Different antimuscarinics when combined with atomoxetine have differential effects on obstructive sleep apnea severity
Different antimuscarinics when combined with atomoxetine have differential effects on obstructive sleep apnea severity
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DOI：
10.1152/japplphysiol.01074.2020
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发表时间：
2021-05-01
影响因子：
3.3
通讯作者：
Eckert, Danny J.
中科院分区：
文献类型：
--
作者：
Aishah, Atqiya;Lim, Richard;Eckert, Danny J.
去甲肾上腺素能药物托莫西汀与抗毒蕈碱奥昔布宁的组合最近已被证明可改善上气道生理学并降低阻塞性睡眠呼吸暂停（OSA）的严重程度。然而，不同抗毒蕈碱药物与托莫西汀联合使用时的作用有限。本研究旨在确定托莫西汀联合两种不同M亚型受体选择性的抗毒蕈碱药物对OSA严重程度和上气道生理学的影响。10名严重OSA患者完成了一项双盲、随机、安慰剂对照、交叉试验。参与者在80 mg托莫西汀+ 5 mg琥珀酸索利那新（ato-sol）或80 mg托莫西汀+ 2 mg盐酸比哌立登（ato-bip）或安慰剂后完成了3项过夜实验室睡眠研究。比较两种情况下OSA的严重程度、睡眠稳定性（环路增益）、睡眠-觉醒阈值（通过会厌测压）、第二天主观嗜睡[Karolinska嗜睡量表（KSS）]和警觉性。与安慰剂相比，两种药物组合均未改变呼吸暂停/呼吸不足指数（P = 0.63）。Ato-sol导致呼吸事件向轻度转变，阻塞性呼吸暂停频率降低（13 +/- 14 vs. 22 +/- 17事件/h;平均值+/- SD，P = 0.04）和非快速眼动（NREM）期间呼吸不足增加（38 +/- 21 vs. 24 +/- 18起事件/h，P = 0.006），与安慰剂相比（83 +/- 4 vs. 80 +/-8%，P = 0.03），最低氧合改善。与安慰剂相比，两种组合均使环路增益降低了10%;睡眠效率和唤醒阈值没有改变。与安慰剂相比，Ato-bip减少了第二天的嗜睡（KSS = 4.3 +/- 2.2 vs. 5.6 +/- 1.6，P = 0.03）。托莫西汀+盐酸比哌立登可减少感觉到的嗜睡，托莫西汀+索利那新可适度改善OSA患者的上呼吸道功能，但程度低于最近发表的托莫西汀+奥昔布宁（广泛的M亚型受体选择性）结果。这些结果为去甲肾上腺素能和抗毒蕈碱药物对睡眠和呼吸的作用提供了新的机制见解，对OSA的药物治疗开发很重要。新&值得注意的是，与最近的研究结果相反，当托莫西汀与非特异性抗毒蕈碱药物奥昔布宁联合使用时，OSA的严重程度会大幅降低。（广泛的M亚型受体选择性），添加琥珀酸索利那新（M2和M3毒蕈碱受体选择性）或比哌立登（M1毒蕈碱受体选择性）与托莫西汀对睡眠期间的上气道功能有中度影响，其为去甲肾上腺素能和抗毒蕈碱剂对睡眠和呼吸的作用提供了机理上的见解，并且对于OSA的药物治疗开发是重要的。
The combination of the noradrenergic agent atomoxetine plus the antimuscarinic oxybutynin has recently been shown to improve upper airway physiology and reduce obstructive sleep apnea (OSA) severity. However, the effects of different antimuscarinics when combined with atomoxetine is limited. This study aimed to determine the effects of atomoxetine combined with two different antimuscarinics with varying M-subtype receptor selectivity on OSA severity and upper airway physiology. Ten people with predominantly severe OSA completed a double-blind, randomized, placebo-controlled, cross-over trial. Participants completed three overnight in-laboratory sleep studies after either 80 mg atomoxetine + 5 mg solifenacin succinate (ato-sol) or 80 mg atomoxetine + 2 mg biperiden hydrochloride (ato-bip) or placebo. OSA severity, ventilatory stability (loop gain), respiratory-arousal threshold (via epiglottic manometry), next-day subjective sleepiness [Karolinska Sleepiness Scale (KSS)], and alertness were compared between conditions. Neither drug combination altered the apnea/hypopnea index versus placebo (P = 0.63). Ato-sol caused a shift toward milder respiratory events with reduced frequency of obstructive apneas (13 +/- 14 vs. 22 +/- 17 events/h; means +/- SD, P = 0.04) and increased hypopneas during nonrapid eye movement (NREM) (38 +/- 21 vs. 24 +/- 18 events/h, P = 0.006) with improved nadir oxygenation versus placebo (83 +/- 4 vs. 80 +/- 8%, P = 0.03). Both combinations reduced loop gain by similar to 10% versus placebo; sleep efficiency and arousal threshold were unaltered. Ato-bip reduced next-day sleepiness versus placebo (KSS = 4.3 +/- 2.2 vs. 5.6 +/- 1.6, P = 0.03). Atomoxetine + biperiden hydrochloride reduces perceived sleepiness, and atomoxetine + solifenacin modestly improves upper airway function in people with OSA but to a lesser extent versus recently published atomoxetine + oxybutynin (broad M-subtype receptor selectivity) findings. These results provide novel mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.NEW & NOTEWORTHY In contrast to recent findings of major reductions in OSA severity when atomoxetine is combined with a nonspecific antimuscarinic, oxybutynin (broad M-subtype receptor selectivity), addition of solifenacin succinate (M2 and M3 muscarinic receptor selectivity) or biperiden (M1 muscarinic receptor selectivity) with atomoxetine had modest effects on upper airway function during sleep, which provide mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.