Cardiac effects of 5F-Cumyl-PEGACLONE.

Synthetic cannabinoids become increasingly popular as a supposedly safe and legal alternative to cannabis. In order to circumvent the German New Psychoactive Substances Law, producers of so-called herbal mixtures rapidly design new substances with structural alterations that are not covered by the law. Acting as full agonists not only at the cannabinoid receptors 1 and 2, synthetic cannabinoids might have not only desired mental but also serious physical adverse effects. However, knowledge of adverse effects of specific substances is sparse and incomplete. This also accounts for 5F-Cumyl-PEGACLONE, a synthetic cannabinoid, which has been detected regularly in Germany in recent years. By using an animal model, the isolated perfused Langendorff heart, the study at hand aimed on finding out more about possible cardiovascular adverse effects of 5F-Cumyl-PEGACLONE. Hearts of male Wistar rats, which were excised postmortem, were exposed to two different concentrations of 5F-Cumyl-PEGACLONE: 13 hearts were exposed to 50 ng/ml and 12 hearts were exposed to 100 ng/ml. Thirteen control hearts were merely exposed to an additional amount of buffer solution. Functional parameters heart rate, minimal and maximum left ventricular pressure and coronary flow were documented at pre-defined time points during and after the administration of 5F-Cumyl-PEGACLONE/additional buffer solution. Electrocardiograms (ECGs) were documented throughout the experiments and evaluated afterwards. Kruskal-Wallis analysis was performed for each functional parameter as well as for the duration of the QRS complexes and the duration of RR intervals as derived from the ECGs. Furthermore, a multivariate analysis, comprising all functional and ECG parameters, was performed. Kruskal-Wallis analysis revealed only single significant p-values for QRS duration and minimum left ventricular pressure that did not pass a Bonferroni test. The results of the multivariate approach were also comparably homogeneous, but still the model correctly recognized hearts exposed to 100 ng/ml of 5F-Cumyl-PEGACLONE more often than hearts exposed to the low concentration of 5F-Cumyl-PEGACLONE or additional buffer solution. Evaluation of the ECGs presented single cases of ST depression and QT prolongation. Though certainly not unambiguous, these findings support the assumption that 5F-Cumyl-PEGACLONE can cause severe, if not lethal, cardiac adverse effects like arrhythmias or myocardial infarctions especially if it is consumed in combination with other drugs like alcohol or if the consumer suffers from pre-existing heart diseases.

Analysis of tetrahydroisoquinolines formed after simultaneous consumption of ethanol and amphetamine or its derivatives by LC-MS/MS in human blood, brain, and liver tissue.

The effects of the simultaneous consumption of amphetamine or amphetamine derivatives and alcohol have not yet been adequately clarified, particularly concerning potential condensation products resulting from the endogenous reaction between these substances and their metabolites (e.g., acetaldehyde, a metabolite of ethanol). In this study, we developed an LC-MS/MS method employing liquid-liquid extraction for the qualitative detection of some relevant condensation products belonging to the class of tetrahydroisoquinolines and their derivatives in human blood, brain, and liver samples. This includes the analysis of the substrates amphetamine, methamphetamine, methylenedioxymethamphetamine, methylenedioxyamphetamine, as well as the condensation products 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, N-methyl-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, 1,3-dimethyl-7,8-methylenedioxy-1,2,3,4-tetrahydroisoquinoline, and N-methyl-1,3-dimethyl-7,8-methylenedioxy-1,2,3,4-tetrahydroisoquinoline. Therefore, the reference standards of the mentioned tetrahydroisoquinolines were synthesized in advance and the method was validated with regard to the question of the qualitative detection of these compounds. The validation parameters included selectivity, specificity, limit of detection, lower limit of quantification, recovery, matrix effects, and stability for blood, brain, and liver samples. Following the analysis of human blood and post-mortem tissue samples, evidence of the condensation product 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline originating from the interaction between amphetamine and acetaldehyde was identified in two liver samples. On the contrary, no evidence of this or other tetrahydroisoquinolines was found in the remaining tissue and serum samples.

Studies on the phase I metabolism of the new designer drug 3-fluoromethcathinone using rabbit liver slices.

The metabolism of the novel designer drug 3-fluoromethcathinone (3-FMC), sold as "legal highs", was investigated in vitro via cryopreserved rabbit liver slices. The pharmacological properties and toxicological effects of 3-FMC and its metabolites are not known yet. It can be assumed that 3-FMC will cause effects similar to 4-methylmethcathinone (mephedrone) and methcathinone. For the metabolism studies, pretests were performed with rabbit liver slices incubated with kavain to evaluate optimal conditions. Finally, six known metabolites of kavain were revealed and therefore sufficient information about the suitability of the enzyme system of the rabbit liver slices was obtained. Under optimized conditions, 3-FMC was added to Krebs-Henseleit buffer, pH 7.4 containing NADPH and bicarbonate and incubated with a single rabbit liver slice at 37°C. The metabolism was monitored at 5, 30 and 180 min, respectively. The metabolites formed via the former cryopreserved rabbit liver slices were examined by LC/MS-TOF. Metabolites were identified by their exact masses and isotopic patterns. 3-Fluorocathinone, 3-fluorocathinone-imine, hydroxy-3-fluoromethcathinone and 3-fluoromethcathinone-diol were formed as the main metabolites.

Cerebrospinal Fluid System Infection in Children with Cancer: A Retrospective Analysis over 14 Years in a Major European Pediatric Cancer Center.

Infection of a cerebrospinal fluid system is a serious medical complication. We performed a retrospective monocentric analysis on temporary and permanent cerebrospinal fluid devices in children with and without cancer, covering a period of over 14 years. Between 2004 and 2017, 275 children with a cerebrospinal fluid system were seen at our institution. Thirty-eight children suffered from 51 microbiologically proven infectious episodes of the cerebrospinal fluid system (12 children with cancer and 26 children without cancer). Independently of the cerebrospinal fluid system used, the incidence of infection did not significantly differ between children with and without cancer and was the highest in children younger than one year. Infection occurred earlier in external ventricular drain (EVD) than ventriculoperitoneal (VP) shunt, and in EVD significantly earlier in children with cancer compared with patients without cancer. The pathogens isolated were mainly Gram-positive bacteria, in particular Staphylococcus spp., which should be taken into account for empirical antimicrobial therapy.

Analysis of cocaine adulterants in human brain in cases of drug-related death.

For different reasons, street cocaine is often diluted with pharmacologically active substances, the so-called adulterants such as levamisole or hydroxyzine. A controversial debate exists currently on the uptake of adulterants from cocaine preparations and drug-related death. Previous research convincingly argues that serious adverse side effects that affect the central nervous and cardiovascular systems can be a consequence of adulterated cocaine. AIMS: Having identified the presence of adulterants in lung tissue and blood, the concentrations of these substances in brain, an important target location, was of interest. This provides an opportunity to assess their role in cases of drug-related deaths. MATERIALS AND METHODS: We developed and validated a method for the analysis of cocaine, two cocaine metabolites and six adulterants, which can typically be found in cocaine preparations, and one adulterant metabolite in brain tissue by gas chromatography-mass spectrometry (GC-MS)1. Ten brain samples which were tested positive for cocaine were analyzed. The homogenized brain tissue was embedded into drying paper for protein precipitation. During a subsequent solid-phase extraction (SPE), the eluate and one of the wash fractions were collected. After derivatization with N-Methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) in pyridine and isooctane, the extracts were analyzed by GC-MS. RESULTS AND DISCUSSION: The method was fully validated for cocaine (COC), benzoylecgonine (BZE), ecgonine methyl ester (EME), diltiazem (DIL), hydroxyzine (HYD), and levamisole (LEV) and partly validated for cetirizine (CET), lidocaine (LID), phenacetin (PHE), and procaine (PRO) in brain material. By analyzing post-mortem brain tissue of ten cocaine users, LEV, LID, and HYD as well as PHE were identified in contrast to DIL, PRO, and the HYD metabolite CET. HYD and LEV were found in moderate to high concentrations in some cases. Therefore, it cannot be excluded that they have caused adverse side effects. CONCLUSION: Because adulterants can potentially affect the central nervous and cardiac systems, it is likely that they enhance COC toxicity.

Comparison of venous blood alcohol concentrations and breath alcohol concentrations measured with Draeger Alcotest 9510 DE Evidential.

Most comparisons of blood alcohol concentrations (BAC) and breath alcohol concentrations (BrAC) are either derived from drinking trials with rigid drinking protocols or from investigative authorities' data with considerable time differences between the determination of BAC and BrAC. In general, only comparisons of relatively low BAC-BrAC pairs are available. Therefore, the relationship between BAC and BrAC was examined even for high BAC above 2g/kg. The results of a large-scale drinking test under realistic conditions with 78 test persons and short time intervals between BAC and BrAC measurements are presented. It was shown that the conversion factor Q varies greatly (between 1571:1 and 2394:1) and increases with increasing BAC. A constant conversion factor that is suitable for variable forensic purposes could not be presented.

Drug-related death: adulterants from cocaine preparations in lung tissue and blood.

The abuse of drugs such as street cocaine is known to cause a variety of toxic effects, some of which involve the lungs and often induce lethal complications. While the toxicity of cocaine itself is reviewed well, the influence of toxic effects of its adulterants on the human body is not thoroughly studied. Therefore, we examined heart blood, femoral vein blood and lung tissue from 11 cases for typically used adulterants in cocaine preparations and check whether if the concentrations in the lung tissue are higher than in the blood. The adulterants were isolated using solid-phase (SPE) and liquid-liquid extraction (LLE) and quantified via high-pressure-liquid-chromatography-time-of-flight-mass spectrometry (LC/TOF-MS). Five adulterants, i.e., phenacetin, lidocaine, diltiazem, levamisole and hydroxyzine, were detected. We found out that the concentration of these substances was often higher in the lung than in the analogous analysed body fluids. It should therefore be considered whether - for the determination in the cause of death - the lung should be examined in addition to heart blood, urine or brain tissue.