Pharmacodynamics of selective androgen receptor modulators / Donghua Yin, Wenqing Gao, Jeffrey D. Kearbey, Huiping Xu, Kiwon Chung, Yali He, Craig A. Marhefka, Karen A. Veverka, Duane D. Miller, James T. Dalton. - (Journal of Pharmacology and Experimental Therapeutics 304 (2003) 3 (March), p. 1334-1340)

• PMID: 12604714
• DOI: 10.1124/jpet.102.040840

Abstract

The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E(max)) and dose for half-maximal effect (ED(50)) were determined for each compound and compared with that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.

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.

Importance of hemoglobin concentration to exercise : acute manipulations / José A.L. Calbet, Carsten Lundby, Maria Koskolou, Robert Boushel. - (Respiratory Physiology & Neurobiology 151 (2006) 2-3 (28 April); p. 132-140)

• PMID: 16516566
• DOI: 10.1016/j.resp.2006.01.014

Abstract

An acute reduction of blood hemoglobin concentration ([Hb]), even when the circulating blood volume is maintained, results in lower (.)V(O(2)(max) and endurance performance, due to the reduction of the oxygen carrying capacity of blood. Conversely, an increase of [Hb] is associated with enhanced (.)V(O(2)(max) and endurance capacity, that is also proportional to the increase in the oxygen carrying capacity of blood. The effects on endurance capacity appear more pronounced and prolonged than on (.)V(O(2)(max). During submaximal exercise, there is a tight coupling between O(2) demand and O(2) delivery, such that if [Hb] is acutely decreased muscle blood flow is increased proportionally and vice versa. During maximal exercise with either a small or a large muscle mass, neither peak cardiac output nor peak leg blood flow are affected by reduced [Hb]. An acute increase of [Hb] has no effect on maximal exercise capacity or (.)V(O(2)(max) during exercise in acute hypoxia. Likewise, reducing [Hb] in altitude-acclimatized humans to pre-acclimatization values has no effect on (.)V(O(2)(max) during exercise in hypoxia.

Impact of alterations in total hemoglobin mass on VO 2max / Walter Schmidt, Nicole Prommer. - (Exercise and Sport Sciences Reviews 38 (2010) 2 (April); p. 68-75)

• PMID: 20335738
• DOI: 10.1097/JES.0b013e3181d4957a

Abstract

Training and hypoxia-associated changes in maximal oxygen uptake are mediated by different blood adaptations. Training increases blood volume because of plasma and red cell volume expansion, resulting in increased cardiac output, whereas hypoxia increases only red cell volume, leading to increased hemoglobin concentration and oxygen transport capacity. Blood doping mimics the altitude effects, however, by far exceeding its magnitude.

The effects of red blood cell infusion on 10-km race time / A.J. Brien, T.L. Simon. - (Journal of the American Medical Association 257 (1987) 20 (May); p. 2761-2765)

• PMID: 3573270
• DOI: 10.1001/jama.1987.03390200101022

Abstract

The purpose of this study was to investigate the effect of infusion of 400 mL of red blood cells (RBCs) on 10-km track race time, submaximal heart rate, hematocrit, 2,3-diphosphoglycerate, and partial pressure of oxygen at 50% hemoglobin saturation. Six highly trained, male, distance runners twice donated a unit of RBCs, which was frozen for subsequent reinfusion. Eleven weeks after the second donation, they undertook a series of three competitive 10-km races on a standard 400-m track: before infusion, after 100 mL of saline solution, and after 400 mL of autologous, previously frozen deglycerolized RBCs. All subjects took all trials in this double-blind, placebo, crossover, experimental design. Running time was recorded at each 400-m split, and blood was collected prior to each trial. The data were analyzed by analysis of variance. Results following the RBC infusion showed a significantly higher hematocrit concentration, a significantly faster 10-km run, a nonsignificant decrease in submaximal heart rate (10 beats faster 10-km run, a nonsignificant decrease in submaximal heart rate (10 beats per minute), and no significant changes in either 2,3-diphosphoglycerate or partial pressure of oxygen at 50% hemoglobin saturation. Erythrocythemia induced by the infusion of 400 mL of autologous packed RBCs effectively increased performance capacity in a 10-km track race, probably due to an increase in oxygen delivery to the working muscles.

Oxygen delivery enhancers: past, present, and future / P. Borrione, A. Mastrone, R.A. Salvo, A. Spaccamiglio, L. Grasso, A. Angeli. - (Journal of Endocrinological Investigation 31 ( (2008) 2 (February); p. 185-192)

• PMID: 18362513
• DOI: 10.1007/BF03345588

Abstract

In endurance sport the delivery of oxygen to muscles plays a critical role. Indeed, muscle performance declines during prolonged and intense activity as a consequence of the shift from the aerobic to the anaerobic metabolism with an increase of lactate. To enhance the aerobic capacity 2 alternatives may be used: increasing either the transport or the delivery of oxygen. In this setting, blood doping is the practice of illicitly using a drug or blood product to improve athletic performance. Based on this definition, blood doping techniques may include: 1) blood transfusion (autologous or omologous); 2) erythropoiesis-stimulating substances [recombinant human erythropoietin (alpha, beta, omega), darbepoietin-alpha, continuous erythropoiesis receptor activator, hematide]; 3) blood substitutes (hemoglobin-based oxygen carriers, perfluorocarbon emulsions); 4) allosteric modulators of hemoglobin (RSR-13 and RSR-4); 5) gene doping (human erythropoietin gene transfection); 6) gene regulation (hypoxia-inducible transcription factors pathway). In the present overview we will briefly describe the above-mentioned techniques with the aim of underlining potential hematological alternatives to gene doping for increasing aerobic capacity in sport.

CAS 2008/A/1471 FINA vs Tagliaferri and Federazione Italiana Nuoto

CAS 2008/A/1486 WADA v/ CONI and Tagliaferri

CAS 2008/A/1471 Fédération Internationale de Natation (FINA) v. Marco Tagliaferri & Federazione Italiana Nuoto (FIN) and CAS 2008/A/1486 World Anti-Doping Agency (WADA) v. Comitato Olimpico Nazionale Italiano (CONI) & Marco Tagliaferri

• Aquatics (water polo)
• Doping (stanozolol)
• Legitimate interest to have a decision reviewed by the CAS
• Mitigation of the penalty due to the fact that the athlete was minor
• Principle of lex mitior in a doping case

1. The applicable regulations provide that every “interested party” has the right to appeal against decisions by the highest national decision-making body in doping disputes irrespective of whether said “interested party” was a party to the proceedings, in which the decision appealed against was pronounced. Nor does the provision stipulate any limitation to the right to appeal in terms of the “kind” of decision. Whether or not the decision issued deals with procedural issues only is, therefore, irrelevant for the right of appeal. However, not only the wording, but also the intent and purpose of the relevant provision, are a reason for interpreting the right of appeal broadly. The broad right of appeal is supposed to allow all doping-related decisions to be reviewed in order to help harmonize the decisions and to contribute to an equal treatment of all athletes. Even if the decision-making body decided not to punish an athlete for procedural reasons, this does not alter the “nature of the dispute”. It is and remains a doping matter with the consequence that the International Federation and the World Anti-Doping Agency have a legitimate interest to also have this decision reviewed by the CAS.

2. In order to apply mitigating grounds, the athlete has to establish how and because of which surrounding circumstances the prohibited substance was present to the athlete’s body. Whether and how often the athlete ingested the prohibited substance is irrelevant for the extent of the penalty. The fact that the athlete was a minor at the time of the positive doping sample is, in itself, no reason to mitigate the penalty.

3. Because of the principle of lex mitior, the rule that is more favourable to the athlete can be resorted to, even if it was not in force at the time the offence was committed.

On 21 July 2006 the Disciplinary Commission of the Italian Swimming Federation (FIN) decided to revoke to provisional suspension of the minor swimmer Marco Tagliaferri after his sample tested positive for the prohibited substance Stanozolol.

The Athlete had accepted the test result and testified that his father had administered stanozol without his knowledge. Consequently a lifetime ban was imposed on the father.

Following the appeal filed by the International Swimming Federation (FINA) the FIN Appeals Commission decided on 6 November 2007 to impose a 1 year period of ineligibility on the Athlete.

However on 10 January 2008 the CONI Anti-Doping Supreme Court (CONI GUI) deemed that FINA's appeal was inadmissible and annuled the decison of the FIN Appeals Commission.

Hereafter in January and in February 2008 both FINA and WADA appealed the CONI GUI decision with the Court of Arbitration for Sport (CAS). FINA and WADA requested the Panel to annul the Appealed Decision and to impose a 2 year period of ineligibility on the Athlete.

The Panel concludes that the CONI GUI decision of 10 January 2008 was erroneous and must be set aside because the FINA appeal with the Italian FIN Appeals Commission was filed within the set the time limit and therefore admissible.

The Panel rules that as a result of all the inconsistencies in the presentation of the facts, it has not been established to the Panel’s comfortable satisfaction how, and because of what circumstances, the substance Stanozolol entered the Athlete’s system.

The fact that the Athlete was a minor at the time is no reason for a reduced sanction. The Panel finds that a 2 year period of ineligibility muse be imposed backdated and taking into account the time already served by the Athlete.

Therefore the Court of Arbitration for Sport decides on 5 February 2009:

1.) The appeal of the World Anti-Doping Agency against the decision of the Giudice di Ultima Istanza in Materia di Doping (GUI) dated 10 January 2008 is admissible.

2.) The appeal of the Federation Internationale de Natation against the decision of the Giudice di Ultima Istanza in Materia di Doping (GUI) dated 10 January 2008 is admissible inasmuch as it is directed against Mr Marco Tagliaferri. Insofar as the appeal is directed against the Federazione Italiana Nuoto (FIN) it is dismissed.

3.) The decision issued by the Giudice di Ultima Istanza in Materia di Doping (GUI) is set aside.

4.) The Player, Mr Marco Tagliaferri, is declared ineligible from 1 May 2008 until 30 November 2009.

5.) All competitive results obtained by Marco Tagliaferri from 16 March 2006 through 19 December 2008 shall be disqualified with all of the resulting consequences including forfeiture of any medals, points and prizes.

6.) All other motions or prayers for relief are dismissed.

7.) This award is pronounced without costs, except for each of the court office fees of CHF 500 (five hundred Swiss francs) paid by WADA and by FINA, which are retained by CAS.

CAS 2003/A/459 Van Herk v/FINA

On 9 September 2002 the Disciplinary Committee of the Royal Dutch Swimming Federation (KNZB) decided to impose a 4 year period perod of ineligibility on the minor Dutch swimmer (14) Linda van Herk for committing an anti-doping rule violation. 6 months of this sanction was unconditional and 42 months with a probation period of 2 years.

Here the Athlete failed to provide a sample despite several attempts. The Athlete's father requested to stop the sample collection due to business appointments and she left the Doping Control Station while she was warned about the consequences of her refusal.

In September 2002 the Appellant appealed and on 26 October 2002 the KNZB Appeal Committee decided to annul the decision of the KNZB Disciplinary Committee, and to acquit the Athlete.

Thereupon the FINA Disciplinary Committee decided on 11 April 2003 to impose a 2 year period of ineligibility on the Athlete for her refusal to provide a sample.

Hereafter in July 2003 the Athlete appealed the FINA decision with the Court of Arbitration for Sport (CAS).

The Panel considered the arguments filed by the Athlete and finds that it has jurisdiction in this case and that the admitted departure by the KNZB from the doping control procedures is certainly regrettble. However the Panel holds that the non-compliance by officials with the procedures does not justifies an acquittal of the Athlete.

Considering the circumstances the Panel concludes that the Athlete intentionally refused to submit to doping control by providing a sample although there are grounds for a reduced sanction.

Therefore the Court of Arbitration for Sport decides on 20 October 2003:

1.) The appeal filed by ihe Appellant on 8 July 2002 is upheld in part and the decision of the FINA Doping Panel varied in part.

2.) The Appellant's suspension is reduced to one-year period to expire on 25 October 2003. The FINA Doping Panel's decision otherwise stands.

3.) The award is pronounced without costs. except for the Court Office fee of CHF 500.-- (five hundred Swiss francs) aheady paid by the Appellant and to be retained by the CAS.

Response to exercise after blood loss and reinfusion / B. Ekblom, A.N. Goldbarg, B. Gullbring. - (Journal of Applied Physiology 33 (1972) 2 (August); p. 175-180)

• PMID: 5054420
• DOI: 10.1152/jappl.1972.33.2.175

Blood doping and erythropoietin. The effects of variation in hemoglobin concentration and other related factors on physical performance / B. Ekblom. - (American journal of sports medicine 24 (1996) 6 Supp (1 November); p. S40-S42)

• PMID: 8947426
• DOI: 10.1177%2F036354659602406S12