20年前的1995年,戴维·怀特(David White)博士在澳大利亚的一次睡眠会议上被要求凝视未来,并推测我们将如何治疗睡眠呼吸暂停患者。怀特博士说:“如果CPAP仍然是我们在20年内对待睡眠呼吸暂停的方式,我们将成为一个失败的领域!”在观众中,除了科林·沙利文(Colin Sullivan)博士之外,第一个描述了人类持续积极的气道压力(CPAP)的人。
Dr. Sullivan disagreed and speculated that CPAP would still be present but would become as comfortable and normalized as a pair of eyeglasses. As it turns out, it appears that neither of these legendary sleep stalwarts was quite accurate. CPAP is still the primary therapy for most sleep apnea patients. While great strides have been made to CPAP masks and headgear designs, they hardly can be considered as comfortable as eyeglasses.
那么,对于睡眠呼吸暂停治疗和诊断,不久的将来是什么样的?我们生活在睡眠测试设备在比赛中变得越来越强大和动态的时代,成为实验室质量的家庭睡眠测试(HST)选项。这一进展不仅限于我们可以测试和诊断患者的效率和方便程度,而且还限制了如何在诊断后最好地治疗其睡眠呼吸暂停。睡眠药物似乎处于令人兴奋而充满活力的时期。根据怀特博士的说法,以药丸形式的非CPAP面具选项并不遥远。
I had the pleasure to discuss the future of sleep medicine with Dr. White and it was a fascinating and exciting discussion. Dr. White is a legend in the sleep medicine field and has played an important role in the exploration of sleep phenotyping. He has held many titles in his career in sleep medicine, including director of the sleep disorders program at Brigham and Young Hospital, medical officer and consultant for Philips Respironics and past president of the American Academy of Sleep Medicine (AASM).
His work revolves around the mindset that if we can understand the cause of apnea for each individual, then a customized solution can be offered that is specific to the unique needs of each patient. There are several different physiological variables that occur and cause patients to develop sleep apnea. The focus will be on identification of each patient's pathology and physiology. Therefore, treatment will vary from the options available today. Other than CPAP, oral appliances and surgical treatments, few other options are available right now. Of course, CPAP therapy dominates the therapeutic treatment arena.
While many patients are treated and do well with CPAP therapy, many others struggle with the mask and hose option, while others are not even diagnosed, in part because they "don't want to sleep with a mask." What follows is a debrief of my conversation with Dr. White on a new, oral, CPAP alternative.
Dr. White, you are currently involved with a few new alternatives for CPAP, one of which is with Apnimed. You're also involved in and/or knowledgeable about other fascinating therapy modes currently in human trials. One such non-mask option being the Inspire hypoglossal nerve stimulation.
Inspire is doing very well. It's interesting technology! The other one that is out there that you should look at is CRYOSA. CRY means cold. You know how some people do cold sculpting of the stomach to try and get rid of fat? They are doing something similar- cold sculpting the tongue. There is reasonable data that sleep apnea patients have an increased amount of fat in their tongues so researchers are applying cooling to patients' tongues to get rid of "tongue fat" to treat sleep apnea. They are in human trials now so that's evolving.
看来拐角处有有趣的事件!那么,对他们的药理试验的工作到底是什么?
APNIMED的主要产品是AD109,这是两种药物 - 阿诺西汀和芳糖丁蛋白的组合,它们可以一起工作,以减轻睡眠期间气道肌肉的崩溃。阿托西汀是一种去甲肾上腺素的再摄取抑制剂。我们选择这样的药物的原因是,动物(大鼠)数据表明,睡眠过程中肌肉激活的损失,尤其是在非比型眼运动期间咽部扩张器肌肉激活(NREM)睡眠的损失,主要是由于去甲肾上腺素输入减少了控制肌肉的运动神经元,即产生去甲肾上腺素的大脑中的神经元降低了发射率。它们直接投射到激活您上呼吸道肌肉的神经上。当您入睡时,这些去甲肾上腺素神经元减少了射击,并最终退出主要是在快速眼动(REM)睡眠中发射。您正在做的是失去这些肌肉的兴奋性神经输入,它们的活性下降了。再摄取抑制剂增加了这些神经元之间突触中的去甲肾上腺素的量并增加了肌肉活性。去甲肾上腺素水平的升高增加了大鼠的肌肉活动。因此,去甲肾上腺素再摄取抑制剂是一种选择。
Aroxybutynin is an anticholinergic. When you go into REM sleep there is active inhibition of virtually all muscles. The skeletal muscles are paralyzed when you are in REM sleep. However, the mechanism of this reduced muscle activity during REM sleep in the upper airway muscles is different from other skeletal muscles. The pharyngeal muscles have active cholinergic inhibition during REM sleep. And so, we thought let's get an anticholinergic to work in REM sleep.
我们认为非快速眼动和去甲肾上腺素再摄取an anticholinergic for REM sleep might work and did a study with this combination on approximately 20 human patients in Boston out of our lab.
研究结果如何?您可以与读者分享任何见解吗?
There was a substantial and clinically important reduction in sleep apnea severity on this drug combination, which we found very exciting. We also demonstrated that muscle activity went up substantially during sleep on these medications.
在此之后,进一步的工作,我们很舒服去甲肾上腺素通过激活肌肉来工作。尚不清楚芳氧基丁素的工作原理尚不清楚。它是纯粹是作为抗毒剂剂作为阻止这种抑制作用的一种手段,还是仅仅使患者镇静并克服了阿托莫西汀的警觉作用?我们目前尚不完全了解这一点,但确实知道两种药物的组合确实很好。
To wrap things up, what are three takeaways that we should know about this new type of "sleeping pill for apnea"?
第一,很有可能在接下来的两到四年中会出现药物来治疗OSA。第二,它将治疗合理的睡眠呼吸暂停患者,但不是每个人。第三,与每个代理相关的副作用将是适中的。
与怀特博士交谈是一个很棒的荣幸,这是对不久的将来的睡眠医学的又一令人着迷的表情。每天我们都会介绍新的诊断和治疗研究与开发。这种进步肯定会成为睡眠医学领域的主要破坏者,并且对于数百万遭受睡眠呼吸暂停的解决方案 - 尤其是那些不会或无法忍受CPAP口罩的解决方案!
Author's Note:自从我与怀特博士的对话以来,Apnimed已获得美国食品药品监督管理局(FDA)快速指定。该名称旨在促进和加快对新药的审查,以满足未满足的医疗需求。根据APNIMED公司新闻发布从2022年6月28日起, they are completing Phase 2 clinical trials and hope to then meet with the FDA to discuss the Phase 3 development program.
Brendan Duffy, RPSGT, RST, CCSH