Peter H. J. Keizers

A cocktail of synthetic stimulants found in a dietary supplement associated with serious adverse events

Food supplements are regularly found to contain pharmacologically active substances. Recently, the food supplement Dexaprine was removed from the Dutch market because it was associated with severe adverse events. Reports to the Dutch Poisons Information Center (DPIC) showed that ingestion of as little as half a tablet caused several cases of nausea, agitation, tachycardia, and palpitations and even one case of cardiac arrest. The remaining tablets of four patients were sent in by different healthcare professionals. Analysis by ultra-performance liquid chromatography quadrupole time of flight mass-spectrometry (UPLC-QTOF-MS) confirmed the presence of synephrine, oxilofrine, deterenol, yohimbine, caffeine, and theophylline. Two more compounds were found which were tentatively identified as β-methyl-β-phenylethylamines. This incident is only the next in a series of similar incidents involving dietary supplements with (undeclared) active substances that are either unsafe or have no known safety profile.

Dose-to-dose variations with single packages of counterfeit medicines and adulterated dietary supplements as a potential source of false negatives and inaccurate health risk assessments

In this report, we show three examples of how the variability in dose units in single packages of counterfeit medicines and adulterated dietary supplements may contribute to a false negative screening result and inaccurate health risk assessments. We describe a counterfeit Viagra 100mg blister pack and a box of an instant coffee both containing dose units with and without an active pharmaceutical ingredient (API). We also describe a purportedly herbal slimming product with capsules that mutually differed in API and impurities. The adulterated dietary supplements contained sibutramine, benzyl-sibutramine, N-desmethyl-sibutramine (DMS), N,N-didesmethyl-sibutramine (DDMS) and several other related impurities. Counterfeit medicines and adulterated dietary supplements are a health risk because their quality is unreliable. Health risks are even greater when such unreliability extends to fundamental differences between dose units in one package. Because dose-to-dose variability for these products is unpredictable, the confidence interval of a sample size is unknown. Consequently, the analyses of a selection of dose units may not be representative for the package. In the worst case, counterfeit or unauthorised medicines are not recognised as such or a health risk is not identified. In order to reduce erroneous results particular care should be taken when analysing a composite of dose units, when finding no API in a dietary supplement and when finding conformity in a suspect counterfeit medicine.

Four experimental stimulants found in sports and weight loss supplements: 2-amino-6-methylheptane (octodrine), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylamylamine (1,3-DMAA) and 1,3-dimethylbutylamine (1,3-DMBA)

Abstract Background: The United States Food and Drug Administration banned the stimulant 1,3-dimethylamylamine (1,3-DMAA) from dietary supplements and warned consumers that the stimulant can pose cardiovascular risks ranging from high blood pressure to heart attacks. Objectives: We designed our study to determine if a new stimulant similar in structure to 1,3-DMAA has been introduced as an ingredient in supplements sold in the United States (US). Methods: We analyzed six brands of supplements that listed an ingredient on the label (e.g., Aconitum kusnezoffii, DMHA or 2-amino-isoheptane) that might refer to an analog of 1,3-DMAA. Supplements were analyzed by two separate laboratories using ultra-high-performance liquid chromatography mass spectrometry and reference standards. Results: Two previously unidentified 1,3-DMAA analogs (2-amino-6-methylheptane [octodrine] and 1,4-dimethylamylamine [1,4-DMAA]) and two banned stimulants (1,3-DMAA and 1,3-dimethylbutylamine [1,3-DMBA]) were identified. Octodrine was found at a dose (±95% CI) of 72 ± 7.5 mg per serving. In Europe, octodrine was previously sold as a pharmaceutical in multi-ingredient medications at dosages from 8 to 33 mg. The quantity of octodrine found in our study was more than twice the largest pharmaceutical dose. The other new stimulant, 1,4-DMAA, has not previously been approved for human consumption, and its safety in humans is unknown. 1,4-DMAA was found at dosages between 21 ± 11 mg to 94 ± 48 mg per serving. In addition, two banned stimulants – 1,3-DMAA and 1,3-DMBA – were also identified: 24 ± 7.6 mg to 35 ± 11 mg of 1,3-DMAA and 51 ± 16 mg of 1,3-DMBA. In one product, 24 ± 7.6 mg of 1,3-DMAA was combined with 21 ± 11 mg of 1,4-DMAA. 1,3-DMAA has been investigated as potentially contributing to hemorrhagic strokes and sudden death, whereas the safety of 1,3-DMBA in humans is unknown. Conclusion: Two banned stimulants (1,3-DMAA and 1,3-DMBA) and two previously unidentified stimulants (1,4-DMAA and octodrine) were identified in supplements sold in the United States.

Pharmacologically effective red yeast rice preparations marketed as dietary supplements illustrated by a case report

This paper reports a typical statin-related adverse reaction from a red yeast rice (RYR) supplement and the analytical findings from the supplement. It also examines the regulatory framework governing botanical supplements in Europe. Two key events that shaped the current regulatory framework are reviewed. First, the Hecht-Pharma judgement by the European Court of Justice (ECJ) that inverted the precautionary principle in the Medicines Act to a reactionary principle. Following the Hecht-Pharma judgement, pharmacological active dietary supplements can be sold until sufficient signals of harm show that they are an unregistered medicine, placing a huge burden on regulatory authorities. Secondly, the European Food Safety Authority (EFSA) in 2011 approved the first health claim for pharmacologically active RYR dietary supplements. If the current regulatory status for pharmacologically active RYR dietary supplements does not permit adequate warning and active monitoring of adverse drug reactions, then the current regulatory framework may not be adequate to ensure consumer safety.Copyright

Operation resistance: A snapshot of falsified antibiotics and biopharmaceutical injectables in Europe.

Operation Pangea is an annual international week of action combating pharmaceutical crime. In this study, called Operation Resistance, we asked the national agencies in Europe to search for falsified antibiotics and biopharmaceutical injectables (peptides and proteins) amongst the medicines seized in Pangea 7 (2014). Reports were received from Belgium, Cyprus, Czech Republic, Denmark, France, the Netherlands, Portugal, Sweden, Spain, the United Kingdom, Norway, and Switzerland. The countries reported seizing about 21,000 dose units (e.g. tablets, capsules) of falsified antibiotics in total. Most of the antibiotics were unlicensed medicines with common antibiotic drugs. In this study week, very few falsified biopharmaceutical injectables were reported. Laboratories reported human growth hormone, sermorelin, melanotan II, and no active ingredients. The average shipment size seemed too large for personal use indicating that a substantial part was intended for resale. This study provides a snapshot of the falsified antibiotics and biopharmaceuticals that enter European countries. How much is actually reaching users during Pangea week - in on other weeks - remains unknown. The shipment sizes indicate falsified antibiotics and biopharmaceuticals are imported for both personal use and resale. The use of antibiotics from unreliable sources is a health risk, contributes to antimicrobial resistance, and may obscure a source of infection from health agencies. The falsified biopharmaceuticals are a health risk because they lack all labelling and may contain unlicensed drugs for injection. It seems important to raise awareness among health-care professionals that falsified medicines in Europe are not restricted to erectile dysfunction drugs. Copyright

The quality of sildenafil active substance of illegal source

There must be a large market for active pharmaceutical ingredients of illegal source to support the huge and lucrative business of trade in illegal medicines. The active substances found in illegal pharmaceuticals may differ from their legal counterparts concerning purity and associated risks for the health of the user. In this study we show two examples in which the active substance sildenafil, used in erectile dysfunction products, was not of European Pharmacopeia quality. In one case milligram-scale amounts of a 2-mercaptobenzothiazole contamination were found, in another case the mesylate salt rather than the monograph based citrate was used. For the user of products containing these active substances, the risks of side effects increase through the inherent properties of the impurity and the chance of overdosing. The fact that the users are most likely not aware of the poor quality of the products adds up to the health risk of using prescription medication without consulting medical professionals.

A ‘natural’ weight loss product containing sibutramine

For consumers who want to lose weight, using a product claiming to make that weight loss easier may be an attractive option. Herbal products are often perceived as safe because they are ‘natural’. However, these products are not free of risks. Herbal products themselves can be a cause of adverse drug reactions but these products can also be adulterated with active pharmacological ingredients. A recent Dutch study determined whether herbal food supplements for weight loss on the Dutch market contained active pharmacological ingredients with weight loss properties. This study found that in 50 samples collected from August 2004 to May 2013, in 24 samples sibutramine, desmethylsibutramine (DMS), didesmethylsibutramine (DDMS), rimonabant, sildenafil, and/or the laxative phenolphthalein were identified. Some samples contained multiple active pharmacological ingredients. The presence of these ingredients was not stated on the label. In addition, several other studies have identified sibutramine and other active pharmacological ingredient in supposedly ‘natural’ products. The Netherlands Pharmacovigilance Centre Lareb, located in ’s Hertogenbosch in the Netherlands, collects and analyzes reports of adverse drug reactions (ADRs). By maintaining the reporting system for ADRs, Lareb monitors the safety of medicines and vaccines in the Netherlands. In addition to monitoring the safety of registered drugs and vaccines, healthcare professionals and the general public can also report non-registered herbal products and food supplements including vitamins. In the Netherlands, herbal products can obtain marketing authorization through the Dutch Medicines Evaluation Board (MEB) in the case that the same efficacy and safety data are available as for ‘regular’ drugs. A manufacturer can also apply for a marketing authorization as a ‘traditional herbal drug’ through the MEB, meaning that the efficacy of these products is assessed not by clinical testing but on the basis of a long history of use and experience. If an herbal product is not registered through the MEB, it falls under the Dutch Commodities Act. Information on the reported ADRs of these products under the Dutch Commodities Act is shared with the Netherlands Food and Consumer Product Safety Authority (NVWA). At present, the database of Lareb contains 39 reports about unregistered slimming products, of which 9 were suspected of being adulterated with an illegal active pharmacological ingredient. In an additional 7 cases, high dosages of caffeine were added to weight loss products containing cactus, Aurantii pericarpium (bitter orange), Yerbamate (leaves), Guarana (Seeds), and Kola nut (seeds). For products where such a suspicion arises, Lareb requests the reporter (either a healthcare professional or consumer) to send a

Chemical fingerprinting of silicone-based breast implants

With millions of women worldwide carrying them, silicone-based breast implants represent a large market. Even though silicone breast implants already have a history of use of more than 50 years, the discussion on their safety has not yet come to an end. To improve safety assessment, regulatory authorities should have the availability of a set of tests to be able to determine parameters of implant identity and quality. Therefore, the gels and envelopes of various brands and types of silicone-based breast implants have been subjected to infrared, Raman and NMR spectroscopy. We show that by using a combination of complementary spectroscopic techniques breast implants of various origins can be distinguished on typical chemical hallmarks. It was found that typical silicone-based implants display a surplus of vinyl signals in the gel, cyclosiloxane impurities are tolerable at low levels only and a barrier layer is present in the implant envelope. The techniques presented here and the results obtained offer a good starting point for market surveillance studies.

A high crosslinking grade of hyaluronic acid found in a dermal filler causing adverse effects

Graphical abstract Figure. No caption available. HighlightsA method is developed for the routine analysis of dermal filler products.The method is used to identify modified hyaluronic acid and to quantify the amount of modifications and crosslinks.A product previously retrieved from the market was found to contain a high modification and crosslinking grade, which may be the reason for the high risk for adverse effects of this product.The product retrieved from the market appeared to be unreliable in its composition, regarding the modification grade and presence of a local anesthetic.There is a clear need for analytical methods to test medical devices on a routine basis as shown by the presence of suspicious and substandard products available on the market. ABSTRACT Facial treatments with dermal fillers for medical or esthetic purposes occasionally give rise to adverse effects, ranging from temporary effects such as reddening of the skin, to long term effects such as hardening of tissue. There appears to be a relationship between the lifetime of the filler product and the risk for adverse effects. The lifetime of hyaluronic acid‐based fillers is dependent on the presence and amount of crosslinking agents such as 1,4‐butanediol diglycidyl ether (BDDE). It would therefore make sense to establish methodology to analyze the crosslinking grade of HA‐based filler products on a routine basis. To this end, an analytical method was developed and validated to identify HA‐BDDE‐based fillers and to quantify their modification and crosslinking grade. The method was subsequently applied to products from the legal supply chain and the illegal market. It was found that the product Hyacorp H 1000, previously taken from the market, indeed contains a high modification grade and crosslinking grade, as was the assumed reason for the increased risk for adverse effects of this product. However, it was also shown that the Hyacorp products are highly unreliable in relation to their product composition in general. In this study, authentic products could not be distinguished from the illegal market products based on their modification and crosslinking grade.

The stimulant higenamine in weight loss and sports supplements

Abstract Background: Higenamine is a stimulant with cardiovascular properties recently prohibited in sport by the World Anti-Doping Agency (WADA). Higenamine is also a natural constituent of several traditional botanical remedies and is listed as an ingredient in weight loss and sports supplements sold over-the-counter in the United States. Objectives: We analyzed dietary supplements available for sale in the United States prior to WADA’s prohibition of higenamine in sport for the presence and quantity of higenamine. Methods: All supplements labeled as containing higenamine or a synonym (i.e., norcoclaurine or demethylcoclaurine) available for sale in the United States were identified. For each brand, one sample was analyzed by NSF International (Ann Arbor, MI) and one sample by the Netherland’s National Institute for Public Health and the Environment (RIVM). NSF International carried out qualitative and quantitative analyses using ultra high performance liquid chromatography (UHPLC) with tandem mass spectrometry. RIVM carried out qualitative analysis using UHPLC quadrupole time of flight mass spectrometry for an independent confirmation of identity. Results: Twenty-four products were analyzed. The majority of supplements were marketed as either weight loss (11/24; 46%) or sports/energy supplements (11/24; 46%); two brands did not list a labeled indication. The quantity of higenamine (±95% CI) ranged from trace amounts to 62 ± 6.0 mg per serving. Consumers could be exposed to up to 110 ± 11 mg of higenamine per day when following recommended serving sizes provided on the label. Five products (5/24; 21%) listed an amount of higenamine, but none were accurately labeled; the quantity in these supplements ranged from <0.01% to 200% of the quantity listed on the label. Conclusion: Dosages of up to 62 ± 6.0 mg per serving of the stimulant higenamine were found in dietary supplements sold in the United States.