Safety and Ergogenic Properties of Combined Aminophylline and Ambrisentan in Hypoxia

Abstract

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.

Adjunctive sepsis therapy with aminophylline (STAP): a randomized controlled trial

“…With the extension of application, the improvement in the oxygenation index of the aminophylline group was gradually obvious. Studies have shown that aminophylline can stimulate respiration, enhance respiratory muscle contractility, increase pulmonary ventilation, and improve the tolerance to hypoxia without increasing oxygenation [22,23] . The effect of aminophylline on the oxygenation index of patients with sepsis is reasonable.…”

“…[ 20 , 21 ] In addition, aminophylline can stimulate respiration, enhance respiratory muscle contractions, improve pulmonary ventilation, and even improve tolerance to hypoxia without increasing oxygenation. [ 22 , 23 ] It can also block the purinergic signaling cascade of adenosine to inhibit the tubuloglomerular feedback loop, preventing a decrease in glomerular filtration rate and urine output, and thus provide a possible benefit in renal protection. [ 24 , 25 ] A previous study by Dai et al [ 26 ] has found that aminophylline can increase urine volume, improve oxygenation, and enhance cardiac function in sepsis patients.…”

High-altitude Hypoxia Influences the Activities of the Drug-Metabolizing Enzyme CYP3A1 and the Pharmacokinetics of Four Cardiovascular System Drugs

“…Hypoxia causes a series of physiological changes in body fluids, blood rheology, blood biochemistry, and organ functions, which may affect the absorption, distribution, metabolism, and excretion of drugs [ 14 , 15 , 16 ]. Studies have shown that the in vivo metabolism of propranolol [ 17 ], aminophylline [ 18 ], acetazolamide [ 19 ], and sulfamethoxazole [ 20 ] is significantly affected by hypoxia. Cytochrome P450 (CYP450) is the most important phase I metabolic enzyme, and 57 human CYP450 genes have been identified, which are classified into 18 families and 42 subfamilies according to sequence similarity [ 21 , 22 , 23 ].…”

Aminophylline as anti-hypoxic add-on therapy in the management of COVID-19 in Baghdad: An experience from single center report case study

“…Aminophylline is a bronchodilator that acts by inhibiting the phosphodiesterase enzyme inhibitor leading to an increase in the intracellular level of cyclic adenosine monophosphate which producing a dilatation of the bronchial tree. Several studies showed that aminophylline has pleiotropic effects, including anti-inflammatory [8], antioxidant [9], and anti-hypoxia [10]. It relieves the symptoms associated with hypoxia-like headache and effectively alleviates the hypoxia when it is concomitantly used with other medicine [10].…”

“…Several studies showed that aminophylline has pleiotropic effects, including anti-inflammatory [8], antioxidant [9], and anti-hypoxia [10]. It relieves the symptoms associated with hypoxia-like headache and effectively alleviates the hypoxia when it is concomitantly used with other medicine [10]. In addition, it improves the respiratory muscles, and thereby reduces the status of hypercapnia associated with hypoxia [11].…”