Effects of the Combination of Atomoxetine and Oxybutynin on OSA Endotypic Traits

Taranto‐Montemurro, Luigi; Messineo, Ludovico; Azarbarzin, Ali; Vena, Daniel; Hess, L; Calianese, N.; White, David P.; Wellman, Andrew; Sands, Scott A.

doi:10.1016/j.chest.2020.01.012

Cited by 89 publications

(69 citation statements)

References 21 publications

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“…REM, rapid eye movement; NREM, non-rapid eye movement. in the context of combination therapy with other agents that may reduce the arousal threshold or disrupt sleep architecture (Lim et al 2019;Taranto-Montemurro et al 2020). Zolpidem had no effect on obstructive sleep apnoea severity.…”

Section: Muscle Responsiveness Changes Between Placebo and Zolpidemmentioning

confidence: 99%

Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity

Messineo

Eckert

Lim

et al. 2020

The Journal of Physiology

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A decreased respiratory arousal threshold is one of the main contributors to obstructive sleep apnoea (OSA) pathogenesis. r Several recent studies have sought to find a drug capable of increasing the respiratory arousal threshold without impairing pharyngeal muscle activity to reduce OSA severity, with variable success. r Here we show that zolpidem increases the respiratory arousal threshold by ß15%, an effect size which was insufficient to systematically decrease OSA severity as measured by the apnoea-hypopnoea index. r Unlike recent physiological findings that showed paradoxical increases in pharyngeal muscle responsiveness during transient manipulations of airway pressure, zolpidem did not alter pharyngeal muscle responsiveness during natural sleep. It did, however, increase sleep efficiency without changing apnoea length, oxygen desaturation, next-day perceived sleepiness and alertness. r These novel findings indicate that zolpidem was well tolerated and effective in promoting sleep in people with OSA, which may be therapeutically useful for people with OSA and comorbid insomnia.

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Section: Muscle Responsiveness Changes Between Placebo and Zolpidemmentioning

confidence: 99%

Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity

Messineo

Eckert

Lim

et al. 2020

The Journal of Physiology

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“…Its effect of increasing the level of norepinephrine during sleep could stimulate the motoneurons of the upper airway and reduce airway collapsibility 24 – 26 . In a recent study, atomoxetine alone significantly reduced the arousal threshold and stability of ventilatory control and improved collapsibility, but not muscle compensation during spontaneous breathing while sleeping 23 . Oxybutynin is an antimuscarinic agent frequently used for overactive bladder.…”

Section: Discussionmentioning

confidence: 94%

“…However, several possible mechanisms may explain the results. The research group that conducted a previous pilot study on AOC use and the change in OSA severity further investigated the possible effects of atomoxetine and oxybutynin on the respiratory tract 23 . Atomoxetine is a selective norepinephrine reuptake inhibitor that is used in patients with attention-deficit hyperactivity disorder.…”

Section: Discussionmentioning

confidence: 99%

Long-term atomoxetine-oxybutynin combination use may be beneficial for the prevention of obstructive sleep apnea

Chen

Chung

Chang

et al. 2021

Sci Rep

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One recent study showed that atomoxetine-oxybutynin combination (AOC) use is effective in reducing obstructive sleep apnea (OSA) severity. We used a nationwide database to examine the association between AOC use and the risk of OSA incidence. This retrospective cohort study used Taiwan’s National Health Insurance Research Database between the years 2000 and 2015. The patients who used atomoxetine or oxybutynin were included as an exposed cohort. The exposed and unexposed groups were selected in a ratio of 1:3 with sex, age, and index year matching. We used the multivariate Cox proportional regression model to evaluate the association between AOC use and the risk of an incident diagnosis of OSA. The incidence rates of OSA in the exposed cohort (N = 8940) and the unexposed cohort (N = 26,820), were 21.92 and 22.93 per 100,000 person-years, respectively. The adjusted hazard ratio of oxybutynin use only and AOC with a treatment duration of ≥ 366 days were 0.307 (95% CI 0.204–0.995, P = 0.045) and 0.299 (95% CI 0.102–0.933, P = 0.002), respectively. Long-term atomoxetine-oxybutynin combination therapy may be beneficial to reduce the risk of obstructive sleep apnea. Further studies to examine these mechanisms are warranted.

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“…Direct stimulation of the XII nerve [37] can decrease pharyngeal collapsibility [38], relieves airflow obstruction [39], and can decrease OSA severity [40]. Pharmacological treatments are limited, but clinical trials targeting the noradrenergic and cholinergic systems show promise [41][42][43] and may suggest targets for gene therapy. Desipramine, a norepinephrine reuptake inhibitor, can reduce OSA severity in some patients [43].…”

Section: Tongue Motor Impairmentsmentioning

confidence: 99%

Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

et al. 2021

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Dysfunction and/or reduced activity in the tongue muscles contributes to conditions such as dysphagia, dysarthria, and sleep disordered breathing. Current treatments are often inadequate, and the tongue is a readily accessible target for therapeutic gene delivery. In this regard, gene therapy specifically targeting the tongue motor system offers two general strategies for treating lingual disorders. First, correcting tongue myofiber and/or hypoglossal (XII) motoneuron pathology in genetic neuromuscular disorders may be readily achieved by intralingual delivery of viral vectors. The retrograde movement of viral vectors such as adeno-associated virus (AAV) enables targeted distribution to XII motoneurons via intralingual viral delivery. Second, conditions with impaired or reduced tongue muscle activation can potentially be treated using viral-driven chemo- or optogenetic approaches to activate or inhibit XII motoneurons and/or tongue myofibers. Further considerations that are highly relevant to lingual gene therapy include (1) the diversity of the motoneurons which control the tongue, (2) the patterns of XII nerve branching, and (3) the complexity of tongue muscle anatomy and biomechanics. Preclinical studies show considerable promise for lingual directed gene therapy in neuromuscular disease, but the potential of such approaches is largely untapped.

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Effects of the Combination of Atomoxetine and Oxybutynin on OSA Endotypic Traits

Cited by 89 publications

References 21 publications

Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity

Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity

Long-term atomoxetine-oxybutynin combination use may be beneficial for the prevention of obstructive sleep apnea

Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

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