Pharmacotherapy for obstructive sleep apnea: targeting specific pathophysiological traits

References

• Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019;7(8):687–698. doi: 10.1016/S2213-2600(19)30198-5
   PubMed Web of Science ®Google Scholar
• Young T, Palta M, Dempsey J, et al. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin sleep cohort study. WMJ. 2009;108(5):246–249.
   PubMedGoogle Scholar
• Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006–1014. doi: 10.1093/aje/kws342
   PubMed Web of Science ®Google Scholar
• Heinzer R, Vat S, Marques-Vidal P, et al. Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study. Lancet Respir Med. 2015;3(4):310–318. doi: 10.1016/S2213-2600(15)00043-0
   PubMed Web of Science ®Google Scholar
• Dempsey JA, Veasey SC, Morgan BJ, et al. Pathophysiology of sleep apnea. Physiol Rev. 2010;90(1):47–112. doi: 10.1152/physrev.00043.2008
   PubMed Web of Science ®Google Scholar
• Sánchez-de-la-Torre M, Campos-Rodriguez F, Barbé F. Obstructive sleep apnoea and cardiovascular disease. Lancet Respir Med. 2013;1(1):61–72. doi: 10.1016/S2213-2600(12)70051-6
   PubMed Web of Science ®Google Scholar
• Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study JAMA. 2000;283(14):1829–1836. doi: 10.1001/jama.283.14.1829
   Google Scholar
• Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342(19):1378–1384. doi: 10.1056/NEJM200005113421901
   PubMed Web of Science ®Google Scholar
• Hung J, Whitford EG, Parsons RW, et al. Association of sleep apnoea with myocardial infarction in men. Lancet. 1990;336(8710):261–264. doi: 10.1016/0140-6736(90)91799-G
   PubMed Web of Science ®Google Scholar
• Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the sleep heart health study. Am J Respir Crit Care Med. 2001;163(1):19–25. doi: 10.1164/ajrccm.163.1.2001008
   PubMed Web of Science ®Google Scholar
• Gami AS, Howard DE, Olson EJ, et al. Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med. 2005;352(12):1206–1214. doi: 10.1056/NEJMoa041832
   PubMed Web of Science ®Google Scholar
• Martínez-García MA, Campos-Rodríguez F, Catalán-Serra P, et al. Cardiovascular mortality in obstructive sleep apnea in the elderly: role of long-term continuous positive airway pressure treatment: a prospective observational study. Am J Respir Crit Care Med. 2012;186(9):909–916. doi: 10.1164/rccm.201203-0448OC
   PubMed Web of Science ®Google Scholar
• Schwab RJ. Properties of tissues surrounding the upper airway. Sleep. 1996;19(10 Suppl):S170–174. doi: 10.1093/sleep/19.suppl_10.170
   PubMed Web of Science ®Google Scholar
• Eckert DJ, White DP, Jordan AS, et al. Defining phenotypic causes of obstructive sleep apnea. identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013;188(8):996–1004. doi: 10.1164/rccm.201303-0448OC
   PubMed Web of Science ®Google Scholar
• Wellman A, Eckert DJ, Jordan AS, et al. A method for measuring and modeling the physiological traits causing obstructive sleep apnea. J Appl Physiol. 2011;110(6):1627–1637. doi: 10.1152/japplphysiol.00972.2010
   PubMed Web of Science ®Google Scholar
• Wellman A, Edwards BA, Sands SA, et al. A simplified method for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol. 2013;114(7):911–922. doi: 10.1152/japplphysiol.00747.2012
   PubMed Web of Science ®Google Scholar
• Younes M. Contributions of upper airway mechanics and control mechanisms to severity of obstructive apnea. Am J Respir Crit Care Med. 2003;168(6):645–658. doi: 10.1164/rccm.200302-201OC
   PubMed Web of Science ®Google Scholar
• Gleadhill IC, Schwartz AR, Schubert N, et al. Upper airway collapsibility in snorers and in patients with obstructive hypopnea and apnea. Am Rev Respir Dis. 1991;143(6):1300–1303. doi: 10.1164/ajrccm/143.6.1300
   PubMed Web of Science ®Google Scholar
• Loewen AHS, Ostrowski M, Laprairie J, et al. Response of genioglossus muscle to increasing chemical drive in sleeping obstructive apnea patients. Sleep. 2011;34(8):1061–1073. doi: 10.5665/SLEEP.1162
   PubMed Web of Science ®Google Scholar
• Younes M. Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders. J Appl Physiol. 2008;105(5):1389–1405. doi: 10.1152/japplphysiol.90408.2008
   PubMed Web of Science ®Google Scholar
• Wellman A, Jordan AS, Malhotra A, et al. Ventilatory control and airway anatomy in obstructive sleep apnea. Am J Respir Crit Care Med. 2004;170(11):1225–1232. doi: 10.1164/rccm.200404-510OC
   PubMed Web of Science ®Google Scholar
• Weaver TE, Maislin G, Dinges DF, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep. 2007;30(6):711–719. doi: 10.1093/sleep/30.6.711
   PubMed Web of Science ®Google Scholar
• Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc. 2008;5(2):173–178. doi: 10.1513/pats.200708-119MG
   PubMedGoogle Scholar
• Weaver TE, Sawyer AM. Adherence to continuous positive airway pressure treatment for obstructive sleep apnoea: implications for future interventions. Indian J Med Res. 2010;131:245–258.
   PubMed Web of Science ®Google Scholar
• Morrone E, Giordano A, Carli S, et al. Something is changing in adherence to CPAP therapy: real world data after 1 year of treatment in patients with obstructive sleep apnoea. Eur Respir J. 2020;55(3):1901419. doi: 10.1183/13993003.01419-2019
   PubMed Web of Science ®Google Scholar
• Randerath W, Verbraecken J, Raaff C, et al. European respiratory society guideline on non-CPAP therapies for obstructive sleep apnoea. Eur Respir Rev. 2021;30(162):210200. doi: 10.1183/16000617.0200-2021
   PubMed Web of Science ®Google Scholar
• Rosa D, Perger E, Villa G, et al. Pharmacotherapy for obstructive sleep apnoea and coupled life: A descriptive phenomenological study of a complex interaction. Healthcare (Basel). 2022;10(10):1859. doi: 10.3390/healthcare10101859
   PubMedGoogle Scholar
• Rosa D, Amigoni C, Rimoldi E, et al. Obstructive sleep apnea and adherence to Continuous Positive Airway Pressure (CPAP) Treatment: Let’s talk about partners! Healthcare (Basel). 2022;10(5):943. doi: 10.3390/healthcare10050943
   PubMedGoogle Scholar
• Rapelli G, Pietrabissa G, Manzoni GM, et al. Improving CPAP adherence in adults with obstructive sleep apnea syndrome: A scoping review of motivational interventions. Front Psychol. 2021;12:705364. doi:10.3389/fpsyg.2021.705364
   PubMed Web of Science ®Google Scholar
• Perger E, Jutant EM, Redolfi S. Targeting volume overload and overnight rostral fluid shift: A new perspective to treat sleep apnea. Sleep Med Rev. 2018;42:160–170. doi: 10.1016/j.smrv.2018.07.008
   PubMed Web of Science ®Google Scholar
• Schwartz AR, Barnes M, Hillman D, et al. Acute upper airway responses to hypoglossal nerve stimulation during sleep in obstructive sleep apnea. Am J Respir Crit Care Med. 2012;185(4):420–426. doi: 10.1164/rccm.201109-1614OC
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Messineo L, Sands SA, et al. The combination of atomoxetine and oxybutynin greatly reduces obstructive sleep apnea severity. A randomized, placebo-controlled, double-blind crossover trial. Am J Respir Crit Care Med. 2019;199(10):1267–1276. doi: 10.1164/rccm.201808-1493OC
   PubMed Web of Science ®Google Scholar
• Perger E, Taranto Montemurro L, Rosa D, et al. Reboxetine plus oxybutynin for OSA treatment: A 1-week, randomized, placebo-controlled, double-blind crossover trial. Chest. 2022;161(1):237–247. doi: 10.1016/j.chest.2021.08.080
   PubMed Web of Science ®Google Scholar
• Eckert DJ, Malhotra A, Wellman A, et al. Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold. Sleep. 2014;37(4):811–819. doi: 10.5665/sleep.3596
   PubMed Web of Science ®Google Scholar
• Hedner J, Stenlöf K, Zou D, et al. A randomized controlled clinical trial exploring safety and tolerability of sulthiame in sleep apnea. Am J Respir Crit Care Med. 2022;205(12):1461–1469. doi: 10.1164/rccm.202109-2043OC
   PubMed Web of Science ®Google Scholar
• Sforza E, Bacon W, Weiss T, et al. Upper airway collapsibility and cephalometric variables in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2000;161(2 Pt 1):347–352. doi: 10.1164/ajrccm.161.2.9810091
   PubMed Web of Science ®Google Scholar
• Kirkness JP, Schwartz AR, Schneider H, et al. Contribution of male sex, age, and obesity to mechanical instability of the upper airway during sleep. J Appl Physiol (1985). 2008;104(6):1618–1624. doi: 10.1152/japplphysiol.00045.2008
   PubMed Web of Science ®Google Scholar
• Malhotra A, Huang Y, Fogel RB, et al. The male predisposition to pharyngeal collapse: importance of airway length. Am J Respir Crit Care Med. 2002;166(10):1388–1395. doi: 10.1164/rccm.2112072
   PubMed Web of Science ®Google Scholar
• Schwab RJ, Pasirstein M, Pierson R, et al. Identification of upper airway anatomic risk factors for obstructive sleep apnea with volumetric magnetic resonance imaging. Am J Respir Crit Care Med. 2003;168(5):522–530. doi: 10.1164/rccm.200208-866OC
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Sands S, Azarbarzin A, et al. Impact of cold and flu medication on obstructive sleep apnoea and its underlying traits: A pilot randomized controlled trial. Respirology. 2021;26(5):485–492. doi: 10.1111/resp.14009
   PubMed Web of Science ®Google Scholar
• Perger E, Blaise S, Vermorel C, et al. Subjects with venous insufficiency have high risk of obstructive sleep apnea in relationship to fluid shift. Sleep Med. 2020;72:135–137. doi:10.1016/j.sleep.2020.03.033
   PubMed Web of Science ®Google Scholar
• Lyons OD, Bradley TD. Heart failure and sleep apnea. Can J Cardiol. 2015;31(7):898–908. doi: 10.1016/j.cjca.2015.04.017
   PubMed Web of Science ®Google Scholar
• Lin CH, Perger E, Lyons OD. Obstructive sleep apnea and chronic kidney disease. Curr Opin Pulm Med. 2018;24(6):549–554. doi: 10.1097/MCP.0000000000000525
   PubMed Web of Science ®Google Scholar
• White LH, Bradley TD. Role of nocturnal rostral fluid shift in the pathogenesis of obstructive and central sleep apnoea. Journal Of Physiology. 2013;591(5):1179–1193. doi: 10.1113/jphysiol.2012.245159
   PubMed Web of Science ®Google Scholar
• Hudgel DW, Patel SR, Ahasic AM, et al. The role of weight management in the treatment of adult obstructive sleep apnea. An official american thoracic society clinical practice guideline. Am J Respir Crit Care Med. 2018;198(6):e70–e87. doi: 10.1164/rccm.201807-1326ST
   PubMed Web of Science ®Google Scholar
• Young T, Peppard PE, Taheri S. Excess weight and sleep-disordered breathing. J Appl Physiol. 2005;99(4):1592–1599. doi: 10.1152/japplphysiol.00587.2005
   PubMed Web of Science ®Google Scholar
• Schwartz AR, Patil SP, Laffan AM, et al. Obesity and obstructive sleep apnea: pathogenic mechanisms and therapeutic approaches. Proc Am Thorac Soc. 2008;5(2):185–192. doi: 10.1513/pats.200708-137MG
   PubMedGoogle Scholar
• Perger E, Aron-Wisnewsky J, Arnulf I, et al. Diagnostic approach to sleep disordered-breathing among patients with grade III obesity. Sleep Med. 2021;82:18–22. doi: 10.1016/j.sleep.2021.03.024
   PubMed Web of Science ®Google Scholar
• Genta PR, Schorr F, Eckert DJ, et al. Upper airway collapsibility is associated with obesity and hyoid position. Sleep. 2014;37(10):1673–1678. doi: 10.5665/sleep.4078
   PubMed Web of Science ®Google Scholar
• Wang SH, Keenan BT, Wiemken A, et al. Effect of weight loss on upper airway anatomy and the apnea-hypopnea index. The importance of tongue fat. Am J Respir Crit Care Med. 2020;201(6):718–727. doi: 10.1164/rccm.201903-0692OC
   PubMed Web of Science ®Google Scholar
• Jung SY, Park DC, Kim SH, et al. Role of obesity in otorhinolaryngologic diseases. Curr Allergy Asthma Rep. 2019;19(7):34. doi: 10.1007/s11882-019-0865-3
   PubMed Web of Science ®Google Scholar
• Sands SA, Eckert DJ, Jordan AS, et al. Enhanced upper-airway muscle responsiveness is a distinct feature of overweight/obese individuals without sleep apnea. Am J Respir Crit Care Med. 2014;190(8):930–937. doi: 10.1164/rccm.201404-0783OC
   PubMed Web of Science ®Google Scholar
• Jones RL, Nzekwu MM. The effects of body mass index on lung volumes. Chest. 2006;130(3):827–833. doi: 10.1378/chest.130.3.827
   PubMed Web of Science ®Google Scholar
• Chirinos JA, Gurubhagavatula I, Teff K, et al. CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med. 2014;370(24):2265–2275. doi: 10.1056/NEJMoa1306187
   PubMed Web of Science ®Google Scholar
• Bailly S, Fabre O, Cals-Maurette M, et al. Impact of a weight-loss rehabilitation program on sleep apnea risk and subjective sleepiness in patients with overweight/obesity: The Dietsleep study. J Clin Med. 2022;11(23):6890. doi: 10.3390/jcm11236890
   PubMed Web of Science ®Google Scholar
• Cornier MA. A review of current guidelines for the treatment of obesity. Am J Manag Care. 2022;28(15 Suppl):S288–s296.
   PubMed Web of Science ®Google Scholar
• Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013;37(11):1443–1451. doi: 10.1038/ijo.2013.120
   PubMed Web of Science ®Google Scholar
• Jelsing J, Vrang N, Hansen G, et al. Liraglutide: short-lived effect on gastric emptying – long lasting effects on body weight. Diab Obes Metab. 2012;14(6):531–538. doi: 10.1111/j.1463-1326.2012.01557.x
   PubMed Web of Science ®Google Scholar
• Friedrichsen M, Breitschaft A, Tadayon S, et al. The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity. Diab Obes Metab. 2021;23(3):754–762. doi: 10.1111/dom.14280
   PubMed Web of Science ®Google Scholar
• Greenway FL, Whitehouse MJ, Guttadauria M, et al. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring). 2009;17(1):30–39. doi: 10.1038/oby.2008.461
   PubMed Web of Science ®Google Scholar
• Rucker D, Padwal R, Li SK, et al. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ. 2007;335(7631):1194–1199. doi: 10.1136/bmj.39385.413113.25
   PubMed Web of Science ®Google Scholar
• Tanriover C, Ucku D, Akyol M, et al. Potential use of SGLT-2 inhibitors in obstructive sleep apnea: A new treatment on the horizon. Sleep Breath. 2022;27(1):77–89. doi: 10.1007/s11325-022-02606-1
   PubMed Web of Science ®Google Scholar
• Gaisl T, Haile SR, Thiel S, et al. Efficacy of pharmacotherapy for OSA in adults: A systematic review and network meta-analysis. Sleep Med Rev. 2019;46:74–86. DOI:10.1016/j.smrv.2019.04.009
   PubMed Web of Science ®Google Scholar
• Blackman A, Foster GD, Zammit G, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE sleep apnea randomized clinical trial. Int J Obes (Lond). 2016;40(8):1310–1319. doi: 10.1038/ijo.2016.52
   PubMed Web of Science ®Google Scholar
• Sprung VS, Kemp GJ, Wilding JP, et al. Randomised, cOntrolled multicentre trial of 26 weeks subcutaneous liraglutide (a glucagon-like peptide-1 receptor agonist), with or without contiNuous positive airway pressure (CPAP), in patients with type 2 diabetes mellitus (T2DM) and obstructive sleep apnoEa (OSA) (ROMANCE): study protocol assessing the effects of weight loss on the apnea-hypnoea index (AHI). BMJ Open. 2020;10(7):e038856. doi: 10.1136/bmjopen-2020-038856
   PubMed Web of Science ®Google Scholar
• Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–216. doi: 10.1056/NEJMoa2206038
   PubMed Web of Science ®Google Scholar
• Srivastava G, Apovian C. Future pharmacotherapy for obesity: New anti-obesity drugs on the horizon. Curr Obes Rep. 2018;7(2):147–161. doi: 10.1007/s13679-018-0300-4
   PubMed Web of Science ®Google Scholar
• Redolfi S, Yumino D, Ruttanaumpawan P, et al. Relationship between overnight rostral fluid shift and obstructive sleep apnea in nonobese men. Am J Respir Crit Care Med. 2009;179(3):241–246. doi: 10.1164/rccm.200807-1076OC
   PubMed Web of Science ®Google Scholar
• Inami T, Lyons OD, Perger E, et al. Effect of ultrafiltration on sleep apnea and cardiac function in end-stage renal disease. Am J Nephrol. 2020;51(2):139–146. doi: 10.1159/000505445
   PubMed Web of Science ®Google Scholar
• Lyons OD, Inami T, Perger E, et al. The effect of fluid overload on sleep apnoea severity in haemodialysis patients. Eur Respir J. 2017;49(4):1601789. doi: 10.1183/13993003.01789-2016
   PubMed Web of Science ®Google Scholar
• Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med. 2001;344(2):102–107. doi: 10.1056/NEJM200101113440204
   PubMed Web of Science ®Google Scholar
• Redolfi S, Arnulf I, Pottier M, et al. Attenuation of obstructive sleep apnea by compression stockings in subjects with venous insufficiency. Am J Respir Crit Care Med. 2011;184(9):1062–1066. doi: 10.1164/rccm.201102-0350OC
   PubMed Web of Science ®Google Scholar
• Bucca CB, Brussino L, Battisti A, et al. Diuretics in obstructive sleep apnea with diastolic heart failure. Chest. 2007;132(2):440–446. doi: 10.1378/chest.07-0311
   PubMed Web of Science ®Google Scholar
• Fiori CZ, Martinez D, Montanari CC, et al. Diuretic or sodium-restricted diet for obstructive sleep apnea—a randomized trial. Sleep. 2018;41(4):zsy016. doi: 10.1093/sleep/zsy016
   Web of Science ®Google Scholar
• Gaddam K, Pimenta E, Thomas SJ, et al. Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: a preliminary report. J Hum Hypertens. 2010;24(8):532–537. doi: 10.1038/jhh.2009.96
   PubMed Web of Science ®Google Scholar
• Kasai T, Bradley TD, Friedman O, et al. Effect of intensified diuretic therapy on overnight rostral fluid shift and obstructive sleep apnoea in patients with uncontrolled hypertension. J Hypertens. 2014;32(3):673–680. doi: 10.1097/HJH.0000000000000047
   PubMed Web of Science ®Google Scholar
• Revol B, Jullian-Desayes I, Bailly S, et al. Who may benefit from diuretics in OSA?: A propensity score-match observational study. Chest. 2020;158(1):359–364. doi: 10.1016/j.chest.2020.01.050
   PubMed Web of Science ®Google Scholar
• Kotsis V, Stabouli S, Papakatsika S, et al. Mechanisms of obesity-induced hypertension. Hypertens Res. 2010;33(5):386–393. doi: 10.1038/hr.2010.9
   PubMed Web of Science ®Google Scholar
• Malhotra A, Mesarwi O, Pepin JL, et al. Endotypes and phenotypes in obstructive sleep apnea. Curr Opin Pulm Med. 2020;26(6):609–614. doi: 10.1097/MCP.0000000000000724
   PubMed Web of Science ®Google Scholar
• Nicholas CL, Jordan AS, Heckel L, et al. Discharge patterns of human tensor palatini motor units during sleep onset. Sleep. 2012;35(5):699–707. doi: 10.5665/sleep.1834
   PubMed Web of Science ®Google Scholar
• Wilkinson V, Malhotra A, Nicholas CL, et al. Discharge patterns of human genioglossus motor units during sleep onset. Sleep. 2008;31(4):525–533. doi: 10.1093/sleep/31.4.525
   PubMed Web of Science ®Google Scholar
• Horner RL, Hughes SW, Malhotra A. State-dependent and reflex drives to the upper airway: basic physiology with clinical implications. J Appl Physiol. 2014;116(3):325–336. doi: 10.1152/japplphysiol.00531.2013
   PubMed Web of Science ®Google Scholar
• Younes M, Loewen AH, Ostrowski M, et al. Genioglossus activity available via non-arousal mechanisms vs. that required for opening the airway in obstructive apnea patients. J Appl Physiol. 2012;112(2):249–258. doi: 10.1152/japplphysiol.00312.2011
   PubMed Web of Science ®Google Scholar
• Perger E, Taranto-Montemurro L. Upper airway muscles: influence on obstructive sleep apnoea pathophysiology and pharmacological and technical treatment options. Curr Opin Pulm Med. 2021;27(6):505–513. doi: 10.1097/MCP.0000000000000818
   PubMed Web of Science ®Google Scholar
• Strollo PJ, Soose RJ, Maurer JT, et al. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med. 2014;370(2):139–149. doi: 10.1056/NEJMoa1308659
   PubMed Web of Science ®Google Scholar
• de Beeck S O, Wellman A, Dieltjens M, et al. Endotypic mechanisms of successful hypoglossal nerve stimulation for obstructive sleep apnea. Am J Respir Crit Care Med. 2021;203(6):746–755. doi: 10.1164/rccm.202006-2176OC
   PubMed Web of Science ®Google Scholar
• Nokes B, Baptista PM, de Apodaca PMR, et al. Transoral awake state neuromuscular electrical stimulation therapy for mild obstructive sleep apnea. Sleep Breath. 2022;27(2):527–534. doi: 10.1007/s11325-022-02644-9
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Messineo L, Wellman A. Targeting endotypic traits with medications for the pharmacological treatment of obstructive sleep apnea. A review of the current literature. J Clin Med. 2019;8(11):1846. doi: 10.3390/jcm8111846
   PubMed Web of Science ®Google Scholar
• Chan E, Steenland HW, Liu H, et al. Endogenous excitatory drive modulating respiratory muscle activity across sleep-wake states. Am J Respir Crit Care Med. 2006;174(11):1264–1273. doi: 10.1164/rccm.200605-597OC
   PubMed Web of Science ®Google Scholar
• Grace KP, Hughes SW, Horner RL. Identification of the mechanism mediating genioglossus muscle suppression in REM sleep. Am J Respir Crit Care Med. 2013;187(3):311–319. doi: 10.1164/rccm.201209-1654OC
   PubMed Web of Science ®Google Scholar
• Grace KP, Hughes SW, Horner RL. Identification of a pharmacological target for genioglossus reactivation throughout sleep. Sleep. 2014;37(1):41–50. doi: 10.5665/sleep.3304
   PubMed Web of Science ®Google Scholar
• Grace KP, Hughes SW, Shahabi S, et al. K+ channel modulation causes genioglossus inhibition in REM sleep and is a strategy for reactivation. Respir Physiol Neurobiol. 2013;188(3):277–288. doi: 10.1016/j.resp.2013.07.011
   PubMed Web of Science ®Google Scholar
• Horner RL, Grace KP, Wellman A. A resource of potential drug targets and strategic decision-making for obstructive sleep apnoea pharmacotherapy. Respirology. 2017;22(5):861–873. doi: 10.1111/resp.13079
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Edwards BA, Sands SA, et al. Desipramine increases genioglossus activity and reduces upper airway collapsibility during non-REM sleep in healthy subjects. Am J Respir Crit Care Med. 2016;194(7):878–885. doi: 10.1164/rccm.201511-2172OC
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Sands SA, Edwards BA, et al. Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation. Eur Respir J. 2016;48(5):1340–1350. doi: 10.1183/13993003.00823-2016
   PubMed Web of Science ®Google Scholar
• Sangal RB, Sangal JM, Thorp K. Atomoxetine improves sleepiness and global severity of illness but not the respiratory disturbance index in mild to moderate obstructive sleep apnea with sleepiness. Sleep Med. 2008;9(5):506–510. doi: 10.1016/j.sleep.2007.07.013
   PubMed Web of Science ®Google Scholar
• Brownell LG, West P, Sweatman P, et al. Protriptyline in obstructive sleep apnea: a double-blind trial. N Engl J Med. 1982;307(17):1037–1042. doi: 10.1056/NEJM198210213071701
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Messineo L, Azarbarzin A, et al. Effects of the combination of atomoxetine and oxybutynin on obstructive sleep apnea endotypic traits. Chest. 2020;157(6):1626–1636. doi: 10.1016/j.chest.2020.01.012
   PubMed Web of Science ®Google Scholar
• Lim R, Carberry JC, Wellman A, et al. Reboxetine and hyoscine butylbromide improve upper airway function during nonrapid eye movement and suppress rapid eye movement sleep in healthy individuals. Sleep. 2019;42(4). doi: 10.1093/sleep/zsy261
   Web of Science ®Google Scholar
• Lim R, Messineo L, Grunstein R, et al. Reboxetine and hyoscine butylbromide reduce obstructive sleep apnoea severity. J Sleep Res. 2019;28(S1):e66_12912.
   PubMedGoogle Scholar
• Chancellor M, Boone T. Anticholinergics for overactive bladder therapy: central nervous system effects. CNS Neurosci Ther. 2012;18(2):167–174. doi: 10.1111/j.1755-5949.2011.00248.x
   PubMed Web of Science ®Google Scholar
• Thomson L, Landry S, Joosten SA, et al. A randomized, placebo-controlled, double-blind crossover trial assessing the combination of noradrenergic/serotonergic reuptake inhibitor and an antimuscarinic agent for the treatment of obstructive sleep apnea. ATS 2020.
   Google Scholar
• Schweitzer PK, Maynard JP, Wylie PE, et al. Efficacy of atomoxetine plus oxybutynin in the treatment of obstructive sleep apnea with moderate pharyngeal collapsibility. Sleep Breath. 2023;27(2):1–9. doi: 10.1007/s11325-022-02634-x
   PubMed Web of Science ®Google Scholar
• Aishah A, Lim R, Sands SA, et al. Different antimuscarinics when combined with atomoxetine have differential effects on obstructive sleep apnea severity. J Appl Physiol. 2021;130(5):1373–1382. doi: 10.1152/japplphysiol.01074.2020
   PubMed Web of Science ®Google Scholar
• Taranto Montemurro L, Sands SA, Azarbarzin A, et al. The combination of atomoxetine and fesoterodine improves obstructive sleep apnea severity in patients with low upper airway collapsibility. 2020.
   Google Scholar
• Messineo L, Taranto-Montemurro L, Calianese N, et al. Atomoxetine and fesoterodine combination improves obstructive sleep apnoea severity in patients with milder upper airway collapsibility. Respirology. 2022;27(11):975–982. doi: 10.1111/resp.14326
   PubMed Web of Science ®Google Scholar
• Rosenberg R, Abaluck B, Thein S. Combination of atomoxetine with the novel antimuscarinic aroxybutynin improves mild to moderate OSA. J Clin Sleep Med. 2022;18(12):2837–2844. doi: 10.5664/jcsm.10250
   PubMed Web of Science ®Google Scholar
• Sands SA, Edwards BA, Terrill PI, et al. Phenotyping pharyngeal pathophysiology using polysomnography in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2018;197(9):1187–1197. doi: 10.1164/rccm.201707-1435OC
   PubMed Web of Science ®Google Scholar
• Perger E, Castiglioni P, Faini A, et al. Impact of reboxetine plus oxybutynin treatment for obstructive sleep apnea on cardiovascular autonomic modulation. Sci Rep. 2023;13(1):3178. doi: 10.1038/s41598-023-29436-9
   PubMed Web of Science ®Google Scholar
• Altree TJ, Aishah A, Loffler KA, et al. The norepinephrine reuptake inhibitor reboxetine alone reduces obstructive sleep apnea severity: a double blind, placebo controlled, randomized, cross-over trial. J Clin Sleep Med. 2022;19(1):85–96. doi: 10.5664/jcsm.10256
   Web of Science ®Google Scholar
• Berger M, Solelhac G, Marchi NA, et al. Effect of oxybutynin and reboxetine on obstructive sleep apnea: a randomized, placebo-controlled, double-blind, crossover trial. Sleep. 2023;46(7). doi: 10.1093/sleep/zsad051
   Web of Science ®Google Scholar
• Gell LK, Vena D, Messineo L, et al. Pathophysiological mechanisms of exacerbated OSA with lighter sleep. Sleep Med. 2022;100:S263. doi:10.1016/j.sleep.2022.05.710
   Web of Science ®Google Scholar
• Goldstein SA, Bockenhauer D, O’Kelly I, et al. Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci. 2001;2(3):175–184. doi: 10.1038/35058574
   PubMed Web of Science ®Google Scholar
• Wirth KJ, Steinmeyer K, Ruetten H. Sensitization of upper airway mechanoreceptors as a new pharmacologic principle to treat obstructive sleep apnea: investigations with AVE0118 in anesthetized pigs. Sleep. 2013;36(5):699–708. doi: 10.5665/sleep.2630
   PubMed Web of Science ®Google Scholar
• Gaisl T, Turnbull CD, Weimann G, et al. BAY 2253651 for the treatment of obstructive sleep apnoea: a multicentre, double-blind, randomised controlled trial (SANDMAN). Eur Respir J. 2021;58(5):2101937. doi: 10.1183/13993003.01937-2021
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Sands SA, Azarbarzin A, et al. Effect of 4-aminopyridine on genioglossus muscle activity during sleep in healthy adults. Ann Am Thorac Soc. 2017;14(7):1177–1183. doi: 10.1513/AnnalsATS.201701-006OC
   PubMed Web of Science ®Google Scholar
• Osman AM, Mukherjee S, Altree TJ, et al. Topical K+ channel blockage improves pharyngeal collapsibility: A translational, placebo-controlled trial. Chest. 2022;163(4):953–965. doi: 10.1016/j.chest.2022.11.024
   PubMed Web of Science ®Google Scholar
• Dutschmann M, Dick TE. Pontine mechanisms of respiratory control. Compr Physiol. 2012;2(4):2443–2469.
   PubMed Web of Science ®Google Scholar
• Long S, Duffin J. The neuronal determinants of respiratory rhythm. Prog Neurobiol. 1986;27(2):101–182. doi: 10.1016/0301-0082(86)90007-9
   PubMed Web of Science ®Google Scholar
• Kubin L, Alheid GF, Zuperku EJ, et al. Central pathways of pulmonary and lower airway vagal afferents. J Appl Physiol. 2006;101(2):618–627.
   PubMed Web of Science ®Google Scholar
• Javaheri S, Kazemi H. Metabolic alkalosis and hypoventilation in humans. Am Rev Respir Dis. 1987;136(4):1011–1016. doi: 10.1164/ajrccm/136.4.1011
   PubMedGoogle Scholar
• Khoo MC, Kronauer RE, Strohl KP, et al. Factors inducing periodic breathing in humans: a general model. J Appl Physiol Respir Environ Exerc Physiol. 1982;53(3):644–659. doi: 10.1152/jappl.1982.53.3.644
   PubMed Web of Science ®Google Scholar
• Ghazanshahi SD, Khoo MC. Estimation of chemoreflex loop gain using pseudorandom binary CO2 stimulation. IEEE Trans Biomed Eng. 1997;44(5):357–366. doi: 10.1109/10.568911
   PubMed Web of Science ®Google Scholar
• White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med. 2005;172(11):1363–1370. doi: 10.1164/rccm.200412-1631SO
   PubMed Web of Science ®Google Scholar
• Messineo L, Eckert DJ, Taranto-Montemurro L, et al. Ventilatory drive withdrawal rather than reduced genioglossus compensation as a mechanism of obstructive sleep apnea in REM sleep. Am J Respir Crit Care Med. 2022;205(2):219–232. doi: 10.1164/rccm.202101-0237OC
   PubMed Web of Science ®Google Scholar
• Sands SA, Edwards BA, Terrill PI, et al. Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy. Eur Respir J. 2018;52(3):1800674. doi: 10.1183/13993003.00674-2018
   PubMed Web of Science ®Google Scholar
• Edwards BA, Sands SA, Owens RL, et al. The combination of supplemental oxygen and a hypnotic markedly improves obstructive sleep apnea in patients with a mild to moderate upper airway collapsibility. Sleep. 2016;39(11):1973–1983. doi: 10.5665/sleep.6226
   PubMed Web of Science ®Google Scholar
• Xie A, Teodorescu M, Pegelow DF, et al. Effects of stabilizing or increasing respiratory motor outputs on obstructive sleep apnea. J Appl Physiol. 2013;115(1):22–33. doi: 10.1152/japplphysiol.00064.2013
   PubMed Web of Science ®Google Scholar
• Winslow DH, Bowden CH, DiDonato KP, et al. A randomized, double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults. Sleep. 2012;35(11):1529–1539. doi: 10.5665/sleep.2204
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Landry S, Orr JE, et al. Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta-analyses and physiological model simulations. Physiol Rep. 2021;9(20):e15071. doi: 10.14814/phy2.15071
   PubMed Web of Science ®Google Scholar
• Perger E, Baillieul S, Esteve F, et al. Nocturnal hypoxemia, blood pressure, vascular status and chronic mountain sickness in the highest city in the world. Ann Med. 2022;54(1):1884–1893. doi: 10.1080/07853890.2022.2091791
   PubMed Web of Science ®Google Scholar
• Eskandari D, Zou D, Grote L, et al. Acetazolamide reduces blood pressure and sleep-disordered breathing in patients with hypertension and obstructive sleep apnea: A randomized controlled trial. J Clin Sleep Med. 2018;14(3):309–317. doi: 10.5664/jcsm.6968
   PubMed Web of Science ®Google Scholar
• Nakayama H, Smith CA, Rodman JR, et al. Effect of ventilatory drive on carbon dioxide sensitivity below eupnea during sleep. Am J Respir Crit Care Med. 2002;165(9):1251–1260. doi: 10.1164/rccm.2110041
   PubMed Web of Science ®Google Scholar
• Lumb AB, Thomas CR. Nunn’s applied respiratory physiology eBook. Elsevier Health Sciences; 2020. p. 456. https://shop.elsevier.com/books/nunn-and-lumbs-applied-respiratory-physiology/lumb/978-0-7020-7908-5.
   Google Scholar
• Berger AJ, Mitchell RA, Severinghaus JW. Regulation of respiration (third of three parts). N Engl J Med. 1977;297(4):194–201. doi: 10.1056/NEJM197707282970406
   PubMed Web of Science ®Google Scholar
• Dempsey JA, Smith CA, Przybylowski T, et al. The ventilatory responsiveness to CO(2) below eupnoea as a determinant of ventilatory stability in sleep. J Physiol. 2004;560(Pt 1):1–11. doi: 10.1113/jphysiol.2004.072371
   PubMed Web of Science ®Google Scholar
• Edwards BA, Sands SA, Eckert DJ, et al. Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea. J Physiol. 2012;590(5):1199–1211. doi: 10.1113/jphysiol.2011.223925
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Landry SA, Orr JE, et al. Acetazolamide for OSA and central sleep apnea: A comprehensive systematic review and meta-analysis. Chest. 2020;158(6):2632–2645. doi: 10.1016/j.chest.2020.06.078
   PubMed Web of Science ®Google Scholar
• Hedner JA, Hoff E, Strassberger C, et al. Impact of sulthiame on endotypic traits in OSA - a RCT. Eur Respir J. 2022;60(suppl 66):3795.
   Google Scholar
• Gleeson K, Zwillich CW, White DP. The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Dis. 1990;142(2):295–300. doi: 10.1164/ajrccm/142.2.295
   PubMed Web of Science ®Google Scholar
• Messineo L, Eckert DJ. Obstructive sleep apnea phenotyping to understand pathophysiology and improve treatment and outcomes. In: Janes S, editor. Encyclopedia of respiratory medicine. Second ed: Academic Press; 2022. p. 22–33. doi: 10.1016/B978-0-08-102723-3.00123-2.
   Google Scholar
• Jordan AS, White DP, Lo Y-L, et al. Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep. 2009;32(3):361–368. doi: 10.1093/sleep/32.3.361
   PubMed Web of Science ®Google Scholar
• Younes M, Ostrowski M, Atkar R, et al. Mechanisms of breathing instability in patients with obstructive sleep apnea. J Appl Physiol. 2007;103(6):1929–1941.
   PubMed Web of Science ®Google Scholar
• Edwards BA, Connolly JG, Campana LM, et al. Acetazolamide attenuates the ventilatory response to arousal in patients with obstructive sleep apnea. Sleep. 2013;36(2):281–285. doi: 10.5665/sleep.2390
   PubMed Web of Science ®Google Scholar
• Butler MP, Emch JT, Rueschman M, et al. Apnea-hypopnea event duration predicts mortality in men and women in the sleep heart health study. Am J Respir Crit Care Med. 2019;199(7):903–912. doi: 10.1164/rccm.201804-0758OC
   PubMed Web of Science ®Google Scholar
• Shahrbabaki SS, Linz D, Hartmann S, et al. Sleep arousal burden is associated with long-term all-cause and cardiovascular mortality in 8001 community-dwelling older men and women. Eur Heart J. 2021;42(21):2088–2099. doi: 10.1093/eurheartj/ehab151
   PubMed Web of Science ®Google Scholar
• Borker PV, Reid M, Sofer T, et al. Non-REM apnea and hypopnea duration varies across population groups and physiologic traits. Am J Respir Crit Care Med. 2021;203(9):1173–1182. doi: 10.1164/rccm.202005-1808OC
   PubMed Web of Science ®Google Scholar
• Mason M, Cates CJ, Smith I. Effects of opioid, hypnotic and sedating medications on sleep-disordered breathing in adults with obstructive sleep apnoea. Cochrane Database Syst Rev. 2015;2015(7):Cd011090. doi:10.1002/14651858.CD011090.pub2
   Google Scholar
• Biberdorf DJ, Steens R, Millar TW, et al. Benzodiazepines in congestive heart failure: effects of temazepam on arousability and Cheyne-stokes respiration. Sleep. 1993;16(6):529–538. doi: 10.1093/sleep/16.6.529
   PubMed Web of Science ®Google Scholar
• Heinzer RC, White DP, Jordan AS, et al. Trazodone increases arousal threshold in obstructive sleep apnoea. Eur Respir J. 2008;31(6):1308–1312. doi: 10.1183/09031936.00067607
   PubMed Web of Science ®Google Scholar
• Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci. 2011;120(12):505–514. doi: 10.1042/CS20100588
   PubMed Web of Science ®Google Scholar
• Carter SG, Berger MS, Carberry JC, et al. Zopiclone increases the arousal threshold without impairing genioglossus activity in obstructive sleep apnea. Sleep. 2016;39(4):757–766. doi: 10.5665/sleep.5622
   PubMed Web of Science ®Google Scholar
• Carberry JC, Fisher LP, Grunstein RR, et al. Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects of zolpidem. Eur Respir J. 2017;50(6):1701344. doi: 10.1183/13993003.01344-2017
   PubMed Web of Science ®Google Scholar
• Messineo L, Carter SG, Taranto-Montemurro L, et al. Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial. Respirology. 2021;26(9):878–886. doi: 10.1111/resp.14110
   PubMed Web of Science ®Google Scholar
• Messineo L, Eckert DJ, Lim R, et al. Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity. J Physiol. 2020;598(20):4681–4692. doi: 10.1113/JP280173
   PubMed Web of Science ®Google Scholar
• Smales ET, Edwards BA, Deyoung PN, et al. Trazodone effects on obstructive sleep apnea and non-REM arousal threshold. Ann Am Thorac Soc. 2015;12(5):758–764. doi: 10.1513/AnnalsATS.201408-399OC
   PubMed Web of Science ®Google Scholar
• Corser B, Eves E, Warren-McCormick J, et al. Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway. J Clin Sleep Med. 2023;19(6):1035–1042. doi: 10.5664/jcsm.10464
   PubMed Web of Science ®Google Scholar
• Messineo L, Gell L, Calianese N, et al. Effect of pimavanserin on the respiratory arousal threshold from sleep: A randomized trial. Ann Am Thorac Soc. 2022;19(12):2062–2069. doi: 10.1513/AnnalsATS.202205-419OC
   PubMed Web of Science ®Google Scholar
• Sweetman A, Lack L, McEvoy RD, et al. Cognitive behavioural therapy for insomnia reduces sleep apnoea severity: a randomised controlled trial. ERJ Open Res. 2020;6(2):00161–02020. doi: 10.1183/23120541.00161-2020
   PubMedGoogle Scholar