阿托莫西汀联合大麻隆治疗阻塞性睡眠呼吸暂停：一项剂量递增、开放标签试验。
The combination of atomoxetine and dronabinol for the treatment of obstructive sleep apnea: a dose-escalating, open-label trial.
机构信息
Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.
Santa Monica Clinical Trials, Los Angeles, California.
出版信息
J Clin Sleep Med. 2023 Jul 1;19(7):1183-1190. doi: 10.5664/jcsm.10528.
STUDY OBJECTIVES
The potential sedative effect of dronabinol and the high expression of cannabinoid receptors on the hypoglossal motor nuclei makes this agent a good candidate for obstructive sleep apnea (OSA) pharmacotherapy to be tested with atomoxetine, a noradrenergic reuptake inhibitor that reduced OSA severity in combination with oxybutynin. Here we tested the effect of atomoxetine 80 mg plus dronabinol (Ato-Dro) at 2 different doses (5 and 10 mg) vs. baseline and atomoxetine alone in a 2-center, open-label, dose-escalating trial. The primary outcome was the effect of Ato-Dro vs. baseline on OSA severity (apnea-hypopnea index, hypopneas associated with 4% oxygen desaturation). Safety of the combination and self-reported outcomes were also assessed.
METHODS
Fifteen patients with OSA received progressively increasing Ato-Dro doses (dose escalation was performed every week, starting from Ato-Dro 40-2.5 mg, then 80-5 mg and finally 80-10 mg). A clinical, in-lab polysomnography was performed at baseline, on Ato-Dro 80-5 and Ato-Dro 80-10 mg.
RESULTS
Ato-Dro 80-10 mg did not significantly reduce apnea-hypopnea index, hypopneas associated with 4% oxygen desaturation, and hypoxic burden and yielded limited clinical benefit vs. baseline and atomoxetine alone. However, Ato-Dro 80-5 mg did improve OSA severity (Δapnea-hypopnea index = 8.3[0.3, 16.3] events/h; mean [confidence interval]; Δhypoxic burden = 37.7[12.5, 62.7] %min/h) and multiple self-reported outcomes vs. baseline and/or atomoxetine alone. Ato-Dro administration was characterized by several potentially harmful side effects and treatment discontinuation in 1/3 of cases.
CONCLUSIONS
Ato-Dro 80-5 mg might be useful to reduce OSA severity and lead to self-reported improvement in those who could tolerate the combination. However, given the numerous side effects and the exploratory nature of this open-label study, our results warrant further validation in larger trials.
CLINICAL TRIAL REGISTRATION
Registry: ClinicalTrials.gov; Title: Study for Efficacy and Dose Escalation of AD313 + Atomoxetine (SEED) (SEED); URL: https://clinicaltrials.gov/ct2/show/NCT05101122; Identifier: NCT05101122.
CITATION
Messineo L, Norman D, Ojile J. The combination of atomoxetine and dronabinol for the treatment of obstructive sleep apnea: a dose-escalating, open-label trial. . 2023;19(7):1183-1190.
研究目的
大麻隆具有潜在的镇静作用，大麻素受体在舌下运动核中的高表达，这使得这种药物成为阻塞性睡眠呼吸暂停（OSA）药物治疗的候选药物，可以与托莫西汀联合使用进行测试，托莫西汀是一种去甲肾上腺素再摄取抑制剂，与奥昔布宁联合使用可降低 OSA 的严重程度。在这里，我们在一项双中心、开放标签、剂量递增试验中测试了托莫西汀 80mg 加大麻隆（Ato-Dro）在 2 种不同剂量（5mg 和 10mg）与基线和托莫西汀单药治疗的效果。主要结局是 Ato-Dro 与基线相比对 OSA 严重程度（呼吸暂停低通气指数、与 4%氧去饱和相关的低通气）的影响。还评估了该组合的安全性和自我报告的结果。
方法
15 名 OSA 患者接受了递增的 Ato-Dro 剂量（剂量递增每周进行一次，从 Ato-Dro 40-2.5mg 开始，然后是 80-5mg，最后是 80-10mg）。在基线、Ato-Dro 80-5 和 Ato-Dro 80-10mg 时进行了临床、实验室多导睡眠图检查。
结果
Ato-Dro 80-10mg 并未显著降低呼吸暂停低通气指数、与 4%氧去饱和相关的低通气、缺氧负担，与基线和托莫西汀单药治疗相比，临床获益有限。然而，Ato-Dro 80-5mg 确实改善了 OSA 严重程度（Δ呼吸暂停低通气指数=8.3[0.3, 16.3]次/小时；均值[置信区间]；Δ缺氧负担=37.7[12.5, 62.7]%min/h）和多项自我报告的结果，与基线和/或托莫西汀单药治疗相比。Ato-Dro 给药的特点是有几种潜在的有害副作用，在 1/3 的病例中导致治疗中断。
结论
Ato-Dro 80-5mg 可能有助于降低 OSA 严重程度，并导致那些能耐受该联合用药的患者自我报告改善。然而，鉴于众多副作用和这项开放标签研究的探索性性质，我们的结果需要在更大的试验中进一步验证。
临床试验注册
ClinicalTrials.gov；标题：AD313+托莫西汀（SEED）（SEED）的疗效和剂量递增研究；网址：https://clinicaltrials.gov/ct2/show/NCT05101122；标识符：NCT05101122。
参考文献
Messineo L, Norman D, Ojile J. 联合使用托莫西汀和大麻隆治疗阻塞性睡眠呼吸暂停：一项递增剂量、开放标签试验。 （2023）；19(7)：1183-1190。
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