Physiology and pharmacology of erythropoietin / Wolfgang Jelkmann. - (Transfusion Medicine and Hemotherapy 40 (2013) 5 (October); p. 302-309)

• PMID: 24273483
• PMCID: PMC3822280
• DOI: 10.1159/000356193

Abstract

Human erythropoietin (Epo) is a 30.4 kDa glycoprotein hormone composed of a single 165 amino acid residues chain to which four glycans are attached. The kidneys are the primary sources of Epo, its synthesis is controlled by hypoxia-inducible transcription factors (HIFs). Epo is an essential factor for the viability and proliferation of erythrocytic progenitors. Whether Epo exerts cytoprotection outside the bone marrow still needs to be clarified. Epo deficiency is the primary cause of the anemia in chronic kidney disease (CKD). Treatment with recombinant human Epo (rhEpo, epoetin) can be beneficial not only in CKD but also for other indications, primarily anemia in cancer patients receiving chemotherapy. Considering unwanted events, the administration of rhEpo or its analogs may increase the incidence of thromboembolism. The expiry of the patents for the original epoetins has initiated the production of similar biological medicinal products ('biosimilars'). Furthermore, analogs (darbepoetin alfa, methoxy PEG-epoetin beta) with prolonged survival in circulation have been developed ('biobetter'). New erythropoiesis-stimulating agents are in clinical trials. These include compounds that augment erythropoiesis directly (e.g. Epo mimetic peptides or activin A binding protein) and chemicals that act indirectly by stimulating endogenous Epo synthesis (HIF stabilizers).

Phytosterol consumption and the anabolic steroid boldenone in humans: a hypothesis piloted / M.M. Ros, S.S. Sterk, H. Verhagen, A.F.H. Stalenhoef, N. de Jong. - (Food Additives & Contaminants 24 (2007) 7 (July); p. 679-684)

• PMID: 17613052
• DOI: 10.1080/02652030701216727

Abstract

The presence of the anabolic steroid boldenone in animals has become a research topic as its occurrence is proposed to be a marker for illegal hormone administration. However, boldenone can also be formed from beta-sitosterol, a phytosterol present in animal feed, as well as from endogenous sources. The observations in animals together with the increased consumption of phytosterol-enriched foods in the Western population led the authors to the hypothesis that consumption of phytosterol-enriched foods might possibly lead to increased boldenone levels in humans. The authors performed a pilot study among female volunteers (n = 10) to investigate whether boldenone concentrations in urine were detectable after consumption of 25 g day(-1) of phytosterol-enriched margarines for 1 week. Urine samples were collected at days 0, 3 or 4, and 7. Urine of a sitosterolemia (a rare autosomal recessively inherited lipid metabolic disorder) patient was collected as a positive control case. No traces of boldenone were detected in either the volunteers or in the patient. In conclusion, there is no evidence of formation of boldenone in women after consumption of the recommended amount of phytosterol-enriched margarines.

Phytosterols and anabolic agents versus designer drugs / H.F. De Brabander, K. Verheyden, V. Mortier, B. Le Bizec, W. Verbeke, D. Courtheyn, H. Noppe. - (Analytica Chimica Acta 586 (2007) 1-2 (14 March); p. 49-56)

• PMID: 17386696
• DOI: 10.1016/j.aca.2006.07.031

Abstract

Cholesterol is a well-known component in fats of animal origin and it also is the precursor of natural hormones. Phytosterols appear in plants and only differ slightly in structure from cholesterol. An important difference however is the low absorption in the gut of phytosterols and their saturated derivatives, the phytostanols. As a result, there is time for all kind of reactions in faecal material inside and outside of the gut. Determination of the abuse of natural hormones may be based on gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). Abuse of natural hormones changes the 13C/12C ratio of some metabolites during a relatively long time. The formation of (natural) hormones in the gut may interfere with this method. Designer drugs are mainly known from sports doping. In animal fattening, designer drugs may be used as well. Small changes in the structure of (natural) hormones may lead to a new group of substances asking for new strategies for their detection and the constatation of their abuse.

Pilot study on the effects of intravesical oxybutynin hydrochloride instillations on the validity of doping control urine samples / Katja Walpurgis, Anja B. Scheiff, Meike Welz, Jutta Müller‐Reul, Nick Webborn, Christian Görgens, Sven Guddat, Gregor Fußhöller, Josef Dib, Mario Thevis. - (Drug Testing and Analysis (2019) 30 October 2019).
- PMID: 31670462.
- DOI: 10.1002/dta.2705

Abstract

According to class M2.1 of the World Anti‐Doping Agency's (WADA's) Prohibited List, the manipulation of doping control urine samples to alter their integrity and validity is prohibited both in‐ and out‐of‐competition. However, some paraplegic athletes with an overactive bladder need to be regularly treated with anti‐cholinergic and anti‐spasmodic drugs such as oxybutynin, which are often administered intravesically to reduce the substantial side effects observed after oral application. So far, it remains unclear whether such bladder instillations have a negative impact on analytical procedures and thus represent an anti‐doping rule violation.

Within this pilot study, urine samples were collected from five paraplegic athletes before and after an intravesical oxybutynin hydrochloride instillation. The samples were routinely tested for the presence of performance‐enhancing drugs and afterwards fortified with 25 model compounds representing different classes of doping agents (anabolic agents, cannabinoids, diuretics, glucocorticoids, hormone and metabolic modulators, and stimulants) at low and medium concentrations. Additionally, the pH‐value and specific gravity were measured and the presence of oxybutynin was qualitatively determined by GC‐MS.

In initial testing procedures, all samples were tested negative. Oxybutynin was present in most of the samples but found to have no significant effect on the detectability of the 25 model compounds subsequently added to each urine specimen. Therefore, it can be concluded that intravesical instillations with oxybutynin hydrochloride do not alter the integrity and validity of doping control urine samples.

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.

Plasma and urinary markers of oral testosterone undecanoate misuse / Shi Hua Peng, Jordi Segura, Magí Farré, Jose Carlos González, Xavier de la Torre. - (Steroids 67 (2002) 1 (January); p. 39-50)

• PMID: 11728520
• DOI: 10.1016/s0039-128x(01)00128-3

Abstract

Orally administered testosterone undecanoate (TU), an anabolic, androgenic steroid, can potentially be abused by athletes. Indirect evidence for detecting oral TU intake could be deduced from the changes in steroid profile post-administration. Direct evidence could be obtained by detection of unchanged TU in plasma. To this end, both urinary and plasma steroid profiles of six healthy male subjects given a single oral dose of 120 mg of TU were studied by gas chromatography/mass spectrometry (GC/MS) and gas chromatography/tandem mass spectrometry (GC/MS/MS). The increased concentration of glucuronidated testosterone in plasma appears to be the most characteristic sign of oral TU intake. The testosterone glucuronide (TG)/nonconjugated testosterone (T) ratio, TG/17-hydroxyprogesterone (17OHP) ratio, and TG/luteinizing hormone (LH) ratio were observed to be significantly elevated above their basal levels for 10 h, 10 h, and 6 h, respectively. Urinary ratios of TG/epitestosterone glucuronide (EG) were found to be higher than the cut-off value of 6 for the period 4 approximately 8 h post-administration, but only in three subjects. One subject failed to respond with respect to all of the above-mentioned indirect markers, as TG was not significantly increased in either plasma or urine. Unchanged TU was directly detected in plasma of all six subjects from 1 approximately 1.5 h to 4 approximately 6 h after oral TU intake by GC/MS/MS, providing unequivocal proof of exogenous testosterone intake. Distinct and complementary markers for detecting oral TU intake could be obtained from plasma and urine, respectively.

Monfort N, Ventura R, Platen P, Hinrichs T, Brixius K, Schänzer W, Thevis M, Geyer H, Segura J.Transfusion. 2012 Mar;52(3):647-57. doi: 10.1111/j.1537-2995.2011.03331.x. Epub 2011 Sep 2.
Bioanalysis Research Group, IMIM Hospital del Mar Research Institute, the Universitat Pompeu Fabra, Barcelona, Spain.

BACKGROUND:
Misuse of autologous blood transfusions in sports remains undetectable. The metabolites of the plasticizer di-(2-ethylhexyl)phthalate (DEHP) were recently proposed as markers of blood transfusion, based on high urinary concentrations of these compounds observed in patients subjected to blood transfusion. This study evaluates DEHP metabolites in urine for detecting autologous blood transfusion.

STUDY DESIGN AND METHODS:
One blood bag was drawn from moderately trained subjects and the red blood cells (RBCs) were reinfused after different storage periods. Group 1 (12 subjects) was reinfused after 14 days, and Group 2 (13 subjects), after 28 days of storage. Urine samples were collected before and after reinfusion for determination of the concentrations of three DEHP metabolites, mono-(2-ethylhexyl)phthalate, mono-(2-ethyl-5-hydroxyhexyl)phthalate, and mono-(2-ethyl-5-oxohexyl)phthalate.

RESULTS:
Concentrations of DEHP metabolites on the days before reinfusion were in agreement with those described after common environmental exposure. A few hours after the reinfusion a significant increase was observed for all metabolites in all volunteers. Concentrations 1 day later were still higher (p < 0.05) than before reinfusion. Variations in urine dilution supported normalization by specific gravity. Concentrations of DEHP metabolites tended to be higher after longer storage times of RBCs.

CONCLUSION:
Autologous transfusion with RBCs stored in plastic bags provokes an acute increase in the urinary concentrations of DEHP metabolites, allowing the detection of this doping malpractice. The window of detection is approximately 2 days. The method might be applied to urine samples submitted for antidoping testing.

Beleidsstandpunt inzake doping en sport / [samenstelling] W. Boersma .... [et al.]. - Oosterbeek : Nationaal Instituut voor de Sportgezondheidszorg (NISGZ), 1985

• Met lit. opg.
• ISBN 90-71001-05-9

Doping in sport tarnishes the sport in its broadest sense and should be fought on the base of ethical and medical aspects. In this fight however, human dignity should not be lost and a nuanced approach is needed, in which the doping control is never a goal in itself, but should be understood as a protection of the sport and its practitioners.
The most desirable structure of the doping control would be that the laboratory analysis reports concerning unambiguous identification and quantification are interpret by a body. This interpretation serves as a base for the sentence to be determined by a disciplinary body. The gravity of the penalty should be equal to the seriousness of the offense and the related social consequences for the athlete. The procedures and the rights and obligations of the parties involved in a doping control should be recorded in doping regulations. More clarity on the so-called "doping lists" is urgently needed. The aim for a single international doping list of resources that have performance-enhancing effects is required.
In addition, information is needed about the nature, effects and side effects of doping related products. In this area still further research needs to be done.
It is desirable to draw up a "statute" for supervisors and conduct for physicians relating to the provision or administration of (prescription) drugs. Sports organizations should give priority to the quality of support personal and provide information to the latter.
The government needs to make restrictions for the provision of doping substances and provide financial means for education, research and control.
Above central coordinating of the analysis, research and information supply and all further doping issues necessary for which a Netherlands Centre for Doping Affairs, with close ties to the NISGZ seems to be the designated body.
Discussing the above findings in a national and international context is desirable for more unity in activities.

On 28 June 2017 the Disciplinary Panel of the Polish Anti-Doping Agency (POLANDA) decided to impose a 2 year period of ineligibility on the judoka after his A and B samples tested positive for the prohibited substance Clomifene. 

In first instance and in the appeals filed hereafter the Athlete argued with assistance of an expert witness that the findings of the Panels were erroneous, his right of defence violated and that the International Standard of Laboratories (ISL) was incorrectly applied. 

The Athlete asserted that several irregularties had been established during the analysis of his A and B samples and that these departures of the ISL would invalidate these test results. Nevertheless the Poland Appeal Panel decided on 12 March 2018 to uphold the Appealed Decision of 28 June 2017. 

Again the Athlete appealed with the Court of Arbitration for Sport of the Polish Olympic Committee (PKOL). Yet after assessment of the Athlete’s assertions the Tribunal concluded that the Athlete failed to establish that there were any departures of the ISL that would invalidate the test results. Accordingly the PKOL Tribunal decided on 17 December 2018 to dismiss the Athlete’s appeal. 

Hereafter in February 2019 the Athlete filed a cassation appeal with the Supreme Court of of Poland against the Decision of the PKOL Court of Arbitration for Sport. However the Supreme Court deems on 9 October 2019 that the Athlete’s allegations are unfounded and that there are insufficient grounds to accept and handle the cassation appeal.

Polydrug use and drug market intersections within powerlifting cultures in remote South-West England / Luke A. Turnock. - (Performance Enhancement & Health (2021) 100186 (21 January)

• DOI: 10.1016/j.peh.2021.100186

Abstract

With the rising use of Image and Performance Enhancing Drugs (IPEDs), research has increasingly pointed to a need for in-depth understanding of users' consumption behaviours, in order to form effective harm reduction policy. With polydrug use prevalent in IPED-using cultures, both among ‘hardcore’ and non-competitive trainers, it is clear there is a need to understand this use, and its socio-cultural contexts, as well as how drug access and supply occurs within these cultures.

This paper offers an exploration of the motivations and contexts of hardcore powerlifters' polydrug use, as well as their experiences of IPED and other illicit drug market intersections, through findings drawn from 18 qualitative interviews with participants involved in these lifting cultures and gyms in South-West England, supported by ethnographic fieldwork conducted in nine gyms in the region over a four year period, including five ‘hardcore’ powerlifting and bodybuilding gyms, as well as four commercial gym establishments.

Results first demonstrate how cultural narratives around what is drug ‘use’ versus ‘abuse’ influenced powerlifters' consumption and perceptions of polydrugs, with a number of illicit drugs and other medicines used by these sportsmen, despite cultural opposition to other drug consumption considered to be harmful, and associated by powerlifters with ‘gym rats’, or YOLO type trainers. This leads into exploration of where powerlifters' polydrug consumption behaviours present the greatest risk, particularly in relation to the acceptance of benzodiazepine use as a form of ‘steroid accessory drug’ for long periods, as well as the common sharing and use of opioid painkillers to allow continued training through injury, and discussion of where harm reduction policy might therefore be most appropriately targeted for this population.

Findings then turn to an exploration of how polydrug supply occurs within powerlifting culture and gyms, and the intersections between IPED markets and other illicit drug markets perceived to exist in the region. This documents the prevalence of social supply norms of polydrugs following patterns observed for IPEDs in the existing literature, before discussing the extent to which individuals with links to criminal organisations may be ‘pushing out’ culturally-embedded IPED suppliers in the region, and the impacts this is having on risk for IPED buyers. This is followed by further discussion of relevance to policy, and avenues for future research into polydrug use and supply from a harm reduction perspective, as well as the limitations of this study as specific to a remote region of the UK.