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Seizures are a recognized and potentially serious complication of recreational drug use. This study examined a large international data set of presentations to Emergency Departments with acute recreational drug toxicity, the European Drug Emergencies Plus (Euro-DEN Plus) Network, to compare presentations with and without seizures and estimate incidence and associated drugs. Amongst 23,947 presentations between January 2014 and December 2017, there were 1013 (4.2%) with reported seizures. Clinical and demographic features were similar between individuals who had a seizure and those who did not, although rates of coma, cardiac arrest, intubation, intensive care admission, and death were significantly higher in those with seizures. There was a significant association between specific drugs and a higher seizure incidence, including fentanyl (odds ratio 2.63, 95% confidence interval 1.20-5.80), and synthetic cannabinoids (OR 2.90, 95% CI 2.19-3.84). Other drugs were associated with a lower seizure incidence, including heroin (OR 0.46, 95% CI 0.35-0.61), clonazepam (OR 0.22, 95% CI 0.06-0.91), and cannabis (OR 0.65, 95% CI 0.50-0.86). This substantiates observations that the synthetic cannabinoids as a group of novel psychoactive substances are clinically different in consequence of intoxication than cannabis, and that individuals who suffer a seizure in the context of recreational drug intoxication are likely to have worse outcomes overall. Utilising this information of what substances have a greater risk of seizures, could provide tailored harm reduction and education strategies to users to reduce the risk of seizures and their associated complications.

In this article we summarize the cardiovascular adverse events that were observed in three patients during their treatment for COVID-19 and discuss their association with lopinavir/ritonavir (LPV/r) and hydroxychloroquine (HCQ). The cases were reported to our regional pharmacovigilance centre in April 2020. All three patients were above 75 years in age, male and multimorbid, and had been hospitalized for treatment of COVID-19. As part of their treatment, all of them received a very strictly monitored off-label therapy with LPV/r and HCQ, for which they had given their prior, written, informed consent. In one patient, erythromycin was also administered. All three patients developed a significant QTc time prolongation during or shortly after therapy with the above drugs. On account of this, the treatment had to be discontinued early in each case and QTc time recovered in all three patients.

3,4-Methylenedioxymethamphetamine (MDMA) remains one of the most commonly used recreational drugs in Europe. Monitoring of Emergency Department (ED) presentations with acute toxicity associated with MDMA is important to determine trends in MDMA use and harms. Data were extracted from the European Drug Emergencies Network (Euro-DEN) Plus database for all ED presentations with acute toxicity involving MDMA use, alone or in combination with other substances, between 1 January 2014 and 31 December 2017. Geographical distribution, time trends, patient demographics, clinical features, management and outcome were analysed. Out of 23,947 presentations, 2013 (8.4%) involved MDMA, used alone (88, 4.4%) or with other substances (1925, 95.6%). The proportion of MDMA presentations varied by country, from over 15% in France to less than 5% in Norway. For the 15 sentinel centres where data were available for all four years, MDMA-related presentations peaked in 2016 (10.4% versus 8.1% in 2015, p p = 0.0002). 1436 (71.3%) presentations involved males. Females were significantly younger than males (median 23 years, interquartile range, IQR, 20–27 years, versus median 25 years, IQR 21–30 years, p versus 43.9%, p = 0.02), were more frequently medically discharged directly from the ED (74.7% versus 62.4%, p = 0.03), and less frequently received sedation (43.5% versus 66.5%, p = 0.003). This large multicentre series of MDMA presentations to EDs showed geographical variation and changes in time trends and in patient demographics. Triangulation with data from complementary sources including seizures, prevalence of use and wastewater analysis, will enable a greater understanding of the public health implications of MDMA use in Europe.

AIMS To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P-glycoprotein (P-gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban. METHODS Open-label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P-gp phenotyping using low-dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks' treatment with the H. perforatum extract. RESULTS The geometric mean ratios for the area under the concentration-time curve and Cmax of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect-time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding Tmax (median 1.5 vs 1 h, P = .26) and terminal elimination half-life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P-gp activity, as evidenced by phenotyping. CONCLUSION The CYP3A4/P-gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin-containing H. perforatum extracts with rivaroxaban.

BACKGROUND Concomitant use of cannabis and other psychoactive substances is common and it is often difficult to differentiate its acute effects from those of other substances. This study aimed to characterize the acute toxicity of cannabis with and without co-use of other substances. METHODS Retrospective analysis of cases presenting at the emergency departments of three large hospitals in Switzerland due to acute toxicity related to cannabis recreational use. RESULTS Among 717 attendances related to acute cannabis toxicity, 186 (26 %) were due to use of cannabis alone. The median patient age was 26 years (range 14-68), and 73 % were male. Commonly reported symptoms/signs in lone-cannabis cases included nausea/vomiting (26 %), palpitations (25 %), anxiety (23 %), and chest pain (15 %); there were no fatalities and most intoxications were of minor severity (61 %). Most patients (83 %) using cannabis alone were discharged from the emergency department, 8 % were referred to psychiatric, and two (1 %) to the intensive care; severe complications included psychosis (7 %), coma (6 %), and seizures (5 %) and one patient (

Ethanol intake can increase the sedative effects of gamma-hydroxybutyrate/gamma-butyrolactone (GHB/GBL), although the real clinical impact is unknown. We studied the clinical impact of the co-ingestion of ethanol in patients presenting to the Emergency Department (ED) with acute toxicity related to GHB/GBL use.We performed a secondary analysis of the Euro-DEN Plus Registry (14 countries, 22 EDs) which includes 17,371 consecutive patients presenting to the ED with acute recreational drug toxicity over 39 consecutive months (October 2013 - December 2016). We compared the epidemiological and clinical characteristics and ED management of patients identified as presenting with acute toxicity related to lone GHB/GBL (Group A) or GHB/GBL combined with ethanol (Group B) without other concomitant drugs.A total of 609 patients were included (age 32 (8) years; 116 women (19%); Group A: 183 patients and Group B: 426). The most common features were reduction in consciousness (defined as Glasgow Coma Score13 points: 56.1%) and agitation/aggressiveness (33.6%). Those with ethanol co-ingestion were younger patients (Group A/B: 31.5/33.1 years, p = 0.029) and ethanol co-ingestion was associated with a lower frequency of bradycardia (23.5%/15.7%, p = 0.027) and more frequent arrival at the ED by ambulance (68.3/86.6%; p 0.001), reduction in consciousness (58.9%/49.1%; p = 0.031), need for treatment in the ED (49.2%/60.4%; p = 0.011), use of sedatives (20.1%/12.8%; p = 0.034), admission to critical care units (22.4%/55.3%; p 0.001), and longer hospital stay (stay longer than 6 h: 16.9%/28.4%; p = 0.003).Co-ingestion of ethanol increases the adverse effects of patients intoxicated by GHB/GBL, leading to greater depression of consciousness, need for treatment, admission to the ICU and longer hospital stay.

Learning objectiveRecognize neuropsychiatric symptoms as possible adverse drug reactions (ADR) associated with the leukotriene receptor antagonist Montelukast in childrenClinical CaseAn 11-year-old boy suffering from asthma presented to his pediatrician with an acute onset of nervousness, restlessness and irritability. The teacher noticed a decline in school performance with a reduced attention span. The patient had been treated with Salbutamol (Ventolin®) and Salmeterol/Fluticasone (Seretide®) for the last few years. A treatment with Montelukast chewable tablets was started four months ago. The ADR was reported to the Regional Pharmacovigilance Centre (RPVC) Bern. The termination of the therapy with Montelukast lead to an amelioration of the symptoms. According to the WHO-UMC Causality Categories,1 the causality of Montelukast and the described symptoms was classified as ‘probable’. The causality of the comedication was considered ‘unlikely’ as it had been used for several years without complications. After work-up at the RPVC, the case was reported anonymously to the National Pharmacovigilance Center of the Swiss Agency for Therapeutic Products Swissmedic.DiscussionMontelukast is a cysteinyl-leukotriene type 1-receptor antagonist used in the treatment of bronchial asthma in adults and children. Psychiatric disorders such as agitation, psychomotor hyperactivity (including irritability and restlessness), disorders of attention and memory impairment (and others) are listed as known ADRs of Montelukast.2 3 The WHO pharmacovigilance database VigiBase® lists a total of 20’897 ADR reports for Montelukast, of which 4’705 (22.5%) refer to nervous system disorders and 6’828 (32.7%) to psychiatric disorders. Within the group of nervous system disorders 256 (5.4%) reports of psychomotor hyperactivity, 232 (4.9%) reports of disturbance in attention and 91 (1.9%) reports of memory impairment were recorded.4 The most common symptoms in the group of psychiatric disorders are depression (1’311, 19.2%) and aggressive behavior (1’175, 17.2%). If psychiatric ADRs occur, the risks and benefits of Montelukast should be reassessed.ReferencesThe use of the WHO-UMC system for standardised case causality assessment. Available from:https://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdfMarchand MS, Jonville-Bera AP, Autret-Leca E, [Psychiatric disorders associated with montelukast: data from the National Pharmacovigilance Database]. Arch Pediatr 2013;20(3):269–73.Aldea Perona A, Garcia-Saiz M, Sanz Alvarez E. Psychiatric disorders and montelukast in children: A disproportionality analysis of the vigibase((R)). Drug Saf 2016;9(1):69–78.Disclosure(s)Nothing to disclose

Applications by fire brigades expose the composite cylinders to harsh temperature and handling conditions. Standards have been used for certifying composite cylinders, which are designed for transport of dangerous goods and do not reflect service conditions specific to fire brigades. In this paper, the residual safety of a design type (fully wrapped with aluminum and carbon fiber composite) at the end of their service life of 15 yrs is analyzed. One sample underwent hydraulic load cycle (LC) tests, another conventional burst tests, and the third slow burst tests (SBTs). The statistical evaluation and the handling of an unexpected high amount of early failures are shown.

Emergency response units increasingly use pressure cylinders made from fibre composites for breathing air as elements of personal protective equipment (PPE). Such applications expose the composite cylinders to harsh temperature and handling conditions. At least in Europe, standards have been used for certifying PPE, which are designed and mandatory for the approval of pressure receptacles for the transport of dangerous goods. Therefore, service conditions specific to PPEs are not accounted for in these standards. In this paper, BAM (Federal Institute for Materials Research and Testing) investigates the residual safety of a composite cylinder design at the end of their designated service life of 15 years. The cylinders (test pressure PH 450 bars; 6.8 Litres) are of one design type with aluminium liner and fully wrapped with carbon fibres, which is commonly considered a “Type III” cylinder. All cylinders were used as PPE by the Berlin fire department and randomly picked in three samples of 25 cylinders each before tested. At BAM, the cylinder samples underwent hydraulic load cycle tests (LCT), conventional burst tests (BT) and so called slow burst tests (SBT). A concept for quantification of strength degradation already introduced by BAM was applied. This concept is based on a probabilistic assessment of the average strength and scatter of each sample of cylinders. The strength distributions of the used PPE-cylinders is shown and analysed. Some unexpected effects are shown and a refinement of the statistical assessment is introduced.