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WO2007047575A2 - Traitements pharmacologiques contre des troubles du sommeil - Google Patents

Traitements pharmacologiques contre des troubles du sommeil Download PDF

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Publication number
WO2007047575A2
WO2007047575A2 PCT/US2006/040362 US2006040362W WO2007047575A2 WO 2007047575 A2 WO2007047575 A2 WO 2007047575A2 US 2006040362 W US2006040362 W US 2006040362W WO 2007047575 A2 WO2007047575 A2 WO 2007047575A2
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Prior art keywords
sleep
vanilloid receptor
vanilloid
serotonin
receptor
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WO2007047575A3 (fr
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David W. Carley
Miodrag Radulovacki
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University of Illinois at Urbana Champaign
University of Illinois System
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University of Illinois at Urbana Champaign
University of Illinois System
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention generally relates to methods for pharmacological treatment of breathing disorders and, more specifically, to administration of agents or compositions having vanilloid receptor activity for the alleviation of sleep apnea (central and obstructive) and other sleep-related breathing disorders.
  • 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.
  • sleep apnea is defined as an intermittent cessation of airflow at the nose and mouth during sleep.
  • apneas of at least 10 seconds in duration have been considered important; however, in most individuals, apneas are 20-30 seconds in duration and may be as long as 2-3 minutes. While there is some uncertainty as to the minimum number of apneas that should be considered clinically important, by the time most individuals come to a doctor's attention they have at least 10 to 15 events per hour of sleep.
  • Sleep apneas have been classified into three types: central, obstructive (the most common type), and mixed.
  • central sleep apnea the neural drive to all respiratory muscles is transiently abolished.
  • obstructive sleep apneas airflow ceases despite continuing respiratory drive because of occlusion of the oropharyngeal airway.
  • Mixed apneas which consist of a central apnea followed by an obstructive component, are a variant of obstructive sleep apnea.
  • Obstructive sleep apnea syndrome has been identified in as many as 24% of working adult men and 9% of similar women, with peak prevalence in the sixth decade. Habitual heavy snoring, which is an almost invariant feature of OSAS, has been described in up to 24% of middle aged men, and 14% of similarly aged women, with even greater prevalence in older subjects.
  • a definitive event of obstructive sleep apnea syndrome 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 sleeping state, thereby restoring airway patency and airflow.
  • the other major manifestations are cardiorespiratory in nature and are thought to arise from the recurrent episodes of nocturnal asphyxia.
  • Most individuals demonstrate a , cyclical slowing of the heart during the apneas to 30 to 50 beats per minute, followed by tachycardia of 90 to 120 beats per minute during the ventilatory phase.
  • a small number of individuals develop severe bradycardia with asystoles of 8 to 12 seconds in duration or dangerous tachyarrhythmias, including unsustained ventricular tachycardia.
  • OSAS also aggravates left ventricular failure in patients 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 intrathoracic pressure, 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.
  • a 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.
  • PAP positive airway pressure
  • an individual wears a tight- fitting plastic mask over the nose when sleeping.
  • the mask is attached to a compressor, which forces air into the nose creating a positive pressure within the patient's airways.
  • the principle of the method is that pressurizing the airways provides a mechanical "splinting" action that prevents airway collapse and therefore, obstructive sleep apnea.
  • acetazolamide a carbonic anhydrase inhibitor that produced variable improvement in individuals with primarily central apneas, but caused an increase in obstructive apneas
  • medroxyprogesterone a progestin that has demonstrated no consistent benefit in OSAS
  • theophylline a compound usually used for the treatment of asthma that may benefit patients with central apnea, but appears to be of no use in adult patients with obstructive apnea.
  • adenosine a ubiquitous compound within the body that is elevated in individuals with OSAS, has been shown to stimulate respiration and is somewhat effective in reducing apnea in an animal model of sleep apnea.
  • OSAS pharmacological treatment options
  • agents that stimulate brain activity or are opioid antagonists include agents that stimulate brain activity or are opioid antagonists.
  • central stimulants or opioid antagonists were thought to be a helpful treatment of OSAS.
  • doxapram a compound that stimulates the central nervous system and carotid body chemoreceptors, was found to decrease the length of apneas, but did not alter the average arterial oxygen saturation in individuals with obstructive sleep apnea.
  • the opioid antagonist naloxone which is known to stimulate ventilation, was only slightly helpful in individuals with obstructive sleep apnea.
  • Buspirone a specific serotonin subtype 1 receptor agonist that stimulates respiration (Mendelson et al, 1990, Am. Rev. Respir. Dis. 141: 1527-1530), has been shown to reduce apnea index in 4 of 5 patients with sleep apnea syndrome (Mendelson et ah, 1991, J. CHn. Psychopharmacol. 11: 71-72) and to eliminate post-surgical apneustic breathing in one child (Wilken et al, 1997, J. Pediatr.
  • serotonin antagonists also have been examined as drug treatments for sleep apnea in humans and in animal models of sleep related breathing disorders.
  • the serotonin antagonists ondansetron, R-zacopride, and mirtazapine all have been shown to reduce apnea frequency.
  • Mirtazapine was able to reduce apnea frequency by 50% in one study of OSAS patients, whereas ondansetron failed to demonstrate any effect in another study.
  • several patents have been issued describing the use of serotonin antagonists to treat OSAS (U.S. Patent Nos.
  • cannabinoid receptor agonist ⁇ 9-tetrahydrocannabinol and the endogenous fatty acid amide oleamide were shown to reduce sleep apneas in an animal model (Carley et al., 2002, Sleep 25: 391-398; U.S. Patent Application Publication No. 20040127572 describes this approach).
  • U.S. Patent No. 6,933,301 suggests the use of vanilloid receptor agonists for treatment of upper airway breathing disorder with effectiveness defined as decreased sensation from the upper airway and decrease in snoring.
  • WO 2005/080350 provides support for the use of carmabinoid receptor modulators for treating pain.
  • U.S. Patent Application Publication No. 20050234030 provides support the modulation of CRTH2, COX-2 and FAAH for the treatment of pain and inflammation. While these references suggest co-administration with vanilloid receptor ligands and treatment of a sleep-related breathing disorder, no clinical data is provided to support this suggestion. Nonetheless, no pharmacological agent or therapeutic regimen using a pharmaceutical formulation yet attempted has resulted in an efficacious treatment for any type of sleep apnea.
  • the invention is directed generally to providing pharmacological treatments for prevention or amelioration of sleep-related breathing disorders such as sleep apnea syndrome.
  • the invention is specifically directed to methods for preventing or ameliorating sleep-related breathing disorders, said methods comprising the step of administering an effective dose of a vanilloid receptor ligand to a patient in need of a therapy for preventing or ameliorating sleep-related breathing disorders.
  • the present invention is also directed to methods comprising the step of administering to a patient in need thereof a combination of vanilloid receptor ligands for preventing or ameliorating sleep-related breathing disorders.
  • the vanilloid receptor ligand or combination thereof is administered about 12 hours prior to sleep time (for example, in the morning for an individual who has a diurnal sleep pattern).
  • the vanilloid receptor ligand or combination thereof is administered no more than once every 7-14 days.
  • the combination of vanilloid receptor ligands may be directed to a single vanilloid receptor subtype or to more than one vanilloid receptor subtype.
  • the vanilloid receptor ligand or combination of vanilloid receptor ligands may have effects including, but not limited to, agonism, antagonism, partial agonism, and inverse agonism of the vanilloid receptor of one or a plurality of subtypes.
  • the invention is further directed to methods for preventing or ameliorating sleep- related breathing disorders comprising the step of administering to a patient in need thereof one or a combination of vanilloid receptor ligands in conjunction with a one or more serotonin receptor agonists for preventing or ameliorating sleep-related breathing disorders.
  • the combination of vanilloid receptor ligands may be directed to a single vanilloid receptor subtype or to more than one vanilloid receptor subtype and the combination of serotonin receptor agonists may be directed to a single serotonin receptor subtype or to more than one serotonin receptor subtype.
  • the vanilloid receptor ligand or combination thereof is administered about 12 hours prior to sleep time (for example, in the morning for an individual who has a diurnal sleep pattern).
  • the vanilloid receptor ligand or combination thereof is administered no more than once every 7-14 days.
  • the invention is further directed to methods for preventing or ameliorating sleep- related breathing disorders comprising the step of administering to a patient in need thereof one or a combination of vanilloid receptor ligands in conjunction with a one or more cannabimimetic agents including cannabinoid receptor agonists, endocannabinoid breakdown inhibitors, or endocannabinoid transporter inhibitors for preventing or ameliorating sleep-related breathing disorders.
  • the combination of vanilloid receptor ligands may be directed to a single vanilloid receptor subtype or to more than one vanilloid receptor subtype and the combination of cannabinoid receptor agonists may be directed to a single cannabinoid receptor subtype or to more than one cannabinoid receptor subtype.
  • the vanilloid receptor ligand or combination thereof is administered about 12 hours prior to sleep time (for example, in the morning for an individual who has a diurnal sleep pattern).
  • the vanilloid receptor ligand or combination thereof is administered no more than once every 7-14 days.
  • the invention is also directed to methods for preventing or ameliorating sleep- related breathing disorders comprising the step of administering to a patient in need thereof one or a combination of vanilloid receptor ligands in conjunction with a serotonin reuptake inhibitor for preventing or ameliorating sleep-related breathing disorders.
  • the combination of vanilloid receptor ligands may be directed to a single vanilloid receptor subtype or to more than one vanilloid receptor subtype.
  • the vanilloid receptor ligand or combination thereof is administered about 12 hours prior to sleep time (for example, in the morning for an individual who has a diurnal sleep pattern).
  • the vanilloid receptor ligand or combination thereof is administered no more than once every 7-14 days.
  • the invention is also directed to methods for preventing or ameliorating sleep- related breathing disorders comprising the step of administering to a patient in need thereof one or a combination of vanilloid receptor ligands in conjunction with a noradrenalin reuptake inhibitor for preventing or ameliorating sleep-related breathing disorders.
  • the combination of vanilloid receptor ligands may be directed to a single vanilloid receptor subtype or to more than one vanilloid receptor subtype.
  • the vanilloid receptor ligand or combination thereof is administered about 12 hours prior to sleep time (for example, in the morning for an individual who has a diurnal sleep pattern).
  • the vanilloid receptor ligand or combination thereof is administered no more than once every 7-14 days.
  • the invention is also directed to methods for preventing or ameliorating sleep- related breathing disorders comprising the step of administering to a patient in need thereof one or a combination of vanilloid receptor ligands in conjunction with a combination of serotonin or noradrenalin reuptake inhibitors for preventing or ameliorating sleep-related breathing disorders.
  • the combination of vanilloid receptor ligands may be directed to a single vanilloid receptor subtype or to more than one vanilloid receptor subtype and the combination of serotonin or noradrenalin reuptake inhibitors may directed to either serotonin reuptake or to noradrenalin reuptake, or to both serotonin and noradrenalin reuptake inhibitors.
  • the vanilloid receptor ligand or combination thereof is administered about 12 hours prior to sleep time (for example, in the morning for an individual who has a diurnal sleep pattern).
  • the vanilloid receptor ligand or combination thereof is administered no more than once every 7-14 days.
  • the invention is also directed to methods for preventing or ameliorating sleep- related breathing disorders comprising the step of administering to a patient in need thereof one or a combination of vanilloid receptor ligands in conjunction with inhibitors of vanilloid synthesis or vanilloid release.
  • the vanilloid receptor ligand or combination thereof is administered about 12 hours prior to sleep time (for example, in the morning for an individual who has a diurnal sleep pattern).
  • the vanilloid receptor ligand or combination thereof is administered no more than once every 7-14 days.
  • Figure 1 shows suppression of apnea by vanilloid type 1 receptor ligands.
  • Figure IA shows the apnea-hypopnea index (AHI) ratio of four test subjects (D3, D15, D19, and D23) receiving AM404 as compared to placebo.
  • Figure IB shows the AHI ratio of four test subjects (D4, D12, D24, and D28) receiving capsazepine as compared to placebo.
  • AHI apnea-hypopnea index
  • the invention provides methods for preventing or suppressing sleep-related breathing disorders, and in particular central, mixed and obstructive sleep apneas, by administering one or a combination of vanilloid receptor ligands, directed at one or a plurality of vanilloid receptor subtypes.
  • the vanilloid receptor ligands are administered according to the inventive methods either per se or in combination with other agents, including but not limited to serotonin receptor agonists, serotonin reuptake inhibitors, noradrenaline reuptake inhibitors, combined serotonin/noradrenalin reuptake inhibitors, cannabimimetic agents including cannabinoid receptor agonists and endocannabinoid breakdown inhibitors, and inhibitors of vanilloid synthesis.
  • agents including but not limited to serotonin receptor agonists, serotonin reuptake inhibitors, noradrenaline reuptake inhibitors, combined serotonin/noradrenalin reuptake inhibitors, cannabimimetic agents including cannabinoid receptor agonists and endocannabinoid breakdown inhibitors, and inhibitors of vanilloid synthesis.
  • Effective treatments for preventing or suppressing sleep-related breathing disorders include systemic administration of one or more vanilloid receptor ligands either alone or in combination with other agents.
  • the vanilloid receptor ligand or combination of ligands has activity only in the peripheral nervous system and/or does not cross the blood-brain barrier.
  • the vanilloid receptor ligand or combination of ligands displays activity to one or more vanilloid receptor types.
  • vanilloid receptor ligand includes vanilloid receptor agonists and antagonists.
  • vanilloid agonists may be combined with vanilloid antagonists.
  • said administration can be achieved wherein the agonist(s) serves to desensitize endogenous vanilloid receptors (a phenomenon that may last at least 7 - 14 days) and the antagonist(s) serves to further block activity at the remaining receptors.
  • agonist(s) is preferably administered once every 7 - 14 days, whereas the antagonist preferably is administered daily before bedtime.
  • the vanilloid receptor ligand or combination of ligands display agonist activity or antagonist activity at one or more vanilloid receptor types.
  • the vanilloid receptor antagonist or combination of vanilloid receptor antagonists are administered in a therapeutically effective dose once per day before bedtime.
  • the vanilloid receptor agonist or combination of vanilloid receptor agonists are administered in a therapeutically effective dose once per week.
  • the vanilloid receptor agonist or combination of vanilloid receptor agonists are administered in a therapeutically effective dose once every two weeks.
  • the vanilloid receptor agonist or combination of vanilloid receptor agonists are administered once per week or once per two weeks in combination with one or more other agents administered once per day before bedtime, preferably about 1 hours prior to bedtime.
  • these other agents may include but are not limited to vanilloid receptor antagonists, serotonin receptor agonists, serotonin reuptake inhibitors, noradrenaline reuptake inhibitors, combined serotonin/noradrenalin reuptake inhibitors, cannabimimetic agents including cannabinoid receptor agonists and endocannabinoid breakdown inhibitors, endocannabinoid transporter inhibitors, inhibitors of vanilloid synthesis and inhibitors of vanilloid release.
  • Exemplary vanilloid receptor ligands include, but are not limited to, unsaturated N- acyldopamines, lipoxygenase products of arachidonic acid and anandamide and anadamide congeners that include, but are not limited to, N-arachidonoyldopamine, N- oleoyldopamine, 12-(S)-hydroperoxyeicosatetraenoic acid, 15-(S)-hydroperoxyeicosa- tetraenoic acid, and other vanilloid receptor ligands (Van Der Stelt & Di Marzo, 2004, Eur J Biochem 271:1827-1834).
  • Additional exemplary vanilloid receptor ligands include, but are not limited to, resiniferatoxin, capsaicin, scutigeral, isovelleral, capsazepine, ruthenium red, dynorphin, arvanil, olvanil (Szallasi, 2001, Drugs and Aging 18:561-573).
  • Additional exemplary vanilloid receptor ligands include, but are not limited to, N-(4-tert- butylphenyl)-4-pyridine-2-yl-benzamide, N-(4-te ⁇ -butylphenyl)-4-(3-methylpyridine-2- yl)benzamide, MK-180, AMG-9810, N-2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl)-N_- [4-(methylsulfonylamino)benzyl]thiourea, N-(3-acyloxy-2-benzylopropyl)-N_-[4-
  • Additional exemplary vanilloid receptor ligands include, but are not limited to, palmitoylethanolamide, anandamide, methanandamide, 0-2142, O-2093, 0-1861, 0-1986, 0-1988, O-2094, O-1839, 0-1811, 0-1812, O-1860, 0-1861, 0-1856, and 0-1895 (Di Marzo et al, 2002, J Pharm Exp Ther 300:984-991).
  • Additional exemplary vanilloid receptor ligands include, but are not limited to, icilin and icilin analogs as disclosed in US patent application Publication No. 20030206866 to Wei.
  • Additional exemplary vanilloid receptor ligands include, but are not limited to, 2-Benzyl-3-isothiocyanatopropyl benzenecarboxylate, 2-Benzyl-3- isothiocyanatopropyl 3,4-dimethylbenzenecarboxylate, 2-Benzyl-3-isothiocyanatopropyl 4-tert-butylbenzenecarboxylate, 2-(3,4-Dimethyl benzyl)-3-isothiocyanatopropyl pivalate, 2-(3 ,4-Dimethylbenzyl)-3 -isothiocyanatopropyl benzenecarboxylate, 2-(4-tert-
  • Exemplary serotonin receptor agonists include, but are not limited to, 8-OH- DPAT, almotriptan, sumatriptan, L694247 (2-[5-[3-(4-methylsulphonylamino)benzyl- l,2,4-oxadiazol-5-yl]- 33 lH-indol-3yl]ethanamine), tegaserod, buspirone, ainitidan, zaiospirone, ipsapirone, gepirone, zolmitriptan, elitriptan, naratriptan, frovatriptan, rizatriptan, 311C90, a-Me-5-HT, BW723C86 (l-[5(2-thienylmethoxy)-lH-3- indolyl[propan-2-amine hydrochloride), MCPP (m-chlorophenylpiperazine), MK-212, bufotenin, l
  • serotonin reuptake inhibitors include, but are not limited to, fluoxetine, norfluoxetine, R(+)-fluoxetine, S(-)-fluoxetine, paroxetine, zimelidine, pirandamine, fluvoxamine, citalopram escitalopram, ORG6582, p-bromo EXP561, LM5008, sertraline, as well as other serotonin reuptake inhibitors can be used in conjunction with vanilloid receptor ligands to prevent or ameliorate sleep-related breathing disorders.
  • noradrenalin reuptake inhibitors include, but are not limited to, desipramine, nortriptyline, reboxetine, nisoxetine, atomoxetine, LY139603 (tomoxetine), as well as other noradrenalin reuptake inhibitors can be used in conjunction with vanilloid receptor ligands to prevent or ameliorate sleep-related breathing disorders.
  • Exemplary combined serotonin/noradrenalin reuptake inhibitors include, but are not limited to, venlafaxine, milnacipran, duloxetine, pregabalin, LY248686, strattera, as well as other combined serotonin/noradrenalin reuptake inhibitors can be used in conjunction with vanilloid receptor ligands to prevent or ameliorate sleep-related breathing disorders.
  • cannabimimetic agents include, but are not limited to: cannabinoid receptor agonists including, but not limited to, cannabinoid CBl agonists such as arachidonyl-2'-chloroethylamide, arachidonylcyclopropylamide, and methanandamide; cannabinoid CB2 agonists such as L-759633, L-759656, JWH-133, HU-308, and palmitoylethanolamide; endocannabinoids such as oleamide, linoleoylethanolamide, and oleoylethanolamide; inhibitors of cannabinoid metabolism such as phenylmethylsulphonyl fluoride, palmitylsulphonyl fluoride, stearylsulphonyl fluoride, methyl arachidonyl fluorophosphonate, and 0-1887; inhibitors of endocannabinoid membrane transport inhibitors such as AM404, VDMIl, and ar
  • cannabinoid-related compounds can be useful according to the methods herein including, but not limited to, 9-tetrahydrocannabinol, 8- tetrahydrocannabinol, HU-210, CP55940, WIN55,212-2, O-1057, 2-arachidonoyl glycerol, anandamide, dexanabinol, nabilone, levonantradol, and N-(2- hydroxyethyl)hexadecanoamide; and the like.
  • Vagal afferents can be pharmacologically activated by intravascular administration of agents such as serotonin (5-HT) (Jacobs & Comroe, 1971, Ore.
  • capsaicin also increased spontaneous sleep-related apneas during non-dreaming sleep (Carley et al., 2004, Sleep & Breathing 8: 147-154), but this effect was not blocked by pretreatment with a capsaicin antagonist
  • the receptor that binds capsaicin has recently been identified as the vanilloid receptor subtype 1 (VRl receptor).
  • the VRl receptor is a non-selective ion channel with high permeability for calcium (Caterina, 1997, Nature 389:816-824).
  • the VRl receptor now has been cloned in rat (Caterina, 1997, Nature 389:816-824) and in man (Hayes et al., 2000, Pain 88:205-215; Touchman et al., 2000, Genome Res 10:165-173).
  • vanilloid receptor ligands At least 4 distinct subtypes of vanilloid receptor have now been identified (identified as VRl - VR4 or, alternatively, as TRPVl - TRPV4 (Bender et al, 2005, Cell Physiol Biochem 15:183- 194).
  • Several groups of endogenous vanilloid receptor ligands have now been identified (Van Der Stelt and Di Marzo, 2004, Eur J Biochem 10:1827-1834), providing a rationale for therapeutic uses of vanilloid receptor ligands.
  • capsaicin acts at VRl receptors to produce vagus-nerve reflex apnea in anesthetized animals (Coleridge et al., 1964, J Physiol 170:272-285; Hedner et al., 1985, J Neural Trans 61:239-252) and, as expected, this effect can be blocked by the VRl receptor antagonist capsazepine (Lee and Lundberg, 1994, J Appl Physiol 76:1848-1855).
  • VRl receptor desensitization is associated with profound changes with regard to the expression of receptors and neuromediators in the affected cells, and may last for several weeks following a single agonist exposure (Szallasi & Blumberg, 1996, Pain 68:195-208).
  • vanilloid receptor ligands also can protect against spontaneous sleep-related apnea. This consequence of vanilloid receptor activity is not contemplated in the prior art, because inter alia vagus nerve reflex apnea and sleep apnea are actually quite different. Reflex apnea occurs because of an external stimulus (e.g., fluid or foreign body aspiration, irritant inhalation, or excessive lung inflation), both in awake and in sleeping individuals, whereas sleep apnea occurs spontaneously and specifically during sleep. An agent useful to block one of these forms of apnea is not necessarily able to affect the other form of apnea.
  • an external stimulus e.g., fluid or foreign body aspiration, irritant inhalation, or excessive lung inflation
  • vanilloid receptor ligands are able to reduce expression of reflexive apnea (see e.g., Szolcsanyi et al., 1990, J Pharmacol Exp Ther 255:923-928; Lee and Lundberg, 1994, J Appl Physiol 76:1848- 1855) does not render obvious the use of a vanilloid receptor ligands in the treatment of sleep-related breathing disorders.
  • anti-histamines can effectively reduce reflexive apnea (Downs et al., 1995, Laryngoscope, 105(8 Pt. 1): 857-861), but they worsen sleep apnea (Ponsonby et al., 1997, J. Paediatr. Child Health, 33(4): 317-323).
  • application of positive airway pressure produces immediate reflex apnea (Coon, 1994, J. Appl. Physiol., 76(6): 2546-2551), but treats sleep apnea (Haniffa et al, 2004, Cochrane Database Syst.
  • any agent or combination of agents that interferes with the activity of endogenous vanilloid receptor ligands can be used as an effective treatment for sleep-related breathing disorders.
  • the presumptive mechanism for this effect is interference with the activation of vagus sensory neurons by endogenous vanilloid receptor ligands.
  • such interference may be due to mechanisms including but not limited to: competitive receptor antagonism, non-competitive receptor antagonism, receptor densensitization, or inhibition of endogenous vanilloid synthesis.
  • the following Examples illustrate this testing of the effects of vanilloid receptor ligand administration, and in particular the ability of these ligands to cause suppression of spontaneous apneas during NREM and especially during REM sleep.
  • the following Examples also illustrate testing of the capacity of vanilloid receptor agonists to induce spontaneous apnea expression, and the ability of vanilloid receptor antagonists to block this effect.
  • the following Examples further describe the pharmacological profiles best suited for single agents or combinations of agents to successfully prevent or ameliorate sleep-related breathing disorders, including: (a) a single agent or combination of agents having activity at one or more vanilloid receptor subtypes; or
  • an endocannabinoid breakdown inhibitor e.g., a fatty acid amide hydrolase inhibitor
  • sleep related breathing disorders can be effectively prevented or suppressed via systemic administration of:
  • agents that exhibit both the proper antagonistic and agonistic pharmacological profile i.e., an agent that is both an agonist/mimetic and an 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;
  • an agent or combination of agents wherein the cannabimimetic agent is a cannabinoid precursor or prodrug or both;
  • an agent or combination of agents that have the ability to inhibit reuptake of serotonin and/or noradrenalin and that possess the antagonistic profile discussed above i.e., a vanilloid receptor antagonist and/or a desensitizing vanilloid receptor agonist; or
  • Sleep-related breathing disorders include, but are not limited to, obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount, or dose, of a compound that treats sleep- related breathing disorders.
  • compositions can be prepared together with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and/or adjuvant.
  • the term “agent” denotes a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials.
  • the term “pharmaceutical composition” refers to a composition comprising a pharmaceutically acceptable carrier, excipient, or diluent and a chemical compound, peptide, or composition as described herein that is capable of inducing a desired therapeutic effect when properly administered to a patient, specifically for treating sleep-related disorders.
  • the term “therapeutically effective amount” refers to the amount of a pharmaceutical composition of the invention or a compound identified in a screening method of the invention determined to produce a therapeutic response in a mammal, specifically for treating sleep-related disorders. Such therapeutically effective amounts are readily ascertained by one of ordinary skill in the art and using methods as described herein.
  • substantially pure means an object species that is the predominant species present ⁇ i.e., on a molar basis it is more abundant than any other individual species in the composition).
  • a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis or on a weight or number basis) of all macromolecular species present.
  • a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all macromolar species present in the composition.
  • the object species is purified to essential homogeneity (wherein contaminating species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.
  • the term "patient" includes human and animal subjects. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
  • an individual diagnosed with a sleep-related breathing disorder is administered either a composition or agent according to the invention 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, inhaled, or by other routes of administration; osmotic mini-pumps and timed-released pellets or other depot forms of administration may also be used.
  • the pharmaceutical compositions may be administered by bolus injection or continuously by infusion, or by implantation device.
  • the pharmaceutical composition also can be administered locally via implantation of a membrane, sponge or another appropriate material onto which the desired molecule has been absorbed or encapsulated. Where an implantation device is used, the device may be implanted into any suitable tissue or organ, and delivery of the desired molecule may be via diffusion, timed-release bolus, or continuous administration.
  • the only limitation for administration route according to the methods of this invention is that the route of administration results in the ultimate delivery of the pharmacological agent to the appropriate receptor.
  • Acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed.
  • the pharmaceutical composition can contain formulation materials for modifying, maintaining or preserving, for- example, pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition.
  • Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta- cyclodextrin); fillers; monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophil
  • compositions can be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format and desired dosage. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, Id. Such compositions may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the antibodies of the invention.
  • the primary vehicle or carrier in a pharmaceutical composition may be either aqueous or non-aqueous in nature.
  • a suitable vehicle or carrier may be water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration.
  • Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • Pharmaceutical compositions can comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which may further include sorbitol or a suitable substitute therefor.
  • compositions of the invention can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents (REMINGTON'S PHARMACEUTICAL SCIENCES, Id.) in the form of a lyophilized cake or an aqueous solution. Further, the compositions can be formulated as a lyophilizate using appropriate excipients such as sucrose.
  • optional formulation agents REMINGTON'S PHARMACEUTICAL SCIENCES, Id.
  • Formulation components are present in concentrations that are acceptable to the site of administration. Buffers are advantageously used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.
  • the pharmaceutical compositions of the invention can be delivered parenterally.
  • the therapeutic compositions for use in this invention may be in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising the desired compound identified in a screening method of the invention in a pharmaceutically acceptable vehicle.
  • a particularly suitable vehicle for parenteral injection is sterile distilled water in which the compound identified in a screening method of the invention is formulated as a sterile, isotonic solution, appropriately preserved.
  • Preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, that may provide controlled or sustained release of the product which may then be delivered via a depot injection.
  • Formulation with hyaluronic acid has the effect of promoting sustained duration in the circulation.
  • Implantable drug delivery devices may be used to introduce the desired molecule.
  • the compositions may be formulated for inhalation.
  • an antagonist or agonist as disclosed herein can be formulated as a dry powder for inhalation, or inhalation solutions may also be formulated with a propellant for aerosol delivery, such as by nebulization.
  • Pulmonary administration is further described in PCT Application No. PCT/US94/001875, which describes pulmonary delivery and is incorporated by reference.
  • the pharmaceutical compositions of the invention can be delivered through the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the skill of the art.
  • An antagonist or agonist as disclosed herein that are to be administered in this fashion can be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules.
  • a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized.
  • Additional agents can be included to facilitate absorption of the antagonist or agonist as disclosed herein. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders may also be employed.
  • a pharmaceutical composition can involve an effective quantity of an antagonist or agonist as disclosed herein in a mixture with non-toxic excipients that are suitable for the manufacture of tablets.
  • excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.
  • sustained- or controlled-delivery formulations including formulations involving appropriate receptor antagonists or agonists as disclosed herein in sustained- or controlled-delivery formulations.
  • Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio- erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. See, for example, PCT Application No. PCT/US93/00829, which describes the controlled release of porous polymeric microparticles for the delivery of pharmaceutical compositions.
  • Sustained-release preparations may include semipermeable polymer matrices in the form of shaped articles, e.g.
  • films, or microcapsules polyesters, hydrogels, polylactides (e.g., U.S. Patent No. 3,773,919 and European Patent No. 058,481), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al., 1983, Biopolymers 22: 547-556), poly (2-hydroxyethyl-methacrylate) (Langer et al, 1981, J. Biomed. Mater. Res. 15: 167-277 and Langer, 1982, Chem. Tech.
  • polylactides e.g., U.S. Patent No. 3,773,919 and European Patent No. 058,481
  • copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al., 1983, Biopolymers 22: 547-556), poly (2-hydroxyethyl-methacrylate) (Langer
  • Sustained release compositions may also include liposomes, which can be prepared by any of several methods known in the art. See e.g., Eppstein et al., 1985, Proc. Natl Acad. ScL USA 82: 3688-3692; European Patent Publication No. 036,676; European Patent Publication No. 088,046, and European Patent Publication No. 143,949.
  • compositions to be used for in vivo administration typically are sterile. In certain embodiments, this may be accomplished by filtration through sterile filtration membranes. In certain embodiments, where the composition is lyophilized, sterilization using this method may be conducted either prior to or following lyophilization and reconstitution. In certain embodiments, the composition for parenteral administration may be stored in lyophilized form or in a solution. In certain embodiments, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
  • composition of the invention may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder.
  • Such formulations may be stored either in a ready-to-use form or in a form (e.g., lyophilized) that is reconstituted prior to administration.
  • Kits according to the invention can each contain both a first container having a dried antagonist or agonist compound as disclosed herein and a second container having an aqueous formulation, including for example single and multi-chambered pre-filled syringes (e.g., liquid syringes, lyosyringes or needle-free syringes).
  • aqueous formulation including for example single and multi-chambered pre-filled syringes (e.g., liquid syringes, lyosyringes or needle-free syringes).
  • an effective amount of a pharmaceutical composition of the invention to be employed therapeutically will depend, for example, upon the therapeutic context and objectives.
  • One skilled in the art will appreciate that the appropriate dosage levels for treatment, according to certain embodiments, will thus vary depending, in part, upon the antagonist or agonist delivered, the indication for which the pharmaceutical composition is being used, the route of administration, and the size (body weight, body surface or organ size) and/or condition (the age and general health) of the patient.
  • a clinician may titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.
  • Typical dosages range from about 0.1 ⁇ g/kg to up to about 100 mg/kg or more, depending on the factors mentioned above. In certain embodiments, the dosage may range from 0.1 ⁇ g/kg up to about 100 mg/kg; or 1 ⁇ g/kg up to about 100 mg/kg; or 5 ⁇ g/kg up to about 100 mg/kg.
  • Dosing frequency will depend upon the pharmacokinetic parameters and pharmacological properties of an antagonist or agonist as disclosed herein in the formulation. For example, a clinician administers the composition until a dosage is reached that achieves the desired effect. Such a composition may therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement towards establishing an appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages may be ascertained through use of appropriate dose-response data.
  • compositions of the invention can be administered alone or in combination with other therapeutic agents, in particular, in combination with other sleep disorder agents.
  • Example 1 describes how experimental animals are prepared for treatment with one or more vanilloid receptor ligands, either alone or in combination with other agents, and subsequent physiological recording and testing.
  • Example 2 describes physiological recording methods that are used in treated and control animals and interpretation of results that can be obtained from administration of one or more vanilloid receptor ligands.
  • Example 3 describes interpretation of results that can be obtained from experimental animals first treated by vanilloid receptor agonist administration followed by vanilloid receptor antagonist administration.
  • Example 4 describes physiological recording methods useful for treated and control animals and interpretation of results that can be obtained from administration of one or more vanilloid receptor ligands in combination with one or more other agents.
  • Example 5 describes agents or compositions that possess a specific vanilloid receptor-related pharmacological activity that is used to effectively suppress or prevent sleep-related breathing disorders.
  • Acclimatized animals are anesthetized using a mixture of ketamine (80 mg/mg) and xylazine (5 mg/kg) at a volume of 1 ml/kg body weight for the implantation of cortical electrodes for electroencephalogram (EEG) recording and neck muscle electrodes for electromyogram (EMG) recording.
  • EEG electroencephalogram
  • EMG electromyogram
  • the surface of the skull is exposed surgically and cleaned with a 20% solution of hydrogen peroxide followed by a solution of 95% isopropyl alcohol.
  • a dental preparation of sodium fluoride (Flura-GEL®, Saslow Dental, Mt. Prospect, IL) is applied to harden the skull above the parietal cortex and allowed to remain in place for 5 minutes.
  • the fluoride mixture is then removed from the skull above the parietal cortex.
  • the EEG electrodes consisting of four stainless steel machine screws, having leads attached thereto, are threaded into the skull to rest on the dura over the parietal cortex.
  • a thin layer of Justi ® resin cement (Saslow Dental, Mt. Prospect, IL) is applied to cover the screw heads (of screws implanted in the skull) and surrounding skull to further promote the adhesion of the implant.
  • EMG electrodes consisting of two ball-shaped wires are inserted into the bilateral neck musculature. All leads ⁇ i.e., EEG and EMG leads) are soldered to a miniature connector (39Fl 401, Newark Electronics, Schaumburg, IL). Lastly, the entire assembly is fixed to the skull with dental cement.
  • Physiological parameters from each animal prepared as set forth in Example 1 are recorded on 2 occasions in random order, with recordings for an individual animal separated by at least 3 days. Fifteen minutes prior to each recording an animal receives a systemic injection (1 ml/kg intraperitoneal bolus) of either saline (control) or an active dose of a drug treatment.
  • Respiration is recorded by placing each animal, unrestrained, inside a single chamber plethysmograph (PLYUN1R/U; Buxco Electronics, Sharon, CT; dimension 6 in. x 10 in. x 6 in.) ventilated with a bias flow of fresh room air at a rate of 2 L/min.
  • a cable plugged onto the animal's connector and passed through a sealed port is used to collect the bioelectrical activity from the head implant.
  • Respiration, EEG activity, and EMG activity are 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 are assessed using software developed by Benington et al. (1994, Sleep 17: 28-36) to analyze the biparietal EEG and nuchal EMG signals on 10- second epochs.
  • This software discriminates 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 is measured as the percentage of total recorded epochs staged as NREM or REM sleep.
  • the duration requirement of 2.5 seconds represents 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 obstructed or occluded airways would generate an increased plethysmographic signal, rather than a pause.
  • Apnea indexes (Al) defined as apneas per hour in a stage are separately determined for NREM and REM sleep.
  • the effects of sleep stage (NREM vs. REM) and injection (control vs. dose of active test drug) are tested using ANOVA with repeated measures. Multiple comparisons are controlled using Fisher's protected least significant difference (PLSD) test.
  • vanilloid receptor ligands including, but not limited to, any of the vanilloid receptor ligands mentioned above, and the like may be used to prevent or ameliorate sleep-related breathing disorders. Further, those of skill in the art will also recognize that the results that are obtained using this animal model can be readily correlated to other mammals, especially primates (e.g., humans).
  • Example 2 Administration of vanilloid receptor antagonists or vanilloid receptor agonists alone and in combination to produce respiratory responses in anesthetized animals is performed as set forth above in Example 2.
  • An increased rate of sleep apneas after a low dose of one or more vanilloid receptor agonists and a blockade of this effect by treatment with one or more vanilloid receptor antagonists is indicative of the therapeutic efficacy of the antagonist to treat sleep apnea and other sleep-related breathing disorders.
  • vanilloid receptor ligands alone and in combination with one or more other agents (e.g., including, but not limited to, serotonin agonists, cannabimimetics, SSRIs, or SNRIs) to produce respiratory responses in anesthetized animals is performed as set forth above in Example 2. Isobolographic analysis is used as an accepted, art-recognized and definitive standard for detecting and characterizing drug interactions (Luszczki & Czuczwar, 2003, Epilepsy Res. 56: 27-42).
  • an "interaction index” has been proposed (Tallarida, 2002, Pain 98: 163-168) to quantify drug synergism, and this index is also useful to characterize synergism when one of the two compounds lacks independent efficacy (e.g., an SSRI; see Kraiczi et al., 1999, Sleep 22: 61-66). Isobolographic analysis and the interaction index rely on statistical estimation of the ED 5O . Thus, it is important to have adequate power in the preclinical tests to confidently measure a 50% reduction in apnea expression. For this form of efficacy determination, dose-dependent changes in sleep apnea expression are determined for each agent (i.e., the vanilloid receptor ligand and the second agent) alone and combined in various ratios.
  • agent i.e., the vanilloid receptor ligand and the second agent
  • a decreased rate of sleep apneas after administration of any formulation is indicative of the therapeutic efficacy of the formulation to treat sleep apnea and other sleep-related breathing disorders.
  • a preferred combination of agents exhibits greater suppression of apneas than either agent alone, or equivalent suppression of apneas at lower doses than either agent alone.
  • endovanilloids can play an important role in apnea genesis. More specifically, the nodose ganglia of the vagus nerves appear to be a crucial target site for vanilloid receptor ligands.
  • sleep related breathing disorders can be effectively prevented or suppressed via systemic administration of pharmacological agents exhibiting activity at one or more vanilloid receptors.
  • Effective treatment for the prevention or suppression of sleep related breathing disorders can include, but are not limited to, systemic or local administration of one or more vanilloid receptor ligands.
  • vanilloid receptor ligands can be administered in combination with one or more of the other compounds disclosed herein, including, but not limited to, serotonin re-uptake inhibitors (SSRI) or serotonin/noradrenalin reuptake inhibitors (SNRI), serotonin receptor agonists, compounds with cannabinoid receptor subtype 1 or cannabinoid receptor subtype 2 activity, endocannabinoid breakdown inhibitors, cannabimimetic agents, and the like.
  • the compounds will have activity in the peripheral nervous system and will not cross the blood-brain barrier.
  • Vanilloid receptor ligands may also be used to enhance the activity of vanilloid receptor ligands (See e.g. U.S. Patent No. 6,331,536). Specifically, antagonism of presynaptic ⁇ 2 adrenergic receptors located on brain stem serotonergic neurons (heteroreceptors) enhances serotonin release. Selective receptor antagonists have been shown to block presynaptic and postsynaptic receptors (See e.g., de Boer, 1996, J. Clin. Psychiatry 57: 19-25; Devane, 1998, J. Clin. Psychiatry 59: 85-93; Puzantian, 1998, Am. J. Health Syst.
  • An individual diagnosed with a sleep related breathing disorder can be administered a compound, composition, agent or formulation thereof having any of the pharmacological activities disclosed herein, namely vanilloid receptor ligands, etc., in an amount effective to prevent or suppress such sleep related breathing disorders.
  • the specific dose can be calculated as disclosed herein according to body weight or body surface. Appropriate dosages can be determined through the use of established assays for setting dosages.
  • the pharmacological treatment can be administered to the person, patient, or subject in need of such treatment immediately before sleep or at any time prior to sleep with the appropriate slow release or delayed release dosage forms as required for the circumstances.
  • AM404 is a vanilloid type 1 receptor agonist with additional secondary activity as an endocannibinoid membrane transport inhibitor (Zygmunt, et ah, 2000, Eur J Pharmacol 396:39-42).
  • the average reduction was 65%, and in 2 of 4 animals, the reduction was by more than 85%.
  • Capsazepine is a vanilloid receptor antagonist and synthetic analog of capsaicin (Bevan, et ah, 1992, Br. J. Pharmacol. 107:544). Capsazepine administered by intraperitoneal injection at a dose of 0.025 mg/kg reduced apnea frequency with respect to placebo control injection in each of 4 test animals (Figure IB). The average reduction was 95% and in 2 of 4 animals apnea was eliminated throughout the 6-hour recording. These observations demonstrate the utility of employing vanilloid receptor ligands to ameliorate or eliminate the expression of sleep-related apnea.

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Abstract

L'invention concerne des méthodes pour prévenir ou améliorer des troubles de la respiration associés au sommeil. La méthode consiste à administrer à un patient une dose efficace d'un ligand ou d'une combinaison de ligands du récepteur vanilloïde. Le ligand ou la combinaison de ligands du récepteur vanilloïde peuvent être administrés en conjonction avec un ou plusieurs agonistes du récepteur de sérotonine, un ou plusieurs agents cannabimimétiques, un ou plusieurs inhibiteurs de recaptage de sérotonine, un ou plusieurs inhibiteurs de recaptage de noradrénaline, une combinaison d'inhibiteurs de recaptage, un ou plusieurs inhibiteurs de synthèse ou de libération de vanilloïde ou une combinaison quelconque de ces substances.
PCT/US2006/040362 2005-10-14 2006-10-13 Traitements pharmacologiques contre des troubles du sommeil Ceased WO2007047575A2 (fr)

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Cited By (4)

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EP2408434A4 (fr) * 2009-03-16 2013-11-27 Ipintl Llc Traitement de la maladie d'alzheimer et de l'ostéoporose, et réduction du vieillissement
EP3677265A4 (fr) * 2017-08-31 2020-10-21 Amorepacific Corporation Composition pour prévenir ou traiter les troubles du sommeil
US11878008B2 (en) 2017-08-31 2024-01-23 Amorepacific Corporation Composition for preventing or treating atopic dermatitis
WO2024124172A1 (fr) * 2022-12-09 2024-06-13 The Trustees Of The University Of Pennsylvania Compositions et procédés pour stimuler et/ou améliorer la motivation d'exercice et/ou les performances physiques

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JP5093967B2 (ja) * 2001-04-06 2012-12-12 ザ ボード オブ トラスティーズ オブ ザ ユニバーシティ オブ イリノイ 睡眠時の自律的安定性に関するカンナビノイドの機能的役割
KR100556157B1 (ko) * 2001-09-27 2006-03-06 (주) 디지탈바이오텍 바닐로이드 수용체의 효현제로서 강력한 진통효과를나타내는 단순구조의 레시니페라톡신 동족체 및 이를함유하는 약학적 조성물
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US8053413B2 (en) * 2005-06-06 2011-11-08 The Board Of Trustees Of The University Of Illinois Methods for treating sleep disorders by cholecystokinin (CCK) receptor B antagonists

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Publication number Priority date Publication date Assignee Title
EP2408434A4 (fr) * 2009-03-16 2013-11-27 Ipintl Llc Traitement de la maladie d'alzheimer et de l'ostéoporose, et réduction du vieillissement
EP3677265A4 (fr) * 2017-08-31 2020-10-21 Amorepacific Corporation Composition pour prévenir ou traiter les troubles du sommeil
US11382900B2 (en) 2017-08-31 2022-07-12 Amorepacific Corporation Composition for preventing or treating sleep disorders
US11878008B2 (en) 2017-08-31 2024-01-23 Amorepacific Corporation Composition for preventing or treating atopic dermatitis
WO2024124172A1 (fr) * 2022-12-09 2024-06-13 The Trustees Of The University Of Pennsylvania Compositions et procédés pour stimuler et/ou améliorer la motivation d'exercice et/ou les performances physiques

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