A case of fatal multidrug intoxication involving flualprazolam: distribution in body fluids and solid tissues.

PURPOSE: Designer benzodiazepines (DBZDs) increasingly emerged on the novel psychoactive substance (NPS) market in the last few years. They are usually sold as readily available alternatives to prescription benzodiazepines (BZDs) or added to counterfeit medicines. BZDs are generally considered relatively safe drugs due to the low risk of serious acute adverse effects in mono-intoxication, though e.g., alprazolam seems to display an elevated risk of respiratory depression. Here we report on a fatal intoxication involving the novel DBZD flualprazolam. METHODS: A complete postmortem examination was performed. General unknown screenings and analysis of drugs of abuse were performed on postmortem samples by immunoassay, gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. The standard addition method was employed to quantify flualprazolam in postmortem blood and tissues. Finally, a toxicological significance score (TSS) was assigned. RESULTS: Flualprazolam was detected in heart serum (25.4 ng/mL) and peripheral blood (21.9 ng/mL) as well as in urine, stomach contents, brain, liver and kidney (65.2-323 ng/g). The cause of death was deemed as central nervous system (CNS) and respiratory depression with agonal aspiration of stomach contents, in the setting of a multiple drug intake. Given the concentration levels of the co-consumed CNS depressants, the contribution of flualprazolam to the death was considered likely (TSS of 3). CONCLUSIONS: Our results support that highly potent DBZDs like flualprazolam carry an elevated risk for unintended toxicity, especially in association with other CNS depressants. A multidisciplinary evaluation of fatalities remains mandatory, especially when pharmacological/toxicological data on intoxicating compounds are lacking. To our knowledge this is the first report of flualprazolam concentrations in solid tissues in human.

Effect of new legislation in Germany on prevalence and harm of synthetic cannabinoids.

CONTEXT: New psychoactive substances (NPS) have become an ongoing threat to public health. To prevent the emergence and spread of NPS, a new German law, the 'NpSG' took effect in November 2016. This study presents an overview of analytically confirmed synthetic cannabinoid (SC) intoxications from January 2015 to December 2018. In order to demonstrate effects of the NpSG, the results of 23 month before and 25 month after the introduction of the law were compared. METHODS: Within the scope of a prospective observational study blood and urine samples were collected from emergency patients with suspected NPS intoxication. Comprehensive drug analyses were performed by LC-MS/MS analysis. RESULTS: In the period considered, 138 patients were included. Within these, SC intake was verified in 65 patients (73%) in the period before the law change, and in 30 patients (61%) after. The median age increased significantly from 19.5 to 26 years. Seizures and admission to the ICU were reported significantly less frequently (seizures 29% versus 6.7%, p = 0.0283; ICU admission 42% versus 13%, p = 0.0089). 34 different SCs were detected, including four SCs (Cumyl-PEGACLONE, 5 F-MDMB-P7AICA, EG-018, 5 F-Cumyl-P7AICA) not covered by the NpSG at the time of detection. In the first period the most prevalent SC was MDMB-CHMICA (n = 24). 5 F-ADB was the most prevalent SC overall, detected in 7 patients (11%) in the first, and in 24 patients (80%) in the second period. CONCLUSION: The number of SC intoxications decreased overall after the implementation of the NpSG. The shift in the detected SCs can be considered a direct effect of the NpSG but unfortunately the market supply does not appear to have been reduced. Although changes in the age distribution and in the severity of intoxications may be seen as secondary effects of the law, the main objectives of the new law to prevent the emergence and spread of further chemical variations of known scheduled drugs, have apparently not been achieved from the perspective of this study.

Hemoadsorption eliminates remdesivir from the circulation: Implications for the treatment of COVID-19.

Both antiviral treatment with remdesivir and hemoadsorption using a CytoSorb® adsorption device are applied in the treatment of severe COVID-19. The CytoSorb® adsorber consists of porous polymer beads that adsorb a broad range of molecules, including cytokines but also several therapeutic drugs. In this study, we evaluated whether remdesivir and its main active metabolite GS-441524 would be adsorbed by CytoSorb® . Serum containing remdesivir or GS-441524 was circulated in a custom-made system containing a CytoSorb® device. Concentrations of remdesivir and GS-441524 before and after the adsorber were analyzed by liquid chromatography-tandem mass spectrometry. Measurements of remdesivir in the outgoing tube after the adsorber indicated almost complete removal of remdesivir by the device. In the reservoir, concentration of remdesivir showed an exponential decay and was not longer detectable after 60 mins. GS-441524 showed a similar exponential decay but, unlike remdesivir, it reached an adsorption-desorption equilibrium at ~48 µg/L. Remdesivir and its main active metabolite GS-441524 are rapidly eliminated from the perfusate by the CytoSorb® adsorber device in vitro. This should be considered in patients for whom both therapies are indicated, and simultaneous application should be avoided. In general, plasma levels of therapeutic drugs should be closely monitored under concurrent CytoSorb® therapy.

Use of the CytoSorb adsorption device in MDMA intoxication: a first-in-man application and in vitro study.

BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") abuse is frequent, and overdosing might cause severe and eventually lethal multi-organ failure. To date, there is no causal therapy of MDMA intoxication and removal of MDMA from the circulation might be a reasonable measure to prevent adverse courses after overdosing. We present here first-in-man experience and in vitro data supporting a potential role of an adsorber device in severe MDMA overdosing. RESULTS: We applied a CytoSorb adsorber device in a 21-year-old male presenting with severe MDMA intoxication and multi-organ failure, including neurological impairment, hyperpyrexia, rhabdomyolysis, oliguric renal failure, liver failure, and coagulopathy with disseminated gastrointestinal and intramuscular bleeding. Use of the adsorber device was associated with a decline in MDMA concentrations in serum from 540 to 140 ng/ml within the first 24 h, a decrease of interleukin 6 and myoglobin levels, and subsequent clinical improvement. The patient was discharged from hospital after restoration of organ function and full neurological recovery. Effective elimination of MDMA by the adsorber device could be confirmed in vitro, when the device lowered MDMA concentrations to non-detectable levels. CONCLUSIONS: We report here first-in-man experience and in vitro data showing the capacity of a CytoSorb adsorber device for MDMA removal. Early integration of CytoSorb use may enhance the management of severe MDMA intoxication, though we cannot prove whether clinical improvement was directly related to elimination of MDMA or beneficial effects on rhabdomyolysis, hyperinflammation, or liver failure. Our findings encourage further investigation of the CytoSorb adsorber device in a prospective study and to evaluate its use for other intoxications.

Acute severe intoxication with cyclopropylfentanyl, a novel synthetic opioid.

BACKGROUND: Since 2016 an increase has been observed in the availability of new synthetic opioids (NSO) in Europe. Cyclopropylfentanyl is a very potent and selective µ-opioid agonist, which was reported for the first time in August 2017 in Europe. METHODS: The case was included in a prospective observational study of patients treated in emergency departments after the intake of novel psychoactive substances (NPS). Clinical features were acquired using a structured questionnaire for physicians. Serum and/or urine samples of ED patients were analyzed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) screening methods for NPS. CASE REPORT: Within 10 min after intranasal intake of fentanyl, a 25-year-old male developed nausea, profuse sweating and dyspnoe. Because soon afterwards coma and respiratory insufficiency was noticed, the patient was admitted to hospital. After administration of naloxone (0.8 mg) breathing stabilized. However, the patient displayed recurrent decreases of oxygen saturation for 12 h. The intake of cyclopropylfentanyl was analytically confirmed. CONCLUSION: The constantly growing diversity of NSO still poses a high risk for drug users and can be a challenging task for clinicians and forensic toxicologists. Clinicians treating opioid overdoses should be aware of the potentially long lasting respiratory depression induced by fentanyl analogs.

Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: Final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG).

BACKGROUND: Desmoid tumours describe a rare monoclonal, fibroblastic proliferation characterised by an often unpredictable clinical course. Surgery is one therapeutic option for progressing patients, except if mutilating and associated with considerable function loss. Different systemic treatment approaches have been investigated and promising results could be demonstrated using imatinib. PATIENTS AND METHODS: We initiated a phase II trial within the German Interdisciplinary Sarcoma Group (GISG) evaluating imatinib to induce progression arrest in desmoid tumour patients being Response Evaluation Criteria in Solid Tumours (RECIST) progressive, not amenable to surgical resection with R0 intent or accompanied by unacceptable function loss (NCT01137916). Thirty-eight patients (median age 44 years [range: 19-80]; 68% female; 90% Eastern Cooperative Oncology Group (ECOG) performance status 0) were treated with a daily dose of 800 mg imatinib planned over 2 years. The progression arrest rate after 6 months of imatinib treatment (PAR6mo) was the primary end-point. Patients showing disease progression under imatinib could be treated with nilotinib 800 mg daily. Accrual started in July 2010 in four GISG centres and finalised in September 2013. RESULTS: The final analysis for the primary end-point in the evaluable patients of the full analysis set revealed a PAR6mo of 65%. Subsequent progression arrest rates at 9, 12, 15, 18, 21 and 24 months were 65%, 59%, 53%, 53%, 50% and 45%, respectively. None of the patients died within the study observational period. Best reported response was seven partial responses at 21 months revealing an overall response rate of 19%. Eight patients treated with nilotinib demonstrated a PAR at 3 months of 88% (7/8); no more disease progressions occurred until end of study. In general imatinib adverse events were mild to moderate. CONCLUSIONS: Imatinib induces sustained progression arrest in RECIST progressive desmoid tumour patients. In addition, nilotinib had the potential to stabilise desmoid tumour growth after treatment failure with imatinib.

Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG).

BACKGROUND: Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. Trabectedin's introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest. METHODS: We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose. RESULTS: Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m2 on day 1 and gemcitabine 700 mg/m2 on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity (DLT) in both patients (elevated transaminases and thrombocytopenia), an additional three patients were treated on dose level -1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2. Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing. CONCLUSION: The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.