The formulation described has been approved by 12 European countries from 16 th June 2018 under the name of Ventizolve (Respinal in Sweden), produced by Sanivo Pharma AS. Sponsor of this trial was AS Den Norske Eterfabrikk. Ola Dale (OD) was engaged by AS Den Norske Eterfabrikk as Principle Investigator in this study for which OD receives no personal honorarium. OD´s employer Norwegian University of Science and Technology (NTNU) and its subsidiary Technical Transfer Office have signed Pharmacokinetics of a novel, approved, 1.4 mg intranasal naloxone formulation for reversal of opioid overdose-a randomised controlled trial. Preprint for Open Access 4

Hypoxemia can be life-threatening, both acutely and chronically. Because hypoxemia causes vascular dysregulation that further restricts oxygen availability to tissue, it can be pharmacologically addressed. We hypothesized that theophylline can be safely combined with the β2-adrenergic vasodilator bambuterol to improve oxygen availability in hypoxemic patients. Ergogenicity and hemodynamic effects of bambuterol and theophylline were measured in rats under hypobaric and normobaric hypoxia (12% O). Feasibility in humans was assessed using randomized, double-blind testing of the influence of combined slow-release theophylline (300 mg) and bambuterol (20 mg) on adverse events (AEs), plasma K, pulse, blood pressure, and drug interaction. Both drugs and their combination significantly improved hypoxic endurance in rats. In humans, common AEs were low K (<3.5 mmol/L; bambuterol: 12, theophylline: 4, combination: 13 episodes) and tremors (10, 0, 14 episodes). No exacerbation or serious AE occurred when drugs were combined. A drop in plasma K coincided with peak bambuterol plasma concentrations. Bambuterol increased heart rate by approximately 13 bpm. Drug interaction was present but small. We report promise, feasibility, and relative safety of combined theophylline and bambuterol as a treatment of hypoxemia in humans. Cardiac safety and blood K will be important safety endpoints when testing these drugs in hypoxemic subjects.

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 Tmax of the bambuterol metabolite terbutaline and delaying t1/2 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 InformationThis 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