The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men

28 Mar 2012

The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men / Shehzad Basaria, Lauren Collins, E. Lichar Dillon, Katie Orwoll, Thomas W. Storer, Renee Miciek, Jagadish Ulloor, Anqi Zhang, Richard Eder, Heather Zientek, Gilad Gordon, Syed Kazmi, Melinda Sheffield-Moore, Shalender Bhasin. - (The Journals of Gerontology: Series A 68 (2013) 1 (January); p. 87–95)

  • PMID: 22459616
  • PMCID: PMC4111291
  • DOI: 10.1093/gerona/gls078

Abstract

Background: Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones.

Methods: In this placebo-controlled study, 76 healthy men (21-50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention.

Results: LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone-binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation.

Conclusions: LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function and health outcomes in select populations.

Dietary Supplement and Food Contaminations and Their Implications for Doping Controls

27 Jul 2020

Dietary Supplement and Food Contaminations and Their Implications for Doping Controls / Katja Walpurgis, Andreas Thomas, Hans Geyer, Ute Mareck, Mario Thevis. - (Foods 9 (2020) 8 (27 July); p. 1-21)

  • PMID: 32727139
  • DOI: 10.3390/foods9081012

Abstract

A narrative review with an overall aim of indicating the current state of knowledge and the relevance concerning food and supplement contamination and/or adulteration with doping agents and the respective implications for sports drug testing is presented. The identification of a doping agent (or its metabolite) in sports drug testing samples constitutes a violation of the anti-doping rules defined by the World Anti-Doping Agency. Reasons for such Adverse Analytical Findings (AAFs) include the intentional misuse of performance-enhancing/banned drugs; however, also the scenario of inadvertent administrations of doping agents was proven in the past, caused by, amongst others, the ingestion of contaminated dietary supplements, drugs, or food. Even though controversial positions concerning the effectiveness of dietary supplements in healthy subjects exist, they are frequently used by athletes, anticipating positive effects on health, recovery, and performance. However, most supplement users are unaware of the fact that the administration of such products can be associated with unforeseeable health risks and AAFs in sports. In particular anabolic androgenic steroids (AAS) and stimulants have been frequently found as undeclared ingredients of dietary supplements, either as a result of cross-contaminations due to substandard manufacturing practices and missing quality controls or an intentional admixture to increase the effectiveness of the preparations. Cross-contaminations were also found to affect therapeutic drug preparations. While the sensitivity of assays employed to test pharmaceuticals for impurities is in accordance with good manufacturing practice guidelines allowing to exclude any physiological effects, minute trace amounts of contaminating compounds can still result in positive doping tests. In addition, food was found to be a potential source of unintentional doping, the most prominent example being meat tainted with the anabolic agent clenbuterol. The athletes' compliance with anti-doping rules is frequently tested by routine doping controls. Different measures including offers of topical information and education of the athletes as well as the maintenance of databases summarizing low- or high-risk supplements are important cornerstones in preventing unintentional anti-doping rule violations. Further, the collection of additional analytical data has been shown to allow for supporting result management processes.

Identification of S22 (ostarine) in human nails and hair using LC-HRMS. Application to two authentic cases

20 Jul 2020

Identification of S22 (ostarine) in human nails and hair using LC-HRMS : Application to two authentic cases / Pascal Kintz, Laurie Gheddar, Alice Ameline, Jean-Sébastien Raul. - (Drug Testing and Analysis (2020) 20 July)

  • PMID: 32688441
  • DOI: 10.1002/dta.2902

Abstract

Ostarine, also known as S22 or MK2866 and enobosarm, is a selective androgen receptor modulator (SARM). It has high anabolic potency, in addition to limited androgenic effects. At this time, ostarine has no therapeutic use, but can be abused for performance-enhancing purposes using the oral route, at dosages of 10-25 mg per day. As the drug can easily be obtained via the Internet or some fitness centers, athletes and more and more amateurs can use it without undergoing the deleterious physiological side effects that are generally associated with testosterone-related compounds. Since 2008, the World Anti-Doping Agency (WADA) has prohibited SARMs at-all-times in the category of "other anabolic agents" under section S1.2 of the WADA List. In a case of trafficking/abuse, ostarine was identified in nail (subject 1) and hair (subject 2) by LC/HRMS after incubation of 50 mg of matrix in a pH 9.5 buffer, followed by extraction with organic solvents. The drug was quantitated by LC-MS/MS. Ostarine tested positive at 61 pg/mg (toenails) and 111 pg/mg (fingernails) for subject 1. Ostarine was present at 146, 168, 93, and 101 pg/mg in the 4 × 3 cm hair sections of subject 2, clearly demonstrating long-term use.

Systematic Review: Nonmedical Use of Prescription Stimulants: Risk Factors, Outcomes, and Risk Reduction Strategies

18 Jul 2019

Systematic Review : Nonmedical Use of Prescription Stimulants: Risk Factors, Outcomes, and Risk Reduction Strategies / Stephen V. Faraone, Anthony L. Rostain, C. Brendan Montano, Oren Mason, Kevin M. Antshel, Jeffrey H. Newcorn. - (Journal of the American Academy Child & Adolescent Psychiatry 59 (2020) 1 (January); p. 100-112)

  • PMID: 31326580
  • DOI: 10.1016/j.jaac.2019.06.012


Abstract

Objective: To review all literature on the nonmedical use (NMU) and diversion of prescription stimulants to better understand the characteristics, risk factors, and outcomes of NMU and to review risk-reduction strategies.
Method: We systematically searched PubMed, PsycINFO, and SCOPUS from inception to May 2018 for studies containing empirical data about NMU and diversion of prescription stimulants. Additional references identified by the authors were also assessed for inclusion.
Results: A total of 111 studies met inclusion criteria. NMU and diversion of stimulants are highly prevalent; self-reported rates among population samples range from 2.1% to 58.7% and from 0.7% to 80.0%, respectively. A variety of terms are used to describe NMU, and most studies have examined college students. Although most NMU is oral, non-oral NMU also occurs. The majority of NMU is associated with no, or minor, medical effects; however, adverse medical outcomes, including death, occur in some individuals, particularly when administered by non-oral routes. Although academic and occupational performance enhancement are the most commonly cited motivations, there is little evidence that academic performance is improved by NMU in individuals without attention-deficit/hyperactivity disorder.
Conclusion: NMU of stimulants is a significant public health problem, especially in college students, but variations in the terms used to describe NMU and inconsistencies in the available data limit a better understanding of this problem. Further research is needed to develop methods to detect NMU, identify individuals at greatest risk, study routes of administration, and devise educational and other interventions to help reduce occurrence of NMU. Colleges should consider including NMU in academic integrity policies.

Doping in sport: Lance Armstrong, a case study

1 Sep 2014

Doping in sport : Lance Armstrong, a case study / Iain Adams, Josh Carine, David Emmerson. - (Chapter 22, pp. 169-190)

Published in:

The sports monograph: critical perspectives on socio-cultural sport, coaching and Physical Education. SSTO Publications, Preston, 2014. - 392 p.

978-0-9566270-6-3


Contents:

Introduction
Values and ethics of sport and doping
Lance Armstrong - the doping saga
The evidence
Beyond the bike
Conclusion

Anabolic steroids detected in bodybuilding dietary supplements - a significant risk to public health

7 Jul 2015

Anabolic steroids detected in bodybuilding dietary supplements - a significant risk to public health / V. Abbate, A.T. Kicman, M. Evans-Brown, J. McVeigh, D.A. Cowan, C. Wilson, S.J. Coles, C.J. Walker. - (Drug Testing and Analysis 7 (2015) 7 (7 July); p. 609-618)

  • PMID: 25284752
  • DOI: 10.1002/dta.1728

Abstract

Twenty-four products suspected of containing anabolic steroids and sold in fitness equipment shops in the United Kingdom (UK) were analyzed for their qualitative and semi-quantitative content using full scan gas chromatography-mass spectrometry (GC-MS), accurate mass liquid chromatography-mass spectrometry (LC-MS), high pressure liquid chromatography with diode array detection (HPLC-DAD), UV-Vis, and nuclear magnetic resonance (NMR) spectroscopy. In addition, X-ray crystallography enabled the identification of one of the compounds, where reference standard was not available. Of the 24 products tested, 23 contained steroids including known anabolic agents; 16 of these contained steroids that were different to those indicated on the packaging and one product contained no steroid at all. Overall, 13 different steroids were identified; 12 of these are controlled in the UK under the Misuse of Drugs Act 1971. Several of the products contained steroids that may be considered to have considerable pharmacological activity, based on their chemical structures and the amounts present. This could unwittingly expose users to a significant risk to their health, which is of particular concern for naïve users.

UFC 2019 Gilbert Melendez vs USADA

7 Jul 2020

The American MMA Athlete Gilbert Melendez was tested on 16 October 2019 but previously in late September or early October 2019 the UFC had decided to terminate the contracts of several athletes, including the contract of Gilbert Melendez.

Hereafter UFC failed to notify the United States Anti-Doping Agency (USADA) that the Athlete should be removed from the UFC Registered Testing Pool (UFC RTP). The Athlete was also not notified that the UFC had terminated his contract. The Athlete believed that he was in the UFC RTP on 16 October 2019 when he agreed to provided a sample to USADA. 

In November 2019 USADA reported an anti-doping rule violation against the Athlete after his sample tested positive for the prohibited substance GHRP-6. After notification a provisional suspension was ordered. The Athlete filed a statement in his defence and he was heard for the UFC Arbitration Panel. 

The Athlete did not challenge the test result but argued that the UFC, and consequently USADA, had no jurisdiction because at the time of the sample collection in October 2019 he was not subjected anymore to the UFC ADP as a result of the termination of his contract. 

USADA contended it had jurisdiction to collect the Athlete’s sample on 16 October 2019 because the Athlete’s contract as a fighter with the UFC was in effect, he was a member of the UFC RTP on this date, and neither he nor USADA was notified that the UFC terminated his contract before his sample was collected. 

Considering the evidence in this matter the Arbitrator establish that the UFC did not notify USADA until 5 December 2019 that the Athlete should be removed from the UFC RTP because it had terminated his contract. After this USADA removed the Athlete from the UFC RTP on 6 December 2019. 

The Arbitrator deems in his decision rendered of 1 May 2020 that USADA has proven by clear and convincing evidence that the Athlete was still under contract with the UFC on 16 October 2019, which is supported by his compliance with his obligations under the UFC ADP. The Arbitrator concludes that USADA retains jurisdiction under the UFC ADR to complete results management process regarding the Athlete’s anti-doping rule violation, although he ceased to be under contract with the UFC thereafter. 

Furthermore the Arbitrator finds that the presence of a prohibited substance has been established in the Athlete’s sample and accordingly that he committed an anti-doping rule violation. The test result was undisputed by the Athlete and he failed to produce any evidence or to even deny that his positive test was caused by something other than his voluntary usage of a product containg it. 

Therefore the UFC Arbitration Panel decides on 7 July 2020 to impose a 2 year period of ineligibility on the Athlete starting on the date of the provisional suspension, i.e. on 1 November 2019.

UFC 2016 Josh Barnett vs USADA

23 Mar 2018

In December 2016 the United States Anti-Doping Agency (USADA) has reported an anti-doping rule violation against the American MMA Athlete Josh Barnett after his sample tested positive for the prohibited substance Ostarine.

The Athlete fully cooperated with the investigation, filed a statement with evidence in his defence and he was heard for the UFC Arbitration Panel. 

Previously in June 2009 the California State Athletic Commission (CSAC) had denied the Athlete’s application for a license after he tested positive for the prohibited substance Drostanolone. He made a new application in 2012 which was granted by the CSAC. During their investigations USADA discovered the 2009 CSAC positive test report and considered this a first violation. 

Analysis of the Athlete’s dietary supplements revealed that a batch of Tributestin was contaminated with Ostarine. Further USADA was ultimately able to trace the Ostarine to contamination also found in sealed packages of Tributestin that it had procured independently. As a result USADA accepted that the Athlete was the victim of a Contaminated Product which contained a Prohibited Substance. 

The Athlete accepted the test result of his sample of 9 December 2016 but challenged USADA’s finding that the 2009 CSA Sample meets all of the necessary criteria to be counted as a first violation under the UFC ADP. The Athlete asserted that the CSAC acquisition of the sample was unusual and irregular under the UFC ADP. It could not be really considered an out-of-competition test contrary to the current UFC ADP. Because of these shortcomings encountered in 2009 the Athlete started a very elaborate scheme for dealing with his supplement regime. 

The Arbitrator agrees that the 2009 CSAC’s sample collection was invalid under the UFC ADR and the process before the CSAC was unfair. Because of these irregularities of the collection and analytical processes of the CSAC the Arbitrator deems that the 2009 CSAC Sample can’t be considered a first violation under the UFC ADP. 

The Arbitrator regards that the Athlete had adopted a practice of keeping each original container of any supplement he used and ensuring that a small portion of its content remained and could be analyzed due to his belief that the 2009 CSAC positive sample was the result of contamination. The Arbitrator finds that the Athlete acted very meticulous and careful in recording his supplement regime and due to this supplement regime the Athlete could establish the source of the positive test result.

The Arbitrator deems that the Athlete’s degree of fault to be at the low end of the scale, justifying a minimal sanction. Therefore the UFC Arbitration Panel decides on 23 March 2018 to impose only a reprimand and no period of ineligibility on the Athlete.

UFC 2017 Jon Jones vs USADA

13 Sep 2018

Related case:

UFC 2016 Jon Jones vs USADA
November 6, 2016

In August 2017 the United States Anti-Doping Agency (USADA) has reported second anti-doping rule violation against the American MMA Athlete Jon Jones after he tested positive for the prohibited M3 metabolite in an extremely low concentration.

Previously the Athlete had served a 1 year period of ineligibility until 5 July 2017 related to the use of a contaminated product.

After notification a provisional suspension was ordered. The Athlete's competitive results of a bout were disqualified, the California State Athletic Commission (CSAC) revoked his license and fined him in February 2018.

USADA requested the Panel to impose a reducted sanction on the Athlete for his second violation due the substantial assistance he provided in this case.

The Athlete could not explain how the substance had entered his system and explained that after the first violation he took a number of steps to avoid consuming any supplement that could be contaminated with a prohibited substance. He identified 14 supplements he had used but no prohibited substance was listed on the labels of these product and  analysis revealed no prohibited substances.

The Arbitrator concludes that the violation was not intentional nor could the found substance have enhanced the Athlete's performance. The Arbitrator establish that the Athlete bears some degree of fault and that there are ground for a reduced sanction.

Therefore the UFC Arbitration Panel decides on 13 September 2018 to impose a 15 month period of ineligibility on the Athlete starting on the date of the sample collection, i.e. on 28 July 2017.

UFC 2016 Jon Jones vs USADA

6 Nov 2016

Related case:

UFC 2017 Jon Jones vs USAD
September 13, 2018

In July 2016 the United States Anti-Doping Agency (USADA) has reported an anti-doping rule violation against the American MMA Athlete Jon Jones after his A and B samples tested positive for the prohibited substances Clomifene and Letrozole. After notification a provisional suspension was ordered. The Athlete filed a statement in his defence and he was heard for the UFC Arbitration Panel.

The Athlete accepted the test resultts and denied the intentional use as a result of a contamined product. Analysis in the Salt Lake City Lab of the supplement Tadalafil he had used confirmed that it was contaminated with the prohibited substances.

USADA contended that there were errors, omissions and inconsistencies in the Athlete's testomony regarding the purchase and use of the supplement in question. Further he failed to mention the use of the product on the Doping Control Form.

Considering the evidence in this case the Panel finds that the Athlete managed to establish how the subtances entered his system. The Panel concludes that the Athlete is not a drugs cheat and was unaware that the tablet he took contained prohibited substances. However the Panel finds that the Athlete acted with a high degree of fault since he failed to check the product before using.

Therefore the UFC Arbitration Panel decides on 6 November 2016 to impose a 1 year period of ineligibility on the Athlete starting on the date of the provisional suspension, i.e. on 6 July 2016 until 5 July 2017.

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