Peter Hultén

Identification of novel psychoactive drug use in Sweden based on laboratory analysis – initial experiences from the STRIDA project

Abstract Aim. The study aimed to collect information concerning the increasing use of new psychoactive substances, commonly sold through online shops as ‘Internet drugs’ or ‘legal highs’, or in terms of masked products such as ‘bath salts’ and ‘plant food’. Methods. The Karolinska Institutet and Karolinska University Laboratory and the Swedish Poisons Information Centre have initiated a project called ‘STRIDA’ aiming to monitor the occurrence and trends of new psychoactive substances in Sweden, and collect information about their clinical symptoms, toxicity and associated health risks. A liquid chromatographic-tandem mass spectrometric (LC-MS/MS) multi-component method has been developed, currently allowing for the determination of > 80 novel psychoactive compounds or metabolites thereof. This study focused mainly on the particular drug substances identified and the population demographics of the initial STRIDA cases. Results. In urine and/or blood samples obtained from 103 consecutive cases of admitted or suspected recreational drug intoxications in mostly young subjects (78% were ≤ 25 years, and 81% were males) presenting at emergency departments all over the country, psychoactive substances were detected in 82%. The substances comprised synthetic cannabinoids (‘Spice’; JWH analogues), substituted cathinones (‘bath salts’; e.g. butylone, MDPV and methylone) and tryptamines (4-HO-MET), plant-based substances (mitragynine and psilocin), as well as conventional drugs-of-abuse. In 44% of the cases, more than one new psychoactive substance, or a mixture of new and/or conventional drugs were detected. Conclusion. The initial results of the STRIDA project have documented use of a broad variety of new psychoactive substances among mainly young people all over Sweden.

Topical treatments for hydrofluoric acid burns: a blind controlled experimental study

Background: Calcium gluconate gel, applied after initial rinsing with water, has a documented effect as first aid treatment for hydrofluoric acid burns. Hexafluorine® is a novel liquid compound developed especially for emergency decontamination of hydrofluoric acid eye and skin exposures. However, scientific documentation of the effect of Hexafluorine is insufficient. This study was undertaken to compare Hexafluorine with water rinsing plus topical calcium and with water rinsing alone. Methods: Thirty-five Sprague–Dawley rats were anesthetized and their backs shaved. Four filter papers 10 mm in diameter were soaked in 50% hydrofluoric acid and applied on the shaved area of each rat for 3 minutes. Thirty seconds later, the acid-exposed skin areas were rinsed with 500 mL Hexafluorine for 3 minutes (group H, n=10), 500 mL water for 3 minutes (group W, n=10) or 500 mL water for 3 minutes followed by a single application of 2.5% calcium gluconate gel (group Ca, n=10), or received no treatment (controls, n=5). The animals were closely observed for 5 days. Daily at 4 P.M. each of the four burns on every rat was rated on a modified Draize scale graded from 0 to 5 (0=no visible injury, 1=diffuse erythema, 2=distinct erythema, 3=distinct erythema plus wounds or discolored spots, 4=distinct erythema plus wounds or discolored areas covering >50% of the burn, 5=a necrotic wound covering the whole burn). The mean of the four scores was then calculated for each animal and day. The rating procedure was performed by one laboratory assistant who was unaware of the treatment given. Kruskal–Wallis analysis was used to evaluate possible differences between treatment groups on each of the 5 days. If the p-value obtained was <0.05, correction for multiple comparisons was made. Results: The mean severity score in group H was significantly higher than that in group Ca on days 2 and 3. Moreover, Hexafluorine showed a consistent trend towards a worse outcome, both in comparison to water plus topical calcium and to water rinsing alone. Conclusion: Based on these observations it is concluded that water rinsing followed by topical calcium should remain the standard first aid treatment for skin exposure to hydrofluoric acid.

Bioanalytical and clinical evaluation of 103 suspected cases of intoxications with psychoactive plant materials

Introduction. Problems associated with the increasing abuse of plant-derived psychoactive substances have recently attracted attention. This study involved bioanalytical and clinical examinations of intoxication cases suspected to be linked to such plant materials. Methods. Urine samples were collected at emergency wards in Sweden from patients who either admitted or were suspected of ingestion of psychoactive plant materials. The bioanalytical investigation employed a liquid chromatography-tandem mass spectrometry multicomponent method covering 10 plant-derived substances (atropine, dimethyltryptamine, ephedrine, harmaline, harmine, ibogaine, lysergic acid amide, psilocin, scopolamine, and yohimbine) and a gas chromatography-mass spectrometry method for asarone. Routine testing for illicit drugs was also performed. Results. Over a 4-year period, 103 urine samples collected from mainly young people (age range 13–52 years, median 19) were studied. Among 53 cases where ingestion of any of the 11 plant-derived substances covered in this study was admitted or suspected, 41 (77%) could be confirmed bioanalytically. Nine of the 11 substances tested for were detected, the exceptions being ibogaine and yohimbine. Psilocin, originating from ingestion of hallucinogenic mushrooms, was the most frequent drug accounting for 54% of the cases. The most common means of drug acquisition (56%) was purchase over the Internet. Conclusion. The patients using psychoactive plant materials were mainly young and commonly used the Internet for drug acquisition. Having access to bioanalytical methods for detection of plant-derived psychoactives is therefore considered important, when providing clinical toxicology service.

Intoxications of the new psychoactive substance 5-(2-aminopropyl)indole (5-IT): A case series from the Swedish STRIDA project

Abstract Context. 5-(2-aminopropyl)indole (5-IT) is a new psychoactive substance (NPS; “legal high” or “research chemical”) structurally related to indoleamines and substituted phenethylamines and implicated in several fatalities. We describe the clinical characteristics and results of laboratory investigations of 14 analytically confirmed nonfatal cases of 5-IT intoxication within the Swedish STRIDA project. Study design. Observational case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals in Sweden in 2012. Patients and methods. Blood and/or urine samples were collected from intoxicated patients presenting to emergency departments and intensive care units over the country. Analysis of NPS was performed using an LC–MS/MS multi-component method. Clinical data were collected when caregivers consulted the Poisons Information Centre and also retrieved from medical records. The severity of poisoning was graded retrospectively using the Poisoning Severity Score (PSS). Results. Eleven male and three female patients (age: 21–53 years, median: 27) tested positive for 5-IT in 2012, all cases appearing in April–July. The 5-IT concentration in serum ranged between 0.015 and 0.59 μg/mL (median: 0.22; n = 8) and in urine between 0.005 and 24.7 μg/mL (median: 5.95; n = 12). Five intoxications were indicated to be caused by 5-IT alone, whereas additional psychoactive substances were detected in the other nine cases. Six (43%) of fourteen cases were graded as severe (PSS 3), five (36%) as moderate (PSS 2), and three (21%) as minor (PSS 1) poisonings. In the severe cases, agitation, hallucinations, dilated pupils without light reaction, tachycardia, hypertension, hyperthermia, myoclonus, muscle rigidity, arrhythmias, seizures, rhabdomyolysis, and/or renal failure were noted. Conclusions. The results demonstrated that severe clinical toxicity was commonly present in patients with analytically confirmed 5-IT exposure. The clinical features are consistent with a sympathomimetic toxidrome, and some patients also displayed symptoms associated with serotonin toxicity.

Hexafluorine vs. Standard Decontamination to Reduce Systemic Toxicity After Dermal Exposure to Hydrofluoric Acid

Introduction. Dermal exposure to hydrofluoric acid (HF) may cause severe burns and systemic toxicity. Hexafluorine® (Prevor, France) is a product marketed as an emergency decontamination fluid for HF skin and eye exposures. Documentation concerning Hexafluorine is scanty, and a recent study indicates that its ability to reduce HF burns is at most equal to that of water. Objective. The present study was conducted to evaluate Hexafluorines capacity to reduce HF‐induced systemic toxicity. Methods. Sprague Dawley rats were anesthetized, catheterized in the left femoral artery, and shaved on their back. A filter paper (3.5 × 6 cm) was soaked in 50% HF and applied on the back of each rat for 3 min. Thirty seconds after removal of the paper, a 3‐min rinsing with either 500 mL Hexafluorine (group H), 500 mL water (group W), or 500 mL water followed by a single application of 2.5% calcium gluconate gel (group Ca) was carried out. Blood samples were analyzed for ionized calcium and potassium (before injury and 1, 2, 3, and 4 h after) and also for ionized fluoride (1, 2, and 4 h after injury). Results. The animals developed hypocalcemia, hyperkalemia, and hyperfluoridemia after the HF exposure. The only significant difference observed among the groups was in serum potassium at 1 h between group Ca and group W. However, there was a constant trend toward milder hypocalcemia and less pronounced hyperkalemia in group Ca compared to the other groups. There were no differences in the electrolyte disturbances between the Hexafluorine‐treated animals and those treated with water only. Five of 39 animals died before completion of the experiment as a result of the HF exposure, one from group Ca and two from each of the other two groups. Conclusion. In this experimental study, decontamination with Hexafluorine was not more effective than water rinsing in reducing electrolyte disturbances caused by dermal exposure to hydrofluoric acid.

Laboratory and clinical evaluation of on-site urine drug testing

Abstract Aim. Products for on-site urine drug testing offer the possibility to perform screening for drugs of abuse directly at the point-of-care. This is a well-established routine in emergency and dependency clinics but further evaluation of performance is needed due to inherent limitations with the available products. Methods. Urine drug testing by an on-site product was compared with routine laboratory methods. First, on-site testing was performed at the laboratory in addition to the routine method. Second, the on-site testing was performed at a dependency clinic and urine samples were subsequently sent to the laboratory for additional analytical investigation. Results. The on-site testing products did not perform with assigned cut-off levels. The subjective reading between the presence of a spot (i.e. negative test result) being present or no spot (positive result) was difficult in 3.2% of the cases, and occurred for all parameters. The tests performed more accurately in drug negative samples (specificity 96%) but less accurately for detecting positives (sensitivity 79%). Of all incorrect results by the on-site test the proportion of false negatives was 42%. The overall agreement between on-site and laboratory testing was 95% in the laboratory study and 98% in the clinical study. Conclusion. Although a high degree of agreement was observed between on-site and routine laboratory urine drug testing, the performance of on-site testing was not acceptable due to significant number of false negative results. The limited sensitivity of on-site testing compared to laboratory testing reduces the applicability of these tests.

Accuracy of on-site urine drug tests : an experimental study

Objective: On-site drug tests (ODTs) are frequently used in hospitals to screen the urine of patients admitted for suspected poisoning. The purpose of this study is to evaluate the accuracy of such ...1. Methanol outbreak in the Czech Republic in 2012: Epidemiology and clinical features Daniela Pelclova1, Sergej Zakharov1, Tomas Navratil1 Knut Erik Hovda2 1Toxicological Information Centre, 1st Medical Faculty, Charles University in Prague, Czech Republic; 2The Norwegian Center for NBC Medicine, Department of Acute Medicine, Oslo University Hospital, Norway Objective: Mass methanol poisonings are a challenge for treating physicians due to the unpredictable onset and scenario, diagnostic difficulties, severe toxicity, expensive treatment, high mortality and frequently serious sequelae.1–4 We report the features of a large methanol outbreak that started in the Czech republic in September 2012 due to the illegal production and sale of adulterated spirits. Methods: Discharge reports and questionnaires of hospitalized patients with confirmed methanol poisoning, received by the Toxicological Information Centre were analyzed. Statistical evaluation used: normality of distribution, arithmetic mean, standard deviation, skew, median, mode, Student’s t-test, F-test, confidence intervals, correlation coefficient, and Chi-Square-test. Results: A total of 73 discharge reports were analyzed. A further 20 patients died at home or before hospital and 5 reports of recently deceased subjects could not yet be analyzed. Among the 73 hospitalized patients, 56 (77%) were males, mean age 51 (range 25–79) years, and 17 (23%) females, mean age 54 (range 23–69) years. Only 9 patients (12%) were admitted within 12 hours of ingestion, 50% after 12–48 hours, and 38% later. All patients who died were admitted 12 or more hours after ingestion. The methanol content of the beverage drunk (25–50%) was known in 42/73 patients (58%), 18/73 (25%) subjects drank other alcoholic beverages (wine, beer, whisky, home-made spirits) in addition. There were 32/73 (44%) daily alcohol users. Admission data: Median serum methanol was 0.939 g/L (range 0–7.307), i.e. 29.4 mmol/L (range 0–229); median ethanol level 0.437 g/L, (range 0–4.460), i.e. 9.6 mmol/L (range 0–98). Median pH was 7.17 (6.57–7.46; N 7.37–7.43), median pCO2 4.07 kPa (0.97-14.9 kPa; N 4.3-6.0), median HCO3  8.8 mmol/L (2–25.5; N 21.8-27.6), median base deficit 17.2 mmol/L (range 0.1–38.1; N 3–3), median lactic acid 3 mmol/L (0–19.4; N 0.6–2.1), median anion gap 28.8 mmol/L (range 11.1–54.8; N 16–20), median osmolality 348 mmol/kg (283–529, N 275–295), and osmolal gap 45.8 mmol/kg (2.4–235, N 10–25). Clinical symptoms: Only 12/73 patients (26%) were asymptomatic on admission, 7 appeared inebriated; at least 3 of them without measurable ethanol in blood. Among the 61 symptomatic patients, the most frequent symptoms were gastrointestinal (63%), visual disturbances (59%), dyspnoea (46%), coma (29%) and chest pain (17%). Other symptoms included fatigue, headache, dizziness, hangover, somnolence, anxiety, tremor, seizures, alcoholic delirium, respiratory and cardiac arrest. Treatment included alkalinization in 64%, ethanol in 79%, fomepizole in 5%, or a combination of antidotes in 12% patients. because there was limited availability of fomepizole, it was only recommended for the most severely poisoned subjects with methanol level above 0.500 g/L (15.65 mmol/L) or formic acid above 0.400 g/L (8.7 mmol/L) or pH lower than 7.0. Folates were administered in 72% of subjects (folic acid in 33 patients, folinic acid in 20 patients); whereas haemodialysis was performed in 58/73 (79.5%) subjects and started on average 4 hours after admission to the hospital (range 0.5–44). Continuous veno-venous haemodialysis (CVVHD) was performed in 50% of subjects; lasting a median of 36 hours (range 3.5–95). Conventional intermittent haemodialysis (IHD) was performed for a median duration of 8 hours (range 4–18.5). Outcomes: There were 13/73 (18%) fatalities, 44/73 (60%) survivors without sequelae, and 16/73 (22%) survivors with sequelae: visual impairment alone in 7/73 (10%), central nervous system (CNS) impairment in 5/73 (6.5%) and both visual and CNS damage in 4/73 (5.5%). The mortality was 75% among the patients admitted with respiratory arrest and 52% among those comatose on admission. The patients who died were more (p  0.05) acidotic (median pH 6.75, median base deficit 30 mmol/L) than the survivors with sequelae (median pH 7.02, median base deficit 19 mmol/L) and than those without (median pH 7.26, median base deficit 8 mmol/L), (p  0.05). No significant differences were found between the 3 groups regarding serum methanol, osmolal gap, and HCO3 . The groups differed only in pCO2, pH and base deficit (all p  0.05). Among the patients who recovered without sequelae, there was a trend towards lower pCO2 when pH was decreasing, whilst the trend was the opposite amongst the victims (pH decreased and pCO2 increased). The difference between these groups was highly significant (p  0.001). Lactic acid was significantly higher in victims than survivors (p  0.01). Among the 58 patients treated with ethanol, 9 (16%) died, 9 (16%) survived with sequelae, and 40 (68%) recovered fully. Among the 13 patients treated with fomepizole or the combination of antidotes, 3 (23%) died, 6 (46%) survived with sequelae, and 4 (31%) recovered, i.e. the outcome was worse in the second group (p  0.023). There was no difference in survival between the patients treated with continuous veno-venous haemodialysis (CVVHD) and IHD (p  0.17).Background: Of the 90,000 exposures involving children younger than 6 years of age reported to German poison centers (PCs) every year a !fth are caused by plants. A list of especially poisonous plants, which should not be planted in children’s playgrounds, was published in the “Bundesanzeiger” (Federal Gazette) in 2000. The BfR-Committee “Assessment of Intoxications” founded a work- ing group to re-assess the toxicity of plants to protect especially children from severe plant poisoning. Methods: The members of the working group de!ned criteria for risk assessment of plants in the close proximity of children’s playgrounds. Human exposure data, provided by the German PCs in Berlin, Freiburg and Erfurt and by the Swiss PC Zurich were reviewed as well as scienti!c publications about human exposures and about toxicity of ingredients of plants. Following the assess- ment of the toxicity of chemicals in analogy to the German Regula- tions on Dangerous Substances, poisonous plants were re-classifed into three categories, namely plants which could lead to minor poisoning, moderate poisoning and severe or deadly poisoning. Results: Out of 43,000 con!rmed accidental plant exposures from PCs in Freiburg and Berlin moderate or severe poisoning was expe- rienced in 1.3% restricted to 39 plants. Altogether, 280 plants were re-evaluated. Risk assessment changed for some of the especially poisonous plants of the 2000 list. For example the formerly moder- ate poisonous plants Lantana camara, Ilex spec., and Euonymus spec. were re-assessed as minor poisonous, and the formerly minor toxic Chelidonium majus was re-assessed as moderately toxic for the eyes. Conclusion: Human data about the risk of health damage after accidental ingestion of small amounts or by accidental dermal or ocular contact are mainly restricted to published case reports. The toxicity of ingredients and of preparations of plants for medical or psychoactive purposes may be completely different. The exposure data of PCs are very useful for risk assessment of plants present in the close proximity of children’s playgrounds, kindergartens, etc. The re-assessment and the !nal table of especially poisonous plants will be published again in the “Bundesanzeiger”.Background On the 21st June 2010, the management advice on TOXBASE® (the UK poisons database) for toothpaste ingestion changed, from advising medical assessment in patients developing anything other than minor gastrointestinal symptoms to advising observations in patients ingesting over 5 mg/kg fluoride, and further management in those ingesting over 10 mg/kg fluoride. We investigated the amounts ingested, features present, and advice given in cases of acute toothpaste ingestion reported to the NPIS three years before, and two years after, this change.Background: In 2009, in a joint cooperation, the Federal Institute for Risk Assessment (BfR) carried out an investigation concerning the poisoning situation of children, but with indifferent results for the poisoning risks in migrants. Between 2010 and 2011 some scientific assumptions were published in Germany that migrants could carry a higher risk of childhood poisoning. A feasibility study in Berlin, however, evaluated the options for achieving access to families with a migrant background in order to develop a framework for further, enlarged and systematically established scientific studies. Method: Existing data on migration background were evaluated regarding risks of chemical consumer products being responsible for childhood household poisoning accidents. The main instrument was a semi-standardised questionnaire for parents. Subject matter was focused on poisoning accidents which had occurred; knowledge about chemical products; attitudes towards the use of those products, their household storage and safety aspects and an important item “looking through the keyhole”. This means that if respondents agreed an expert would make a home-visit to evaluate real household product knowledge together with poisoning risks for children. Results: Regarding the cases of childhood poisoning accidents, the study did not support the assumption of a higher rate of relevant accidents in families with a migrant background - on the contrary, accidents occurred mainly in families with minor chemical use. There was no obvious correlation between age of the parents, family status, job, dwelling, knowledge about the products or their possible risks and causes of poisonings. In three-quarters of the cases, the affected children were the eldest. Possible impacts to be evaluated are e.g. the knowledge which might well have its origin in a specific cultural setting - about handling and risks of chemical products and the level of knowledge of the German language. Furthermore, more than half of the respondents agreed to an expert’s visit to their home. Conclusion: In order to develop adequate means of prevention in childhood poisoning, the focus has to be taken to special target groups and the evaluation of specific instruction materials. It is of nationwide importance to get personal access to the migrants. A combination of legal and educationally oriented measures seems promising.Objective: Since 20 January 2009, the EU-CLP Regulation (EC) No. 1272/2008 (Classification, labelling and packaging of substances and mixtures) has been in effect. Article 45 stipulates compulsory reporting of formulations of mixtures by industry for emergency health services. For adaptation of the CLP Regulation on a national level, the German government implemented Art. 45 CLP-Regulation into the § 16e (Chemicals Law - Chemikaliengesetz). For a transition period (9th November 2011 limited to the 1st July 2014) German industry can already start to use “Art. 45-Electronic Product Notification” via an adapted BfR-Electronic Product Notification Portal. Methods: Since 2007, notification of formulations of detergents and cleaning agents has been performed by file transfer in XML-format. This procedure was developed by the BfR and had been well adopted by industry. This format was refined by the BfR to ensure that data on all notifiable products and data reported on a voluntary basis can be transmitted in XML-format. This prototype and the procedures have been practice-tested in cooperation with a major enterprise (Henkel, Dusseldorf). After final testing the BfR-database has been adapted to the new requirements of the CLP-Regulation on e.g. labelling and all important data, including clear identifiers (e.g. product identification element) which can be exchanged in the new format. Results: The § 16e (new) has been successfully adapted to the CLP Regulation (EC) No. 1272/2008: 1) governed by public law with a transition period in awaiting the EU-harmonisation dataset for product notifications and 2) technical in having an adapted BfR-XML Electronic Notification Portal which carries all the requirements for the rapid adaptation to the future EU standard data set. With the new § 16e the notification of dangerous mixtures is considerably extended. Products with all hazard identifiers – commercial/non-commercial – have to be notified. The increase is already visible in 2012. From January to October 38,735 dangerous mixtures (excluding biocides) had been notified. This represents a 25-fold increase compared to 2011. Conclusion: A universal electronic notification procedure for industry will enable BfR to considerably increase the number of product notifications received, processed and communicated to German PCCs.Background A survey of all European Poisons Centres (PCs) was carried out in 2012 by the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) in order to identify staffing, organisation, In 2012 all centres required information staff to have at least a university degree, with the exception of one that employed nongraduate nurses (96.9% compared with 81.7% requiring a university degree in 2000). services provided, research and training. The objective was to describe the working of the centres and perhaps to provide help where needed in the future.