Safety and Ergogenic Properties of Combined Aminophylline and Ambrisentan in Hypoxia

We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactio...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2018-05, Vol.103 (5), p.888-898
Main Authors: Schroeder, Thies, Piantadosi, Claude A., Natoli, Michael J., Autmizguine, Julie, Cohen‐Wolkowieczs, Michael, Hamilton, Karyn L., Bell, Christopher, Klawitter, Jelena, Christians, Uwe, Irwin, David C., Noveck, Robert J.
Format: Article
Language:English
Subjects:
Adenosine - metabolism
Adolescent
Adult
Altitude
Aminophylline - adverse effects
Aminophylline - therapeutic use
Double-Blind Method
Drug Therapy, Combination - adverse effects
Endothelins - drug effects
Endothelins - metabolism
Exercise - physiology
Female
Humans
Hypoxia - drug therapy
Hypoxia - metabolism
Male
Middle Aged
Phenylpropionates - adverse effects
Phenylpropionates - therapeutic use
Pyridazines - adverse effects
Pyridazines - therapeutic use
Signal Transduction - drug effects
Young Adult
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Summary:We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500 mg) plus ambrisentan (5 mg) in normoxic volunteers. Subsequently, a placebo‐controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267 m). No serious adverse events occurred. Drug interaction was minimal or absent. Aminophylline alleviated hypoxia‐induced headaches. Aminophylline, ambrisentan, and their combination all significantly (P < 0.05 vs. placebo) improved submaximal hypoxic exercise performance (19.5, 20.6, and 19.1% >placebo). Single‐dose ambrisentan increased blood oxygenation in resting, hypoxic subjects. We conclude that combined aminophylline and ambrisentan offer promise to safely increase exercise capacity in hypoxemic humans without relying on increasing blood oxygen availability.
ISSN:0009-9236
1532-6535
DOI:10.1002/cpt.860