Pharmacological therapy in obstructive sleep apnea - Methodology and interventional aspects of carbonic anhydrase modulation

Abstract

BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent disease with potential severe short- and long-term consequences such as daytime sleepiness and cardiovascular disease. Recurrent total or partial collapse of the upper airway during sleep leads to sleep fragmentation and intermittent hypoxia/hypercapnia. The underlying mechanisms include a collapsible upper airway, unstable ventilation, low arousal threshold and insufficient muscle compensation in the pharynx region. The main treatments, positive airway pressure (PAP) and mandibular advancement devices, mainly address anatomical causes of OSA. In many patients, these treatments are not tolerated or not efficient enough. Improved understanding of pathophysiological mechanisms in OSA have paved the way for new treatment targets. In this thesis, carbonic anhydrase (CA) activity as a biomarker for OSA is investigated together with studies on CA inhibition as a therapy in OSA, in addition to a systematic evaluation of placebo effects in drug treatments of OSA.

METHODS AND RESULTS: In paper I, we studied a cohort of 33 PAP-treated subjects with OSA and 9 OSA patients treated with PAP, the CA inhibitor acetazolamide (ACT) and a combination of PAP+ACT. We could show that CA activity in whole blood was higher in hypertensive compared to normotensive participants and PAP treatment per se did not reduce CA activity. Further, CA activity was numerically reduced by ACT. Paper II contained a detailed analysis of 58 patients participating in a randomised controlled trial of the CA inhibitor sulthiame (STM) in moderate to severe OSA. By using a PSG-based analysis method, we investigated the effects of STM on underlying pathomechanisms of OSA. STM reduced ventilatory instability and increased the upper airway stability. In paper III, the effect of STM on potential biochemical markers of OSA was investigated. CA activity in whole blood was reduced by STM and this effect remained two weeks after the last drug intake. Hypoxia-inducible factor 1α, a key factor in the cellular response to hypoxia, was reduced during treatment and at two weeks after last drug intake, suggesting an overall improvement of overnight O2 saturation following STM. In paper IV we analysed the placebo effect of drug treatments in OSA by means of a systematic review with meta-analyses. Objective measures of OSA were not systematically affected by placebo whereas placebo effects in subjective symptoms like excessive daytime sleepiness need to be accounted for.

CONCLUSIONS: The CA system plays an important part in OSA pathophysiology and appears to be a promising treatment target. Further studies are needed to evaluate CA activity in whole blood as a diagnostic biomarker in OSA. The CA inhibitor STM had dual effects in OSA including a reduction of ventilatory instability and an increase in upper airway stability. Future studies in pharmacological treatment of OSA need to be significantly sized and placebo controlled for subjective outcomes.