Substance Use and Its Impact on Athlete Health and Performance / Todd Stull, Eric Morse, David R. McDuff. - (Psychiatric Clinics of North America 44 (2021) 3 (September); p. 405-417)

• PMID: 34372997
• DOI: 10.1016/j.psc.2021.04.006

Abstract

The pressure to gain mass, power, explosiveness, and endurance and to obtain a performance edge continues to a part of sports. Anabolic agents, including selective androgen receptor modulators along with peptides, hormones, and metabolic modulators, continues to evolve. Methods to promote transcription to modify gene expression are a part of the evolution. In order to monitor and improve doping detection, the Athlete Biological Passport has been created. This article provides an up-to-date review of alcohol, anabolic androgens and related agents, stimulants, opioids, and cannabis and related compounds and their effects on athlete health and performance.

Biotin as a masking agent in chorionic gonadotropin assays utilizing biotinylated antibodies / Tim Sobolevsky, Brian Ahrens

• Drug Testing and Analysis 13 (2021) 11-12 (November-December), p. 1929-1935
• Special Issue: The 39th Manfred Donike workshop on doping analysis
• PMID: 34378342
• DOI: 10.1002/dta.3141

Abstract

Biotin interference in streptavidin/biotin-based immunoassays has been recently recognized as a confounding factor in clinical settings. Depending on the nature of the assay, the presence of excess biotin in patient samples can cause falsely high or low results. One of the platforms known to be affected, Roche Cobas, is widely used in anti-doping laboratories to test for intact chorionic gonadotropin (hCG) in urine. While biotin levels in blood have been well studied, less is known about urinary biotin due to its limited clinical significance. Having analyzed over 4,000 urine samples, we have established a reference range for urinary biotin with a median concentration of approximately 12 ng/ml. However, a significant number of samples contain much higher amounts, with a maximum approaching 10 μg/ml, suggesting biotin supplementation. Consequently, the tolerance of hCG STAT assay towards biotin was investigated over a wide concentration range. The apparent hCG concentration was found to decrease almost linearly as biotin increased from 100 to 1,000 ng/ml, with only 10% of the expected value reported by the assay as biotin reached 1,000 ng/ml. Further increase of biotin resulted in a progressive, albeit more moderate, decline in measured hCG concentration. To avoid a false negative result in the context of anti-doping analysis, it is highly recommended to monitor biotin in urine and perform diafiltration before hCG measurement in samples with elevated biotin to remove the interference.

Mass spectrometric characterization of urinary hydrafinil metabolites for routine doping control purposes / Andre Knoop, Gregor Fußhöller, Nadine Haenelt, Christian Goergens, Sven Guddat, Hans Geyer, Mario Thevis. - (Drug Testing and Analysis (2021) 10 August; 3137)

• PMID: 34378339
• DOI: 10.1002/dta.3137

Abstract

Little information on the human metabolism and urinary elimination of hydrafinil (9-fluorenol) exists. In order to support preventive anti-doping activities concerning compounds such as hydrafinil, a pilot elimination study was conducted with three healthy male volunteers receiving a single oral dose of 50 mg of hydrafinil. Urine samples were collected prior to and up to 72-h post-administration and were subjected to both gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry, which allowed for the identification of the intact drug as well as Phase I and Phase II metabolites, primarily hydroxylated and/or glucuronidated or sulfo-conjugated hydrafinil. The identity of these metabolites was corroborated by high-resolution/high-accuracy tandem mass spectrometry, and the applicability of routine doping control workflows for the detection of hydrafinil and its main metabolites was assessed. Therefore, two findings of hydrafinil and its metabolites were recorded, which concerned out-of-competition doping control samples and, hence, were not pursued with confirmatory analyses. Yet, the initial testing procedure results indicate that hydrafinil might require consideration in sports drug testing programs to ensure its detection, if classified as prohibited by the World Anti-Doping Agency (WADA).

Meldonium residues in milk : A possible scenario for inadvertent doping in sports? / Sven Guddat, Christian Görgens, Tim Sobolevsky, Mario Thevis. - (Drug Testing and Analysis (2021) 26 August)

• PMID: 34448364
• DOI: 10.1002/dta.3145

Abstract

Lately, the veterinary drug Emidonol® has been discussed as a possible scenario for inadvertent doping in sports. Emidonol® is approved for use in livestock breeding, exhibiting antihypoxic and weak sedative effects. The veterinary drug rapidly dissociates into meldonium, a substance prohibited in sports, and is excreted largely in its unchanged form into urine. To investigate if residues of meldonium in edible produce may result in adverse analytical findings in sports drug testing, a pilot study was conducted with three volunteers consuming a single dose of 100 ml meldonium-spiked milk at a concentration of 500 ng/ml (Study 1), and multiple doses of 100 ml of meldonium-spiked milk (500 ng/ml) on five consecutive days (Study 2). In the single dose study, urinary meldonium concentrations peaked between 2 and 6 h post-administration with maximum values of 7.5 ng/ml, whereas maximum meldonium concentrations of 18.6 ng/ml were determined after multiple doses 4 h post-administration. All samples were analyzed using an established and validated protocol based on HILIC-HRMS/MS.

A fast screening method for the detection of CERA in dried blood spots / Angela Rocca, Laurent Martin, Tiia Kuuranne, Magnus Ericsson, Alexandre Marchand, Nicolas Leuenberger. - (Drug Testing and Analysis (2021) 11 August); p. 1-6)

• PMID: 34380180
• DOI: 10.1002/dta.3142

Abstract

Continuous erythropoietin receptor activator (CERA) is a third-generation erythropoiesis-stimulating agent that was developed for the treatment of anemia. However, misuse of CERA for doping in endurance sports has been reported. Previous studies have shown blood as the matrix of choice for the detection of CERA, due to its high molecular weight. The use of dried blood spots (DBSs) for anti-doping purposes constitutes a complementary approach to the standard urine and venous blood matrices and could facilitate sample collection and increase the number of blood samples available for analysis due to reduced costs of sample collection and transport. Here, we investigated whether CERA could be indirectly detected in extracts of single DBSs using an erythropoietin-specific immunoassay that is capable of providing results within approximately 2 h. Reconstituted DBS samples were prepared from mixtures of red blood cell pellets and serum samples. The samples were collected in a previous clinical study in which six healthy volunteers were injected with a single, 200 μg dose of CERA. Using a commercially available ELISA kit, CERA was detected in the DBSs with a detection window of up to 20 days post-injection. Furthermore, in order to demonstrate the fitness-for-purpose, three authentic doping control serum samples, which were identified as containing CERA, were analyzed by the presented methodological approach on DBS. The testing procedure described here could be used as a fast and cost-effective method for the detection of CERA abuse in sport.

In March 2021 World Rugby has reported an anti-doping rule violation against the Russian rugby player Stanislav Selskii after his sample tested positive for the prohibited substance Clomifene.

After notification the Athlete gave a prompt admission, waived his right for a hearing, accepted a provisional suspension and the sanction proposed by World Rugby.

Because of the Athlete's early admission and acceptance of sanction World Rugby decides on 11 August 2021 to impose a reduced 3 year period of ineligibility on the Athlete, starting on the date of the provisional suspension, i.e. on 26 March 2021.

In May 2021 World Rugby has reported an anti-doping rule violation against the Colombian rugby player Juan David Herrera after his sample tested positive for the prohibited substances 19-norandrosterone (Nandrolone) and Boldenone.

After notification the Athlete gave a prompt admission, waived his right for a hearing, accepted a provisional suspension and the sanction proposed by World Rugby.

Because of the Athlete's early admission and acceptance of sanction World Rugby decides on 11 August 2021 to impose a reduced 3 year period of ineligibility on the Athlete, starting on the date of the provisional suspension, i.e. on 20 May 2021.

Influence of synthetic isoflavones on selected urinary steroid biomarkers : Relevance to doping control / Michele Iannone, Francesca Alberti, Maria Cristina Braganò, Xavier de la Torre, Francesco Molaioni, Francesco Botrè. - (Steroids 174 (2021) October; 108900)

• PMID: 34391799
• DOI: 10.1016/j.steroids.2021.108900

Abstract

In this work we have investigated the influence of the intake of two synthetic isoflavones, methoxyisoflavone and ipriflavone, on the urinary concentration of endogenous steroids, and on their relative ratios, of doping relevance. Specifically, the concentrations of testosterone (T), epitestosterone (E), androsterone (A), etiocholanolone (Etio), 5α-androstan-3α,17α-diol (5αAdiol), 5β-androstan-3α,17α-diol (5βAdiol), and the ratios T/E, A/T, A/Etio, 5αAdiol/5βAdiol, 5αAdiol/E, were considered, in the framework of the Steroidal Module of the Athlete Biological Passport (ABP). The above set of parameters were complemented by the urinary levels of luteinizing hormone (total LH) and the ratio between T and LH (T/total LH), to assess the possible effects on the biosynthesis of the mentioned steroids. Five healthy Caucasian male volunteers were selected for the study. Urine samples were collected before and during the administration of (i) methoxyisoflavone (Methoxyisoflavone, MyProtein) and (ii) ipriflavone (Osteofix ®, Chiesi Farmaceutici). For the analysis of the urinary steroid profile, after enzymatic hydrolysis with β-glucuronidase from Escherichia Coli (E. Coli) and liquid-liquid extraction with tert-buthylmethyl ether, all samples were analyzed by gas chromatography coupled to tandem mass spectrometry (GC-MS/MS), while for the determination of total LH all urine samples were directly analyzed by a chemiluminescent immunometric assay technique (Siemens Immulite 2000 LH). Our results show that the administration of either methoxyisoflavone or ipriflavone causes an alteration of the urinary concentrations and concentration ratios of the investigated steroids, in the range 55-80% from the baseline values. Furthermore, an oversecretion of LH after the daily intake of methoxyisoflavone or ipriflavone was also recorded in all volunteers, corresponding to an increase in the biosynthesis and excretion of T and some of its metabolites. These changes trigger a disregulation in the pattern of urinary excretion of the steroids included in the Steroidal Module of the ABP, which makes more difficult the interpretation of the longitudinal steroid profile based on the definition of individual normality ranges for each athlete. Our data are also consistent with previous evidence regarding the in vitro effects of natural and synthetic isoflavones, suggesting that their monitoring in doping control routine analysis would be very beneficial for the result management activities.

Related case:

TJD-AD 2021-023 Appeal Decision - Football
September 30, 201

In March 2021 the Brazilian Doping Control Authority (ABCD) reported an anti-doping rule violation against the football player after his A and B samples tested positive for the prohibited substances Hydrochlorothiazide and Sibutramine.

After notification a provisional suspension was ordered. The Athlete filed a statement in his defence and he was heard for the Brazilian Sports Justice Anti-Doping Tribunal (TJD-AD).

The Athlete denied the intentional use of the substances and he requested for a reduced sanction. He believed that the medical herbal supplement he had used - purchased on the internet - was the source of the prohibited substances.

Analysis of the open bottle of this supplement in question in the Rio Lab confirmed the presence of the prohibited substances, yet not in the sealed bottles of this product from the same batch that had been analysed.

The TJD-AD Rapporteur finds that the presence of  prohibited substances has been established in the Athlete's samples and accordingly that he committed an anti-doping rule violation. 

The Rapporteur considered the circumstances and the Athlete's conduct in this case in view of the setbacks in his personal life and deems that the violation was not intentional.

The Rapporteur establishes that the label of the product did not list the prohibited substances although the Athlete failed to demonstrate sufficiently that this product in question was the source of the substances.

Further the Rapporteur regards that the Athlete acted with some degree of negligence whereas he had received anti-doping education and had not mentioned the supplement on the Doping Control Form.

Therefore the TJD-AD decides on 16 August 2021 to impose an 8 month period of ineligibility on the Athlete, starting on the date of the provisional suspension, i.e. on 9 March 2021.

Pitch-side Acute Severe Pain Management Decisions in European Elite football / Maeve Claire Doheny, Gerard Bury. - (International Journal of Sports Medicine (2021) 9 (16 August))

• PMID: 34399429
• DOI: 10.1055/a-1588-7931

Abstract

This is the first study on acute severe pain management involving sport and exercise medicine Doctors who are leaders in football medicine in their respective countries. An online survey was designed describing the management of acute severe pain in this expert cohort. The survey captured participant sex, age, years working in sports medicine, core specialty and use of clinical practice guidelines (CPGs). Finally, three clinical vignettes exploring the management of acute pain were presented. Forty-four senior team doctors across 55 European countries completed the survey. There were no consistent guidelines proposed, with 33 (75%) participants indicating they did not use any. Methoxyflurane was proposed by 14 (32%) and 13 (30%) participants for female anterior cruciate ligament rupture and male ankle fracture, respectively. Strong opioids were not used in 17 (39%) and 6 (14%) participants regarding female cruciate injuries and male fractures, respectively. Despite 75% of participants having paediatric life support training, eight (18%) participants expressed uncertainty administering medications in this population, and 15 (34%) would avoid using strong opioids altogether. There is a tendency to undertreat pain and avoid strong opioids for reasons including lack of monitoring equipment, anti-doping concerns and lack of comfort treating paediatric patients with opioids.