{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:51:42Z","timestamp":1790034702387,"version":"4.0.1"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2016,11,1]],"date-time":"2016-11-01T00:00:00Z","timestamp":1477958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Obstructive sleep apnea (OSA) has multiple pathophysiological causes. A low respiratory arousal threshold (ArTh) and a high loop gain (unstable ventilatory control) can contribute to recurrent respiratory events in patients with OSA. Prior studies have shown that donepezil, an acetylcholinesterase inhibitor, might improve OSA, but the mechanism is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine whether a single dose of donepezil lowers the apnea\u2013hypopnea index by modulating the ArTh or loop gain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this randomized, double-blind, crossover trial, 41 subjects with OSA underwent two polysomnograms with ArTh and loop gain evaluated, during which 10 mg of donepezil or placebo was administered.<\/jats:p>\n                    <jats:p>Measurements and Main Results: Compared with placebo, sleep efficiency (77.2 vs. 71.9%; P\u2009=\u20090.015) and total sleep time decreased with donepezil (372 vs. 351 min; P\u2009=\u20090.004). No differences were found in apnea\u2013hypopnea index (51.8 vs. 50.0 events\/h; P\u2009=\u20090.576) or nadir oxygen saturation as determined by pulse oximetry (80.3 vs. 81.1%; P\u2009=\u20090.241) between placebo and donepezil, respectively. ArTh was not significantly changed (\u201318.9 vs. \u201318.0 cm H2O; P\u2009=\u20090.394) with donepezil. As a whole group, loop gain (ventilatory response to a 1-cycle\/min disturbance) did not change significantly (P\u2009=\u20090.089).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A single dose of donepezil did not appear to affect the overall severity of OSA in this patient group, and no consistent effects on ArTh or loop gain were observed. Donepezil may have minor effects on sleep architecture.<\/jats:p>\n                    <jats:p>Clinical trial registered with www.clinicaltrials.gov (NCT02264353).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1513\/annalsats.201605-384oc","type":"journal-article","created":{"date-parts":[[2016,7,21]],"date-time":"2016-07-21T13:48:25Z","timestamp":1469108905000},"page":"2012-2018","source":"Crossref","is-referenced-by-count":30,"title":["The Effect of Donepezil on Arousal Threshold and Apnea\u2013Hypopnea Index. A Randomized, Double-Blind, Cross-Over Study"],"prefix":"10.1093","volume":"13","author":[{"given":"Yanru","family":"Li","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China"},{"name":"Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Owens","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Sands","sequence":"additional","affiliation":[{"name":"Division of Sleep Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"},{"name":"Department of Allergy, Immunology and Respiratory Medicine and Central Clinical School, Alfred and Monash University, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Orr","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Moraes","sequence":"additional","affiliation":[{"name":"Department of Psychobiology, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, Brazil; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"DeYoung","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Smales","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Jen","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California"},{"name":"Division of Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atul","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,11,1]]},"reference":[{"key":"2026020502580751000_bib1","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1093\/aje\/kws342","article-title":"Increased prevalence of sleep-disordered breathing in adults","volume":"177","author":"Peppard","year":"2013","journal-title":"Am J Epidemiol"},{"key":"2026020502580751000_bib2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1513\/pats.200708-119MG","article-title":"Adherence to continuous positive airway pressure therapy: the challenge to effective treatment","volume":"5","author":"Weaver","year":"2008","journal-title":"Proc Am Thorac Soc"},{"key":"2026020502580751000_bib3","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1164\/rccm.201303-0448OC","article-title":"Defining phenotypic causes of obstructive sleep apnea: identification of novel therapeutic targets","volume":"188","author":"Eckert","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"2026020502580751000_bib4","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1164\/rccm.201106-0975OC","article-title":"Termination of respiratory events with and without cortical arousal in obstructive sleep apnea","volume":"184","author":"Jordan","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026020502580751000_bib5","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1152\/japplphysiol.00649.2013","article-title":"Arousal from sleep: implications for obstructive sleep apnea pathogenesis and treatment","volume":"116","author":"Eckert","year":"2014","journal-title":"J Appl Physiol (1985)"},{"key":"2026020502580751000_bib6","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1152\/japplphysiol.00561.2007","article-title":"Mechanisms of breathing instability in patients with obstructive sleep apnea","volume":"103","author":"Younes","year":"2007","journal-title":"J Appl Physiol (1985)"},{"key":"2026020502580751000_bib7","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1513\/AnnalsATS.201408-399OC","article-title":"Trazodone Effects on obstructive sleep apnea and non-REM arousal threshold","volume":"12","author":"Smales","year":"2015","journal-title":"Ann Am Thorac Soc"},{"key":"2026020502580751000_bib8","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1042\/CS20100588","article-title":"Eszopiclone increases the respiratory arousal threshold and lowers the apnoea\/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold","volume":"120","author":"Eckert","year":"2011","journal-title":"Clin Sci (Lond)"},{"key":"2026020502580751000_bib9","doi-asserted-by":"crossref","first-page":"811","DOI":"10.5665\/sleep.3596","article-title":"Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold","volume":"37","author":"Eckert","year":"2014","journal-title":"Sleep"},{"key":"2026020502580751000_bib10","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1113\/jphysiol.2011.223925","article-title":"Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea","volume":"590","author":"Edwards","year":"2012","journal-title":"J Physiol"},{"key":"2026020502580751000_bib11","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.resp.2008.05.019","article-title":"Effect of oxygen in obstructive sleep apnea: role of loop gain","volume":"162","author":"Wellman","year":"2008","journal-title":"Respir Physiol Neurobiol"},{"key":"2026020502580751000_bib12","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.sleep.2011.09.014","article-title":"Beneficial effect of donepezil on obstructive sleep apnea: a double-blind, placebo-controlled clinical trial","volume":"13","author":"Sukys-Claudino","year":"2012","journal-title":"Sleep Med"},{"key":"2026020502580751000_bib13","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1378\/chest.07-1446","article-title":"Donepezil improves obstructive sleep apnea in Alzheimer disease: a double-blind, placebo-controlled study","volume":"133","author":"Moraes","year":"2008","journal-title":"Chest"},{"issue":"10","key":"2026020502580751000_bib14","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1016\/j.metabol.2006.07.007","article-title":"The pharmacology of wakefulness","volume":"55","author":"Miller","year":"2006","journal-title":"Metabolism"},{"key":"2026020502580751000_bib15","doi-asserted-by":"crossref","first-page":"e0130130","DOI":"10.1371\/journal.pone.0130130","article-title":"Silencing of cholinergic basal forebrain neurons using archaerhodopsin prolongs slow-wave sleep in mice","volume":"10","author":"Shi","year":"2015","journal-title":"PLoS One"},{"key":"2026020502580751000_bib16","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S1569-9048(02)00043-5","article-title":"Contribution of cholinergic systems to state-dependent modulation of respiratory control","volume":"131","author":"Bellingham","year":"2002","journal-title":"Respir Physiol Neurobiol"},{"key":"2026020502580751000_bib17","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1113\/jphysiol.2006.121889","article-title":"Genioglossus premotoneurons and the negative pressure reflex in rats","volume":"579","author":"Chamberlin","year":"2007","journal-title":"J Physiol"},{"key":"2026020502580751000_bib18","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1152\/japplphysiol.90670.2008","article-title":"Hypoglossal premotor neurons of the intermediate medullary reticular region express cholinergic markers","volume":"105","author":"Volgin","year":"2008","journal-title":"J Appl Physiol (1985)"},{"key":"2026020502580751000_bib19","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1093\/sleep\/22.5.667","article-title":"Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research: the report of an American Academy of Sleep Medicine Task Force","volume":"22","author":"American Academy of Sleep Medicine Task Force","year":"1999","journal-title":"Sleep"},{"key":"2026020502580751000_bib20","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1164\/rccm.201404-0718OC","article-title":"Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea","volume":"190","author":"Edwards","year":"2014","journal-title":"Am J Respir Crit Care Med"},{"key":"2026020502580751000_bib21","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1183\/09031936.00062914","article-title":"Quantifying the ventilatory control contribution to sleep apnoea using polysomnography","volume":"45","author":"Terrill","year":"2015","journal-title":"Eur Respir J"},{"key":"2026020502580751000_bib22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0306-4522(00)00335-3","article-title":"Donepezil dose-dependently inhibits acetylcholinesterase activity in various areas and in the presynaptic cholinergic and the postsynaptic cholinoceptive enzyme-positive structures in the human and rat brain","volume":"101","author":"Kasa","year":"2000","journal-title":"Neuroscience"},{"key":"2026020502580751000_bib23","doi-asserted-by":"crossref","first-page":"199","DOI":"10.2165\/00002512-200016030-00005","article-title":"Donepezil: a review of its use in Alzheimer\u2019s disease","volume":"16","author":"Dooley","year":"2000","journal-title":"Drugs Aging"},{"key":"2026020502580751000_bib24","doi-asserted-by":"crossref","first-page":"555","DOI":"10.5665\/sleep.2544","article-title":"A mechanism for upper airway stability during slow wave sleep","volume":"36","author":"McSharry","year":"2013","journal-title":"Sleep"},{"key":"2026020502580751000_bib25","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1152\/japplphysiol.90408.2008","article-title":"Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders","volume":"105","author":"Younes","year":"2008","journal-title":"J Appl Physiol (1985)"},{"key":"2026020502580751000_bib26","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1038\/sj.npp.1300906","article-title":"Differential effects of the muscarinic M1 receptor agonist RS-86 and the acetylcholine-esterase inhibitor donepezil on REM sleep regulation in healthy volunteers","volume":"31","author":"Nissen","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"2026020502580751000_bib27","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1055\/s-2006-950396","article-title":"The effect of donepezil on sleep in elderly, healthy persons: a double-blind placebo-controlled study","volume":"39","author":"Schredl","year":"2006","journal-title":"Pharmacopsychiatry"},{"key":"2026020502580751000_bib28","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S0006-3223(01)01287-2","article-title":"The effects of an orally administered cholinergic agonist on REM sleep in major depression","volume":"51","author":"Perlis","year":"2002","journal-title":"Biol Psychiatry"},{"key":"2026020502580751000_bib29","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1093\/sleep\/19.6.485","article-title":"Nocturnal polysomnography with and without continuous pharyngeal and esophageal pressure measurements","volume":"19","author":"Skatvedt","year":"1996","journal-title":"Sleep"},{"key":"2026020502580751000_bib30","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1007\/s00405-013-2771-y","article-title":"The influence of pharyngeal and esophageal pressure measurements on the parameters of polysomnography","volume":"271","author":"Stuckenbrock","year":"2014","journal-title":"Eur Arch Otorhinolaryngol"},{"key":"2026020502580751000_bib31","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0022-3956(01)00019-X","article-title":"The first-night effect may last more than one night","volume":"35","author":"Le Bon","year":"2001","journal-title":"J Psychiatr Res"}],"container-title":["Annals of the American Thoracic Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/annalsats\/article-pdf\/13\/11\/2012\/66768940\/annalsats_13_11_2012.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/annalsats\/article-pdf\/13\/11\/2012\/66768940\/annalsats_13_11_2012.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T07:58:18Z","timestamp":1770278298000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/annalsats\/article\/13\/11\/2012\/8449540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,1]]},"references-count":31,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2016,11,1]]},"published-print":{"date-parts":[[2016,11,1]]}},"URL":"https:\/\/doi.org\/10.1513\/annalsats.201605-384oc","relation":{},"ISSN":["2329-6933","2325-6621"],"issn-type":[{"value":"2329-6933","type":"print"},{"value":"2325-6621","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,11]]},"published":{"date-parts":[[2016,11,1]]}}}