Characterization and Detection of Prolonged Endothelin Receptors Antagonists Administration
Condition: Pulmonary Hypertension
MeSH terms: Hypertension, Pulmonary
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Endothelin receptors antagonists (ERA), such as bosentan and ambrisentan, are a class of
      vasoactive drugs that have been developed for the treatment of pulmonary arterial
      hypertension. It has been anecdotally reported that ERA is frequently used among top-level
      athletes to counteract exercise-induced rise in pulmonary vascular pressures and increase
      exercise performance. Yet, the effects of ERA on exercise capacity in healthy humans are
      puzzling, with the drugs not included in the current Prohibited List, since the ergogenic
      potential is yet to be fully understood and determined. Furthermore, the urinary excretion of
      ERA metabolites following administration has not been studied systematically at rest and
      during exercise in athletes, as a way to detect its intake if performance-enhancing potential
      is confirmed. In the planned study ERA will be administered in newly approved doses for 8
      weeks in order to assess the presumed doping potential for both male and female athletes, and
      to monitor serum and urinary ERA excretion dynamics after single- and multiple-dose
      administration. The possible effects of prolonged ERA administration in higher doses on
      exercise performance may be relevant, if further confirmed, in terms of their possible
      fraudulent utilization to influence exercise performance in sports, raising the difficult
      question of whether, particularly in some circumstances, the ERA might be considered as
      prohibited substances in athletes.
    

Detailed description: 
      Preliminary findings of our research group indicated that ERA enhances exercise performance
      (particularly aerobic) after 7-day intake of higher doses of non-selective ERA bosentan
      (doses used were approved for pulmonary arterial hypertension treatment). This is in part in
      accordance with results of previous research (Faoro et al. 2009), although authors
      administered regular single dose (62.5 mg) of bosentan in hypoxic healthy subjects. Our study
      should examine metabolic profiles of athletes after receiving significantly higher doses of
      two oral ERA as compared to previous research, along with assessment of ergogenic potential
      with 8 weeks of administration in placebo-control and randomized design. We expect that ERA
      will increase time to exhaustion during endurance test, increase the maximal oxygen uptake
      and rate of ultra-short term heart rate recovery after exercise, and affecting blood and
      urine cortisol, testosterone and dehydroepiandrosterone following administration. Moreover,
      we will clearly evaluate 24-h pharmacokinetic profile of ERA in blood and urine and collect
      data for concentration-time profiles of ERA and main active metabolites, in aim to provide
      more rationale basis for identification and detection for doping control.
    

Intervention name(s): Bosentan; Ambrisentan; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): tablet, 250 mg per day, twice per day, 8 weeks; tablet, 10 mg per day, single per day, 8 weeks; Tablet, 10 mg per day, single per day, 8 weeks
Intervention MeSH terms: Bosentan; Ambrisentan
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Pharmacokinetics; Exercise performance; Athletes