Nonlinear pharmacokinetic properties of mildronate capsules: a randomized, open-label, single- and multiple-dose study in healthy volunteers / Jun Zhang, Li-Jing Cai, Jian Yang, Qi-Zhi Zhang, Wen-Xing Peng. – (Fundamental & Clinical Pharmacology 23 (2013) 1 (February) p. 120-128)

• doi: 10.1111/j.1472-8206.2011.00962.x. Epub 2011 Jun 16.

Abstract:

Mildronate has been used as antianginal drug in parts of Europe for many years, but its pharmacokinetic (PK) properties in humans remain unclear. This study was designed to assess and compare the PK properties of mildronate capsules after single escalating oral dose and multiple doses in healthy Chinese volunteers. Volunteers were randomly assigned to receive a single dose of 250, 500, 1000, 1250 or 1500 mg of mildronate capsules. Those who received the 500-mg dose continued on the multiple-dose phase and received 500 mg three times a day for 13 days. Plasma drug concentrations were analysed by ultraperformance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Tolerability was assessed throughout the study. A total of 40 Chinese volunteers were enrolled in the study. No period or sequence effect was observed. Area under the concentration and C(max) were increased proportionally with the dose levels, whereas t(1/2) and V(d)/f were dependent on the dose. Nonlinear PK properties were found at doses of 250-1500 mg. There was an accumulation after multiple-dose administration. No serious adverse events (AEs) were reported in the PK study. The formulation was well tolerated.

Affidavit Leonardo Bertagnolli [USADA vs Lance Armstrong October 10, 2012]
May 18, 2011

Mr. Leonardo Bertagnolli is a Italian professional cyclist between 2002 and 2012 and rode in the professional teams of Saeco Macchine per Caffè-Longoni Sport, Cofidis, Liquigas, Amica Chips-Knauf, Diquigiovanni-Androni and Lampre-ISD.
Bertagnolli admitted to the Italian procecutor the use of erythropoietin (EPO), testosterone, growth hormone (hGH), and blood doping. He testified about the use, possession, trafficking, and distribution of prohibited substances and methods in the professional cycling teams, his involvement and the involvement of the team doctor Michele Ferrari.

Detecting growth hormone abuse in athletes / Richard I.G. Holt. - (Analytical and Bioanalytical Chemistry 401 (2011) 2 (August); p. 449-462).

• PMID: 21590497.
• DOI: 10.1007/s00216-011-5068-2

Abstract

It is believed that athletes have been abusing growth hormone (GH) for its anabolic and lipolytic effects since the early 1980s, at least a decade before endocrinologists began to treat adults with GH deficiency. There is an on-going debate about whether GH is performance enhancing. Although many of the early studies were negative, more recent studies suggest that GH improves strength and sprint capacity, particularly when it is combined with anabolic steroids. Although use of GH is banned by the World Anti-Doping Agency (WADA), its detection remains challenging. Two approaches have been developed to detect GH abuse. The first is based on measurement of pituitary GH isoforms; after injection of recombinant human GH, which comprises solely the 22-kDa isoform, endogenous production is down-regulated leading to an increase in the 22-kDa isoform relative to other isoforms. The second is based on measurement of markers of GH action. Insulin-like growth factor-I (IGF-I) and N-terminal pro-peptide of type III collagen (P-III-NP) increase in response to GH administration in a dose-dependent manner. When combined with discriminant function analysis, use of these markers differentiates between individuals taking GH and placebo. Subsequent studies have shown that the test is applicable across different ethnicities and is unaffected by injury. WADA regulations state that when analytes are measured by immunoassay, two assays are needed. Final validation of the marker test is currently being undertaken with modern commercially available immunoassays to finalise the threshold values to be used to determine whether a doping offence has been committed.

Annual Report 2010 / Spanish Agency for the Protection of Health in Sport (AEPSAD). - Madrid : Agencia Española de Protección de la Salud en el Deporte, 2011

Rapportage 17 : januari t/m december 2010 ten behoeve van de Algemene vergadering NOC*NSF / M.I. van Dijk, S.J.U. Veen-van der Wielen, S.W.A. van Haarlem. - Arnhem : Audit Commissie Doping, 2011.
- Rapportage t.b.v. de Algemene vergadering NOC*NSF 17 mei 2011.
- Jaarlijkse rapportage aan de Algemene Vergadering van NOC*NSF, de staatssecretaris van Volksgezondheid, Welzijn en Sport, het bestuur van de Dopingautoriteit en het bestuur van het Instituut Sport Rechtspraak.

Inhoud:

- Hoofdstuk 1 Inleiding
- Hoofdstuk 2 Werkwijze Auditcommissie Doping
- Hoofdstuk 3 Overzicht dopinggevallen
- Hoofdstuk 4 Conclusies
- Hoofdstuk 5 Aanbevelingen
- Bijlage 1 Lijst met topsportbonden
- Bijlage 2 Lijst van verboden stoffen en methoden

VA Bocci, I Zanardi & V Travagli. Ozone acting on human blood yields a hormetic dose-response relationship. Journal of Translational Medicine 2011, 9:66.

Studies of the pharmacology of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol, a synthetic anti-inflammatory androstene / Clarence N. Ahlem, Michael R. Kennedy, Theodore M. Page, Christopher L. Reading, Steven K. White, John J. McKenzie, Phaedra I. Cole, Dwight R. Stickney, James M. Frincke. - (International Journal of Clinical and Experimental Medicine 4 (2011) 2 (23 April); 119-135)

• PMID: 21686136
• PMCID: PMC3113500

Abstract

17α-Ethynyl-androst-5ene-3β, 7β, 17β-triol (HE3286) is an orally bioavailable analogue of androst-5-ene-3β,7β,17β-triol, a non-glucocorticoid anti-inflammatory metabolite of the adrenal steroid, dehydroepiandrosterone. The pharmacology of HE3286 was characterized in preparation for clinical trials in type 2 diabetes mellitus and other diseases of inflammation. Interactions with nuclear hormone receptors and P450 enzymes were measured in vitro. Drug metabolism was studied preclinically in mice, rats, dogs, and monkeys. Neurological and cardiopulmonary safety and dose-ranging and chronic toxicity studies were conducted in rats and dogs in accordance with FDA guidelines. Pharmacokinetics and metabolites were measured in Phase I clinical trials. HE3286 was differentially metabolized between species. HE3286 and metabolites did not bind or transactivate steroid binding nuclear hormone receptors or inhibit P450 enzymes. There were no adverse effects in safety pharmacology and canine toxicology studies. Although HE3286 did not elicit systemic toxicity in rats, mild estrogenic effects were observed, but without apparent association to hormonal changes. Safety margins were greater than 20-fold in rats and dogs with respect to the most commonly used clinical dose of 10 mg/day. The terminal half-life in humans was 8 hours in males and 5.5 hours in females. HE3286 is the first derivative of the DHEA metabolome to undergo a comprehensive pharmacological and safety evaluation. The results of these investigations have shown that HE3286 has a low potential for toxicity and possesses pharmacological properties generally suitable for use in human medicine. The favorable profile of HE3286 warrants further exploration of this new class of anti-inflammatory agents.

Keywords: HE3286; Toxicology; androstene; metabolism; pharmacokinetics; pharmacology.

Adverse Analyzing : A European Study of Anti Doping Organization Reporting Practices and the Efficacy of Drug Testing Athletes : Executive Summary / Walter Palmer, Simon Taylor, Andrew Wingate. - Nyon : UNI Global Union, 2011

Adverse Analyzing : A European Study of Anti Doping Organization Reporting Practices and the Efficacy of Drug Testing Athletes / Walter Palmer, Simon Taylor, Andrew Wingate. - Nyon : UNI Global Union, 2011

Anti-doping in sport is a multi-million Euro industry employing thousands of people that impacts upon the day-to-day lives of every professional athlete. It relies upon cutting-edge biological, chemical and medical investigations. However there is a paucity of publicly available statistical evidence to support current policies and practices on drug testing programmes for athletes.
The lack of statistical evidence to support an effective, proportional and efficient drug testing regime raises serious questions about WADA’s management of the World Anti-Doping Code.
It is hard to avoid the conclusion that the World Anti-Doping Agency has little or no evidence about the effectiveness of international drug testing for athletes. This has serious implications for its drug testing policies and procedures; if they are not based on hard statistical evidence then we must question how these policies are being developed and monitored.
WADA is already aware of the lack of statistical evidence on the efficacy of international drug testing yet has done little to address the shortcoming. There are clear and obvious failings in the limited statistics that WADA does publish. These omissions combined with the lack of detail renders them almost meaningless for any detailed analysis of anti-doping statistics. The findings of this report strongly suggest that WADA is in breach of the World Anti- Doping Code with regards to Article 14.4. It is failing to collect and publish comprehensive national anti-doping statistics despite being required to do so by its own Code.

Contents:

Section 1: Factors Limiting Data Collection
1.) Limited Availability of NADO Annual Reports
a.) Table: Availability of NADO Annual Reports
b.) Lack of centralized information on NADO websites
c.) Table: WADA reporting – 2008 vs. 2009
d.) Potential Code Violations
2.) Lack of a standard approach to the listing of sports and sport categories
3.) Ambiguous or general sport categories
4.) Lack of complete reporting
5.) Lack of a standard approach on third party testing
a.) Overview and Comments
b.) Table: Comparison of Report Contents
c.) Summary
d.) Interesting Individual Cases
i.) Germany
ii.) Latvia
iii.) Netherlands
iv.) United Kingdom
6.) Variation of Reporting Practices in Key Areas
a.) Violations
b.) Substances
c.) Positives (Adverse Analytical Findings – AAFs)
d.) Therapeutic Use Exemptions
e.) Missed tests
f.) Reporting failures
Section 2: Analysis of the Available Data
1.) Testing
a.) Total Number of Reported Tests – (Table)
b.) Number of tests in and out-of-competition
2.) Violations
a.) Total number of reported violations
i.) Interesting Individual Cases
1.) Belgium
2.) Germany
3.) Netherlands
4.) Luxembourg
5.) United Kingdom
b.) Sports in Which Violations occurred in 2009
c.) Number of Violations per Sport
d.) Analysis – Number of Violations per Sport
e.) Breakdown of Violations by Sport
f.) Number of violations in and out of competition
g.) Number of violations in and out of competition per sport
h.) Analysis – In and Out-of-Competition
i.) Table: Table – Ratios: Number of tests to number of violations per NADO
j.) Interesting individual cases
3.) Substances
a.) Introduction
b.) Initial Plan
c.) Problems of categorization and substance identification
d.) The amended table
e.) Table description
f.) Table: Violations: Total number of violations per sport categorized by substance
g.) Interesting Individual Cases
h.) “Multiple Violations”
i.) Non-identified substances
j.) General analysis of substances and violations
k.) General analysis of substances and sports
l.) Cannabis
Section 3: Executive Summary

Ms. Kristina Antoniychuk (Respondent) is an Ukrainian tennis player. On 22 February 2010 Respondent competed at the 2010 Abierto Mexicano TELCEL presentado por HSBC in Acapulco, Mexico, where she provided a sample for doping control.

The International Tennis Federation (ITF) has reported an anti doping rule violation against Respondent after her sample tested positive for the prohibited substance furosemide.

Respondent stated she used furosemide to treat a medical condition she has for two years. She presented medical records confirming the diagnosis, and further confirming that in January 2010, when the condition worsened, she was prescribed furosemide by a doctor. Respondent stated she was not aware the medication prescribed to her contained any prohibited substance.
Respondent acknowledged that she did not consult a sports medicine specialist, nor did she ensure that the doctor she consulted understood the strict anti-doping rules to which she is subject.

The Tribunal concluded that 19 years old Respondent was inexperienced in relation to doping matters. The ITF finds a reduction of eight months appropriate in this case.

The International Tennis Federation Independent Anti-Doping Tribunal decides that Respondent had committed an anti-doping rule violation and that the following consequences should be imposed:
(a) A fourteen-month period of ineligibility, backdated to commence on 22 February 2010 and therefore ending on 21 April 2011.
(b) Disqualification of her results achieved in 6 tennis competitions, including the forfeiture of the ranking points and prize money awarded.