Диетические добавки, содержащие запрещенные вещества
РезюмеИспользование биологически активных добавок к пище (БАД) у спортсменов для повышения физической работоспособности привело к широкой конкуренции производителей подобной продукции. В результате количество используемых диетических добавок, содержащих запрещенные стимуляторы физической активности, может значительно возрасти, что и описано в данном обзоре литературы. В связи с этим появляются новейшие сложные и все более чувствительные и специфичные аналитические методы для идентификации этих компонентов не только в составе БАД, но и в образцах крови и мочи спортсменов. Несмотря на существующие списки запрещенных препаратов и компонентов, множество таких химических соединений (эфедрин и псевдоэфедрин, сибутрамин, метилгексанамин, прогормоны, пептидные гормоны, классические анаболические стероиды, кленбутерол и др.) производится в коммерческих целях на фармацевтических предприятиях во многих странах мира. Компании используют агрессивные маркетинговые стратегии, нередко эта информация поступает через средства массовой информации, например через Интернет. Можно ожидать увеличения числа специализированных пищевых продуктов для питания спортсменов, содержащих "дизайнерские" стероиды и другие более "новые" молекулы. Методы хроматографии и масс-спектрометрии в значительной степени позволяют идентифицировать молекулярные фрагменты и составные элементы запрещенных препаратов. Чтобы предотвратить случайное поступление допинговых соединений, необходима полная информация о составе БАД и специализированных продуктов, которая должна быть предоставлена спортсменам, тренерам и спортивным врачам на всех уровнях тренировочного процесса и соревнований. Риски случайного приема допинга при употреблении БАД могут быть минимизированы при помощи списка безопасных продуктов. Эти списки есть в базах данных разных стран, в частности в Нидерландах и в Германии.
Ключевые слова:диетические добавки, запрещенные вещества, спортсмены, идентификация запрещенных веществ
Вопр. питания. - 2013. - № 6. - С. 6-13.
While it is well recognised that a balanced diet is the foundation for developing optimal training and performance, competitive sport and strenuous physical activity make demands on the human body beyond its normal physiological range . Some athletes may therefore benefit from additional supplements to help maintain homeostasis with adequate nutrients and energy in specific circumstances, especially where food intake or choice is restricted. For this reason dietary supplements have been used by athletes for many years to boost, even by small margins, their strength and performance [4, 10, 17]. Pressure to perform and the potential rewards coupled with success is a powerful driving force for many top athletes to continue striving for that chemical competitive edge and using these dietary supplements as part of their regular training or competition routine, even if the rationale for using these products is not always underpinned by solid evidence-based research . Supplements commonly used include vitamins, minerals, protein, creatine and various ergogenic compounds. While some supplements indeed enhance athletic performance, many have no proven benefits, are of uncertain content and purity and may have serious adverse effects, including death.
The practice of using dietary supplements amongst the population at large and athletes at all levels of competition has led to a huge continuously growing, multi-billion dollar industry with a world wide market estimated at more than $142 billion for 2011 and expected to rise to $205 billion by 2017 . Coupled with aggressive marketing techniques in which bold as well as unsubstantiated claims are frequently made, this explosive growth was further fuelled in many countries world wide which have acts similar to the Dietary Supplement Health and Education Act (DSHEA) which was passed by the US Congress in 1994. In essence all these acts allow substances that are marketed as dietary supplements to be regulated as foods rather than as pharmaceuticals. A dietary supplement is a product taken orally that contains a ‘dietary ingredient’ intended to supplement the diet. The ‘dietary ingredients’ in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites . Dietary supplements can also be extracts or concentrates, and may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders. They can also be in other forms, such as a bar, but if they are, information on their label must not represent the product as a conventional food or a sole item of a meal or diet . Whatever their form may be, DSHEA places dietary supplements in a special category under the general umbrella of ‘foods’, not drugs, and requires that every supplement be labelled a dietary supplement . Other than for pharmaceuticals, in which regulatory authorities scrutinise data on safety and efficacy before giving marketing approval, supplement manufacturers do not have to prove efficacy for their products, providing that they do not claim that their preparations can be used to diagnose, cure, mitigate, treat or prevent diseases. Furthermore, manufacturers of dietary supplements do not have to demonstrate their safety and the burden rests on regulatory authorities to show that a particular product is harmful before steps can be taken to ensure its removal from the market.
These dietary supplement regulations have facilitated their bringing onto the market not only to the population at large and non-competing amateurs, but especially to professional athletes in whom their use, often in megadoses, is widespread [28, 30]. Estimated use in the latter group of individuals varies between 44% and 100%; however, this very much depends not only on the type of sport in which they participate, but also on the level of competition as well as the age and gender of athletes [8, 23, 28, 29]. Large quantities of nutrients, commonly found in normal human diets, are consumed without there being much knowledge of possible health risks and the maximum daily safe doses involved. Over the past decade a new hazard related to dietary supplement use has been identified in that some products, marketed under the aegis of the regulatory requirements for foods, have been shown to contain unapproved pharmaceutically active ingredients. These dietary regulations have allowed manufacturers to bypass the necessity of providing safety and efficacy data for their products. It is of great concern that a wide variety of dietary supplements contain ingredients not adequately chemically identified on their package labels. These ingredients which are sometimes listed as ‘natural’, ‘herbal’ or otherwise, may constitute prohibited substances. They may have inadvertently entered the product, possibly due to accidental cross-contamination in manufacturing plants, or may have been intentionally added to the supplement, posing a potential health hazard to all consumers [10, 11].
While concentrations of these non-approved substances may be too small to achieve any health or performance-enhancing effects they may be large enough for athletes to fail a doping test and scandals appear to be more frequent . In recent years there has been an increase in the numbers of dietary supplements, containing unapproved pharmaceutical ingredients, recalled by the FDA . With as many as 150 million citizens in the US consuming dietary supplements in some form or another, the challenges that are posed by this growing and unregulated industry are enormous.
Ephedrine and Pseudoephedrine
Although stimulants can easily be detected in laboratories, they are still popular among athletes. Because the list of legal and illegal stimulants is extensive, only a selection will be discussed here.
Studies have shown that certain dietary supplements contained prohibited substances such as ephedrine and its analogues (pseudoephedrine, methylephedrine etc), caffeine, 3,4-methylenedioxy-N-methylamphetamine (MDMA) (‘ecstasy’) and other amphetaminerelated compounds, which may or may not be declared on the package labels . Ephedrine and its congeners are used as nasal decongestants and as pressor agents for hypotension. While caffeine is no longer considered a prohibited substance by the World AntiDoping Agency (WADA) since 2004, the use of ephedrine and its analogues as well as MDMA is banned during competition by this organisation . On certain food supplement labels natural sources of ephedrine, e.g. Ephedra sinica, a species of ephedra (ma huang), which contains the alkaloids ephedrine and pseudoephedrine, are mentioned instead of the chemical entities of ephedrine and its analogues. Similarly synephrine is obtained from Citrus aurantium and both plant products have been found in dietary supplements which were labelled as ‘ephedrine free’. Apart from the doping infringement aspects of supplements containing prohibited stimulants there are potential health risks involved which should not be neglected. Ephedrine has structural similarities with amphetamine and therefore has similar modes of action as well as a comparable side-effect profile. Both ephedrine and pseudoephedrine are stimulants, but they affect physical achievement differently. Ephedrine adversely affected running time over 10 km, but anaerobic performance of athletes was increased [2, 3]. Supporting evidence found in a meta-analysis of 8 studies was, however, insufficient to demonstrate clear benefits in performance with ephedrine . Similarly, improvements in fatigue and cycling performance with pseudoephedrine ingestion could not be found, but in a limited study an improvement in running times over 1.5 km following the use of this pharmaceutical agent was shown [6, 13, 16].
Adverse effects of ephedrine may be serious. A 2-3fold risk of anxiety, increased irritability and agitation (psychiatric symptoms), insomnia, tremors (autonomic system symptoms) and heart palpitations (cardiac symptoms) were found on analysis of 71 case reports and 50 clinical trials . In the foregoing analysis of cases of death, myocardial infarction, cerebrovascular accident, seizure and psychosis were found in some reports. Regarding pseudoephedrine anxiety, gastrointestinal disturbances and tremors have been reported . Both ephedrine and pseudoephedrine have been declared prohibited substances by the WADA .
Sibutramine Dietary supplements adulterated with sibutramine, an anti-obesity agent, that do not mention the presence of this compound on the package label have also appeared on the market. Sibutramine has been found in products advertised as ‘pure herbal’ slimming capsules and ‘natural’ tea [18, 20, 34]. Urinary metabolites of sibutramine were found in detectable quantities, 50 h after administration of a single ‘dose’ of tea to a volunteer . This synthetic anorectic drug, which only has market approval as a prescription anti-obesity agent, has been on the WADA prohibited list since 2006. Furthermore, market withdrawal of sibutramine was recommended by the European Medicines Agency at the beginning of 2010. This agent produces severe adverse effects, blood pressure elevation and cardiac effects (tachycardia), and patients using sibutramine are required to be monitored by a physician experienced in the treatment of obesity and familiar with this agent, on a regular basis.
Methylhexaneamine, a stimulant which was originally intended to be marketed as a nasal decongestant, has been detected as an ingredient of dietary supplements and was declared a prohibited compound by the WADA in 2009 . The serious adverse effects of this stimulant have recently been highlighted by a case report on the death of two US soldiers who were taking commercially available dietary supplements which contained methylhexaneamine. Both soldiers collapsed during physical exertion from cardiac arrest and ultimately died . The issues surrounding this stimulant have been complicated by the fact that methylhexaneamine is found on package labels under a very wide variety of chemical and non-chemical names, e.g. 1,3-dimethylamylamine, 1,3-dimethylpentylamine, 2-amino-4-methylhexane, 2-hexanamine, 4-methyl-2hexanamine, 4-methyl-2-hexylamine, 4-methylhexan2-amine, dimethylamylamine (DMAA), methylhexaneamine (MHA), dimethylpentylamine (DMP), floradrene, forthan, forthane, fouramin, geranamine, geranium extract, geranium flower extract, geranium oil, geranium stems and leaves, metexaminum, methexaminum, etc. Only the names methylhexaneamine and dimethylpentylamine appear on the WADA 2011 list of prohibited agents creating even further confusion amongst consumers and complicating identification. While geranium root extract or geranium oil are mentioned as natural sources of methylhexaneamine, the presence of this compound in these plant products could not be demonstrated on analysis, strengthening the suspicion that it was added during or after the manufacturing process .
It was shown in a previous study that approximately 15% of dietary supplements consisting of mainly vitamins, minerals, proteins and creatine contained undisclosed anabolic androgenic steroids . These steroids were mainly prohormones, referring to androgenic precursors which are enzymatically activated in vivo to the ‘real anabolic steroid’ testosterone and its derivatives. In the aforementioned study it was assumed that these prohormones were probably the result of contamination before or during manufacturing processes.
Nevertheless these prohormone-contaminated supplements in the quantities detected could have resulted in infringements of doping regulations. Prohormones are viewed by many consumers as ‘natural’ compounds to promote strength and muscle mass, change body composition and improve general feelings of wellness with less adverse effects than testosterone itself or other synthetic androgenic steroids . Also prohormones are perceived and commercially promoted as ‘legal alternatives’ to testosterone with comparable anabolic effects. However prohormones are listed as prohibited substances on the WADA list and are illegal to sell or import in many countries.
Cholesterol is metabolised by multiple enzyme systems into testosterone via a number of androgenic intermediates (prohormones), including dihydroepiandrosterone (DHEA) (Fig. 1). The biosynthetic pathway via DHEA leads to the production of androstenedione (DIONE) and androstenediol (DIOL). These intermediates can also be converted to the estrogens, which may cause gynecomastia and hepatic dysfunction. To counteract these adverse effects some athletes use prohormones out of the competition season in cycles lasting 4-12 weeks, either alone or in a ‘stacking manner’, i.e. taking multiple compounds with different estrogenic potential simultaneously. Alternatively, users may follow a ‘pyramid’ mode taking the highest doses in midcycle. Additionally, selective estrogen receptor modulators or aromatase inhibitors (Fig. 1) may be taken to attenuate estrogenic effects and androgenic herbal products taken to diminish the ‘low’ period between cycles [14, 19]. However, two well-conducted clinical studies have not shown DHEA, DIONE or DIOL to produce any advantageous anabolic or ergogenic effects at all, but have confirmed the risk of adverse effects. In particular, in one of the studies LDL-Cholesterol/HDLCholesterol ratios were increased by 11%, significantly elevating the risk for cardiovascular disease and also luteinising hormone levels were reduced, which may decrease testicular and adrenal testosterone production . Other prohormones, e.g. those of the much used/abused anabolic steroid 19-nortestosterone (nandrolone) have also appeared on the market . One of these prohormones, norandrostendione, administered as a single-dose, has been shown to lead to detectable urinary quantities of the main metabolite (19-norandrosterone) of the parent steroid nandrolone for a period longer than ten days .
‘Classic’ anabolic steroids
Steroid structures have perhydrocyclopentanophenanthrene nuclei comprising four rings (A, B, C & D) as represented by the structure of testosterone (Fig. 2). Loci where modifications occur as well as examples of typical reactions, resulting in structural modifications to the steroid nucleus, are also shown.
Furthermore, steroids can be classified into six groups according to the number of carbon atoms, i.e. C 17 gonanes, C 18 estranes (e.g. estradiol and estrone), C 19 androstanes (e.g. testosterone and androstenedione), C 21 pregnanes (e.g. progesterone and cortisol), C 24 cholanes (e.g. cholic acid and desoxycholic acid) and C 27 cholestanes (e.g. cholesterol). With the exception of the cholanes, steroids are precursors or natural hormones that, depending on their in vivo functions, can be divided into estrogens, androgens, glucocorticoids and mineralocorticoids. The steroid category of compounds includes the ‘classic’ anabolic steroids, e.g. metandienone, stanozol, boldenone, oxandrolone, dehydrochloromethyl-testosterone etc., which were found in high amounts (>1 mg/g) in certain dietary supplements and vitamin preparations freely available on the market. These steroid ingredients were either listed on package labels under some other chemical/nonapproved name or not disclosed at all. Concentrations of these steroids in the supplements were of such orders that even within the limits of recommended supplement intake, supratherapeutic doses of these substances would be ingested. Many athletes and other individuals in the population at large, including women, adolescents and children, regularly consume dietary supplements in quantities beyond the safe daily recommended doses and therefore adverse effects in these groups of users could be severe. In men acne, testicular atrophy, prostate enlargement, decreased spermatogenesis, infertility, impotence and changes in libido may occur .
Furthermore, gynecomastia, which may require surgical intervention, can also occur and some male users of steroids concurrently use tamoxifen or other agents to prevent or treat this condition. In women using steroids, acne, potentially irreversible masculinisation, clitoris enlargement, menstrual irregularities and changes in libido may result. In both sexes psychiatric effects, e.g. aggression (‘roid’ rage), psychoses, manic episodes, panic disorders, depression etc have been documented. Long-term steroid use has also been associated with dependency and a withdrawal syndrome associated with suicidal thoughts, an increased incidence of tumours and premature mortality . Of particular concern are the effects of steroids on cholesterol and lipid metabolism, hypercalcemia, electrolyte and fluid disturbances, hypertension, thrombotic events, e.g. emboli, myocardial infarction, cerebrovascular accidents, the latter two conditions possibly resulting from an increase in platelet aggregation and erythrogenesis. In adolescents and children virilisation and premature closure of the epiphyseal plates, which may result in stunted growth, have been described. Most of the ‘classic’ anabolic steroids are methylated in the 17-position of the D-ring of the perhydrocyclopentanophenanthrene nucleus (Fig. 2), a molecular feature which is associated with high hepatoxicity and carcinogenicity . While the commercial sources of these steroids on the world market are not always known, it appears as if many of them are sourced from Chinese bulk manufacturers and are intentionally incorporated into dietary supplements by unscrupulous companies .
These steroid molecules were synthesized some five decades ago and evaluated in pre-clinical studies for their anabolic and androgenic effects . They are not listed as components of any currently available pharmaceuticals for clinical use, are not on WADA’s list of prohibited substances and are manufactured exclusively for the dietary supplement ‘black’ market.
Examples of such agents, to name but a few, are prostanozol, methasterone, andostatrienedione, etc., but to date more than forty such ‘designer’ steroid molecules have been detected in laboratories . Little is known regarding their pharmacological actions and safety profiles in humans. They are either listed under some other chemical/nonapproved name or not disclosed at all on dietary supplement labels. Should metabolites of these ‘designer’ steroids be detected in an athlete’s urine, doping infringement charges will probably ensue.
Many athletes who claim that they suffer from asthma or exercise-induced asthma use metered-dose inhaled β2-agonists for alleviating their symptoms of bronchoconstriction. While the inhalational β2-agonists such as terbutaline, albuterol and salmeterol are permitted for use by athletes by WADA, oral and injectable forms of these pharmaceuticals are not. However, some of these β2-agonists, e.g. clenbuterol, are considered anabolic substances by some sports-governing agencies. Hitherto two cases have been described in which dietary supplements contained therapeutic and supratherapeutic doses of 30 μg/tablet and 2 mg/capsule of clenbuterol, respectively . In the supratherapeutic preparation, containing 100 times the therapeutic dose of clenbuterol, the presence of this β2-agonist was not disclosed on the package label.
Over-the-counter dietary supplements are frequently promoted by manufacturers as being able to increase human growth hormone levels in the body. However, a review has shown that while human growth hormone does increase lean body mass, it has no beneficial effect on strength or exercise capacity in trained athletes .
However, the hormones’ use was associated with higher rates of soft tissue edema, arthralgias and carpal tunnel syndrome. Furthermore, dietary supplements, advertised as having anabolic, fat-reducing and anticatabolic properties and containing the prohibited growth hormone-releasing peptide-2 (GHRP-2), were detected a few years ago. The presence of such substances may lead to inadvertent doping infringements. While GHPR-2
itself is not specifically barred by the WADA for use by athletes, it is a releasing factor which belongs to a prohibited substance group on their list .
Other ‘newer’ molecules
A selective androgen receptor modulator (SARM) and agonists of the peroxisome proliferator-activated receptor delta (PPAR-δ), which will produce anabolic effects and enhance endurance, respectively, have been found on the ‘black’ market .
It has also come to the attention of WADA that another substance for increasing endurance, GW501516, has been available for some time on the ‘black’ market, through the internet and elsewhere. Anti-doping authorities have already seen its use by athletes, as there have been a number of positive cases. This developmental drug has not been approved for clinical use anywhere in the world and has been withdrawn from further investigation by pharmaceutical companies due to its serious toxicity profile .
Identification and determination of prohibited substances
While a wide variety of analytical techniques have been used in the past to detect prohibited drugs in biological fluids, rapid improvements in mass spectrometry have allowed accredited laboratories to develop specific and comprehensive screening methods which are able to detect amounts of drugs and/or their metabolites in quantities as low as 1 g/l in urine . Over many years gas chromatography (GC) has proven itself in laboratories to be a useful technique for separating and identifying individual components in mixtures of chemical compounds on various chromatographic columns in terms of their retention characteristics (relative to an internal standard compound), as well as for quantifying them. A variety of detectors e.g. flame ionization detectors (FID), thermal conductivity detectors (TCD) and electron capture detectors (ECD) have been used for this purpose. However, for the successful application of this technique it is a prerequisite that for compounds to be separated using this technique, they are volatile, usually after the necessary derivatisation steps. Samples may also have to be hydrolyzed to release steroid metabolites from their glucuronic acid conjugates usually by means of the enzyme -glucoronidase, which may result in the generation of related steroidal compounds or incomplete deconjugation. For the purpose of volatilisation, the mixtures to be analysed are often trimethylsilylated (TMS) prior to injection onto GC columns. The more volatile TMS ethers of the individual components are then distributed between gaseous and solid phases, separated and detected. By feeding gaseous effluents from a GC into a mass spectrometer (MS) further improvement in identification and quantitation of compounds in mixtures can be expected. However, this technique of GC/MS is not so eminently suitable for routine clinical analysis, but has better applications as a screening tool of prohibited compounds in dietary supplements or urinary metabolites because of the high labour intensiveness, high cost and relatively poor sensitivity. The latter is of relevance when samples are analysed for compounds which have low thermal stabilities, e.g steroids such a trenbolone and gestrinone .
In recent years, another chromatographic tool, i.e. liquid chromatography (LC) coupled to ultraviolet (UV) or diode-array detectors (DAD), has become increasingly important in drug-assaying laboratories.
However, similar to GC this method is not sensitive enough to detect trace levels of compounds and is not well suited for the identification of new substances with unknown chemical and physical properties.
Coupled with MS it provides specificity, precision and high sensitivity, allowing the detection of very low quantities of polar and non-polar compounds, a requirement being that the methodology be extensively validated. LC/MS has high throughput capabilities, requires small sample volumes, minimal sample preparation and thermal stability is usually not a factor.
Furthermore, if required, a number of components can be identified and quantified in a single analysis within the dynamic calibration range of the instrumentation which can span four orders of magnitude.
Furthermore, because of the absence of hydrolysis or derivatisation steps, LC/MS can be used to measure concentration ratios for steroids between conjugated and free forms, thereby lowering the risk of false positive or misleading outcomes. The use of ultra-high performance LC (UHPLC) has further improved chromatographic resolution, thereby lowering the possibility of missing possibly important co-eluting analytes and critical pairs of isomers may be separated and detected. Coupled with high acquisition rate mass analysers such as triple quadrupole mass spectrometers in tandem LC/MS(/MS), exceptionally powerful techniques have evolved in e.g. the detection of steroids with marginal GC properties [5, 26, 31]. Methodologies such as these have enabled the identification of characteristic product ions of common steroid structures and nuclei . These powerful analytical tools provide means of detecting a wide variety of unknown steroids based on common chemical structural properties, new metabolites, as well as new ‘designer’ steroids (likely to be added to dietary supplements) made to circumvent anti-doping controls.
Dietary supplement use among athletes to enhance performance is proliferating as more individuals strive for obtaining that chemical competitive edge. As a result the concomitant use of dietary supplements containing performance-enhancing substances of those falling in the categories outlined in the current review, can also be expected to rise. This despite ever-increasing sophisticated analytical methodology techniques being used to assay dietary supplement and urine samples in doping laboratories. The reasons for this include that a variety of these chemical entities, many of them on the prohibited drug list of the WADA, are being produced on commercial scales in factories around the world, aggressive marketing strategies are being employed by companies and these supplements can be easily ordered via e.g. the internet. It can also be anticipated that there will be an increase in the number of supplements containing ‘designer’ steroids and other ‘newer’
molecules. Chromatographic techniques combined with mass spectrometry leading to identification of molecular fragments and product ions will assist in determining these substances. To prevent accidental doping, information regarding dietary supplements must be provided to athletes, coaches and sports doctors at all levels of competition. The risks of accidental doping via dietary supplement ingestion can be minimized by using ‘safe’ products listed on databases, e.g. such as those available in the Netherlands and Germany . Finally, athletes must be reminded that if they test positive for a prohibited substance not disclosed on the package label of supplements, it would constitute a doping violation with all the consequences thereof.
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