Combined methazolamide and theophylline improves oxygen saturation but not exercise performance or altitude illness in acute hypobaric hypoxia

Abstract

A limited number of small studies have suggested that methazolamide and theophylline can independently reduce symptoms of acute mountain sickness (AMS) and, if taken together, can improve aerobic exercise performance in normobaric hypoxia. We performed a randomized, double-blind, placebo-controlled, cross-over study to determine if the combination of oral methazolamide and theophylline could provide prophylaxis against AMS and improve aerobic performance in hypobaric hypoxia (∼4875 m). Volunteers with histories of AMS were screened at low altitude (1650 m) and started combined methazolamide (100 mg BID) and theophylline (300 mg BID) treatment, or placebo, 72 h prior to decompression. Baseline AMS (Lake Louise Questionnaire), blood (haemoglobin, haematocrit), cognitive function, ventilatory and pulse oximetry (S pO 2) measures were assessed at low altitude and repeated between 4 and 10 h of exposure to hypobaric hypoxia (P B = 425 mmHg). Aerobic exercise performance was assessed during a 12.5 km cycling time trial (TT) after 4 h of hypobaric hypoxia. Subjects repeated all experimental procedures after a 3-week washout period. Differences between drug and placebo trials were evaluated using repeated measures ANOVA (= 0.05). The drugs improved resting S pO 2 by ∼4% (P < 0.01), but did not affect the incidence or severity of AMS or cognitive function scores relative to placebo. Subjects' performance on the 12.5 km TT was ∼3% worse when taking the drugs (P < 0.01). The combination of methazolamide and theophylline in the prescribed dosages is not recommended for use at high altitude as it appears to have no measurable effect on AMS and can impair aerobic performance. K E Y W O R D S acute mountain sickness, carbonic anhydrase, cognitive function, cycling time trial, methylxanthine 1 INTRODUCTION Despite advances in our understanding of the physiological responses to high altitude, there are few effective pharmacological countermeasures to offset associated symptoms of acute mountain sickness (AMS) and reductions in aerobic exercise performance upon rapid ascent. The most common and effective prophylactic treatments for

Theophylline for the management of respiratory disorders in adults in the 21st century: A scoping review from the American College of Clinical Pharmacy Pulmonary Practice and Research Network

“…[12][13][14][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] Four studies assessed theophylline in the management of obstructive sleep apnea (7.3%) [58][59][60][61] and two studies evaluated theophylline use to manage hypoxia (3.6%). 64,65 The respiratory disorders with the fewest clinical studies were hyposmia (n = 1, 1.8%), 62 ventilatorinduced diaphragmatic dysfunction (n = 1, 1.8%), 63 and spinal cord injury-related respiratory function (n = 1, 1.8%). 66 Thirty studies (54.5%) reported a positive impact of theophylline on the study's primary outcome: asthma (n = 14, 25.5%), [19][20][21][22][23][24][26][27][28][30][31][32][33][34] COPD (n = 9, 16.4%), 27,…”

“…[73][74][75][76] Theophylline positively influenced primary outcomes across four studies. [62][63][64][65] Both oral and intranasal theophylline improved sense of smell and smell acuity in adults with hyposmia and hypogeusia. 62 One retrospective cohort study of 40 patients in the medical intensive care unit (ICU) with ventilator-induced diaphragmatic dysfunction taking oral theophylline 200-400 mg daily found a significant improvement in bilateral diaphragmatic movement at 72 h without any reported drug-related ADE.…”

“…66 Adverse effects were reported in four clinical studies. [62][63][64][65] No patients exhibited adverse effects when theophylline was assessed for a miscellaneous respiratory condition. [62][63][64][65]…”

Experimental Physiology special issue: Extreme environmental physiology

“…and colleagues report that respiratory alkalosis and vertebral artery dilatation are associated with the onset of AMS(Barclay et al, 2021), and Subudhi and colleagues address the question of whether the combination Experimental Physiology. 2021;106:1-3.wileyonlinelibrary.com/journal/eph 2 EDITORIAL of methazolamide and theophylline reduce the symptoms of AMS and improve aerobic performance in acute hypobaric hypoxia(Subudhi et al, 2021). Townsend and colleagues look at performance rather than pathology, examining the impact of hypoxia on central and peripheral muscle fatigue following repeated sprinting(Townsend, Brocherie, Millet, & Girard, 2021).…”

“…Cerebral haemodynamics and oxygenation are addressed in two papers (Manferdelli, Marzorati, Easton, & Porcelli, 2021; Marillier et al., 2021), one of which examines the relationship between these variables and acute mountain sickness (AMS) (Manferdelli et al., 2021). In connection with this critical medical condition, Barclay and colleagues report that respiratory alkalosis and vertebral artery dilatation are associated with the onset of AMS (Barclay et al., 2021), and Subudhi and colleagues address the question of whether the combination of methazolamide and theophylline reduce the symptoms of AMS and improve aerobic performance in acute hypobaric hypoxia (Subudhi et al., 2021). Townsend and colleagues look at performance rather than pathology, examining the impact of hypoxia on central and peripheral muscle fatigue following repeated sprinting (Townsend, Brocherie, Millet, & Girard, 2021).…”