Title of Invention

A COMPOSITION FOR TREATMENT OF SLEEP APNEA

Abstract

A pharmaceutical composition for treating sleep apnea comprising at least one of serotonin receptor antagonist selected form the group consisting of zatosetron, granisetron, tropisetron, dolasetron, oxetorone, and olanzapine and a serotonin receptor agonist as the free base or quartazised form and at least one serotonin receptor agonist selected from 5-hydroxytryptamine or 5-hydroxytryptamine2 receptor agonist

Full Text

i'HAKMACOLOGICAL TREATMENT FOR SLEEP APNEA Prion:;-' is claimed to U.S. Patent Appi. No. 100016,901. filed December 14, 2001, which Naims priority to U.S. Paten: Appl. No. 09 622,523. nied August 23, 2000, now U.S. Patent No. 6.331,536 issued December 18, 2001. which claims ;:-onty International Patent Appi. No. ?C7/US99'C-34~. filed February 2c. 1099. ■.vhich claims nriority to U.S.. Prov. Paten: And. No. 60.076.216. ail of which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION Field of the Invention This invention generally relates to methods for the pharmacological treatment "of breathing disorders and? more specifically, to the administration of agents or compositions having serotonin-related recentor activity for the alleviation of sieeo apnea (central and obstructive) and other sleep-related breathing disorders. Related Technology ... Over the past several years much effort has been devoted to the study of a discrete group of brsaflaag-'misordcrs- that occur primarily during sleep with consequences that may persist throughout ihe waking hours in the form of sleepiness, thereby manifesting itself into substantial economic loss (e.g., thousands oflost man-hours) or employment safety factors (e.g., employee non-attentiveness during operation of heavy-machinery). Sleep-related breathing disorders are characterized by repetitive reduction in breathing (hypopnea), periodic cessation of breathing (apnea), or a continuous or sustained reduction in ventilation. In general sleep apnea is defined as an intermittent cessation of airflow at the nose and mouth during sleep. By convention, apneas of at least 10 seconds in duration have been considered important, but in most individuals the apneas are 20-30 seconds in duration.and may be as long as 2-2 minutes. While there is some uncertainty as to the minimum number of i-neas that should be considered clinically important, by the time most individuals come to attention of the medical community they have at least 10 to 15 events per hour cf sleep. Sleep apneas have been classified int: three rypes: centra;, abstractive, and mixed. In centra! sleep armea the neural drive :o ail resciratory muscles is transients abolished. Ln obstructive sieeo apneas, airflow ceases despite continuing resoiratorv * *■ • —- * _, dnve because of occlusion of the cropharmgeal air.vay. Mixed apneas, 'vhich consist or a centra, apnea tonowea by an abstractive component, are a variant of obstructive sleep apnea. The most common type of apnea is cbstractive sleep apnea. ■^T: hr1'2'^ r^^PT"'^^! ' ^ 'T1 In "1"*rj/^ "^ f* r*-*-*.--*.-" 1,^ ■■: -^.^n r-i ^a»-> orri ' -l'~V,, ■** *" ?i rpT ^ " r' v acTt=»P women, with even greater prevalence in older subjects. Obstructive sleen acnea syndrome's definitive event is the occlusion of* the upper airway, frequently at the level of the oropharynx. The resultant apnea generally leads to a progressive-type asphyxia until the individual is briefly aroused from the sieenins state, therebv restoring airway patencv and thus restoring airflow. An important factor that leads to the collaose of the unper airwav in OS AS is the generation of a critical subatmospheric pressure during the act of inspiration that exceeds the ability of the airway dilator and abductor muscles to maintain-airway ' stability. Sleep plays axrucial role■ by-reducing the activity of the muscles of the upper airways including the dilator and. abductor muscles. In most individuals with OSAS the patency of the airway is also compromised structurally and is therefore predisposed to occlusion. In a minority of individuals the structural compromise is usually due to obvious anatomic abnormalities, L a, adenotonsillar hypertrophy, retrognathia, or macroglossia. However, in the majority of individuals predisposed to OSAS, the structural abnormality is simply a subtle reduction in airway size, u., "pharyngeal crowding." Obesity also frequently contributes to the reduction in size seen in the upper airways. The act of snoring, which is actually a high-frequency vibration of the palatal and pharyngeal soft tissues that results from the decrease in the size of the upper airway lumen, usually aasravates the narrowing via the nroduction of edema in the soft tissues. The recurrent episodes of nocturnal asphyxia and of arousal from sleep that characterize OSAS lead to a series of secondary physiologic events, which in turn (yuve rise to the clinical complications of the syndrome. The most common manifestations are neuropsychiatry and behavioral disturbance: that are thought to arise from me fragmentation of sleep and less of s;c--.v-,vave ::eep induced bv the recurrent arousal responses. Nocturnal cerebral Iv-ovi: also may play an important role. The most per-'asive manifestation :s excessive daytime sleepiness. OSAS is now recognized as a leading cause of daytime sleenir.es: and has been Implicated as an important risk factor for such problems as mcror veltltle acc:aen:s. Other related The other major manifestations are card;:respirat;ry in nature and are thought to arise from the recurrent enisodes of nocturnal asnh'-ccia. Most individuals demonstrate a cyclical slowing of the heart during the apneas to 50 to 50 beats per minute, followed by tachycardia of 90 to 120 beats per minute curing the ventilatory nhase. A small number of individuals develoo severe bradveardia with asvstcies of S i i * J to 12 seconds in duration or danaerous tachvarrh'-thinias, including unsustamed ventricular tachycardia. OSAS also aggravates left ventricular failure Tln catients with underlying heart disease. This complication is most likely due to the combined effects of increased left ventricular afterload during each obstructive event, secondary to increased negative intratiK>racic._px2ssure, recurrent nocturnal Hypoxemia, and chronically elevated sympathoadrenal activity. Central sleep apnea is less prevalent as a syndrome than OSAS, but can be identified in a wide spectrum of patients with medical, neurological, and/or neuromuscular disorders associated with diurnal alveolar hypoventilation or periodic breathing. The definitive event in central sleep apnea is transient abolition of central drive to the ventilatory muscles. The resulting apnea leads to a primary sequence of events similar to those of OSAS. Several underlying mechanisms can result in cessation of respiratory drive during sleep. First are defects in the metabolic respiratory control system and respiratory neuromuscular apparatus. Other central sleep apnea disorders arise from transient instabilities in an otherwise intact respiratory control system. Many healthy individuals demonstrate a small number of central apneas during sleep, particularly at sleep onset and in REM sleep. Tnese apneas are not associated with any physiological or clinical disturbance. In individuals with clinically significant central sleep apnea, the primary sequence o: events that characterize the disorder leads to prominent physiological and clinical consequences. In those individuals with central sleep apnea nv-oiar hypoventilation syndrome, daytime hypercapnia and hypoxemia are usually evident and the clinical picture is :.^^.U^Ui-^. ui.U m^LL..^ iUiI-dUC ^.i.U o)C-v> ...Ceo -i - ^,:IJ wi'vunnvi.w. ^, ■-«. 4uoc, m recurrent nocturnal awakenings, mcming fatigue, and daytime sleepiness. Currently, the most common and most effective treatment, for adults with sleep apnea and other sleep-related breathing disorders are mechanical forms of therapy that deliver positive airway pressure (?A?). Under PA? treatment, an individual wears a tisht-futins plastic mask over the nose when sleeoina. The mask is attached to a compressor, which forces air into the nose creating a positive pressure within the patient's airways. Tne principle of the method is that pressurizing the airways provides a mechanical "splinting" action, which prevents airway collapse and therefore, obstructive sleep apnea. Although an effective therapeutic response is observed in most patients who undergo PAP treatment many patients cannot tolerate the apparatus or pressure and refuse treatment. Moreover, recent cover, monitoring studies clearly demonstrate that long-term compliance with PA? treatment is very poor. A variety of upper airway and craniofacial surgical procedures have been attempted for treatment of OSAS. Adenotonsillectomy appears to be an effective cure for OSAS in many children, but upper airway surgery is rarely curative in adult patients with OSAS. Surgical "success" is generally taken to be a 50% reduction in apnea incidence and there are no useful screening methods to identify the individuals that would benefit from the surgery versus those who would not derive a benefit. Pharmacological treatments of several types have been -attempted in patients with sleep apnea but, thus far, none have proven to be generally useful. A recent systematic review of these attempts is provided by Hudgel [X Lab. Clin. Med,, 126:13-18 (1995)]. A number of compounds have been tested because of their expected respiratory stimulant properties. These include (1) acetazolamide, a carbonic anhydrase inhibitor that produced variable improvement in individuals with primary central apneas but caused an increase in obstructive apneas. (2) medroxyprogesterone, a progestin that has aemcrstrated no consistent benefit in OS AS, and \2) theophylline, a zoxTiVoyczc asua.ly used tor the treatment :f asthma, which may benefit patients \vi:h centra: acnea :at arpears to be :■: n: use in adult oatients with obstructive annea. 4. w u„ „i autuiu'wwu Jlia.il i.atuit lilCu.* .. ^^........ L ...^.ul.wj w'w _'■„,. c.-i.Ui. Ot. adenosine, adenosine analogs and adenosine reamaxe inhibitors V.5. ?ztent No. 5,0"5,290). Specifically, adenosine, which is a ubtcuitous compound '.'-a:hm the ■"•od V and Which 1SV3"N n^^ f=>Ip-">,T^ i-n '--nr'-' -'■• r-- -0 ^ 'v*'**- PI'N A C h" > "-"-"«-; .'"OW"1 to stimulate respiration and is somewhat effective in reducing apnea in an animal model of sleep apnea. Other possible oharmacoiosical treatment ontions for OSA5 include aaents that stimulate the brain activuy or are opioid antagonists. Specifically, since increased cerebral spinal fluid opioid activity has been identified in OSAS. it is a logical conclusion that central stimulants or opioid antagonists would be a helpful treatment of OSAS. In reality, doxapram, which stimulates the central nervous system and carotid body chemoreceptors, was fourA to decrease the length* of apneas but did not alter the averase arterial oxvgen saturation in individuals with obstructive sleep apnea. The opioid antagonist naloxone, which is known to stimulate ventilation was only slightly helpful in individuals with ob stmctive sleep apnea. Because OSAS is strongly correlated with the occurrence of hypertension, agents such as angiotensin-converting enzyme (ACS) inhibitors may be of benefit in treating OSAS individuals with hypertension but this dees not appear to be a viable treatment for OSAS itself. Finally, several agents that act on neurotransmitters and neurotransmitter systems involved in respiration have been tested in individuals with OSAS. Most of these compounds have been developed as anti-depressant medications that work by increasing the activity of monoamine neurotransmitters including norepinephrine, dopamine, and serotonin. Protriptyiine, a tricyclic anti-depressant, has been tested m several small trials with variable results and frequent and significant side effects. As serotonin may promote sleep and stimulate respiration, tryptophan, a serotonin precursor and selective serotonin reuptake inhibitors have been tested in individuals with OS AS. A'hile a patent has been issued for the ase of the serotonin reuptake inhibitor, fluoxetine (U.S. Patent No. 5:2:6,93A initial r-ddence suggests that these sompounds may yield measurable benefits in oniy aporcvimateiy 50% of individuals with OSAS. Therefore in view of the fact that tbe :niy viable treatment for individuals suffering from sleep-related breaming disorders is a mechanical form of therapy ■?A?) for which patient compliance is low. and that hones for pharmacological treatments have yet to come to rhihien. there remains a need :cv simple pharmacologically-based treatments that wouldofferbenents to a bread base cf individuals suffering from a range of sleep-related breathing disorders. There also remains a need for a viable treatment of sleep-related breathing disorders tha: would lend itself to a high rate of patient compliance. SUMMARY OF THE INVENTION The invention is directed to providing pharmacological treatments for the prevention or amelioration of sleep-related breathing disorders. The present invention is directed to methods for the prevention or amelioration of sleep-related breathing disorders, the method comprising the administration of an effective dose of serotoninTreceptor antagonist to a patient in-need^of^such therapy. The present invention :is also directed to methods comprising the administration of a combination of serotonin receptor antagonists for the prevention or amelioration of sleep-related breathing disorders. The combination of serotonin receptor antagonists may be directed to a single serotonin receptor subtype or to more than one serotonin receptor subtype. The present invention is further directed to methods comprising the administration of a combination of serotonin receptor antagonists in conjunction with a combination of serotonin receptor agonists for the prevention or amelioration of sleep-related breathing disorders. The combination of serotonin receptor antagonists as well as the combination of receptor agonist may be directed to a single serotonin receptor subtype OT to more than one serotonin receptor subtype. The present invention is also directed to methods comprising the administration of a combination of serotonin receptor antagonists in conjunction with a c*2 adrenergic receptor subtype antagonist for the prevention or amelioration of sleep-related breathing disorders. The combination of serotonin receptor antagonists may be directed to a single serotonin receptor subtype or tc more than one serotonin receptor subtvoe. Routes of administration for the fcreoomo memoes -ay be bv mv rv'stemic means including oral intraperitoneal, subcmanecus, intravenous, intramuscular, :ransdermai. or by other routes of administration. Csmotic mini-pumps and timed-released pellets or other depot forms of administration may also be ased. The cniv hmitation being that the route of administration results in the ultimate deliver-* of the phannacolomcal agent to the appropriate recemor. Sleep-reiated breathing disorders include, bu; me not limited to. obstructive sleep apnea syndrome, apnea of prematurity, congenital centra: hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome. Cheyne-S cokes respiration, and snoring. A serotonin recentor antagonist can be used in its free base form or as a quaternary ammonium salt form. The quatemization of these serotonin receptor antagonists occurs by conversion of tertiary nitrogen atom into a quaternary ammonium salt with reactive alkyl halides such as, for example, methyl iodide, ethyl iodide, or various benzyl halides.-Some quaternary forms of a serotonin antagonist, specifically, methyiate±'^3fi>S6$Fon, has been shown to lack the ability to cross the blood-brain barrier (Gidda et aL, J. Pharmacol Exp. Thar. 273:695-701 (1995)), and thus only works on the peripheral nervous system. A serotonin receptor antagonist is defined by the chemical compound itself and one of its pharmaceutical^ acceptable salts. Exemplary serotonin receptor antagonists include, but are not limited to, the free base form or a quaternized form of zatosetron, tropisetron, dolasetron, hydrodolasetron, mescaline, oxetorone, homochiorcyclizine, perlapine, ondansetron (GR38032F), ketanserin, loxapine, olanzapine, chlorpromazine, haloperidol, r (+) ondansetron, cisapride, norcisapride, (+) cisapride, (-) cisapride, (+) norcisapride, (-) norcisapride, desmethylolanzapine,- 2-hydroxyme:hylolanzapine, l-(2-fluorcphenyi)-3-(4-hydroxyaminoethyl)-prop-2-en-l-one-0-(2-dimethy!aminoethyd)-oxime. risperidone, cyproheptadine, clozapine, methysergide, granisetron, mianserin, ritanserin, cinanserin, LY-53,S57, metergoline, LY-278,584, methiothepin, p-NPPL, NA\M90, piperazine. SB-206553. SDZ-I05 55". 3-:r:o^nvl-indoIe- w^c.-..-i.^a -, ■ropanyl-mdoie-3-carboxylate methiodide, and other serotonin receptor antagonists and their quatemized forms or one of its rharmaceuticaily acceptable salts. exemplary serotonin receptor agrnists incir.ce. ;um-chiorophenyipiperanine). A serotonin -emptor agonist is denned by ;he onemicai compound itself and one of its pharmaceutical!;-" acceptable salts. Exemplary c<: adrenergic recep antagonist include but are no: limited to phenoxybenzamine. phentolamine tolanoline teranosine doxazosin trimazosin yohimbine indorainin arc239 and orazcsin or one oi its pharmaceutical acceptable salts.> Exemplary selective serotonin reuptake inhibitors include, but are not limited to, fluoxetine, paroxetine, fiuvoxamine, sertraline, cuaiopram, nornuoxetine. r(-) fluoxetine, s(+) fluoxetine, demethylsertratine, demethylcitaicpram, veniafaxine, rnilnacipraa, sibutramine, nefazodone^R-hydroxynefazodone, (-)venlafaxine, and (3) venlafaxine. A selective serotonin reuptake inhibitor is defined by the chemical compound itself and one of its pharmaceutically acceptable salts. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the effect of serotonin antagonist GR3S032F (ondansetron) on the rate of apneas per hour of non-rapid eye movement (NREM) sleep as compared to control. Each data point on the figure represents the mean ± the standard error for 9 rats (p=0.007 versus control). Figure 2 shows the effect of the serotonin antagonist GR3S032F (ondansetron) on the percentage of total recording time spent in NREM sleep as compared to control. Each data point represents the mean ± the standard error for 9 rats (g^OlQCOl versus control). Figure 3 shows the effect of the serotonin antagonist GR33032F (ondansetron) on the rate of apneas per hour of rapid-eye-movement (REM) sleep as compared to control, tach data point represents the mean = the standard error for 9 rats (p=0.Gl versus control). Figure 4 illustrates the effec: of ±t ^::'onin anagcms; GR33032F •ondansetron') on the percentage of ;::ai recsrdin: ;;me spent in REM sleep as compared 10 control. Each data point represents the mean = the standard error ibr 9 rats. ^ Figure 5 shows the effects of the serotcntn antagonist GF3303IF (ondansetron) on the rate o: normalized minute ventilation during wakefulness. "NfREM and REM sleep as compared to control, z'^ data bar represents the mean = the standard error over 6 recording hours w;:h ah animals (?:-9) pooied -minute ventilation was significantly larger following G? "3 S032F administration in ail behavioral states; p Figure 6 shows the effects cf serotonin (0.79 mg'kg). GR3S032F (0.1 mg/kg^serotonin (0.79 mg/kg). and GR3S032F (0.1 mg.kg) on spontaneous apneas in NREM sleep. Each data bar represents the mean ± the standard error over 6 recording hours with all animals (n=10; p = 0.9~*V Figure 7 illustrates the effects of serotonin (0.79 mg/kg), GR3S032 (0.1 mg/kg) -serotonin (0.79 mg/kg), and GR33032F (0.1 mg/kg). oa spontaneous-apneas' during REM sleep. Each data bar represents the mean ± the standard error over 6 recording hours with all animals (/T-IO; p = 0.01 for serotonin administration vs. control; p-0.05 for administration of GR33032F+serotonin vs. serotonin alone; />=0.99 for administration of GR38032F+serotonin vs. control; and p=0.51 for administration of GR38G32F alone). DETAILED DESCRIPTION OF THE INVENTION Previous studies on the effect of serotonin or serotonin analogs on respiratior in several anesthetized (see below) animal species have demonstrated variable responses. For example, administration of serotonin has been shown to cause ai increase i-n the respiratory rate with a decrease in tidal volume in rabbits, hut ai increase in the tidal volume in dogs [Matsumcto.. Arch. Int Pharmacodyn. Titer. 254:232-292 (1981); Armstrong et al, J. Physiol (Lond.J, 365:104 P (19S5); Bisgan et al, Resp. Physiol 37:61-80 (1979); Zucker et al Circ. Res. 47: 509-515 (1980] In studies with cats, serotonin administration produced hyperventilation occasional! preceded by apnea [Black et al. Am. J. Physiol.. 223:1 :9V '.22 ^W; ;accbs ~: a/ Circ. Res., 29:1-15-155 fi9V\ or Aoministratton of 2 hyeroxyu;."p:ar;iine; receptor agonist, in cat .studio caused annea "Butler ^:..aJ. i?v J". Pharmacol. 9^:39"-412 (1983V. Intravenous aanuni-rauon of ser::cn;n, l-~eth-> - * - *j"'^ * ^ A ,■,-;.. -- L^iiiin w d a ai2tn ccs-^ ^ i a~matia' *.- .t - . v-'uro ?:'-or* ~o tamme. a a - * , , i ' ""^ ^ OA* "*" "*""* ' ' O "^ ^ . -_ *.. — _-, ■*' ** , * "", "V "" ■.■«■■■ - '-- —". " i ^> —- ^ (I9SS); Hagan e: al, Eur. J. Pharmacol., 138:203-305 (1937)] as well as by ketanserine and rnethysergide, 5-hydroxytryptamine : receptor antagonists [Yoshioka et al, J- Pharmacol Exp. Ther., 260:917-92-1 (1992)1. In newborn rats, administration oi serotonin precursor L-tryptophan, which activated central serotonin biosynthesis. oroduced recurrent episodes of obstructive aonea often followed bv central aoneas [Hilaire et aL, J. Physiol, 466:367-382 (1993); Morin. NeuroscL Let:.. 160:61-64 (1993)]. I While the forgoing studies revealed significant information concerning the involvement of serotonin in the development of apneas, as stated above one significant problem with all of these studies is that the animals were anesthetized, and thus any results obtained could not be attributed to a specific serotonin agonist or antagonist, i.e., an interaction with the anesthesia or abnormal physiologic conditions associated with the anesthetic could not be ruled out. Activity at serotonin receptors may also promote spontaneous sleep-related central apneas, which have been reported in rats, [Mendelson et al, Physiol. Behav., 43:229-234 (1988); Sato et aL Am. J. Physiol, 259:R232-R287 (1990); Monti et aL Pharmacol 'Biochem. Behav., 125-131 (1995); Monti et al, Pharmacol Biochem. Behav., 53:341-345 (1996); Thomas et al, . 1 Appl Physiol, 78:215-213 (1992); Thomas et al, J. Appl Physiol, 73:1530-1526 (1995); Carley et al Sleep, 19:363-366 (1996); Carley et al, Physiol Behav., 59:327-831 (1996); Radulovacki et al, Sleep, 19:767-773 (1996); Christon et al, J. Appl Physiol, 80:2102-2107 (1996)]. In order o test this hypothesis, experiments were conducted to test the effects of - serotonin mtagonist in freely moving animals in order to assess whether blockade of serotonin •eceptcn would inhibit expression of spontaneous aoneas durin1: >r?L5M sieeo and IEM sleep. Experiments were also conducted ;o :e:t the effects of :er:tonin and serotonin antagonists, singly and in combination, in mealy moving animals m order to assess whether increased serotonergic activity a: peripheral serotonin receivers mav promote sieeo anneas. * Uv- .uiiuw.j^ v.'^lnuUi ulubu-;.■- ,;:^ -^^^i.;; ^; uL..;;i>>-^ aii\.u ^+ ::•-,. \.". O w »* i apneas during non rapid eye movement iXRJEM) and especially during rapid eye movement (REM) sleep. This effect was associated with increased respiratory drive but did not cause cardiovascular changes at the cose tested. The following examples also illustrate the effects of serotonin administration to induce spontaneous apnea expression, which was completely antagonized via the administration of serotonin receptor antagonists, and in particular GR3S0327. The following examples farther describe the pharmacological profiles best suited for single aaents or combinations of agents to successfully orevent or ameliorate sleep-related breathing disorders, i.e., (a) a single agent or combination of agents having either 5-hydroxytryptaminei or 5-hydroxytryptamine3 receptor subtype antagonistic activity or both; (b) a single agent or combination of agents having either 5-hydroxytryptamine: or 5-hydroxytryptamine3 receptor subtype antagonistic activity or both in conjunction with either 5-hydroxytryptaminej or 5-hydrox>tryptamine: receptor subtype agonistic activity or both; or (c) a single agent or combination of agents having either 5-hydroxytryptamine^ or 5-hydroxytryptamine3 receptor subtype antagonistic activity or both in conjunction with c^ adrenergic receptor subtype antagonistic activity. Further aspects of the invention and embodiments will be apparent to those skilled in the art. In order that the present invention is fully understood, the following examples are provided by way of exemplification only and not by way of limitation. cxarr.pie 1 describes the preparation of -he a;;:n:ais for ;rea;ment with either serotonin antagonists or agonists or both and s-^se:uent physiological recording and testins. Example 2 describes the methods tor the oh; s::loaiea! recording of treatment and control animals and results obtained frcrr. t:n:inistration o: a serotonin antagonist. .Example 3 describes results obtained rrcrr. toe administration of serotonin fcilowed by the administration of a serotonin reerncr antagonist. T"* ._ 11'"' • " related pharrr.acoiopinal -activity that is used to effectively suppress or prevent sleep-reiated uieathing disorders. The following examples are illustrative of aspects of the present invention but are not to be construed as limiting. EXAMPLE 1 Preparation of Animals for Physiological Testing and Recording Adult, male Sprague-Dawley rats (Sasco-King, Wilmington, NLA; usually 3 per test group; 300 g) were maintained on a 12-hour light (03:60-20:00'MixjTjl-hour dark (20:00-08:00 hour) cycle for one week, housed in individual cages and siven ad libitum access to food and water. Following the one week of acclimatization, animals were subjected to the following surgical procedures. Acclimatized animals were anesthetized for the implantation of cortical electrodes for electroencephalogram (EEG) recording and neck muscle electrodes for electromyogram (EMG) recording using a mixture of ketamine (Vedco, Inc., St. Joseph, MO; 100 mg/rnl) and acetylpromazine (Vedco, Inc., St. Joseph, MO; 10 mg/ml; 4:1, volume/volume) at a volume of 1 ml/kg body weight. The surface of the skull was exposed surgically and cleaned with a 20% solution of hydrogen peroxide followed by a solution of 95% isopropyl alcohol. Next, a dental preparation of sodium fluoride (Flura-GEL®, Saslow Dental Mt Prospect, IL) was applied to harden the skull above the parietal conex and allowed to remain in place for 5 minutes. The fluoride mixture was then removed from the skull above the parietal cortex. The EEG electrodes consisting of four stainless steel machine screws, having ' leads attached thereto, were threaded into :he skull to rest on the dura over tiue carietal cortex. A thin layer of Justin resin cedent oasiow Dental. Mi. Pros-ecu IUJ was applied to cover the screw heads ('of screws implanted in the skull" and surrounding skull to further pre mote the adhesion :f :he impian:. IMG electr:des :cus:st;ng of two ball-shaped wires were inserted into the bilateral r.e:k musculature. Ah leads : :.3.. HEG and EMG leads') were soldered :: a miniature :cnneotor G??l-01. Newark Electronics. Sohaumburg, IL':. lastly. the emir; assembly was ±:tz to me rural! with Axier surgery, an amma.s were aucwea to rec:v*r :or one wee: EXAMPLE : Physiological Recording and Suppression of Apneas Physiological parameters (see beiow) from each animal were recorded on 2 occasions in random order, with recordings for an individual animal separated for at least 3 days. Fifteen minutes prior to each recording each animal received a systemic injection (lmLTcg intraperitoneal bolus injection^ cf either saline (control) or lmg'lca .of ondansetron (GR38032F; l,2?:\S-:etrahydr6-9-me:hyl-3-[(;2-rne:hyiinnidazoI-i-yl)methyl]carbazole-4-one, hydrochloride, dihydrate; Glaxo Wellcome. Inc.. Research Triangle Park. NC). Poiygraphic recordings were made from hours 10:00-15:00. Respiration was recorded by placing each animal, unrestrained, inside a single chamber plethysmograph (PLYUN1R/U; 3uxco Electronics, Sharon. CT; dimension 6 in. x 10 in. x 6 in.) ventilated with a bias flow of fresh room air at a nate of 2 L/mim A cable plugged onto the animal's connector and passed through a sealed port was used to carry the bioelectrical activity from the head implant. Respiration, blood pressure, EEG activity, and EMG activity were displayed on a video monitor and simultaneously digitized 100 times per second and stored on computer disk (Experimenter's Workbench; Datawave Technologies, Longmont, CO). Sleep and waking states ■■wwrassfeSsed using the bipamt&£EG and nuchal EMG signals on 10-second epochs as~described by Bennington et aL [Sleep, 17:28-36 (1994)]. This software discriminated wakefulness (W) as a high frequency low amplitude EEG with a concomitant high EMG tone, NREM sleep by increased spindle and theta activity together with decreased EMG tone, and REM sleep by a low ratio of a delta to theta activity and an absence of EMG tone. Sleep efficiency was measured as the percentage of total recorded epochs staged as NREM or REM sleep. An accepted physiological animal model [rat; Monti, et aLt Pkaramcol. Biochem. Bekav., 51:125-131 (1995)] of spontaneous sleep apnea was used to assess the effects of GR38032F. More specifically, sleep apneas, defined as cessation of respiratory effort for at least 2.5 seconds, were scored for each recording session and were associated with the stage of sleep in which they occurred: NREM or REM sleep. The duration requirement of 2.5 seconds represented at least 2 "missed" breaths, which is therefore analogous to a 10 second apnea duration requirement in humans, which also reflects 2-3 missed breaths. The events detected represent central apneas 'because decreased ventilation associated with o osiructed or occluded airwavs would generate an increased plethysmography signal, rather than a pause. An apnea index (AI), defined as apneas, per hour in a stage were separately determined for NREM and REM sleep. The effects of sleep stage (NREM vs. REM) and injection (control vs. GR30S32F) were tested using ANOVA with" repeated measures. Multiple comparisons were controlled using Fisher's protected least significant difference (PLSD). In addition, the timing and volume of each breath were scored by automatic analysis (Experimenters' Workbench; Dataware Technologies, Longmonu CO). For each animal the mean respiratory rate (RR; and minute ventilation (MV) was computed xor W throughout the 6 hour control recording and usee as a baseline to normalize respiration during, sleep and during GR3S032F administration in that animal. One way ANOVA was also performed by non-parametric (Kruskai-Wallis) analysis. Conclusions using parametric and non-parame:ric ANOVA were identical in all cases. Similar software (Experimenters' Workbench; Datawave Technologies, Longmont, CO) was employed to analyze the blood pressure waveform; for each beat of each recording, systolic (SB?) and diastolic (DBP) blood pressures and pulse interval were measured^ The pulse interval provided a beat by beat estimate of .HP-Mean BP (MBP) was estimated according to the weighted avcrage:of SBP and DBF for each beat: MBP = DBP + (SBP-DBP)/3. The parameters for each beat were also classified according to the sleep/wake state and recording hour during which they occurred. Results of the administration of the serotonin antagonist GR38032F on the rate of apneas per hour of NREM sleep during the 6 hours of polygraph!c recording (see Figure 1) demonstrated no significant effect of treatment or time over 6 hours (two-way ANOVA). However, there was a significant suppression of apneas during the first 2 hours of recording as determined by paired t-tests (p Results further indicated a significant suppressant effect of GR3S032F on REM sleep apneas throughout the 6 hour recording period (>=0.01 for drug effect on 2-way ANOVA; see Figure 3). This effect was particularly manifest during the first 4 hours of recordings, during which no animal exhibited a single spontaneous apnea in REM sleep. This effect was not a simple reflection of REM suppression durins the first 4 hours. Results set forth in Figure 4 show that GR3S032F did not significantly affect REM sleep. Although REM sleep in drug treated animals was lower than in corresponding controls it did net reach statistical significance overall or curing anv . single recording hour. Results of the administration of GR3S032F on the normalized minute ventilation during W (wake), NREM (non-rapid eye movement) sleep, and REM (rapid eye movement) sleep (see Figure 5) indicate a significant stimulation of ventilation during all behavioral states (p=0.03 for each). Finally, results indicate that GR38032F had no effect on any cardiovascular variable (MBP and HP during W, NREM, and REM sleep) measured (p>0.1 for each variable; see Table 1). Overall these results indicate that the manipulation of serotonergic systems can exert a potent influence on the generation of central apneas in both REM and NREM sleep. Specifically the present findings indicate that systemic administration of a 5-hydroxytryptamine3 receptor antagonist suppresses spontaneous apnea expression; completely abolishing REM-related apnea for at least 4 hours after intraperitoneal injection. This apnea suppression was associated with a generalized respiratory stimulation that was observed as increased minute ventilation during both waking and sleep. These significant respiratory effects were observed at a dose which caused no change in hear rate or biood pressure, ever. Junn- fne firs: I hours, when respiration '.vas maximal. These of skill in the ar: will recognize that exemplary i:r::;nin :ec^o:cr antagonists in its tree base form or as a quaternary ammonium .-alt ;r.z'.-o-e. but are nor limited to (a) ketanserin, cinanserin, LV-53.35", meter :;oiine. LY-2^ 3,534. methiothepim p-N??L, NAN-I90. piperzzire. S30:65:3. SDI-2';5.5:-\ 2-tr:panyl-.auoie-3-carooxylate. 3-tropanyi-indcle-3-carb;:ryiate methiodide. metiv-'serside Research Blochemicais. Inc., Natick, MA":; olanzapine, chlcrpromazine, haloperidol, r (>; :ndanse:rcn, cisapride, ncrcisapride. !-) cisapride. (-) cisapride. (+) ncrcisapride. {'-) ncrcisapride. deanaeihyioianzapine. 2-hydroxymethylolanzapine. l-(2-fluorophenyi)-3-—-hydroxyaminoe:hyl;-proc-2-en~l-c,ne-0-(2-dimethyiaminoe:hyl)-oxime, (?) mescaline, cxetorone. hcmcchioreychzine. -and perlapine and other serotonin receptor antagonists and any of :heir quaternary form or pharmaceutical^ acceptable salts may be used to prevent or ameliorate slesp-reiated breathing disorders. Further, those of skill in the art will also recognize that the results discussed above may be easily correlated to other mamrtmls. especially primates (eg., humans). EXAMPLE 3 Induction and Suppression of Sleep Apneas Administration of serotonin or serotonin analoas produced variable respiratory responses in anesthetized animals of several species (see above, DETAILED DESCRIPTION OF THE INVENTION). As shown above in Example 2, intraperitoneal administration of 1 mg/kg GR33032F, a selective 5-hydroxytryptarnine3 receptor antagonist, suppressed spontaneous central apneas. This effect was especially prominent in REM sleep, during which apneas were completely .abolished for at-]east 4 hours following injection. The aonea suooressant effect or GR.38032F was paralleled by increased resoiratcry drive, but B? and heart rate changes were absent at the dose tested. Suppression of spontaneous apneas during natural sleep by GR2S032F (see Example 2) :s consistent with prior studies in anesthetized rats, wherein 5-hydroxytryptamine and 2-methyio4iydrcx}ir.ytamme. a selective 5-KT; receptor agonist, provoked central apneas that were amaccmnco by GR25C22F. Since 5-hydroxytryptamine does not penetrate :he blood-brain barrier :'3B3\ these results {from the prior studies) indicate ;hat stimulation of peripheral 5-hydro:cytryptainine receptors, and more particularly 5-hydrcxytryp;amire: receptors seemed to have provoked the occurrence of central apneas. In vi-v -f that study, performed in . anesthetized animals, as well as our study (described in Exampie 2 cbov-; in freely moving rats with respect to administration of GR25C22F, we studied the ability-of increased serotonergic activity at peripheral 5-hydroxytryotarnme receptors, and more specifically, 5-hydrexytryptamine3 receptors to promote spontaneous sleep-related central apneas and whether any induction of apneas would be susceptible to antagonism by administration of 5-hydroX;Tryptamme receptor antagonists. Ten adult male Sprague-Dawley rats (Sasco-King, Wilmington, MA; 300 g) were maintained on a 12-h light (08:00-20:00 hour) / 12-hour dark (20:00-08:00) cvcle for one week, housed in individual cases, and sziven ad libitum access to food and water. Following the one week of acclimatization, animals. ..were prepared for physiological testing via the surgical procedures (i.e., implantation of cortical electrodes for EEG recording and neck muscle electrodes for EMG recording, implantation of a radiotelemetry transmitter for BP and HP monitoring) as set forth above in Example 1. After completion of the surgical procedures, animals were allowed a one week recovery period prior to use in the present study. Each animal was recorded on four occasions, with recordings for an individual animal separated by at least three days. Fifteen minutes prior to each recording, each animal received (via intraperitoneal injection), in random order, one of the following: (a) saline solution (control); (b) 0.79 mgrteg serotonin; (c) 0.1 mg/kg GR33032F plus 0.79 mg/kg serotonin; or (d) 0.1 mg/kg GR38032F. For the GR3S032F^serotonin test group, 0.1 mg/kg GR38032F was administered at time 09:30 followed by 0.79 mg/kg serotonin at time 09:45. Polygraphic recordings were made from 10:00-16:00. Respiration BP, EEG, and EMG data were determined and recorded via the experimental procedure as specifically set forth above in Example 2, As in Example 2, sleep apneas, defined as cessation of respiratory effort for at least 2.5 s, were scored , :or each recording session and were associated with "he stage in which thev occurred: NREM or REM sleep. The duration requirement :f '2.5 5 represent a: least two "missed" creaths, which is analogous to a 10-5 apnea duration requirement in humans. The effects of sleep stage (NREM *-'s REV", and injection ^'control vs. administration of either serotonin alone. GR3M32?-se:otomm or 3R38C32F alone) on apnea indexes, respiratory pattern. 3?. and H? were nested using anaivsis of variance (ANOVA; with repeated measures. Multiple comparisons were concrciied using Fisher's protected seast-sigrdficane: difference -?13D;. One-way ANOVA was yarametric and nenparametric ANOVA w-ere identical in ail cases. Results of the administration of either serotonin alone -TT? mgkg). GR3S032F (0.1 mg.l As illustrated in Fisure 7. spontaneous apnea expression durina REM sleep significantly increased following administration of serotonin as compared to control recording (>250% increase). Results also indicate that such an increase was abolished via prior administration of GR38032F. At the lew dose tested (0.1 mg/kg) administration of GR38032F alone had no effect on REM sleep spontaneous apneas. As set forth in Table 2 (percentages of waking, NREM, and REM sieep during 6 hours of polygraphic recording following drag administration), intraperitoneal administration of serotonin alone, GR38C32F+serotonin, or GR3S032F alone had no effect on sleep architecture. Finally, no treatment group tested had a significant effect on RR, VE, mean BP, HP, or PS apnea index (data not shown). * All values reject means ± SE for percent reccrding time. Overall these results indicate :hai manipuiatioR- of oerrherai serotonin receptors exerts a potent influence on :he generation :f central apneas curing REM sleep. Specifically, the present results shcv chat systemic administration of serotonin increases spontaneous apnea expression in sieep. Although :he cone of serotonin employed had no effect on s;eepr cardiovascular variables. RR, or VH. :ne REM-retated spontaneous apnea index increased >2:0° inese nndmgs aemonstrate una: exogenous administration oi o-hvdroxytr-ptamme3 asonists and antagonists at various doses oroduees changes in apnea expression that are specific to REM sleep. Such findings indicate :hat there is a physiologic role for endogenous serotonergic activity in modulating the expression of apnea, especially during REM sleep. Moreover, because serotonin does net cross the blood-brain barrier, the finding that serotonin exerts a converse effect to GR38032F indicates that the relevant receptors are located in the peripheral nervous system. Further, the present data suggest that the action of supraphysiologic levels of serotonin on apneas is receptor mediated in that pretreatment with a low dose (0.1 mg'Tcg) of GR38G32F, which had no independent effect on any measured parameter, including apneas, fully blocked the effects of exogenous serotonin on apnea expression. In view of the foregoing data, the likely peripheral site of action for the observed apnea-promoting effects of serotonin administration is thought to be the nodose ganglia.of the vagus nerve. More specifically, several studies have concluded that the apnea component of the BezoldJarisch reflex results from the action of serotonin at the nodose ganglia in cats [Jacobs et al, Ore. Res.t 29:145-155 (1971), Sampson et ai. Life Set, 15:2157-2165 (1975), Sutton, Pfllugers Arch,, 389:181-187 (1981)] and rats [Yoshioka et ai, 1 Pharmacol Exp. Ther., 260:917-924 (1992) and McQueen et ai, J. Physiol, 5073:843-855 (1998)]. Intravenous administration of serotonin or 5-hydroxytryptamine3 receptor agonists also stimulates pulmonary vagal , receptors [McQueen e: ai, J. Physiol., 5073:S-3-^55 .1998)]. which may contribute significantly to the aoneic resucr.se. Although species differences may be rresen: [Black e: -zi.. Am. ./. ?:r:s:c The serotonin-induced Bezold-Jariseh reflex in anesthetized animals' includes apnea and bradycardia. At the dose employed, serotonin did no: elicit changes in either heart rate or mean BP over the 6 hour recording period. Beat-to-beat heart rate and BP variability, assessed as coefficients of variation, were also unaffected by serotonin at the dose tested. The observed dissociation of cardiovascular and respiratory responses to serotonin indicates that changes in apnea expression were not baroreceptor mediated. Although the Bezold-Jariseh reflex in anesthetized animals and serotonin-induced apneas in REM sleep are not the same phenomenon, they may be related by similar mechanisms. When serotonin receotors are strongly manipulated by exogenous means, i.e., either with serotonergic agonists or antagonists, the expression of spontaneous apneas in REM sleep can be amplified or suppressed. However, our observation that 1 mg/kg GR38032F significantly suppressed REM apneas does not preclude a role for 5-hydroxytryptamine2 or other 5-hydroxytryptamine receptor subtypes in the peripheral regulation of the apnea expression, and infact the invention also contemplates the use of S-hydroxytr/pramine: and f-hydroxyirocamir.e^ alone or in combination as well as serotonin antagonists that exhibit both type 2 and type 3 receptor antagonism (see Example 4). It has been well established [Mendeiscr =: -v. Ph:s;oi 3eh--.. -3:229-234 (I9SS): Sato et aL Am. 1 Physiol, 259:R2S2-IS7 Y990K Monti -: zL Pharmacol. Biochem, 3ehav.. 51:125-131 (1995); Monti e: zL P-icnnccji. 3::cher?:. Behav., :>3:341-34> '*996> Thomas e: ai, J, Aovi Phvsisi. T"3:152":-l5"26 199^) ^r Thomas e: u2, J. Appl Physiol, 7S:2I5-2IS 1995'; that apnea frequency 'in rats increases iron: deep slow-wave sleep to light >*R£M sieen to REM sleet:, as is the ■ease m man. The high incidence of acr.ea exrress:cn during 75:21 sleet: mav be related to respiratory changes that take place during :n;s sleep state. Typically, 'during F2EM sleep, breathing becomes shallow and irregular ;2rem e: u2. P.espir. Physiol.f JU:^OC--59 (.y, /;; Phuhpson. .-i/ira. ^-v. Phys::... -'.:.:J-.:O = .:.- ^; :;:ecK ; ^>., £rp\ Neurol. 67:79-102 (1980) and Sullivan, In:Orems sr a2, eds.. "Physiology in sleep/' Academic Press, New York. Mb pp. 21 3-2~2 ' i9S0Vj and YE is at its lowest point [Hudgei e: al.t J. Appi Physiol, 56:133-13" (1954)]. This background of low respiratory output coupled with strong phasic changes in autonomic activity [Mancia et ai. In; Orem et ai. eds.. "Phvsiolosv in sieeoT Academic Press, New York, NY, OD. 1-55 (19S0)] would render resoiraiorv homeostasis during REM sleet) more vulnerable to interruption by apnea. Thus it is possible that the role of serotonin activity in the peripheral nervous system in REM apnea genesis may arise from a serotonergic modulation of either tonic or phasic "activity of respiratory afferent activity, especially in the vagus nerves. Therefore, the brainstem respiratory integrating areas may be rendered more vulnerable to fluctuating afferent inputs during REM sleep. Overall, the results presented herein indicate that the exacerbation of spontaneous apnea during REM sleep produced by peripherally administered serotonin is receptor mediated. Such findings also indicate a physiologic role for endogenous serotonin in the peripheral nervous system in modulating sleep apnea expression under baseline conditions. EXAMPLE 4 Suppression or Prevention of Sleep Apneas As indicated by the data nresented herein (s^t Examples 2 and 3) serotonin plays an important and integral role in apnea genesis, which is both highly site and receptor subtype specific. More specifically, the efficacy of a serotonin receptor •antagonist :o suppress apnea is based on its activity in :he peripheral —rveus system, with the nodose ganglia of the vagus nerves appearing to be a cruciai target site. 5-hydroxytr.ptamine: and 5-hydroxytryptamine: receptor: at :h:3 site are cleariv-tmpiicated :n serotonin-induced apnea in anesthetized animals [Yoshioka et al. J. Pharmacol. Exv. T-ierp.. 260:917-924 f:992V. in conjunction with ;hese previous findings, the data presented herein (that administration -z: serotonin strictly to the peripheral nervous system exacerbates sieep-related apneas indicates ;he importance of nodose ganglion serotonin receptors of both types in sieep apnea pathogenesis. Moreover, the serotonin-induced increase in apnea -npression was completely blocked by a low dose of GR3S032F, a :-hydroxytr;-p:smme: antagonist. Such a result indicates that the previously demonstrated suppression of apnea by GR3S032? i'see Example 2) most probably resulted from activity in the peripheral nervous svstem. Therefore, in view of the foregoing, sleep related breathing disorders (sleep apnea svndrome, aonea of infancv. Chevne-Stokes restoration, sieen-reiated hypoventilation syndromes) mav be effectivelv prevented or suooressed via svstemic administration of pharmacological agents exhibiting either serotonin :voe 2 or tvoe > receptor antagonism, alone or in combination as well as agents that exhibit both serotonin type 2 and type 3 receptor antagonism. Effective treatments for the prevention or suppression of sleep-related breathing disorders include systemic administration of a S-hydroxytryptamines or 5-hydroxytryptamine3 receptor antagonist either alone or in combination. In a preferred embodiment the serotonin receptor antagonist has activity only in the peripheral nervous system and/or does not cross the blood-brain barrier. In a more preferred embodiment the serotonin receptor antagonist displays both 5-hydroxytryptamine2 and 5-hydroxytryptamine3 receptor subtype antagonism. Current pharmacological treatments for sleep-related breathing disorders also involve apnea suppression via serotonin agonist effects within the central nervous system, and more specifically the brainstem. Indeed, it was in view of their potential to stimulate respiration and upper airway motor outputs that serotonin enhancing druss were originallv tested as pharmacoioeical treatments for sleet) apnea svndrome. One early report suggested that L-tryptophan, a serotonin precursor, may have a beneficial effect on slesc. apnea syndrome [Schmidt, Bull Eur. Physiol Respir., '9:625-629 (19S2)]. More recently fluoxetine ^Han-ei e: a!., Ch~::. i:Q'AlS-42\ 1991)] and paroxetine [Kraiczi c? patients with sleep apnea syndrome. In addition. ::~:;natiens of ser-:::nin precursors md reuptake inhibitors reduced sleep disordered respiration in English bulldog-model :>f sleep apnea syndrome [Veasey e: ai, Sleec Res.. Ai29; 1997 ana Veasey et a/.. im. J. Resp. Crit. Care Med., 157:A:55 ". 99~V Ho*vever, despite cngoina investigations these encouraging early results -.v;;h serotonin enhancing drugs have not been reproduced. A ine teregomg enorts w::h seretorun-eunar.etng crags mateate tnat tne potential utility of serotonin precursors or SSPJs in apnea treatment resides strictly in their central nervous system effects. Therefore, i: is precisely because the serotonin enhancing effects of SSRIs in the peripheral nervous have been left ..unchecked that these compounds have not demonstrated reproducible effects in apnea treatment. In fact buspirone, a specific 5-hydroxyiryptam:neiA agonist, which stimulates respiration [Mendelson et ai, Am. Rev, Respir. Dis.9 141:1527-1530 (1990)], has been shown to reduce apnea index in 4 of 5 patients with sleep apnea syndrome [Mendelson ei aL9 J. Clin. PsychopharmacoL, 11:71-72 (1991)7 and to eliminate post-surgical apneustic breathing in one child [Wilken et al.yl Pediatr., 130:59-94 (1997). Although buspirone acts systemically, 5-hydroxytryptammet receptors in the peripheral nervous system have not been shown to play a role in apnea genesis. Tne modest apnea suppression induced by buspirone is a central nervous system effect that goes unopposed by serotonergic effects in the peripheral nervous system. The rationale for using SSRIs such as fluoxetine or paroxetine to treat sleep apnea syndrome rests in part on their ability to stimulate upper airway motor outputs. Applications of serotonin to the floor of the fourth ventricle [Rose et al, Resp.. Physiol, 101:59-69 (1995)] or into the hypoglossal" motor nucleus [Kubin ei a/., NeuroscL Lett., 139:243-248 (1992)] produce upper airway motor activation in cats; effects which appear to be mediated predominantly by . 5-hydroxytryptamine2 ^ receptors. Conversely, systemic administration of 5-hydroxytryptaminen receptor antagonists to English bulldogs reduces electrical activation of "upper airway muscles, diminishes upper airway cross-sectional area and promotes obstructive apnea [Veasey et al, Am. J. Crit. Care Med., 153:776-786 (1996)]. These observations provide a likely explanation for the improvements in s>ep-disorderec breathing observed in some patients following SSRI treatment. In conjunction with the data presentee herein 'Examples 3 and 3Ni and the foregoing observations, sleep related breathir.i disorder: ('sieep annea svndrome, apnea of infancy, Cheyne-Stokes respiration, sieeo-related hypoventilation syndromes) may be effectively prevented or suppresses '-a systemic administration of (,aj an agent or combinations of agents e;-;hi::::ne either serotonin tvoe Z or type 3 receptor antagonism ('either alone or in combination with one another) and/or in combination with either a 5-hycroxytryptamine; or 5-hvdroxvtrvDtamine- receotor aoonist; * * •■ * — , . (b) an agent or combination of agents or agents that exhibit both serotonin type 2 and type 3 receptor antagonism in combination with either a 5-hydroxytryptaminei or 5~hydrox;.orvptamme;> receptor agonist; or (c) agents that exhibit both the proper antagonistic and agonistic pharmacological profile (2.2., an agent that is both an agonist and antagonist at the receptor subtypes set forth above). Preferred embodiments include the following: (a) an agent or combination of agents wherein the serotonin agonist exhibits only central serotonergic actions; (b) : an agent or combination of agents wherein the serotonin agonist exhibits only central S-hydroxytryptaminez actions; (c) an agent or combination of agents s wherein the serotonin antagonist exhibits only peripheral actions while the serotonin agonist exhibits only central serotonergic actions; (d) an agent or combination of agents that have the ability to induce central nervous system serotonin release and that possess the antagonistic profile discussed above (Le. both a 5-hydroxytryptaminez and 5-hydroxytryptamines receptor antagonist); or (e) an agent or combination of agents that have the ability to induce central nervous svstem serotonin release and possess only peripheral antagonistic effects; Those of skill in the art will recognize that manv serotonin receotor asonists w V at *—* such as, but not limited to 8-OH-DPAT (8-hydroxy-2-(di-;z-propylamino)tetralin, sumatriptan, L694247 (2-[5-[3-(4-methylsulphonyiamino)benzyl-l?2,4-oxadiazol-5-yl]-lB-indoI-3yl]ethanamine)y buspirone, alnitidan, zaiospirone, ipsapirone, gepirone, zolmitriptan. risatriptan. 311C90, o-Me-5-HT, B""~:3C3c ll-oZ-mienylmethoxv)-lH-3-indoiyl[propan-2-amine hydrochloride), MC?? ^-chlcrophenylpiperamne), as weil as others may be used in conjunction with serotonin receptor antagonists to prevent or ameliorate sieep-reiated breathing disorder:. Pharmacological mechanisms of action other man se::-m:r precursors or SSRIs may also be exploited :c enhance centra; oemous sysrem serotonin ao::v;:y. ^id^d. at least one mechanism alleys augmented serotonin release :o he selectively targeted at the central nervous system. Specifically, antagonism of crermapttc c^ adrenergic receptors located en brainstem serotonergic neurons ■ detersreceptors/ enhances serotonin release. Selective 5-hydrcxytryptamme: and 5- hydroxytryptamine} receptor antagonists have been shewn to block presynaptic e;;-adrenoreceptors as well as postsynaptic 5-hydrcxytroptamme: and 5-hydroxytr-ptamine3 receptors f deBoer. J. Clin. ?:ychiczr.? 57i'~Ni: 19-15 (19960; Devane, J. Gin. Psychiatry., 59(20):S5-93 (1998); and Punanuan, Am. J. Heatlk-Sys:. Pharm., 55:4-—9 (199S)], Because the afnnity of such agents for central c;- receptors is 10 times higher than for peripheral ou receptors HPunantian, Am. 1 Hec:!h-Sys:. Pharm., 55:44-49 (1998)], central serotonin release is increased with minimal adrenergic side effects such as hypertension. _Thus because these pharmacological agents are high affinity antagonists at o-hydraxytryptamine^A, S-hydroxytryptamineic and 5-hydroxytryptamine3 receptors, the net effect is increased pcsi-synaptic 5-hydroxytryptaminei activity within the brain and reduced f-hydroxytryptamine^ and 5-hydroxytryptamine3 post-synaptic activity in the central and peripheral nervous systems. Each of these pharmacological effects serve to stimulate respiration and suppress apnea. In view of the foregoing observations, sleep related breathing disorders (sleep apnea syndrome, apnea of infancy, Cheyne-Stokes respiration, sleep-related hypoventilation syndromes) may also be effectively suppressed or prevented via systemic administration of pharmacological agents of combinations of agents having ct2 adrenergic antagonist activity with either serotonin type 2 or £ype 3 receptor antagonist activity (either alone or in combination with one another). Preferred embodiments include: (a) an agent or combination of agents wherein the :.-: adrenergic antagonist effects are exerted centrally; (b) an agent or combination of averts wherein :he serotonin antagonist effects are exerted peripherally; i.c") an agent or combination 01 agents wherein the :-.: adrenergic antagonist effects are exerted centrally ^zc the serotonin antagonist effects are exerted peripherally; ■' {', i '"'. r* p "-- ■: r --. -v. ar.ai *•> "^ ^2 lll-i -iiw-ilU -^liaLl'. ..ibi. ™^*ww*. lo w. *. w* t. w^_» _i_^- ..j."l;CuiI ' , presynaptic hetercreceptcrs on serotonergic neurons; or (:) the agent or combination o: agents or embodiments a-d in which the a: adrenergic antagonist effect is exerted by an agent or combination of agents possessing the following pharmacological profile: ■:<_ adrenergic antagonist activity with both serotonin type or receptor activity.> Those of skill in the art will recognize that many a: adrenergic receptor antagonists such as, but not limited to phenoxvbenzamine, ohentoiamine. tolazoline, w. r . ' A - terazosine, doxazosin, trimazosin, yohimbine, indoramin, ARC239, prazosin as well as others may be used in conjunction with serotonin receptor antagonists to" prevent or ameliorate sleep-related breathing disorders An individual diagnosed with a sleep-related breathing disorder is administered either a composition or agent having any of the foregoing pharmacological profiles in an amount effective to prevent or suppress such disorders. The specific dose may be calculated according to such factors as body weight or body surface. Further refinement of the calculations necessary to determine the appropriate dosage for treatment of sleep-related breathing disorders is routinely made by those of ordinary skill in the art without undue experimentation. Appropriate dosages may be ascertained through use of established assays for determining dosages. Routes of administration for the foregoing methods may be by any systemic means including oral, intraperitoneal, subcutaneous, intravenous, intramuscular, transdermal, or by other routes of administration. Osmotic mini-pumps and timed-released pellets or other depot forms of administration may also be used. Finally, those of skill in the art will -cognize that with respect to the compounds discussed above, such compounds rr.av contain a center of chiralitv Tn„. such agents -ay exist as different enamiomers of enantiomeric mixtures. T :se o*~ ^v one enantiomer alone or contained within an enantiomeric mixture -.\;th :me or more stereoisomers is contemplated by the present invention. Although rhe present invention has been described in terms of ^referred embodiments, it is intended that the present invention mcommass ah modifications and variations that occur to those skilled in ±e art uccn consideration of the disclosure herein, and in particular those embodiments that are -vithin the broadest proper interpretation of the claims and their reouirements. Ail literature cited herein is incorporated by reference. CLAIMS What is claimed is: I- A method of preventing OT ameliorating a sieeo-reiated breathing disorder comprising administering to a ratient in need thereof an effective amount o: at ieast one serotonin receptor antagonist, in free base cr quatemized foma. selected from the group consisting of zatosetron. :rcaise;::n.,do:ase:ran. hydrodolasetron. mescaline, oxetorcne, homochiorcyclimne. oeriarme. 'cotapine. olanzapine, chiorpromamne. haiopericol, r (-) ondansetron, risaprice, norcisapride. (-; cisapride. (-) cisapride. (-) norcisanride, (-') norcisapride. cesmedr/ioianzanine. 2-hydroxymethylolanzapine, and iH'2-flucrcrhenyf.,-3-'--hydroxyaTninoethyf»-prop-2-en-1 -one-0-C-dimethylaminoethyl)-oxime,. 2. The method of claim 1 wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation svndrome, central sleen apnea svndrome, Chevne-Stokes resniration, and snoring. 3. A method of preventing or ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount-ef at least one serotonin receptor antagonist, in quatemized form, selected from the group consisting of ondansetron, ketanserin, risperidone, cyproheptadine, clozapine, methysergide, granisetron, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indoleo-carboxylate, and 3-tropanyl-indole-3-carboxylate methiodide. 4. The method of claim 3 wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring. 5. A method of preventing or ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of (a) at least one of a serotonin receptor antagonist (0 in free base or quaternized form selected from the group consisting of zatosetron, tropisetron, dolasetron, hydrodolasetron, mescaline, oxetorone, homochlorcyclizine, perlapine, loxapine, olanzapine, chlorpromazine, haloperidol, r (~) ondansetron, cisapride, norcisapride, (+) cisapride, (-) cisapride, (+) norcisapride, (-) norcisapride, desmethylolanzapine, 2-hydroxymethylolanzapine, and l-(2-fluorophenyl)-3-(4-hydroxyaminoethyI)-prop-2-en-l-one-0-(2-dLmethylaminoe:hyl)-oxime,; (ii) in quaternized form selected from the group consisting of ondansetron, ketanserin, risperidone, cyproheptadine, clozapine, methysergide, granisetron, mianserin, ritanserin, cinanserin, LY-53.S57, metergoline, LY-27S,5S4, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-carboxylate, and3-tropanyl-indole-3-carbbxylatemethiodide; and (iii) and mixtures thereof; and (b) a serotonin receptor agonist. 6. The method of claim 5 wherein the serotonin receptor antagonist in the quaternized form is methylated, ethylated, orbenzylated. 7. The method of claim 5 wherein the serotonin receptor agonist is selected from the group consisting of 8-OH-DPAT, sumatriptan, L694247, buspirone, alnitidan, zalospirone, ipsapirone, gepirone, zolmitriptan, risatriptan, 311C90, a-Me-5-HT, BW723C86, and MCPR 8. The method of claim 5 wherein the serotonin receptor agonist is a 5-hydroxytryptaminei receptor subtype agonist. 9. The method of claim 5 wherein the serotonin receptor agonist is a 5-hydroxytryptamine2 receptor subtype agonist. 10. The method of claim 5 wherein the effects of the serotonin receptor agonist are exerted in the central nervous system. 11. The method of claim 5 wherein the effects of the serotonin receptor antagonist are exerted in the peripheral nervous system. 12. The method of claim 5 wherein the effects of the serotonin receptor agonist are exerted in the central nervous system and wherein the effects of the serotonin receptor antagonist are exerted in the peripheral nervous system. 13. A method of preventing or ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of (a) at least one of a serotonin receptor antagonist (i) in their free base or quatemized form selected from the group consisting of zatosetron, tropisetron, dolasetron, hydrodolasetron. mescaline, oxetorone, homochlorcyclizine, perlapine. loxapine, olanzapine, chlorpromazine, haloperidol, r (-5-) ondansetron, cisapride, norcisapride, (+) cisapride. (-) cisapride, (-r) norcisapride, (-) norcisapride, desrnethylolanzapine, 2-hydroxymethylolanzapine, l-(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1 -one-0-(2-dimethylaminoethyl)-oxime; (ii) and in their quaternzied form selected from the group consisting of ondansetron, ketanserin, risperidone, cyproheptadine, clozapine, methysergide, granisetron, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPLrNAN-190, piperazine, SB-206553, SDZ-205,33V, 3-tropanyl-indoIeo-carboxylate, and 3-tropanyl-tndole~3-carboxylate methiodide; and (iii) mixtures thereof; and (b) an effective amount of a selective serotonin reuptake inhibitor. 14. The method of claim 13 wherein the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine and paroxetine. 15. The method of claim 13 wherein the selective serotonin reuptake inhibitor is selected from the group consisting of fluvoxamine, sertraline, citalopram, norfluoxetine, r(-) fluoxetine, s(+) fluoxetine, demethylsertraline, demethylcitalopram, venlafaxine, milnacipran/sibutramine, nefazodone, R-hydroxynefazodone, (-)venlafaxine, and (+) venlafaxine. 16. A method of preventing or ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof (a) an effective amount of at least one serotonin receptor antagonist selected from the group consisting of zatosetron, tropisetron, dolasetron, hydrodolasetron, mescaline, oxetorone, homochlorcyclizine, perlapine, ondansetron{GR38032F), ketanserin, loxapine, olanzapine, chlorpromazine, haloperidol, r (+) ondansetron, cisapride, norcisapride, (-f) cisapride, (-) cisapride, (+) norcisapride, (-) norcisapride, desmethylolanzapine, 2-hydroxymethylolanzapine, l-(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop 2-en-I -one-0-(2-dimethylaminoeihyl)-oxime, risperidone, cyproheptadine, clozapine, methysergide, granisetron, mianserin, ritanserin, cinanserin, LY-53,857. metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205?557, 3-tropanyl-indole-3-carboxylate, and 3-tropanyl-indole-3-carboxylate methiodide; and (b) at least one selective serotonin reuptake inhibitor selected from the group consisting of fluvoxamine, sertraline, fluoxetine, paroxetine, citalopram, norfluoxetine, r(-)fluoxetine, s(+)fluoxetine, demethylsertraline, demethylcitalopram, venlafaxine, minacipran, sibutramine, nefazodone, R-hydroxynefazodone, (-) venlafaxine, and (-r)venlafaxine.

Documents:

1058-CHENP-2005 CORRESPONDENCE OTHERS.pdf

1058-CHENP-2005 CORRESPONDENCE PO.pdf

1058-CHENP-2005 FORM-1.pdf

1058-CHENP-2005 FORM-3.pdf

1058-CHENP-2005 FORM-5.pdf

1058-CHENP-2005 PETITIONS.pdf

1058-CHENP-2005 POWER OF ATTORNEY.pdf

1058-chenp-2005 claims granted.pdf

1058-chenp-2005 description (complete) granted.pdf

1058-chenp-2005 drawings granted.pdf

1058-chenp-2005-claims.pdf

1058-chenp-2005-correspondnece-others.pdf

1058-chenp-2005-correspondnece-po.pdf

1058-chenp-2005-description(complete).pdf

1058-chenp-2005-drawings.pdf

1058-chenp-2005-form 1.pdf

1058-chenp-2005-form 18.pdf

1058-chenp-2005-form 3.pdf

1058-chenp-2005-form 5.pdf

1058-chenp-2005-pct.pdf