Safety of combined bambuterol and theophylline as a potential treatment of high altitude‐induced fatigue in humans

Theophylline is moderately effective against high altitude‐induced malaise, but may be more valuable if combined with other compounds. We hypothesized that theophylline can be combined with a β2 adrenergic receptor (β2AR) agonist in humans to treat high altitude‐induced fatigue. We demonstrate that the β2AR agonist bambuterol alone (high dose = 0.05 mg/kg i.p.) significantly improves exercise performance in rats at simulated high altitude. Combined with theophylline (15 mg/kg), low‐dose bambuterol (0.01 mg/kg) was ergogenic in the same model, whereas theophylline or low‐dose bambuterol alone was not. In a phase‐1 human safety trial, neither single‐dose oral theophylline and bambuterol (Theo‐Dur 400 mg and Bambec 20 mg) nor their combination produced any SAEs. Bambuterol alone decreased plasma potassium (from 3.78 mM to a base average of 3.37 mM), which was not aggravated further by the addition of theophylline (3.83 mM to 3.33 mM). Most frequent AEs were K + <3.5mM and tremor. There was a small influence of each drug on the metabolism of the co‐administrate, decreasing T max of the bambuterol metabolite terbutaline and delaying t 1/2 of theophylline. We conclude that the combination of theophylline and bambuterol is promising and feasible in humans and should undergo testing for safety and efficacy at high altitude. Support or Funding Information This work was supported by grants from the Norwegian Armed Forces Medical Service, Institute of Aviation Medicine, the US Defense Advanced Research Projects Agency (DARPA), prime Award Number N66001‐10‐C‐2134, and by the US Office of Naval Research, prime award number N0014‐14‐0699