3-Methylmethcathinone (3-MMC) Poisonings: Acute Clinical Toxicity and Time Trend Between 2013 and 2021 in the Netherlands.

STUDY OBJECTIVE: The synthetic cathinone 3-methylmethcathinone (3-MMC, or metaphedrone) has recently gained popularity. We studied the numbers of 3-MMC poisonings over time and the clinical effects following poisonings with 3-MMC. METHODS: We performed a retrospective study on the numbers of self-reported 3-MMC poisonings to the Dutch Poisons Information Center (DPIC) from 2013 to June 2021. For poisonings reporting 3-MMC only, the symptoms were extracted and the Poisoning Severity Score (PSS) was determined. From 2016 to June 2019, a prospective cohort study on poisonings reporting only 3-MMC was performed, in which details on the clinical courses were collected through telephone interviews. RESULTS: From 2013 to June 2021, the DPIC was consulted on 184 3-MMC poisonings. The number of poisonings increased from 1 in 2013 to 70 in the first half of 2021. In 84 poisonings with only 3-MMC (46%), sympathomimetic symptoms were commonly reported, including tachycardia (n=29, 35%), hypertension (n=17, 20%), and agitation (n=16, 19%). The initial PSS was usually minor (n=37, 44%) to moderate (n=39, 46%). Five patients (6%) experienced severe effects, including 3 patients experienced severe hypertension (systolic blood pressure >180 mmHg; n=3) and nonfatal cardiac arrest (n=1). Sympathomimetic symptoms (n=8) were also reported in the prospective cohort study. The percentage of moderate poisonings increased (n=6, 75%), and 1 (13%) severe poisoning was observed. Analytical confirmation of 3-MMC exposure was performed in 2 cases. CONCLUSION: The number of 3-MMC poisonings reported to the DPIC has increased over time. Most poisonings with 3-MMC resulted in moderate toxicity and involved sympathomimetic effects, while severe effects were observed in 5 cases.

The Clinical Toxicology of 4-Bromo-2,5-dimethoxyphenethylamine (2C-B): The Severity of Poisoning After Exposure to Low to Moderate and High Doses.

STUDY OBJECTIVE: We studied the severity of poisoning after exposure to low to moderate and high doses of 4-bromo-2,5-dimethoxyphenethylamine (2C-B). METHODS: Patients for whom the Dutch Poisons Information Centre was consulted for 2C-B exposure from 2016 to 2018 were included in a prospective cohort study. Data were collected through telephone interviews with the physician or patient. Patients were categorized according to the reported 2C-B dose: low to moderate (up to 20 mg), high (greater than 20 mg), or unknown. Presence of 2C-B was analyzed in leftover drug and biological samples with liquid/gas chromatography-mass spectrometry. The severity of poisoning was graded with the Poisoning Severity Score. RESULTS: We included 59 patients, of whom 32 could be followed up. Low to moderate 2C-B doses were reported by 9 patients (28%), high doses by 17 (53%), and unknown doses by 6 (19%). Poisoning was moderate in the majority of patients in both the low- to moderate-dose and high-dose groups. Frequently reported symptoms included mydriasis, agitation or aggression, hallucinations, confusion, anxiety, hypertension, and tachycardia. The presence of 2C-B was confirmed in 5 patients in urine (n=3) or drug samples (n=4). CONCLUSION: In this study, most 2C-B poisonings resulted in moderate toxicity even at high reported doses up to 192 mg. No severe cases were observed. The clinical course was usually short-lived (up to 24 hours) and typically involved hallucinations in addition to mild somatic effects.

Differentiating samples and experimental protocols by direct comparison of tandem mass spectra.

RATIONALE: Peptide tandem mass spectra can be analyzed by a number of means. They can be compared against predicted spectra of peptides derived from genome sequences, compared against previously acquired and identified spectra, or - sometimes - sequenced de novo. We recently introduced another method which compares spectra between liquid chromatography/tandem mass spectrometry (LC/MS/MS) datasets to determine the shared spectral content, and demonstrated how this can be applied in a molecular phylogenetic study using sera from human and non-human primates. We will here explore if such a method have other, serendipitous uses. METHODS: We used the existing compareMS2 algorithm without modification on a diverse set of experiments. RESULTS: First we conducted a small phylogenetic study, using (mammalian) bone samples to study old material, and human pathogens aiming to distinguish clinically important strains. Although not as straightforward as primate sera analysis, the method shows significant promise for all these applications. We also used the algorithm to compare 24 different protocols for extraction of proteins from muscle tissue. The results provided useful information in comparing protocols. Finally, we applied compareMS2 aiming for quality control of two traceable protein reference standards (troponin) used in clinical chemistry assays, by analysing the effect of storage conditions. CONCLUSIONS: The results illustrate a broad applicability of the metric based on shared tandem mass spectra between LC/MS/MS datasets for analysing protein digests in different types of experiments. There is no reason to assume that our instance of this method is optimal in any of these situations, as it makes limited or no use of accurate mass and chromatographic retention time. We propose that with further improvement and refinement, this type of analysis can be applied as a simple but informative first step in many pipelines for bottom-up tandem mass spectrometry data analysis in proteomics and other fields, comparing or analysing large numbers of samples or datasets.

An Indonesian slimming drug with undeclared ingredients causing harm.

This paper reports the presence of undeclared drugs in the herbal slimming supplement Sulami®. The four cases of the adverse drug reactions related to Sulami® were reported to the Dutch Pharmacovigilance Centre (Lareb) or the Dutch Poisons Information Centre (DPIC). The analysis of all four collected samples revealed adulteration with sibutramine and canrenone. Both drugs can cause serious adverse drug reactions. From a legal point of view, it is clear that Sulami® does not meet the legal requirement for safety. As defined in the European General Food Law Regulation, food business operators are responsible for food safety. This also applies to online store owners who sell herbal preparations. Thus, it is clear that it is forbidden to sell Sulami® on the European and Dutch market. Collaboration between involved national authorities makes it possible to identify risky products. This allows the nationally responsible regulators to take targeted action. They can call on users to report sell points what makes it possible to arrest the sellers and confiscate the dangerous products. Beyond the national, also, the European enforcement organizations should take legal measures where possible, to protect public health. The Heads of Food Safety Agencies Working Group on Food Supplements "an Initiative on European level" is a good example of efforts to improve consumer safety.

[Dangerous herbal preparations being sold by web shops]. / Gevaarlijke kruidenpreparaten te koop via de webshops.

BACKGROUND: A large number of herbal preparations are offered on the internet. Some of these may contain substances not listed on the label. When these are illegal "regular" drugs, this can lead to serious side effects. CASE DESCRIPTION: In January 2021, The Netherlands Pharmacovigilance Centre Lareb received 4 reports of side effects after using the herbal preparation Montalin® from Indonesia. Laboratory analysis showed that effective amounts of paracetamol and meloxicam were also present in this herbal preparation. These have been added illegally and are not listed on the packaging. The five web shops that sold this product were ordered to immediately stop trading by order of the Dutch Food and Consumer Product Safety Authority (NVWA). CONCLUSION: Consumers should be careful when purchasing herbal preparations over the internet. It is not always clear what is in it. Certainly if a clear effect is experienced, it may be that (illegally) effective amounts of pharmacologically active substances have been added.

Current challenges in the detection and analysis of falsified medicines.

Falsified medicines affect public health all around the globe. Complex distribution routes, illegal online webshops and reuse of packaging materials make them hard to detect. In order to tackle this problem, detection methods for the recognition of suspicious medicines and subsequent confirmation of falsification by analytical techniques is required. In this review, we focus on the developments and challenges that existed in the last five years (2015-2020) in the detection and analysis of falsified medicines. These challenges might have not been solved yet or arisen with new types of falsifications, new analytical techniques or detection strategies. Detection of suspicious medicines starts with visual inspection of packaging materials. However, re-use of packaging materials and high-quality imitations complicate visual inspection. Recent developments in the analysis of packaging by microscopic and spectroscopic techniques such as optical microscopy, X-ray fluorescence, infrared spectroscopy and Raman spectroscopy or microscopy, in combination with multivariate analysis show promising results in the detection of falsified medicines. An ongoing big challenge in the analysis of falsified medicines is the affordability of analytical devices. Yet, recent reports showed that lower cost devices, such as Counterfeit Drug Indicator or Counterfeit Detection device version 3 show promising use in the detection of falsified medicines. Furthermore, combining the outcomes of different low-cost analytical techniques, such as Minilab, colorimetry and Counterfeit Drug Indicator significantly increased selectivity and sensitivity in the detection of falsified medicines. Also, recent developments make it possible to link a low-cost technique, such as TLC, to mobile phones. Proper training of personnel has shown room for improvement and remains a challenge, even for relatively simple techniques. With an increased use of analytical fingerprints, an upcoming challenge is the accessibility of the growing pool of data. There is also the need of validated reference libraries on both national and international levels. Developments of the last few years bring us a step closer in the fight against falsified medicines, however challenges remain in the worldwide accessibility of affordable, easily operable and sensitive techniques.

Nine prohibited stimulants found in sports and weight loss supplements: deterenol, phenpromethamine (Vonedrine), oxilofrine, octodrine, beta-methylphenylethylamine (BMPEA), 1,3-dimethylamylamine (1,3-DMAA), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylbutylamine (1,3-DMBA) and higenamine.

BACKGROUND: Weight loss and sports supplements containing deterenol have been associated with serious adverse events including cardiac arrest. OBJECTIVE: To determine the presence and quantity of experimental stimulants in dietary supplements labeled as containing deterenol sold in the United States. METHODS: Dietary supplements available for sale in the US and labeled as containing deterenol or one of its synonyms (e.g., isopropylnorsynephrine and isopropyloctopamine) were purchased online. For each brand, one container or subsample was analyzed by NSF International (Ann Arbor, MI) and one container or subsample by the Netherland's National Institute for Public Health and the Environment (RIVM, Bilthoven, The Netherlands). When differences existed between the two containers or subsamples of the same brand, both products were reanalyzed by Sciensano (Brussels, Belgium). NSF International carried out qualitative and quantitative analyses using ultra-high-performance liquid chromatography (UHPLC) quadrupole-Orbitrap mass spectrometry. RIVM performed qualitative and quantitative analysis using UHPLC quadrupole time-of-flight mass spectrometry. Sciensano carried out qualitative analysis using UHPLC quadrupole-Orbitrap mass spectrometry. RESULTS: Seventeen brands of supplements were analyzed. Many brands included more than one prohibited stimulant in the same product: 4 brands (24%, 4/17) included 2 stimulants, 2 (12%, 2/17) combined 3 stimulants, and 2 (12%, 2/17) combined 4 stimulants. The range of quantities per recommended serving size of the 9 stimulants detected were 2.7 mg to 17 mg of deterenol; 1.3 mg to 20 mg of phenpromethamine (Vonedrine); 5.7 mg to 92 mg of beta-methylphenylethylamine (BMPEA); 18 mg to 73 mg of octodrine; 18 mg to 55 mg of oxilofrine; 48 mg of higenamine; 17 mg of 1,3-dimethylamylamine (1,3-DMAA); 1.8 mg to 6.6 mg of 1,3-dimethylbutylamine (1,3-DMBA); and 5.3 mg of 1,4-dimethylamylamine (1,4-DMAA). CONCLUSION: Weight loss and sports supplements listing deterenol as an ingredient contained 9 prohibited stimulants and 8 different mixtures of stimulants, with as many as 4 experimental stimulants per product. These cocktails of stimulants have never been tested in humans and their safety is unknown.

The effective design of sampling campaigns for emerging chemical and microbial contaminants in drinking water and its resources based on literature mining.

As well as known contaminants, surface waters also contain an unknown variety of chemical and microbial contaminants which can pose a risk to humans if surface water is used for the production of drinking water. To protect human health proactively, and in a cost-efficient way, water authorities and drinking water companies need early warning systems. This study aimed to (1) assess the effectiveness of screening the scientific literature to direct sampling campaigns for early warning purposes, and (2) detect new aquatic contaminants of concern to public health in the Netherlands. By screening the scientific literature, six example contaminants (3 chemical and 3 microbial) were selected as potential aquatic contaminants of concern to the quality of Dutch drinking water. Stakeholders from the Dutch water sector and various information sources were consulted to identify the potential sources of these contaminants. Based on these potential contamination sources, two sampling sequences were set up from contamination sources (municipal and industrial wastewater treatment plants), via surface water used for the production of drinking water to treated drinking water. The chemical contaminants, mycophenolic acid, tetrabutylphosphonium compounds and Hexafluoropropylene Oxide Trimer Acid, were detected in low concentrations and were thus not expected to pose a risk to Dutch drinking water. Colistin resistant Escherichia coli was detected for the first time in Dutch wastewater not influenced by hospital wastewater, indicating circulation of bacteria resistant to this last-resort antibiotic in the open Dutch population. Four out of six contaminants were thus detected in surface or wastewater samples, which showed that screening the scientific literature to direct sampling campaigns for both microbial and chemical contaminants is effective for early warning purposes.