The use of dried blood spots for quantification of 15 antipsychotics and 7 metabolites with ultra-high performance liquid chromatography-tandem mass spectrometry

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Medical emergencies related to ethanol and illicit drugs at an annual, nocturnal, indoor, electronic dance music event

Introduction: Medical problems are frequently encountered during electronic dance music (EDM) events. Problem: There are uncertainties about the frequencies and severity of intoxications with different types of recreational drugs: ethanol, "classical" illicit party drugs, and new psychoactive substances (NPS). Methods: Statistical data on the medical problems encountered during two editions of an indoor electronic dance event with around 30,000 attendants were retrieved from the Belgian Red Cross (Mechelen, Belgium) database. Data on drug use were prospectively collected from the patient (or a bystander), the clinical presentation, and/or toxicological screening. Results: In the on-site medical station, 487 patients were treated (265 in 2013 and 222 in 2014). The most frequent reasons were trauma (n = 171), headache (n = 36), gastro-intestinal problems (n = 44), and intoxication (n = 160). Sixty-nine patients were transferred to a hospital, including 53 with severe drug-related symptoms. Analysis of blood samples from 106 intoxicated patients detected ethanol in 91.5%, 3,4-methylenedioxymethamphetamine (MDMA) in 34.0%, cannabis in 30.2%, cocaine in 7.5%, amphetamine in 2.8%, and gamma-hydroxybutyric acid (GHB) in 0.9% of patients (alone or in combination). In only six of the MDMA-positive cases, MDMA was the sole substance found. In 2014, the neuroleptic drug clozapine was found in three cases and ketamine in one. Additional analyses for NPS were performed in 20 cases. Only in one agitated patient, the psychedelic phenethylamines 25B-NBOMe and 25C-NBOMe were found. Conclusions: At this particular event, recreational drug abuse necessitated on-site medical treatment in one out of 350 attendants and a hospital transfer in one out of 1,000. Ethanol remains the most frequently abused (legal) drug, yet classical illicit recreational drugs are also frequently (co-) ingested. The most worrying observation was high-risk poly-drug use, especially among MDMA users. Regarding NPS, the number of cases was low and the clinical presentations were rather mild. It should be stressed that these observations only apply to this particular event and cannot be generalized to other EDM events

Quantitative liquid chromatographic analysis of anthracyclines in biological fluids

The optimization, validation and application of a liquid chromatographic method with fluorescence detection for the simultaneous determination of the four most important anthracyclines (doxorubicin, epirubicin, daunorubicin and idarubicin) and their toxicologically relevant metabolites in plasma and saliva is described. The thesis also explored the possibilities of liquid chromatography coupled to fluorescence detection for trace analysis of anthracyclines in urine. In Chapter I anthracyclines were introduced. They are widely used in clinical oncology. Current dosing, based on body surface area, leads to marked interindividual variations in efficacy and toxicity. Chapter II gave a literature overview of chromatographic methods for determination of anthracyclines in biological fluids. Chapter III summarized the objectives. The main goal was to develop an analytical method, that can be applied in routine laboratories to gain insight into individual pharmacokinetics of patients treated with anthracyclines. In Chapter IV the synthesis of some commercially unavailable metabolites was described. The optimization of a liquid chromatographic separation was the subject of Chapter V. Inclusion of epidaunorubicin in the assay allows internal standardization of applications. In Chapter VI the extraction of anthracyclines from biological fluids was studied. The first part discussed the extraction of plasma and saliva samples. The second part focused on the extraction for trace-analysis in urine. Chapter VII highlighted the importance of additives to stabilize chloroform, when chloroform is applied for extraction of anthracyclines. In Chapter VIII the developed method for the determination in plasma and saliva was validated according to selectivity, sensitivity, linearity, precision, accuracy, recovery and stability criteria. The methodology was applied to samples from patients receiving FEC-chemotherapy in Chapter IX. As expected, dosage based on body surface area could lead to interindividual variations in plasma concentrations. For these patients, this could be linked to haematological toxicity. Salivary epirubicinol concentrations could not be detected shortly after infusion, and always remained very low. Based on this method, it was impossible to detect an equilibrium between plasma and saliva concentrations for epirubicin within the first hours after dosing. A direct predictive power of saliva concentrations towards mucositis could not be assessed, since none of the patients developed such side effects

Traces of phosgene in chloroform: Consequences for extraction of anthracyclines

Chloroform is commonly used to extract anthracyclines from various biological matrices. However, their determination can be seriously compromised by phosgene traces present as a result of failing stabilization of chloroform. Out of the three varieties in which chloroform exists (not stabilized, stabilized with an alcohol and stabilized with a hydrocarbon) only the ethanol stabilized type minimizes chances on creating artifacts. Chromatographic separation after extraction of four anthracyclines (doxorubicin, epirubicin, daunorubicin and idarubicin) and two metabolites (13-S-dihydrodoxorubicin and 13-S-dihydroepirubicin) with chloroform under various conditions indicate that the appropriate choice of stabilizer in this extraction solvent is highly relevant

Optimization of a liquid chromatographic separation for the simultaneous determination of four anthracyclines and their respective 13-S-dihydro metabolites

The optimization of a liquid chromatographic separation of four anthracyclines (doxorubicin, epirubicin, daunorubicin and idarubicin) and their respective 13-S-dihydro metabolites (doxorubicinol, epirubicinol, daunorubicinol and idarubicinol) is described. Inclusion of epidaunorubicin in the assay allows internal standardization. Potential chromatographic interference of aglycones (doxorubicinone, daunorubicinone, idarubicinone, doxorubicinolone, daunorubicinolone and idarubicinolone) was investigated and tackled. The analyses were performed on a C18 RP column and gradient elutions were performed with a mixture of 0.1% formic acid in water and 0.1% formic acid in ACN. The analytes were measured by fluorescence detection with an excitation wavelength of 480 nm. and emission wavelength of 555 nm, respectively. The separation will potentially allow a broad field of applications, ranging from therapeutic drug monitoring and kinetic studies in cancer patients to monitoring hospital personnel and effluents