixty-four percent of the urine samples of the methadone cases showed positive results for disaccharides (22 times sucrose alone, range 2 to >1,000 mg/L; 6 times lactose and sucrose; and 9 times lactose alone, range 22 to 382 mg/L). The three buprenorphine cases showed positive results for lactose in urine. In blood, it was not possible to detect any disaccharides. Of the 116 fatal methadone intoxications, 49 % were under opiate maintenance treatment (OMT) at the point of death (A-OMT), 30 % were never in OMT (N-OMT) and 21 % were formerly in an OMT, but not at the point of death (F-OMT). Of the deceased in the OMT group, 12 % (n=7) died within the first 2 weeks of treatment, six of them within the first week. Overall, intravenous abuse of methadone plays a relevant role in methadone-related fatal cases of substituted patients and of drug consumers not in therapy. Thus, it is necessary that therapists keep to the statutory regulations and give take-home doses only after at least 6 months of successful therapy and when there is no suspicion of intravenous abuse.

Chiral analysis of amphetamine, methamphetamine, MDMA and MDA enantiomers in human hair samples.

A novel analytical method was developed for the simultaneous quantification of the R/S-enantiomers of amphetamine, methamphetamine, MDA and MDMA in hair samples using liquid chromatography-tandem mass spectrometry (LC-MS-MS). This method involved a straightforward derivatization step with dansyl chloride and the use of a chiral column, enabling the separation and quantification of all eight enantiomers in a single analysis. The method exhibited excellent linearity across a concentration range of 0.03-3.00 ng/mg for each enantiomer. Precision and accuracy were within acceptable limits, with bias and relative standard deviation (RSD) values consistently below 6% and 9%, respectively. Selectivity and specificity assessments confirmed the absence of any interference from contaminants or co-extracted drugs. The method demonstrated high sensitivity, with limits of detection (LOD) below 8 pg/mg and limits of quantification (LOQ) below 19 pg/mg for all analytes. Extraction recovery exceeded 79%, and matrix effects were minimal for all analytes. Processed sample stability evaluations revealed consistent results with deviations below 11% for all analytes. Application of the method to 32 authentic human hair samples provided valuable insights into amphetamine use patterns, allowing differentiation between medical amphetamine consumption and illicit use based on enantiomeric composition. Additionally, the method detected co-use of methamphetamine, MDA or MDMA in some samples, highlighting its applicability in drug monitoring and real-life case scenarios within a forensic institute. This innovative analytical approach offers a sensitive and selective method for enantiomeric differentiation of amphetamine, methamphetamine, MDA and MDMA in human hair samples, providing a valuable tool for forensic and clinical investigations.

Toxicologic analysis of 35 drugs in post mortem human blood samples with focus on antihypertensive and antiarrhythmic drugs.

Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in therapeutic doses, and if they were taken in accidental, intentional, or suicidal overdose scenarios. Therefore, a novel analytical method was developed and validated for the quantification of 35 drugs with toxicological relevance, including antihypertensive and antiarrhythmic drugs (ajmaline, amlodipine, amiodarone, atenolol, bisoprolol, carvedilol, clonidine, desethylamiodarone, diltiazem, donepezil, doxazosin, dronedarone, esmolol, flecainide, lercanidipine, lidocaine, metoprolol, nebivolol, nimodipine, pindolol, prajmaline, propafenone, propranolol, sotalol, urapidil, and verapamil), as well as other medications commonly found in combination (sildenafil, tadalafil, atorvastatin, clopidogrel, dapoxetine, memantine, pentoxifylline, rivastigmine, and ivabradine). The method enables simultaneous identification and quantification in blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Validation exhibited excellent linearity across the concentration range for all analytes. Precision and accuracy were within acceptable limits, with bias and relative standard deviation (RSD) values consistently below 9 % and 10 %, respectively. Selectivity and specificity assessments confirmed the absence of any interference from contaminants or co-extracted drugs. The method demonstrated very high sensitivity, with limits of detection (LOD) as low as 0.01 ng/ml and limits of quantification (LOQ) as low as 0.04 ng/ml. Extraction recovery exceeded 57.5 % for all analytes except atenolol, and matrix effects were <17 % for all analytes except pindolol. Processed sample stability evaluations revealed consistent results with acceptable deviations for all analytes. In addition, the method was specifically tested for the use in post mortem analysis. The applicability of our method was demonstrated by the analysis of two authentic human autopsy blood samples.

Post mortem chiral analysis of MDMA and MDA in human blood and hair.

Drug-related fatalities in the EU are predominantly associated with opioids. MDMA (Ecstasy) consumption results in fewer lethal intoxications despite its widespread use. This study investigates MDMA-related fatalities, focusing on enantiomer ratios of MDMA and its metabolite MDA to explore the role of metabolism in fatal outcomes. MDMA induces euphoria, increased empathy, and physiological effects such as tachycardia, hypertension, and hyperthermia. Metabolism mainly involves CYP1A2 and CYP2D6, with polymorphism of the latter influencing metabolism rates. Our institute observed several MDMA-related fatalities, which prompted an investigation into the potential role of inefficient drug metabolism in these cases. A novel quantitative chiral analysis method was developed and validated for MDMA, MDA, amphetamine and methamphetamine enantiomers in human blood. Analysis of post mortem blood samples from eleven MDMA-related fatalities exhibited a wide range of concentrations and enantiomer ratios. Variability in R/S MDMA ratios, however, could be linked to the time period of metabolism. Hair analysis revealed high MDMA concentrations in all segments, irrespective of prior drug abuse anamnesis. Therefore, hair analysis may not be suitable for the assessment of past drug use in ecstasy-related fatalities. The results indicated that elevated levels of the MDMA enantiomer are correlated with longer survival times in cases of intoxication. However, there was no clear evidence for slowed MDMA metabolism as a cause of lethal intoxications. While challenges remain due to the diversity of cases, this study contributes valuable insights into ecstasy intoxications, aiding future interpretation of post mortem analysis.

Quantitative determination of valproic acid in postmortem blood samples--evidence of strong matrix dependency and instability.

Most of the daily work of forensic toxicologists deals with fatal cases resulting from overdoses of licit and illicit drugs. However, another reason for fatalities in patients suffering from epilepsy can be undetectable or subtherapeutic levels of antiepileptic drugs. Some studies have shown a correlation between "sudden unexpected death in epilepsy" (SUDEP) and the ineffective treatment of epilepsy. Low levels of antiepileptic drugs may be a risk factor for SUDEP. The death of a psychiatric patient also suffering from epilepsy inspired the investigation. Subsequent to the death of the patient, the doctor was accused of providing inadequate therapy for epilepsy. The patient was to be treated with valproic acid. We developed and validated a simple method of determining valproic acid levels by gas chromatography-mass spectrometry for serum, but a transfer of the method from serum to postmortem whole blood failed. The method had to be modified and revalidated for postmortem whole blood specimens. A stability study of valproic acid in postmortem blood was conducted, showing a decline of valproic acid levels by 85 % after storage at room temperature for 28 days. During the storage time, the blood samples showed changes in consistency. Depending on the stage of decomposition, it is necessary to perform a determination by standard addition with an equilibration time of 4 h before extraction to achieve reliable results. For a proper interpretation of quantitative results, it is necessary to keep the postmortem decline of valproic acid concentrations in mind.

Analysis of cyclosporin a in hair samples from liver transplanted patients.

INTRODUCTION: Cyclosporin A (CsA) is one of the most important immunosuppressants currently used to prevent organ rejection after liver transplantation. Therapeutic benefit and adverse toxicity are associated with only small differences in CsA blood concentration. Correct individual dosage and compliance are therefore essential for successful therapy. To this end, we developed a validated analytical assay for the determination of CsA in hair samples. Hair samples from patients treated with CsA after liver transplantation were analyzed to investigate correlations between hair concentrations, blood concentrations, and CsA doses. The aim of this study was to evaluate whether hair analysis could be useful for the long-term follow-up of liver transplantation patients. MATERIALS AND METHODS: Hair samples from patients were segmented and decontaminated. After alkaline hydrolysis and liquid-liquid extraction, CsA was analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: The peptide CsA (molecular weight 1202.6 Da) was detected in all the patient hair segments corresponding to times of CsA intake, whereas all hair segments reflecting times without CsA treatment tested negative. Correlation between CsA hair concentrations and CsA doses was poor. Consequently, it was not possible to verify the amount of CsA intake by hair analysis. A correlation coefficient of r = 0.57 was found for the correlation of average whole blood trough concentrations and hair concentrations. The segmental CsA hair concentrations were found to be much steadier than the whole blood trough concentrations. In patients with stable or slightly changed CsA dosages, a comparable segmental concentration profile with a decrease in CsA hair concentrations from proximal to distal was found. Major modifications in CsA dosage are followed by a corresponding trend in segmental hair concentrations. CONCLUSIONS: Our results suggest that it is not possible to quantify the amount of CsA intake by hair analysis. Segmental hair analysis might be useful in the detection of substantial noncompliance and to detect changes in drug-taking behavior.

[Suicide under the influence of "magic mushrooms"]. / Suizid unter Psilocin-Einfluss.

Psilocybin/psilocin from so-called psychoactive mushrooms causes hallucinogenic effects. Especially for people with mental or psychiatric disorders ingestion of magic mushrooms may result in horror trips combined with the intention of self-destruction and suicidal thoughts. Automutilation after consumption of hallucinogenic mushrooms has already been described. Our case report demonstrates the suicide of a man by self-inflicted cut and stab injuries. A causal connection between suicidal behaviour and previous ingestion of psychoactive mushrooms is discussed.

Stability of PEth 16:0/18:1, 16:0/18:2, 16:0/20:4, 18:0/18:1, 18:0/18:2, and 18:1/18:1 in authentic whole blood samples (at room temperature).

Phosphatidylethanol (PEth) is a direct alcohol biomarker to monitor individuals' drinking behavior that has gained recognition in clinical and forensic settings. The increasing application of the marker makes investigation of the preanalytical handling necessary, and analyte stability deserves major attention. This study was conducted to investigate the change of six PEth homologues' concentration, stored in authentic samples of EDTA blood over a course of 30 days at room temperature (n = 62). The stability criterion of concentration being ±15% of the original concentration was fulfilled at mean for 10, 3, 2, 5, 2, and 7 days for PEth 16:0/18:1, 16:0/18:2, 16:0/20:4, 18:0/18:1, 18:0/18:2, and 18:1/18:1, respectively. Regarding all homologues, there were samples in which concentration had declined by >15% or by more than the critical difference on day 1. Overall, calculated concentration declines were very inhomogeneous, with inter-sample differences of 43%-73% after 30 days. PEth 16:0/18:2, 16:0/20:4, and 18:0/18:2 declined to a greater extent than PEth 16:0/18:1. Blood alcohol concentration was measured >0.1‰ in 25 samples. Three of the six samples that exceeded 115% of initial concentrations were positive for blood alcohol. The study results add to the previously reported information on PEth stability and firstly look at six homologues in comparison. Due to the high scatter of stability among the samples and the observed poor stabilities in some, it can be concluded that transportation and storage times, especially if cooling cannot be provided, must be kept short. If analyzing from dried blood, spotting should preferably be conducted at the site of sampling.

PEth 16:0/18:1 and 16:0/18:2 after consumption of low doses of alcohol-A contribution to cutoff discussion.

Phosphatidylethanol in blood has gained recognition as a direct alcohol biomarker. Although different cutoffs have been suggested, there is no consensus for differentiating abstinence from alcohol consumption. In this study, 75 participants (72% female) consumed 20 g of ethanol on three consecutive evenings. Blood was sampled on each following day and PEth 16:0/18:1 and 16:0/18:2 were determined. PEth 16:0/18:1 ranged from 8.9-21.5, 8.7-19.3, and 8.8-42.3 ng/ml and PEth 16:0/18:2 from 8.7-31.7, 9.0-39.3, and 9.4-43.0 ng/ml after the respective days of ethanol consumption. PEth 16:0/18:1 yielded a sensitivity of 25%, 45%, and 49% and PEth 16:0/18:2 of 40%, 61%, and 68% for the consumption days, respectively (cutoff 10 ng/ml). PEth 16:0/18:1 reached >20 ng/ml in five samples overall. Sensitivity of PEth 16:0/18:2 > 20 ng/ml was better with 35% after the three drinking days. Overall, PEth 16:0/18:1 was >35 ng/ml in one sample and PEth 16:0/18:2 in three samples. Significantly, more women had PEth 16:0/18:1 > 10 ng/ml after the third day of consuming 20 g of alcohol (p = 0.02) and PEth 16:0/18:2 > 10 ng/ml after the second (p = 0.023) and the third (p = 0.002) consumption, which can be led back to the higher blood alcohol concentration women reach after consuming the same alcohol amount as men. Although the response rates of PEth to alcohol uptake are subject to strong interindividual differences, results suggest that PEth cutoff should be lowered for better detection of consumption of low to medium amounts of alcohol. Furthermore, it is advantageous to analyze both PEth 16:0/18:2 and 16:0/18:1.

Beta-Glucuronidase Activity: Another Source of Ethyl Glucuronide.

Numerous classes of endogenous and xenobiotic compounds are conjugated to uridine-5'-diphospho (UDP)-alpha-D-glucuronic acid which is catalyzed by human UDP-Glucuronosyltransferases (UGTs). The resulting beta-D-glucuronides can be hydrolyzed to ß-D-glucuronic acid and the corresponding aglycone in a configuration retaining manner by beta-glucuronidases (GUSBs), which are widely distributed in mammalians, microbiota, insects, molluscs, nematodes, fishes and plants. This study investigates GUSBs' activity in the presence of ethanol (0-70% by volume) using different ß-D-glucuronides (phenolphthalein-ß-D-glucuronide, 4-nitrophenol-ß-D-glucuronide, morphine-3-O-ß-D-glucuronide, quercetin-3-O-ß-D-glucuronide and 1-/2-propyl-ß-D-glucuronide) as substrates. It was found that ß-D-ethyl glucuronide (EtG), which is a minor UGT-derived metabolite of ethanol in man and one of the most frequently used biomarkers of alcohol consumption today, builds up from all investigated ß-D-glucuronides by means of GUSBs in the presence of ethanol. The glucuronyl transfer reaction, which was neither detected in the absence of ethanol nor in absence of GUSBs, is minor at ethanol concentrations which are commonly observed in blood and tißues after consumption of alcoholic beverages, but predominant at higher concentrations of ethanol. In spite of in vitro characteristics, our observations point to an additional biochemical path and another source of EtG, which should be further evaluated in the context of alcohol biomarker applications. The detection of EtG in several settings independent from of human UGT-metabolism (e.g. EtG post post-collection synthesis in E.coli coli-contaminated urine samples, EtG in wine and ethanolic herbal preparations) can be explained by the described mechanism.

[One and a half years of e-scooters in Hamburg]. / Eineinhalb Jahre E-Scooter ­ Zwischenbilanz in Hamburg: Teil 1: alkoholbedingte Auffälligkeiten im Straßenverkehr.

Background: Since electric scooters were introduced as an urban means of transportation in Hamburg in June 2019, a high number of violations of the current laws regarding alcohol consumption by e­scooter riders have been recorded. Objective: The aim of this study is to obtain an overview of traffic offences committed by e­scooter drivers under the influence of alcohol, to classify their relevance in relation to other road user groups, and to draw a first interim balance with respect to their frequency after 1.5 years. Material and methods: The data of all e­scooter drivers (n = 342) examined concerning their blood alcohol values analyzed at the Institute of Legal Medicine of the University Medical Centre Hamburg-Eppendorf between 15.06.2019 and 31.12.2020 were retrospectively evaluated with respect to their demographic information and the medical examination results. These were brought into context with the total number of offences against the road traffic regulations with subsequent blood alcohol measurement. Results: 9.6% of the total number of offences against the road traffic regulations in connection with subsequent determination of the blood alcohol concentration were committed by e­scooter drivers. 87.7% of those examined were male. The blood alcohol concentration was above the limit of 1.10 ‰ for absolute driving incapacity when using a passenger car in 76.9% of those examined. An accumulation of cases was particularly noticeable at night and at weekends.Due to imprecise records, a certain number of unreported e­scooter incidents can be assumed among the unspecified motor vehicles. Conclusion: As e­scooter drivers make up a considerable proportion of drunken road users and the accidents mostly occur at night and at weekends, increased education and, if necessary, a driving ban at these times would seem to make sense.

Acute-on-chronic liver failure alters linezolid pharmacokinetics in critically ill patients with continuous hemodialysis: an observational study.

BACKGROUND: In acute-on-chronic liver failure (ACLF), adequate antibiotic dosing is challenging due to changes of drug distribution and elimination. We studied the pharmacokinetics of linezolid in critically ill patients with ACLF during continuous renal replacement therapy compared to patients without concomitant liver failure (NLF). METHODS: In this prospective cohort study, patients received linezolid 600 mg bid. Linezolid serum samples were analyzed by high-performance liquid chromatography. Population pharmacokinetic modelling was performed followed by Monte-Carlo simulations of 150 mg bid, 300 mg bid, 450 mg bid, 600 mg bid, and 900 mg bid to assess trough concentration target attainment of 2-7 mg/L. RESULTS: Eighteen patients were included in this study with nine suffering from ACLF. Linezolid body clearance was lower in the ACLF group with mean (standard deviation) 1.54 (0.52) L/h versus 6.26 (2.43) L/h for NLF, P < 0.001. A trough concentration of 2-7 mg/L was reached with the standard dose of 600 mg bid in the NLF group in 47%, with 42% being underexposed and 11% overexposed versus 20% in the ACLF group with 77% overexposed and 3% underexposed. The highest probability of target exposure was attained with 600 mg bid in the NLF group and 150 mg bid in the ACLF group with 53%. CONCLUSION: Linezolid body clearance in ACLF was markedly lower than in NLF. Given the overall high variability, therapeutic drug monitoring (TDM) with dose adjustments seems required to optimize target attainment. Until TDM results are available, a dose reduction may be considered in ACLF patients to prevent overexposure.

Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics.

INTRODUCTION: In order to assess the significance of drug levels measured in intensive care medicine, clinical and forensic toxicology, as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. Therefore, it makes sense to offer a carefully referenced compilation of therapeutic and toxic plasma concentration ranges, as well as half-lives, of a large number of drugs and other xenobiotics for quick and comprehensive information. METHODS: Data have been abstracted from original papers and text books, as well as from previous compilations, and have been completed with data collected in our own forensic and clinical toxicology laboratory. The data presented in the table and corresponding annotations have been developed over the past 20 years and longer. A previous compilation has been completely revised and updated. In addition, more than 170 substances, especially drugs that have been introduced to the market since 2003 as well as illegal drugs, which became known to cause intoxications, were added. All data were carefully referenced and more than 200 new references were included. Moreover, the annotations providing details were completely revised and more than 100 annotations were added. RESULTS: For nearly 1,000 drugs and other xenobiotics, therapeutic ("normal") and, if data were available, toxic and comatose-fatal blood-plasma concentrations and elimination half-lives were compiled in a table. CONCLUSIONS: In case of intoxications, the concentration of the ingested substances and/or metabolites in blood plasma 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, and to support forensic and clinical expert opinions.

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.