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.

The Salmeterol Anomaly and the Need for a Urine Threshold / Glenn A. Jacobson, Morten Hostrup. - (Drug Testing and Analysis (2020) 20 April).
- PMID: 32314556.
- DOI: 10.1002/dta.2810

Abstract

Salmeterol is a long acting beta2‐agonist (LABA) widely used for treatment of airways disease. There is evidence that beta2‐agonists, including salmeterol, have the potential for performance enhancing effects when delivered at supratherapeutic doses. For this reason, all beta2‐agonists are currently on the Prohibited List issued by the World Anti‐Doping Agency (WADA) regardless of dosing route with some exemptions for inhaled salbutamol, formoterol, and salmeterol when used at therapeutic inhaled doses. For 2020, salmeterol use is permitted up to a therapeutic dosing threshold of 200 μg daily, but unlike salbutamol and formoterol, there is an anomaly; currently there is no urine threshold to control for supratherapeutic dosing beyond this dosing threshold. Salmeterol, however, is reportable as an Adverse Analytical Finding (AAF) at levels above 10 ng/ml. Complicating matters is that following inhalation, salmeterol parent drug is present at relatively low levels compared to other beta2‐agonists due to rapid metabolism to the metabolite, alpha‐hydroxysalmeterol, which is typically present at higher levels than parent drug. Moreover, peak parent drug levels following permitted therapeutic dosing are below the minimum required performance level (MRPL) of 10 ng/ml for salmeterol (50% of the MRPL that analytical laboratories are required to meet for non‐threshold beta2‐agonists), hence the presence of salmeterol may be unreported. For consistency, a urine threshold should be introduced for salmeterol as matter of priority, to balance the needs of athletes that use salmeterol therapeutically up to the agreed dosing threshold, with the need to control supratherapeutic dosing for doping intentions and athlete harm minimisation.

The science of doping : commentary / Donald A. Berry. – (Nature (2008) 454 (7 August) : p. 692-693) doi:10.1038/454692a

Recently, the international Court of Arbitration for Sport upheld doping charges against cyclist Floyd Landis, stripping him of his title as winner of the 2006 Tour de France and suspending him from competition for two years. The court agreed with the majority opinion of a divided three-member American Arbitration Association (AAA) panel and essentially placed a stamp of approval on a laboratory test indicating that Landis had taken synthetic testosterone. Although Landis asserts his innocence, his options for recourse have all but dried up.
In my opinion, close scrutiny of quantitative evidence used in Landis’s case show it to be non-informative. This says nothing about Landis’s guilt or innocence. It rather reveals that the evidence and inferential procedures used to judge guilt in such cases don’t address the question correctly. The situation in drugtesting labs worldwide must be remedied. Cheaters evade detection, innocents are falsely accused and sport is ultimately suffering.

Related article:
Doping: a paradigm shift has taken place in testing
Doping: probability that testing doesn’t tell us anything new
Doping: ignorance of basic statistics is all too common
/ Pierre-Edouard Sottas, Christophe Saudan, Marial Saugy; Geoffrey Baird; Matthew Fero. – (Nature (2008) 455 (11 September) : p. 166)

J Cachexia Sarcopenia Muscle. 2011 September; 2(3): 153–161.
Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, Morton RA, Steiner MS.

BACKGROUND:

Cachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation.

METHODS:
A 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men (>60 years of age) and postmenopausal women. The primary endpoint was total lean body mass assessed by dual energy X-ray absorptiometry, and secondary endpoints included physical function, body weight, insulin resistance, and safety.

RESULTS:
GTx-024 treatment resulted in dose-dependent increases in total lean body mass that were statistically significant (P < 0.001, 3 mg vs. placebo) and clinically meaningful. There were also significant improvements in physical function (P = 0.013, 3 mg vs. placebo) and insulin resistance (P = 0.013, 3 mg vs. placebo). The incidence of adverse events was similar between treatment groups.

CONCLUSION:
GTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated. GTx-024 may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.

The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women : results of a double-blind, placebo-controlled phase II trial / James T. Dalton, Kester G. Barnette, Casey E. Bohl, Michael L. Hancock, Domingo Rodriguez, Shontelle T. Dodson, Ronald A. Morton, Mitchell S. Steiner. - (Journal of Cachexia, Sarcopenia and Muscle 2 (2011) 3 (September), p. 153-161)

• PMID: 22031847
• PMCID: PMC3177038
• DOI: 10.1007/s13539-011-0034-6

Abstract

BACKGROUND: Cachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation. METHODS: A 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men (>60 years of age) and postmenopausal women. The primary endpoint was total lean body mass assessed by dual energy X-ray absorptiometry, and secondary endpoints included physical function, body weight, insulin resistance, and safety. RESULTS: GTx-024 treatment resulted in dose-dependent increases in total lean body mass that were statistically significant (P < 0.001, 3 mg vs. placebo) and clinically meaningful. There were also significant improvements in physical function (P = 0.013, 3 mg vs. placebo) and insulin resistance (P = 0.013, 3 mg vs. placebo). The incidence of adverse events was similar between treatment groups. CONCLUSION: GTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated. GTx-024 may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.

The Shepherd's Courage : The Olympic Movement Anti-Doping Code / Janwillem Soek, Emile Vrijman. – (International Sports Law Journal (2002) 1 : p. 6-13)

Content:
1.) Introduction
2.) A comparison
2.1.) The description of the doping offence
2.1.1) The definition of doping
2.1.2) Doping as a petty offence
2.1.3) Intentional doping
3.) Liability
3.1.) Strict liability
3.2.) Culpable liability
3.3.) Liability in case of intentional doping
4.) Sanctions
4.1.) Sanctions in case of a regular or "non-aggravated" doping offence
4.2.) Sanctions in case of an aggravated doping offence
4.3.) Competitors and athletes
4.4.) Sports sanctions
4.5.) No possibility of reinstatement
5.) Conducting doping trials
5.1.) The rights of the accused
5.2.) The position of IOC accredited laboratories in doping tials
5.3.) The relationship between the IOC and the CAS
6.) Conclusion

With the appearance in 1995 of the Medical Code the International Olympic Committee (IOC) for the first time united its hitherto fragmented doping regulations in one comprehensive document. In addition to banning the use of prohibited (classes of ) substances and providing directions and guidelines for carrying out doping controls, the IOC Medical Code further strictly banned the trafficking of prohibited (classes of ) substances, provided further instructions with respect to the accreditation and practices of the so-called “IOC accredited doping control laboratories” and, in case of violation of its provisions, established sanctions for both athletes and their entourage.
Because of its’ comprehensive character, the IOC Medical Code has been the focal point over the past years in the debate within the international sports community concerning the harmonisation of anti-doping rules and regulations. Not surprisingly and not widely publicized, one of the first tangible results of the “World Conference on Doping in Sport” which took place in early 1999, turned out to be a revised Medical Code, the so-called “Olympic Movement Anti-Doping Code”.

The IOC motto “Citius, altius, fortius” does not readily apply to the ADC. On the contrary, compared to the MC and from a legal point of view, it is fair to say that matters have deteriorated rather than
improved, especially where the definition of doping is concerned. It seems as if the IOC wishes to depart from the well established and clear principle of strict liability in doping cases in exchange for a more variable system of incurring liability. It is clear that this does not aid the transparency of the subject matter and will probably cause unnecessary confusion.
Finally, one may wonder if and to what extent the IOC and the international sports governing bodies, in their continuing efforts to protect the positive social values of sports by continuing “strengthening” of their anti-doping rules and regulations, are not in effect violating more general fundamental human rights and principles themselves. This can never be the goal of creating effective antidoping rules and regulations. Nevertheless, it now appears as if every sense of direction and proportion is being lost.

The Spirit of Sport and the Medicalisation of Anti-Doping: Empirical and Normative Ethics / Michael McNamee. - (Asian Bioethics Review 4 (2012) 4; p. 374-392)

In this article, I argue to the contrary — that Cannabinoids should be retained on the Prohibited List; that its use may be thought of as doping; and that the Spirit of Sport criterion, though vague, is still a defensible criterion for the demarcation of “doping”. To achieve this, I critically discuss the legitimacy of Cannabinoid inclusion in the light of contemporary literature on “enhancement”, and introduce the findings of a recent empirical investigation into anti-doping policy with a sample of international key actors in antidoping policy.

In the first section, I describe the definition of doping and the current state of policy flux in anti-doping, then I set out the extant and the proposed criteria for a method or substance to be considered doping (i.e., for inclusion on the Prohibited List). I review then one bioethical critique of the Spirit of Sport criterion (Foddy and Savulescu 2010), and a recent challenge by an internationally recognised group of scholars and scientists working in the field of anti-doping (the International Network of Humanistic Doping Research) to remove the criterion. I then included narrative data from key actors on the international scene of anti-doping such as Heads of National Anti-Doping Organisations, Heads of Medicine and Science in Anti-Doping Organisations, and senior members of the World-Anti Doping Agency (WADA), before arguing against their position and for the status quo.

The status quo before the International Standard for Education : Elite adolescent athletes’ perceptions of anti-doping education / Katharina Gatterer, Bernhard Streicher, Andrea Petróczic, Marie Overbye, Wolfgang Schobersberger, Matthias Gumpenberger, Kathrin Weber, Karsten Königstein, Cornelia Blank

• Performance Enhancement & Health 9 (2021) 3-4 (October), 100200
• DOI: 10.1016/j.peh.2021.100200

ABSTRACT

Education is a fundamental pillar of anti-doping. With the International Standard for Education (ISE) coming into effect in 2021, understanding the status quo of anti-doping education is paramount. This study aimed to evaluate young elite athletes’ perceptions of the anti-doping education they receive. A total of 2,232 athletes, participating at any of four Youth Olympic events between 2018 and 2020 (representing 49 sport disciplines and 124 countries) were surveyed using an online questionnaire, including questions about the anti-doping education received, athletes’ views about its usefulness and trust in its content. Additionally, anti-doping education programmes of the countries’ National Anti-Doping Organisations (NADOs) were assessed in terms of scope and extent, and categorised as ‘comprehensive’, ‘selective’, ‘limited’ or ‘information-only’. Perceived usefulness and trust were compared between these groups. Three-quarters (73.3%) of the athletes received anti-doping education, its usefulness and trust were rated as ‘good’ (> 4 out of 5). Based on NADO's anti-doping education, athletes in the ‘information-only’ category had significantly lower values for usefulness and trust, while those in the ‘selective’ category had the highest values. Results confirm the importance of a multifaceted education, recommending the implementation of at least one educational approach above information provision as they were perceived to be more useful and trusted, and could facilitate Code compliance via developing skills as well as knowledge for informed decision making.

The Stigma of Anabolic Steroid Use / Scott Griffiths, Stuart B. Murray, Jonathan M. Mond. - (Journal of Drug Issues 46 (2016) 4 (October); p. 1-11)

• DOI: 10.1177%2F0022042616661837

Abstract

Little is known about the stigma of anabolic steroid use despite clear implications for treatment-seekers and for public policy development. We investigated the predictors of steroid stigma and contextualized the results by comparing steroids with marijuana. Undergraduates (N = 304) completed measures of drug stigma, exposure to drug users, and history of drug use. Participants stigmatized steroid use more than marijuana use—a very large effect. Participants reported less exposure to steroid users. Nevertheless, 15% of participants reported having a steroid-using friend. History of drug use, but not exposure to steroid users, predicted lower steroid stigma. Drug use and exposure both predicted lower marijuana use stigma. The amount of stigma expressed toward steroids is commensurate with that of “hard” drugs, such as heroin, likely constituting a formidable barrier to treatment. The public’s difficulty empathizing with male body image insecurities may partially explain why exposure to steroid users did not predict lower stigmatization.

The stimulant higenamine in weight loss and sports supplements / Pieter A. Cohen, John C. Travis, Peter H.J. Keizers, Frederick E. Boyer, Bastiaan J. Venhuis. - (Clinical Toxicology 57 (2019) 2 (February); 125-130)

• PMID: 30188222
• DOI: 10.1080/15563650.2018.1497171

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.