Overdose of the HIV Medicine Genvoya® in Two Auto-Intoxications.

Toxicological data on overdose with human immunodeficiency virus inhibitors are scarce. We present a case report of two independent suicide attempts by self-administered overdose with the same antiretroviral medicine Genvoya® (emtricitabine/elvitegravir/tenofovir alafenamide/cobicistat). Both patients were admitted to the hospital and presented with a loss of consciousness, lactic acidosis, elevated hepatic transaminase levels and hemodynamic instability. While one patient survived with advanced supportive measures, the other passed away. Emtricitabine levels were measured in vivo in various consecutive serum samples and postmortem urine, peripheral and cardiac serum samples and confirmed excessive use in both cases. This is the first time that emtricitabine levels following overdose are reported. Although measured concentrations for emtricitabine were quite similar in these cases, metabolic acidosis was more pronounced in the fatal case. The difference in outcomes between the two could be due to a difference in physiological status, susceptibility to accumulation and adverse effects, and perhaps a varying interval between ingestion and the start of supportive measures.

Qualitative and semi-quantitative screening of selected psychoactive drugs in blood: Usefulness of liquid chromatography - triple quadrupole and quadrupole time-of-flight mass spectrometry in routine toxicological analyses.

Routine toxicological analysis requires broad screening for a large number of therapeutically prescribed and other compounds, and/or their metabolites. This article specifically focuses on three classes of psychoactive substances: antidepressants (ADs), antipsychotics (APs) and benzodiazepines and Z-drugs (BZDs). Two screening methods were compared for their ease-of-use in a routine setting, based upon the analysis of 105 medico-legal case samples. Analytes of interest were extracted using liquid-liquid extraction and separated using liquid chromatography with a total run time of 12 min per sample. A first detection method used targeted triple quadrupole mass spectrometry, operated in triggered multiple reaction monitoring mode (tMRM). False negative results were noted for 15% of the total number of detected analytes only, the majority of which were either present at sub- to low therapeutic levels or were metabolites of other analytes in the samples. The occurrence of false positive results was rare. A second screening method used quadrupole time-of-flight mass spectrometry (QTOF) for untargeted data acquisition. Data analysis was facilitated by the creation of an in-house, subset mass spectral database. As was seen for the tMRM screening, false negative results were observed in less than 20% of the total number of detected analytes, either for compounds at low concentrations or of which metabolites could be identified in the samples. More false positive results were observed due to an observed bias for prothipendyl. Determination of the exact concentration in a sample may only be required depending on the specific case circumstances. For this purpose, semi-quantification using each of the screening methods was investigated. Excellent results were observed using the tMRM method in combination with a small number of labelled internal standards (n = 12). Semi-quantification using the QTOF screening method was more laborious, but limited results on selected compounds indicated equally good results. Overall, the developed semi-quantitative screening methods performed well and - following further validation on case samples - could be implemented for most compounds in routine toxicological analysis without the need for highly trained or specialised personnel.

Multi-analyte LC-MS/MS quantification of 38 antipsychotics and metabolites in plasma: Method validation & application to routine analyses.

The past decades have seen a rise in the prescription of antipsychotic drugs in the European population, despite the risk of extra-pyramidal, metabolic and cardiac side effects. A multi-analyte liquid chromatography - triple quadrupole mass spectrometry method was developed for the quantification of 38 antipsychotic drugs in plasma. Samples were extracted by a straightforward liquid-liquid extraction with methyl-tertiary-butyl-ether and the compounds of interest were chromatographically separated within 6 min. Calibration curves covered the recommended therapeutic range for all compounds, in addition to sub- and supratherapeutic concentrations for most. The method was successfully validated according to the European Medicines Agency guidelines on bioanalytical method validation. Analysis of medico-legal samples confirmed the relatively common use of the second generation antipsychotics quetiapine and olanzapine, as well as the continued presence of the first generation antipsychotic haloperidol.

Quantification of 54 Benzodiazepines and Z-Drugs, Including 20 Designer Ones, in Plasma.

Benzodiazepines are widely used in the treatment of sleep and anxiety disorders, as well as epileptic seizures and alcohol withdrawal because of their broad therapeutic index and low cost. Due to their central nervous system depressant effects they are also often implicated in traffic accidents and drug-related intoxications. With an increasing number of designer benzodiazepines used in a recreational setting, there is a need for analytical methods to be able to quantify both the prescribed and designer benzodiazepines. A liquid chromatography-triple quadrupole mass spectrometry method was developed for the quantification of 34 prescribed and 20 designer benzodiazepines in plasma. Different sample preparation strategies, including protein precipitation, liquid-liquid extraction, solid-phase extraction and mini-QuEChERS, were tested. The best recoveries for all compounds of interest were obtained with a liquid-liquid extraction using methyl-tertiary-butyl-ether and 500 µL plasma. The method was fully validated according to the European Medicines Agency guidelines for all compounds, except pivoxazepam, which is included for qualitative purposes only. In-sample stability issues were observed for cloxazolam, both at ambient temperature and during long-term storage at -20°C. Due to the large number of compounds included, the simple and time-efficient sample preparation and the relatively inexpensive instrumentation used, the presented method can be readily implemented in both therapeutic drug monitoring and forensic analyses.

Left ventricular rupture: a rare complication and an unusual presentation.

Myocardial infarction (MI) is a relatively common medical condition in the community. A rare complication of acute MI is left ventricular rupture (LV) rupture. This usually follows a transmural infarct. The incidence of this is 2%-4% and this usually happens within 3-7 days of MI. The anterolateral wall is involved in the majority of cases. Atypical presentations can occur several weeks after the initial event. Symptoms may mimic gastrointestinal disorder. The prognosis of this condition is very grim. However, with appropriate treatment, they can make an excellent recovery. The definitive treatment for this is surgical repair. We present the case of a 70-year-old man who had LV rupture and his clinical journey.

The advantages of radial trajectories for vessel-selective dynamic angiography with arterial spin labeling.

OBJECTIVES: To demonstrate the advantages of radial k-space trajectories over conventional Cartesian approaches for accelerating the acquisition of vessel-selective arterial spin labeling (ASL) dynamic angiograms, which are conventionally time consuming to acquire. MATERIALS AND METHODS: Vessel-encoded pseudocontinuous ASL was combined with time-resolved balanced steady-state free precession (bSSFP) and spoiled gradient echo (SPGR) readouts to obtain dynamic vessel-selective angiograms arising from the four main brain-feeding arteries. Dynamic 2D protocols with acquisition times of one minute or less were achieved through radial undersampling or a Cartesian parallel imaging approach. For whole-brain dynamic 3D imaging, magnetic field inhomogeneity and the high acceleration factors required rule out the use of bSSFP and Cartesian trajectories, so the feasibility of acquiring 3D radial SPGR angiograms was tested. RESULTS: The improved SNR efficiency of bSSFP over SPGR was confirmed for 2D dynamic imaging. Radial trajectories had considerable advantages over a Cartesian approach, including a factor of two improvements in the measured SNR (p < 0.00001, N = 6), improved distal vessel delineation and the lack of a need for calibration data. The 3D radial approach produced good quality angiograms with negligible artifacts despite the high acceleration factor (R = 13). CONCLUSION: Radial trajectories outperform conventional Cartesian techniques for accelerated vessel-selective ASL dynamic angiography.

Off-resonance correction for pseudo-continuous arterial spin labeling using the optimized encoding scheme.

Pseudo-continuous arterial spin labeling (PCASL) MRI has become a popular tool for non-invasive perfusion imaging and angiography. However, it suffers from sensitivity to off-resonance effects within the labeling plane, which can be exacerbated at high field or in the presence of metallic implants, leading to spatially varying signal loss and cerebral blood flow underestimation. In this work we propose a prospective correction technique based on the optimized encoding scheme, which allows the rapid calculation of transverse gradient blips and RF phase modulations that best cancel phase offsets due to off-resonance at the locations of the feeding arteries within the labeling plane. This calculation is based upon a rapidly acquired single-slice fieldmap and is applicable to any number and arrangement of arteries. In addition, this approach is applicable to both conventional PCASL and a vessel-selective variant known as vessel-encoded PCASL (VEPCASL). Through simulations and experiments in healthy volunteers it was shown that in the presence of off-resonance effects a strong bias in the strength of the perfusion signal across vascular territories can be introduced, the signal-to-noise ratio (SNR) efficiency of PCASL and VEPCASL can be severely compromised (∼40% reduction in vivo), and that vessel-selective signal in VEPCASL can be incorrectly assigned. Distortion of the spatial regions placed in the label or control conditions in the presence of off-resonance effects was confirmed in phantom experiments. The application of the proposed correction restored SNR efficiency to levels present in the absence of off-resonance effects and corrected errors in the vascular territory maps derived from VEPCASL. Due to the rapid nature of the required calculations and fieldmap acquisition, this approach could be inserted into protocols with minimal effect on the total scan time.

An Optimized Encoding Scheme for Planning Vessel-Encoded Pseudocontinuous Arterial Spin Labeling.

PURPOSE: Vessel-encoded pseudocontinuous arterial spin labeling allows the acquisition of vessel-selective angiograms and vascular territory perfusion maps. The technique generates a periodic variation in inversion efficiency across space that can be manipulated to encode specific combinations of vessels. Currently, the choice of these encodings is limited to scenarios with few vessels and may not optimize the signal-to-noise ratio (SNR). Here we present an automated, rapid method for calculating a minimal number of SNR optimal encodings for any number and arrangement of vessels. THEORY AND METHODS: The proposed optimized encoding scheme (OES) is a Fourier-based method that finds SNR optimized encodings to best match the ideal encodings for a set of vessels. For nine or fewer vessels, the calculation takes less than 3 s. RESULTS: In simulations, the OES method produces encodings for a range of vessel geometries that, on average, have an SNR efficiency 37% greater than that for random encoding. When labeling vessels in the neck in healthy subjects, the OES encodings result in images with higher SNR than other encoding methods. CONCLUSION: The OES results in a minimal number of encodings with a higher SNR efficiency than other encoding methods, regardless of the number or geometry of the vessels.