USOO6555564B1 (12) United States Patent (10) Patent No.: US 6,555,564 B1 Radulovacki et al. (45) Date of Patent: Apr. 29, 2003 (54) NEUROPHARMACOLOGICAL Dutschmann et al, Society for Neutoscience Abstracts, vol. TREATMENTS OF SLEEP-RELATED 23(1-2), p. 725, 1997.* BREATHING DSORDERS Bennington et al., “Methodology: Scoring and Computer ized Methods-Scoring Transitions to REM Sleep in Rats (75) Inventors: Miodrag Radulovacki, Chicago, IL Based on the EEG Phenomena of Pre-REM Sleep: An (US); David W. Carley, Evanston, IL Improved Analysis of Sleep Structure,' Sleep, 17:28-36 (US) (1994). Botez et al., “Can We Treat Respiratory Failure in Friedreich (73) Assignee: The Board of Trustees of the Ataxia?” Archives of Neurology, 54(8): 1030-1033 (1997). University of Illinois, Urbana, IL (US) Chamberlin et al., “A Brainstem Network Mediating Apneic Reflexes in the Rat,” J. Neuroscience, 18(15):6048–6056 (*) Notice: Subject to any disclaimer, the term of this (1998). patent is extended or adjusted under 35 Dutschmann et al., “NMDA and GABAA receptors in the rat U.S.C. 154(b) by 0 days. Kölliker-Fuse area control cardiorespiratory responses (21) Appl. No.: 09/914,900 evoked by trigeminal ethmoidal nerve Stimulation, J. Physiol, 510(3):793–804 (1998). (22) PCT Filed: Mar. 3, 2000 Dutschmann et al., “NMDA- and GABAA-Receptors Relay Trigeminally Induced Apnoea and Cardiac Responses. In The (86) PCT No.: PCT/US00/05834 Rat Kolliker-Fuse Nucleus,” Society for Neuroscience S371 (c)(1), Abstracts, 23(1-2):725 (1997) (Abstract 285.6). (2), (4) Date: Nov. 6, 2001 Feldman et al., “Neural Control of Breathing.” In Develop mental NeuroScience, Chapter 40, Academic PreSS, pp. (87) PCT Pub. No.: WO00/51590 1063-1090 (1999). PCT Pub. 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U.S. PATENT DOCUMENTS Monti et al., “Adenosine Analogues Modulate the Incidence of Sleep Apneas in Rats.” Pharamacol. Biochem. Behav., 5,075.290 A 12/1991 Findley et al. 51:125-131 (1995). 5,182,386 A * 1/1993 Albaugh et al. ............ 540/350 Chapter 42, “Regulation of Respiration, pp. 504-515. 5,240,948 A * 8/1993 Gueremy et al. ........... 514/367 5,356,934. A 10/1994 Robertson et al. International Search Report, PCT/US00/05834, European 5,688.826 A * 11/1997 Massey et al. ... ... 514/443 Patent Office Examination Authority. 5,728,728 A * 3/1998 Kozachuk ......... ... 514/483 * cited by examiner 6,121.265 A * 9/2000 Treiber et al. ... 514/250 6,124.361. A * 9/2000 Chenard ....... ... 514/561 Primary Examiner James H. Reamer 6,136,861. A * 10/2000 Chenard ..................... 514/361 (74) Attorney, Agent, or Firm Marshall, Gerstein & Borun (57) ABSTRACT FOREIGN PATENT DOCUMENTS The present invention relates generally to pharmacological WO WO OO/51590 9/2000 methods for the prevention or amelioration of Sleep-related OTHER PUBLICATIONS breathing disorders via administration of agents or combi nations of agents that possess glutamate-related and/or Hedner et al, Sleep, vol. 19(4), pp. 287-289, 1996.* glycine-related pharmacological activity or that modulate Hudgel et al, Am. J. Respir. Crit. Care Med., vol. 158, pp. the release of either glutamate or glycine (or both) from 691-699, 1998.* Dutschmann et al., J. Physiology, vol. 510(3), pp. 793-804, nerve terminals with the central nervous System. 1998.* 6 Claims, 4 Drawing Sheets U.S. Patent Apr. 29, 2003 Sheet 1 of 4 US 6,555,564 B1 SALNE HGH Figure 1 U.S. Patent Apr. 29, 2003 Sheet 2 of 4 US 6,555,564 B1 Figure 2 U.S. Patent Apr. 29, 2003 Sheet 3 of 4 US 6,555,564 B1 22.5 2O 17.5 15 12.5 1 O 7.5 2.5 Saline High Figure 3 U.S. Patent Apr. 29, 2003 Sheet 4 of 4 US 6,555,564 B1 30 25 2O 15 1 O Saline High Figure 4 US 6,555,564 B1 1 2 NEUROPHARMACOLOGICAL the ability of the airway dilator and abductor muscles to TREATMENTS OF SLEEP-RELATED maintain airway Stability. Sleep plays a crucial role by BREATHING DSORDERS reducing the activity of the muscles of the upper airways including the dilator and abductor muscles. This application claims priority to U.S. Provisional In most individuals with OSAS the patency of the airway Application No. 60/122,846, filed Mar. 4, 1999, which is is also compromised Structurally and is therefore predis incorporated herein by reference in its entirety. posed to occlusion. In a minority of individuals the Structural compromise is usually due to obvious anatomic BACKGROUND OF THE INVENTION abnormalities, i.e., adenotonsillar hypertrophy, retrognathia, 1. Field of the Invention or macroglossia. However, in the majority of individuals predisposed to OSAS, the Structural abnormality is simply a This invention generally relates to methods for the phar Subtle reduction in airway size, i.e., "pharyngeal crowding.” macological treatment of breathing disorders and, more Obesity also frequently contributes to the reduction in size Specifically, to the administration of agents or combinations Seen in the upper airways. The act of Snoring, which is of agents having glutamate-related receptor activity and/or 15 actually a high-frequency vibration of the palatal and pha glycine-related receptor activity or activity that interferes ryngeal Soft tissues that results from the decrease in the size with the release if either glutamate or glycine for the of the upper airway lumen, usually aggravates the narrowing alleviation of Steep apnea (central and obstructive) and other Sleep-related breathing disorders. via the production of edema in the Soft tissues. The recurrent episodes of nocturnal asphyxia and of 2. Related Technology arousal from sleep that characterize OSAS lead to a series of Over the past several years much effort has been devoted Secondary physiologic events, which in turn give rise to the to the Study of a discrete group of breathing disorders that clinical complications of the Syndrome. The most common occur primarily during sleep with consequences that may manifestations are neuropsychiatric and behavioral distur persist throughout the waking hours in the form of bances that are thought to arise from the fragmentation of Sleepiness, thereby manifesting itself into Substantial eco 25 Sleep and loSS of Slow-wave Sleep induced by the recurrent nomic loss (e.g., thousands of lost man-hours) or employ arousal responses. Nocturnal cerebral hypoxia also may play ment safety factors (e.g., employee non-attentiveness during an important role. The most pervasive manifestation is operation of heavy-machinery). Sleep-related breathing dis excessive daytime sleepiness. OSAS is now recognized as a orders are characterized by repetitive reduction in breathing leading cause of daytime sleepiness and has been implicated (hypopnea), periodic cessation of breathing (apnea), or a as an important risk factor for Such problems as motor continuous or Sustained reduction in ventilation. vehicle accidents. Other related Symptoms include intellec In general Sleep apnea is defined as an intermittent tual impairment, memory loSS, personality disturbances, and cessation of airflow at the nose and mouth during sleep. By impotence. convention, apneas of at least 10 Seconds in duration have The other major manifestations are cardiorespiratory in been considered important, but in most individuals the 35 nature and are thought to arise from the recurrent episodes apneas are 20–30 Seconds in duration and may be as long as of nocturnal asphyxia. Most individuals demonstrate a cycli 2-3 minutes. While there is some uncertainty as to the cal slowing of the heart during the apneas to 30 to 50 beats minimum number of apneas that should be considered per minute, followed by tachycardia of 90 to 120 beats per clinically important, by the time most individuals come to minute during the ventilatory phase. A Small number of attention of the medical community they have at least 10 to 40 individuals develop severe bradycardia with asystoles of 8 to 15 events per hour of Sleep. 12 Seconds in duration or dangerous tachyarrhythmias, Sleep apneas have been classified into three types: central, including unsustained Ventricular tachycardia. OSAS also obstructive, and mixed. In central Sleep apnea the neural aggravates left ventricular failure in patients with underlying drive to all respiratory muscles is transiently abolished. In 45 heart disease. This complication is most likely due to the obstructive Sleep apneas, airflow ceases despite continuing combined effects of increased left ventricular afterload dur respiratory drive because of occlusion of the oropharyngeal ing each obstructive event, Secondary to increased negative airway. Mixed apneas, which consist of a central apnea intrathoracic pressure, recurrent nocturnal hypoxemia, and followed by an obstructive component, are a variant of chronically elevated Sympathoadrenal activity. obstructive Sleep apnea. The most common type of apnea is 50 Central Sleep apnea is leSS prevalent as a Syndrome than obstructive sleep apnea. OSAS, but can be identified in a wide spectrum of patients Obstructive sleep apnea syndrome (OSAS) has been with medical, neurological, and/or neuromuscular disorders identified in as many as 24% of working adult men and 9% asSociated with diurnal alveolar hypoVentilation or periodic of Similar women, with peak prevalence in the Sixth decade.